Science.gov

Sample records for receptors nociceptive stimulus

  1. Decoding Subjective Intensity of Nociceptive Pain from Pre-stimulus and Post-stimulus Brain Activities.

    PubMed

    Tu, Yiheng; Tan, Ao; Bai, Yanru; Hung, Yeung Sam; Zhang, Zhiguo

    2016-01-01

    Pain is a highly subjective experience. Self-report is the gold standard for pain assessment in clinical practice, but it may not be available or reliable in some populations. Neuroimaging data, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have the potential to be used to provide physiology-based and quantitative nociceptive pain assessment tools that complements self-report. However, existing neuroimaging-based nociceptive pain assessments only rely on the information in pain-evoked brain activities, but neglect the fact that the perceived intensity of pain is also encoded by ongoing brain activities prior to painful stimulation. Here, we proposed to use machine learning algorithms to decode pain intensity from both pre-stimulus ongoing and post-stimulus evoked brain activities. Neural features that were correlated with intensity of laser-evoked nociceptive pain were extracted from high-dimensional pre- and post-stimulus EEG and fMRI activities using partial least-squares regression (PLSR). Further, we used support vector machine (SVM) to predict the intensity of pain from pain-related time-frequency EEG patterns and BOLD-fMRI patterns. Results showed that combining predictive information in pre- and post-stimulus brain activities can achieve significantly better performance in classifying high-pain and low-pain and in predicting the rating of perceived pain than only using post-stimulus brain activities. Therefore, the proposed pain prediction method holds great potential in basic research and clinical applications.

  2. Decoding Subjective Intensity of Nociceptive Pain from Pre-stimulus and Post-stimulus Brain Activities

    PubMed Central

    Tu, Yiheng; Tan, Ao; Bai, Yanru; Hung, Yeung Sam; Zhang, Zhiguo

    2016-01-01

    Pain is a highly subjective experience. Self-report is the gold standard for pain assessment in clinical practice, but it may not be available or reliable in some populations. Neuroimaging data, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have the potential to be used to provide physiology-based and quantitative nociceptive pain assessment tools that complements self-report. However, existing neuroimaging-based nociceptive pain assessments only rely on the information in pain-evoked brain activities, but neglect the fact that the perceived intensity of pain is also encoded by ongoing brain activities prior to painful stimulation. Here, we proposed to use machine learning algorithms to decode pain intensity from both pre-stimulus ongoing and post-stimulus evoked brain activities. Neural features that were correlated with intensity of laser-evoked nociceptive pain were extracted from high-dimensional pre- and post-stimulus EEG and fMRI activities using partial least-squares regression (PLSR). Further, we used support vector machine (SVM) to predict the intensity of pain from pain-related time-frequency EEG patterns and BOLD-fMRI patterns. Results showed that combining predictive information in pre- and post-stimulus brain activities can achieve significantly better performance in classifying high-pain and low-pain and in predicting the rating of perceived pain than only using post-stimulus brain activities. Therefore, the proposed pain prediction method holds great potential in basic research and clinical applications. PMID:27148029

  3. Decoding Subjective Intensity of Nociceptive Pain from Pre-stimulus and Post-stimulus Brain Activities.

    PubMed

    Tu, Yiheng; Tan, Ao; Bai, Yanru; Hung, Yeung Sam; Zhang, Zhiguo

    2016-01-01

    Pain is a highly subjective experience. Self-report is the gold standard for pain assessment in clinical practice, but it may not be available or reliable in some populations. Neuroimaging data, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have the potential to be used to provide physiology-based and quantitative nociceptive pain assessment tools that complements self-report. However, existing neuroimaging-based nociceptive pain assessments only rely on the information in pain-evoked brain activities, but neglect the fact that the perceived intensity of pain is also encoded by ongoing brain activities prior to painful stimulation. Here, we proposed to use machine learning algorithms to decode pain intensity from both pre-stimulus ongoing and post-stimulus evoked brain activities. Neural features that were correlated with intensity of laser-evoked nociceptive pain were extracted from high-dimensional pre- and post-stimulus EEG and fMRI activities using partial least-squares regression (PLSR). Further, we used support vector machine (SVM) to predict the intensity of pain from pain-related time-frequency EEG patterns and BOLD-fMRI patterns. Results showed that combining predictive information in pre- and post-stimulus brain activities can achieve significantly better performance in classifying high-pain and low-pain and in predicting the rating of perceived pain than only using post-stimulus brain activities. Therefore, the proposed pain prediction method holds great potential in basic research and clinical applications. PMID:27148029

  4. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates

    PubMed Central

    Di Stefano, G.; Stubbs, M. T.; Djeugam, B.; Liang, M.

    2016-01-01

    Abstract Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  5. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates.

    PubMed

    Moayedi, M; Di Stefano, G; Stubbs, M T; Djeugam, B; Liang, M; Iannetti, G D

    2016-01-01

    Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  6. Regulation of AMPA receptors in spinal nociception

    PubMed Central

    2010-01-01

    The functional properties of α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptors in different brain regions, such as hippocampus and cerebellum, have been well studied in vitro and in vivo. The AMPA receptors present a unique characteristic in the mechanisms of subunit regulation during LTP (long-term potentiation) and LTD (long-term depression), which are involved in the trafficking, altered composition and phosphorylation of AMPA receptor subunits. Accumulated data have demonstrated that spinal AMPA receptors play a critical role in the mechanism of both acute and persistent pain. However, less is known about the biochemical regulation of AMPA receptor subunits in the spinal cord in response to painful stimuli. Recent studies have shown that some important regulatory processes, such as the trafficking of AMPA receptor subunit, subunit compositional changes, phosphorylation of AMPA receptor subunits, and their interaction with partner proteins may contribute to spinal nociceptive transmission. Of all these regulation processes, the phosphorylation of AMPA receptor subunits is the most important since it may trigger or affect other cellular processes. Therefore, these study results may suggest an effective strategy in developing novel analgesics targeting AMPA receptor subunit regulation that may be useful in treating persistent and chronic pain without unacceptable side effects in the clinics. PMID:20092646

  7. Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats.

    PubMed

    Barrett, Andrew C; Smith, Eric S; Picker, Mitchell J

    2002-10-01

    Previous studies indicate that in antinociceptive procedures employing thermal, chemical and electrical stimuli, opioids are generally more potent in male than female rodents. The purpose of the present study was to examine nociception and opioid antinociception in male and female rats using a mechanical nociceptive stimulus. Results indicated that males had a higher threshold for nociception, and in tests in which a constant pressure was applied to the hindpaw, the paw withdrawal latencies were consistently longer in males. Opioids with activity at the mu receptor, including levorphanol, morphine, dezocine, buprenorphine, butorphanol and nalbuphine, were generally more potent and/or effective in males. In contrast, sex differences were not consistently observed with the kappa-opioid receptor agonists spiradoline, (5,7,8b)-N-methyl-N[2-1(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U69593), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50488), enadoline, ethylketocyclazocine, and nalorphine. These findings suggest that males and females differ in their responsiveness to mechanical nociception and that sex differences in sensitivity to kappa-, but not mu-, opioid receptor agonists are specific to certain nociceptive stimulus modalities. PMID:12354566

  8. Is electrical stimulation of the rat incisor an appropriate experimental nociceptive stimulus?

    PubMed

    Rajaona, J; Dallel, R; Woda, A

    1986-08-01

    The purpose of this study was to determine whether or not tooth pulp stimulation in the rat can selectively activate the pulp nerve fibers without excitation of the periodontium and to decide if the nerve fibers situated in the pulp of the rat's incisor are involved in the nociceptive reactions caused by an intrapulpal stimulation. The experiments were carried out on 20 awake and freely moving Sprague-Dawley rats. Bipolar stimulating electrodes were inserted into the pulp of the left lower incisor and in the right incisor after removal of the pulp. Special cares were taken to avoid, on the right side, direct stimulation of the stump of the apical nerve. The jaw opening reflexes were recorded from the digastric muscles ipsilaterally to the stimulated teeth and the thresholds were compared. Using the same animals, four typical and reproducible nociceptive behavioral reactions caused by a long tooth pulp stimulation were also observed (shock of 0.5 ms at 50 Hz during 1 s). The stimulus intensity was progressively increased, and the threshold of each reaction was recorded. For each of the 20 rats tested, the jaw opening reflex and the nociceptive reactions did not disappear after removal of the pulp, but the threshold of the responses to the stimulation of the nonvital tooth were significantly above the threshold of the responses to the stimulation of the vital incisor. The conclusion was tooth pulp stimulation activates the periodontal nerve fibers in the rat, and stimulation of the incisor pulp is significant in pain study in the rat because the thresholds of the jaw opening reflex and the nociceptive reactions were increased after the tooth pulp tissue was removed. PMID:3732470

  9. Changes in the nitric oxide system in the shore crab Hemigrapsus sanguineus (Crustacea, Decapoda) CNS induced by a nociceptive stimulus.

    PubMed

    Dyuizen, Inessa V; Kotsyuba, Elena P; Lamash, Nina E

    2012-08-01

    Using NADPH-diaphorase (NADPH-d) histochemistry, inducible nitric oxide synthase (iNOS)-immunohistochemistry and immunoblotting, we characterized the nitric oxide (NO)-producing neurons in the brain and thoracic ganglion of a shore crab subjected to a nociceptive chemical stimulus. Formalin injection into the cheliped evoked specific nociceptive behavior and neurochemical responses in the brain and thoracic ganglion of experimental animals. Within 5-10 min of injury, the NADPH-d activity increased mainly in the neuropils of the olfactory lobes and the lateral antenna I neuropil on the side of injury. Later, the noxious-induced expression of NADPH-d and iNOS was detected in neurons of the brain, as well as in segmental motoneurons and interneurons of the thoracic ganglion. Western blotting analysis showed that an iNOS antiserum recognized a band at 120 kDa, in agreement with the expected molecular mass of the protein. The increase in nitrergic activity induced by nociceptive stimulation suggests that the NO signaling system may modulate nociceptive behavior in crabs.

  10. Effects of the mas-related gene (Mrg) C receptor agonist BAM6-22 on nociceptive reflex activity in naive, monoarthritic and mononeuropathic rats after intraplantar and intrathecal administration.

    PubMed

    Schröder, Wolfgang; Alique, Matilde; Herrero, Juan Fernando

    2016-01-01

    MrgC receptors are selectively expressed on peripheral and central terminals of small calibre nociceptive fibres. Peptide agonists of the MrgC receptor were reported to modulate nociceptive transmission exerting either pro- or antinociceptive effects depending on site of action and pain model used. Here, we investigated the effect of intraplantar and intrathecal administration of the selective MrgC receptor agonist BAM6-22 on mechanically and electrically evoked nociceptive reflex activity as a uniform readout measure in naïve, monoarthritic and mononeuropathic rats. In naïve rats, intraplantar BAM6-22 enhanced, whereas intrathecal BAM6-22 did not modulate mechanically-evoked nociceptive reflex activity. In monoarthritic rats, intraplantar BAM6-22 had no effect, whereas intrathecal BAM6-22 inhibited mechanically evoked nociceptive reflex activity. In mononeuropathic rats, BAM6-22 reduced mechanically evoked nociceptive reflex activity after both intraplantar and intrathecal administration. BAM6-22 did not modulate electrically evoked nociceptive reflex activity in any condition. Thus, the results of the present investigation confirm and add to previous studies demonstrating that site of action, (patho)-physiological state and stimulus modality determine the effect quality of MrgC receptor agonists. It still needs to be explored how concurrent activation of peripheral and spinal MrgC receptors modulates nociceptive processing under conditions of both acute and chronic pain to evaluate the therapeutic potential of putative small molecule MrgC receptor agonists as innovative analgesics.

  11. Are presynaptic GABA-Cρ2 receptors involved in anti-nociception?

    PubMed

    Tadavarty, R; Hwang, J; Rajput, P S; Soja, P J; Kumar, U; Sastry, B R

    2015-10-01

    We investigated the anti-nociceptive effects of GABA-C receptors in the central nervous system. Intracisternal injection of CACA, a GABA-C receptor agonist or isoguvacine, a GABA-A receptor agonist, significantly increased the tail-withdrawal latency. TPMPA, a GABA-C receptor antagonist blocked the effects of CACA but not isoguvacine indicating that GABA-C receptors are involved in regulating pain. Further, double-labelled immunofluorescence studies revealed that GABA-Cρ2 receptors are expressed presynaptically in the spinal dorsal horn, especially, substantia gelatinosa, a region that has been previously implicated in analgesia by regulating nociceptive inflow. These data provide a provenance for future work looking at presynaptic spinal GABA-C receptors in the control of nociception.

  12. Reduced GABAA Receptor α6 Expression in The Trigeminal Ganglion Enhanced Myofascial Nociceptive Response

    PubMed Central

    Kramer, P. R.; Bellinger, L. L.

    2013-01-01

    Activation of the GABAA receptor results in inhibition of neuronal activity. One subunit of this multi-subunit receptor termed alpha 6 (Gabrα6) contributed to inflammatory temporomandibular joint (TMJ) nociception but TMJ disorders often include myofascial pain. To address Gabrα6 role in myofascial pain we hypothesized that Gabrα6 has an inhibitory role in myofascial nociceptive responses similar to inflammatory TMJ arthritis. To test this hypothesis a, myofascial nociceptive response was induced by placing a ligature bilaterally on the tendon attachment of the anterior superficial part of a male rat's masseter muscle. Four days after ligature placement Gabrα6 expression was reduced by infusing the trigeminal ganglia (TG) with small interfering RNA (siRNA) having homology to either the Gabrα6 gene (Gabra6 siRNA) or no known gene (control siRNA). After siRNA infusion nociceptive behavioral responses were measured, i.e., feeding behavior and head withdrawal after pressing upon the region above the ligature with von Frey filaments. Neuronal activity in the TG and trigeminal nucleus caudalis and upper cervical region (Vc–C1) was measured by quantitating the amount of phosphorylated extracellular signalregulated kinase (p-ERK). Total Gabrα6 and GABAA receptor contents in the TG and Vc–C1 were determined. Gabrα6 siRNA infusion reduced Gabrα6 and GABAA receptor expression and significantly increased the nociceptive response in both nociceptive assays. Gabra6 siRNA infusion also significantly increased TG p-ERK expression of the ligated rats. From these results we conclude GABAA receptors consisting of the Gabrα6 subunit inhibit TG nociceptive sensory afferents in the trigeminal pathway and have an important role in the regulation of myofascial nociception. PMID:23602886

  13. Ligand-directed trafficking of receptor stimulus.

    PubMed

    Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2014-12-01

    GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an "off" or "on" conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand-specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as β-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Gα or Gβγ signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist "functional selectivity" (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications.

  14. The mechanism of μ-opioid receptor (MOR)-TRPV1 crosstalk in TRPV1 activation involves morphine anti-nociception, tolerance and dependence

    PubMed Central

    Bao, Yanju; Gao, Yebo; Yang, Liping; Kong, Xiangying; Yu, Jing; Hou, Wei; Hua, Baojin

    2015-01-01

    Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The μ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence. PMID:26176938

  15. Serotonin Enhances Urinary Bladder Nociceptive Processing Via a 5-HT3 Receptor Mechanism

    PubMed Central

    Hall, Jason D.; DeWitte, Cary; Ness, Timothy J.; Robbins, Meredith T.

    2015-01-01

    Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30 min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors. PMID:26247537

  16. Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism.

    PubMed

    Hall, Jason D; DeWitte, Cary; Ness, Timothy J; Robbins, Meredith T

    2015-09-14

    Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors.

  17. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain.

    PubMed

    Jhaveri, Maulik D; Sagar, Devi R; Elmes, Steven J R; Kendall, David A; Chapman, Victoria

    2007-08-01

    The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action.

  18. Mechanisms of G protein-coupled estrogen receptor-mediated spinal nociception

    PubMed Central

    Deliu, Elena; Brailoiu, G. Cristina; Arterburn, Jeffrey B.; Oprea, Tudor I.; Benamar, Khalid; Dun, Nae J.; Brailoiu, Eugen

    2012-01-01

    Human and animal studies suggest estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pro-nociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER) activation. Membrane depolarization, increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological and fluorescent imaging studies, we evaluated GPER involvement in spinal nociceptive processing. Intrathecal challenging of mice with the GPER agonist G-1 results in pain-related behaviors. GPER antagonism with G15 reduces the G-1 induced response. Electrophysiological recordings from superficial dorsal horn neurons indicate neuronal membrane depolarization upon G-1 application, which is G15 sensitive. In cultured spinal sensory neurons G-1 increases intracellular calcium concentration and induces mitochondrial and cytosolic ROS accumulation. In the presence of G15, G-1 does not elicit the calcium and ROS responses, confirming specific GPER involvement in this process. Following G-1 intracellular microinjections, cytosolic calcium concentration elevates faster and with higher amplitude compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium increase, ROS accumulation and neuronal membrane depolarization. Perspective Our results suggest that GPER modulates pain processing in spinal sensory neurons via cytosolic calcium increase and ROS accumulation. These findings extend the current knowledge on GPER involvement in physiology and disease, providing the first evidence of its pro-nociceptive effects at central levels and characterizing some of the underlying mechanisms. PMID:22858342

  19. Caenorhabditis elegans nicotinic acetylcholine receptors are required for nociception

    PubMed Central

    Cohen, Emiliano; Chatzigeorgiou, Marios; Husson, Steven J.; Steuer-Costa, Wagner; Gottschalk, Alexander; Schafer, William R.; Treinin, Millet

    2014-01-01

    Polymodal nociceptors sense and integrate information on injurious mechanical, thermal, and chemical stimuli. Chemical signals either activate nociceptors or modulate their responses to other stimuli. One chemical known to activate or modulate responses of nociceptors is acetylcholine (ACh). Across evolution nociceptors express subunits of the nicotinic acetylcholine receptor (nAChR) family, a family of ACh-gated ion channels. The roles of ACh and nAChRs in nociceptor function are, however, poorly understood. Caenorhabditis elegans polymodal nociceptors, PVD, express nAChR subunits on their sensory arbor. Here we show that mutations reducing ACh synthesis and mutations in nAChR subunits lead to defects in PVD function and morphology. A likely cause for these defects is a reduction in cytosolic calcium measured in ACh and nAChR mutants. Indeed, overexpression of a calcium pump in PVD mimics defects in PVD function and morphology found in nAChR mutants. Our results demonstrate, for the first time, a central role for nAChRs and ACh in nociceptor function and suggest that calcium permeating via nAChRs facilitates activity of several signaling pathways within this neuron. PMID:24518198

  20. Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats.

    PubMed

    Xiao, Zhiying; Reese, Jeremy; Schwen, Zeyad; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2014-04-01

    Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and nonnociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA; 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce nonnociceptive bladder activity. To modulate the bladder reflex, pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly (P < 0.01) reduced bladder capacity to 34.3 ± 7.1% of the saline control capacity, while PNS at 2T and 4T significantly (P < 0.01) increased AA bladder capacity to 84.0 ± 7.8 and 93.2 ± 15.0%, respectively, of the saline control. Picrotoxin (0.4 mg it) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (iv) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly (P < 0.05) reduced 2T PNS inhibition at low doses (0.01-0.1 mg/kg). During saline cystometry, PNS significantly (P < 0.01) increased bladder capacity to 147.0 ± 7.6% at 2T and 172.7 ± 8.9% at 4T of control capacity, and picrotoxin (0.4 mg it or 0.03-0.3 mg/kg iv) also significantly (P < 0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and nonnociceptive reflex bladder activities and in PNS inhibition of these activities. PMID:24523385

  1. Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

    PubMed Central

    Pareek, Tej K.; Keller, Jason; Kesavapany, Sashi; Agarwal, Nitin; Kuner, Rohini; Pant, Harish C.; Iadarola, Michael J.; Brady, Roscoe O.; Kulkarni, Ashok B.

    2007-01-01

    Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. Inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling. PMID:17194758

  2. Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception.

    PubMed

    Raisinghani, Manish; Zhong, Linlin; Jeffry, Joseph A; Bishnoi, Mahendra; Pabbidi, Reddy M; Pimentel, Fátima; Cao, De-Shou; Evans, M Steven; Premkumar, Louis S

    2011-09-01

    Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca(2+)-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca(2+). The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin-induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced

  3. Transient Receptor Potential Melastatin-3 (TRPM3) Mediates Nociceptive-Like Responses in Hydra vulgaris

    PubMed Central

    Malafoglia, Valentina; Traversetti, Lorenzo; Del Grosso, Floriano; Scalici, Massimiliano; Lauro, Filomena; Russo, Valeria; Persichini, Tiziana; Salvemini, Daniela; Mollace, Vincenzo; Fini, Massimo; Raffaeli, William

    2016-01-01

    The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamic acid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom. PMID:26974325

  4. Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

    PubMed Central

    Rouwette, Tom; Avenali, Luca; Sondermann, Julia; Narayanan, Pratibha; Gomez-Varela, David; Schmidt, Manuela

    2015-01-01

    In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles. PMID:26039491

  5. ATP induces sustained facilitation of craniofacial nociception through P2X receptors on neck muscle nociceptors in mice.

    PubMed

    Makowska, A; Panfil, C; Ellrich, J

    2006-06-01

    Noxious input from neck muscles probably plays a key role in tension-type headache pathophysiology. ATP selectively excites group III and IV muscle afferents in vitro. Accordingly, ATP infusion into trapezius muscle induces strong pain and local tenderness in healthy man. The present study addresses the impact of ATP on neck muscle nociception in anaesthetized mice. Craniofacial nociceptive processing was tested by the jaw-opening reflex via noxious electrical tongue stimulation. Within 2 h after injection of 100 nmol/l or 1 micromol/l ATP into semispinal neck muscles, reflex integrals significantly increased by 114% or 328%, respectively. Preceding intramuscular administration of the P2X receptor antagonist PPADS (3-100 nmol/l) suppressed the ATP effect. Subsequent application of PPADS (100 nmol/l) caused a total recovery of facilitated reflex to baseline values. ATP induces sustained facilitation of craniofacial nociception by prolonged excitation of P2X receptors in neck muscles. PMID:16686909

  6. The functional role of ascending nociceptive control in defensive behavior.

    PubMed

    Tambeli, Claudia Herrera; Fischer, Luana; Monaliza, Simone Lamana; Menescal-de-Oliveira, Leda; Parada, Carlos Amílcar

    2012-06-29

    Ascending nociceptive control is a novel spino-striato-rostral ventral medulla pain modulation pathway that mediates heterosegmental pain-induced analgesia, i.e., noxious stimulus-induced antinociception. In this study, we used the dorsal immobility response in rats as a model of the defensive responses. We demonstrated that the activation of ascending nociceptive control by peripheral noxious stimulation and spinal AMPA and mGluR1 receptor blockade significantly potentiated the duration of the dorsal immobility response in rats via an opioid-dependent mechanism in the nucleus accumbens. These results demonstrated the functional role of ascending nociceptive control in the modulation of defensive responses and spinal glutamatergic receptors in the dorsal immobility response. The immobility response is an antipredator behavior that reflects the underlying state of fear, and ascending nociceptive control may modulate fear.

  7. Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity

    PubMed Central

    Drake, R.A.R.; Leith, J.L.; Almahasneh, F.; Martindale, J.; Wilson, A.W.; Lumb, B.

    2016-01-01

    Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase–prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG. SIGNIFICANCE STATEMENT After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary

  8. Effects of imidazoline I2 receptor ligands on acute nociception in rats.

    PubMed

    Sampson, Cristal; Zhang, Yanan; Del Bello, Fabio; Li, Jun-Xu

    2012-01-25

    This study examined the antinociceptive effects of seven imidazoline I2 receptor ligands in a rat warm water tail withdrawal procedure (46 and 50 °C). Agmatine, 2-BFI, phenyzoline, and diphenyzoline produced a significant antinociceptive activity at 46 °C. BU224, S22687, and idazoxan had no effect at 46 °C up to doses that altered the locomotor activity. None of the drugs showed antinociceptive activity at 50 °C. It is suggested that I2 receptor agonists have antinociceptive activity for acute phasic pain under weak noxious stimulus, and the effects are efficacy-dependent. These data explain the findings that I2 receptor agonists enhance the antinociceptive effects of opioids and support developing higher-efficacy I2 receptor agonists for the treatment of pain.

  9. GABA acting on GABAB receptors located in a medullary pain facilitatory area enhances nociceptive behaviors evoked by intraplantar formalin injection.

    PubMed

    Martins, Isabel; Carvalho, Paulina; de Vries, Martin G; Teixeira-Pinto, Armando; Wilson, Steven P; Westerink, Ben H C; Tavares, Isaura

    2015-08-01

    The dorsal reticular nucleus (DRt) plays a key role in facilitation of nociceptive transmission at the spinal cord. In this study, we evaluated the mechanisms involved in GABA-mediated control of the DRt focusing on the role of local GABAB receptors. First, we used in vivo microdialysis to study the release of GABA in the DRt during the course of the formalin test. An increase of GABA levels in comparison with baseline values was detected in the second phase of the test. Because we previously showed that GABAB receptors are expressed by opioidergic DRt neurons, which respond to nociceptive stimuli and inhibit spinally projecting DRt neurons involved in descending pronociception, we then interfered with local GABAB receptors using gene transfer and pharmacological approaches. Lentiviral-mediated knockdown of GABAB1a expression decreased nociceptive responses during the second phase of the test. Local administration of the GABAB receptor antagonist CGP 35348 also decreased nociceptive responses in the second phase of the test, whereas the opposite was detected after injection of the GABAB agonist baclofen. Finally, we determined the GABAergic afferents of the DRt, namely those arising from its main brain afferents, which are located at the telencephalon and diencephalon. For that purpose, we combined retrograde tract-tracing from the DRt with immunodetection of glutamate decarboxylase, the GABA-synthesizing enzyme. The higher numbers of retrogradely labelled glutamate decarboxylase-immunoreactive neurons were located at insular, somatosensory, and motor cortices. Collectively, the results suggest that GABA acting on GABAB receptors may enhance pain facilitation from the DRt during inflammatory pain.

  10. Intraplantar PGE2 causes nociceptive behaviour and mechanical allodynia: the role of prostanoid E receptors and protein kinases

    PubMed Central

    Kassuya, C A L; Ferreira, J; Claudino, R F; Calixto, J B

    2007-01-01

    Background and purpose: Receptor subtypes involved in PGE2-induced nociception are still controversial. The present study investigated the prostanoid E receptor (EP) subtypes and the protein kinase (PK) pathways involved in the nociception induced by PGE2 injection in the mouse paw. Experimental approach: Paw-licking and mechanical allodynia were measured in vivo and protein kinase activation ex vivo by Western blots of extracts of paw skin. Key results: Intraplantar (i.pl.) injection of PGE2 into the mouse paw caused nociceptive behaviour of short duration with mean ED50 of 1.43 nmol. PGE2 produced a longer-lasting mechanical allodynia, with an ED50 of 0.05 nmol. Intraplantar injection of antagonists at EP3 or EP4, but not at EP1 or EP2 receptors inhibited PGE2-induced paw-licking. Paw-licking caused by PGE2 was blocked by an inhibitor of PKA but only partially decreased by inhibition of the extracellular-regulated kinase (ERK). Selective inhibitors of PKC, c-Jun N-terminal kinase (JNK) or p38, all failed to affect PGE2-induced paw-licking. An EP3 antagonist inhibited PGE2-induced mechanical allodynia. However, inhibitors of PKA, PKC or ERK, but not p38 or JNK, also partially inhibited PGE2-induced mechanical allodynia. Western blot analyses confirmed that i.pl. injection of PGE2 activated PKA, PKCα, and mitogen activated kinases (MAPKs) in the paw. Co-treatment with EP3 or EP4 receptor antagonists reduced PGE2-induced PKA and ERK, but not PKCα activation. Conclusions and Implications: The present results indicate that the nociceptive behaviour and mechanical allodynia caused by i.pl. PGE2 are mediated through activation of distinct EP receptors and PK-dependent mechanisms. PMID:17310141

  11. Involvement of kappa-opioid receptors in visceral nociception in mice.

    PubMed

    Larsson, M H; Bayati, A; Lindström, E; Larsson, H

    2008-10-01

    It has been shown that the behavioural responses to chemically evoked visceral nociception are increased in transgenic mice lacking the kappa-opioid receptor (KOR). The aim of the present study was to evaluate the contribution of KOR in mechanically evoked visceral pain by performing colorectal distension (CRD) and monitoring the subsequent visceromotor response (VMR) in control mice (KOR(+/+)) and in mice lacking KOR (KOR(-/-)). Pseudo-affective visceral pain responses were evoked in conscious mice using increasing (10-80 mmHg) and repeated (12 x 55 mmHg) phasic CRD paradigms. The resulting VMR was determined by monitoring the electromyographic activity of the abdominal muscle. The increasing and repeated CRD paradigms, respectively, evoked similar responses in both KOR(+/+) and KOR(-/-) mice. The selective KOR-agonists U-69593 (5 and 25 mg kg(-1), s.c.) and asimadoline (25 mg kg(-1), s.c.) significantly decreased the VMR in KOR(+/+) mice, while having no effect in KOR(-/-) mice. In contrast, the selective mu-opioid receptor agonist fentanyl significantly reduced the VMR in both types of mice and appeared more efficacious in KOR(-/-) mice. The opioid receptor antagonist naloxone (0.3-30 mg kg(-1) s.c.) did not affect the response to CRD in C57BL/6 mice at any dose tested. In conclusion, the data confirm that the KOR agonists used in this study inhibit the VMR to CRD in mice by acting via KOR receptors. In addition, the data suggest that the endogenous opioid system is not likely to modulate the VMR to mechanically evoked visceral pain in mice.

  12. The contribution of activated peripheral kappa opioid receptors (kORs) in the inflamed knee joint to anti-nociception.

    PubMed

    Moon, Sun Wook; Park, Eui Ho; Suh, Hye Rim; Ko, Duk Hwan; Kim, Yang In; Han, Hee Chul

    2016-10-01

    The systemic administration of opioids can be used for their strong analgesic effect. However, extensive activation of opioid receptors (ORs) beyond the targeted tissue can cause dysphoria, pruritus, and constipation. Therefore, selective activation of peripheral ORs present in the afferent fibers of the targeted tissue can be considered a superior strategy in opioid analgesia to avoid potential adverse effects. The purpose of this study was to clarify the role of peripheral kappa opioid receptors (kORs) in arthritic pain for the possible use of peripheral ORs as a target in anti-nociceptive therapy. We administered U50488 or nor-BNI/DIPPA, a selective agonist or antagonist of kOR, respectively into arthritic rat knee joints induced using 1% carrageenan. After the injection of U50488 or U50488 with nor-BNI or DIPPA into the inflamed knee joint, we evaluated nociceptive behavior as indicated by reduced weight-bearing on the ipsilateral limbs of the rat and recorded the activity of mechanosensitive afferents (MSA). In the inflamed knee joint, the intra-articular application of 1μM, 10nM, or 0.1nM U50488 resulted in a significant reduction in nociceptive behavior. In addition, 1μM and 10nM U50488 decreased MSA activity. However, in a non-inflamed knee joint, 1μM U50488 had no effect on MSA activity. Additionally, intra-articular pretreatment with 20μM nor-BNI or 10μM DIPPA significantly blocked the inhibitory effects of 1μM U50488 on nociceptive behavior and MSA activity in the inflamed knee joint. These results implicate that peripheral kORs can contribute to anti-nociceptive processing in an inflamed knee joint. PMID:27378583

  13. Toll-like receptor 4 signaling in neurons of trigeminal ganglion contributes to nociception induced by acute pulpitis in rats

    PubMed Central

    Lin, Jia-Ji; Du, Yi; Cai, Wen-Ke; Kuang, Rong; Chang, Ting; Zhang, Zhuo; Yang, Yong-Xiang; Sun, Chao; Li, Zhu-Yi; Kuang, Fang

    2015-01-01

    Pain caused by acute pulpitis (AP) is a common symptom in clinical settings. However, its underlying mechanisms have largely remained unknown. Using AP model, we demonstrated that dental injury caused severe pulp inflammation with up-regulated serum IL-1β. Assessment from head-withdrawal reflex thresholds (HWTs) and open-field test demonstrated nociceptive response at 1 day post injury. A consistent up-regulation of Toll-like receptor 4 (TLR4) in the trigeminal ganglion (TG) ipsilateral to the injured pulp was found; and downstream signaling components of TLR4, including MyD88, TRIF and NF-κB, and cytokines such as TNF-α and IL-1β, were also increased. Retrograde labeling indicated that most TLR4 positve neuron in the TG innnervated the pulp and TLR4 immunoreactivity was mainly in the medium and small neurons. Double labeling showed that the TLR4 expressing neurons in the ipsilateral TG were TRPV1 and CGRP positive, but IB4 negative. Furthermore, blocking TLR4 by eritoran (TLR4 antagonist) in TGs of the AP model significantly down-regulated MyD88, TRIF, NF-κB, TNF-α and IL-1β production and behavior of nociceptive response. Our findings suggest that TLR4 signaling in TG cells, particularly the peptidergic TRPV1 neurons, plays a key role in AP-induced nociception, and indicate that TLR4 signaling could be a potential therapeutic target for orofacial pain. PMID:26224622

  14. Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

    PubMed

    Haley, Jane E; Dickenson, Anthony H

    2016-08-15

    We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

  15. Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception.

    PubMed

    Mancuso, Giuseppe; Borgonovo, Gigliola; Scaglioni, Leonardo; Bassoli, Angela

    2015-10-16

    Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels.

  16. Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception.

    PubMed

    Mancuso, Giuseppe; Borgonovo, Gigliola; Scaglioni, Leonardo; Bassoli, Angela

    2015-01-01

    Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels. PMID:26501253

  17. D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats

    PubMed Central

    Ohtani, Norimasa; Masaki, Eiji

    2016-01-01

    Background Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats. Methods Male Sprague-Dawley rats (250–300 g) were anesthetized with sevoflurane and an intrathecal (IT) catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole), or a D2-like receptor antagonist (sulpiride) was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision. Results Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect. Conclusion A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold. PMID:27799818

  18. Discriminative stimulus effects of the novel imidazoline I2 receptor ligand CR4056 in rats

    PubMed Central

    Qiu, Yanyan; He, Xiao-Hua; Zhang, Yanan; Li, Jun-Xu

    2014-01-01

    This study examined whether a novel imidazoline I2 receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I2 receptor ligands. Eight male Sprague-Dawley rats were trained to discriminate 10.0 mg/kg CR4056 (i.p.) from vehicle in a two-lever food-reinforced drug discrimination procedure. Once rats acquired the discrimination, substitution and combination studies were conducted to elucidate the underlying receptor mechanisms. All rats acquired CR4056 discrimination after an average of 26 training sessions. Several I2 receptor ligands (phenyzoline, tracizoline, RS45041, and idazoxan, 3.2–75 mg/kg, i.p.) all occasioned > 80% CR4056-associated lever responding. Other drugs that occasioned partial or no CR4056-associated lever responding included methamphetamine, ketamine, the endogenous imidazoline ligand agmatine, the monoamine oxidase (MAO) inhibitor harmane, the α2-adrenoceptor agonist clonidine, the μ-opioid receptor agonists morphine and methadone, and the selective I2 receptor ligands BU224 and 2-BFI. The α1 adrenoceptor antagonist WB4101, α2 adrenoceptor antagonist yohimbine and μ-opioid receptor antagonist naltrexone failed to alter the stimulus effects of CR4056. Together, these results show that CR4056 can serve as a discriminative stimulus in rats, which demonstrates high pharmacological specificity and appears to be mediated by imidazoline I2 receptors. PMID:25308382

  19. The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia

    PubMed Central

    Fan, Hui; Gong, Nian; Li, Teng-Fei; Ma, Ai-Niu; Wu, Xiao-Yan; Wang, Ming-Wei; Wang, Yong-Xiang

    2015-01-01

    BACKGROUND AND PURPOSE Two peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial β-endorphin and pro-inflammatory cytokines. EXPERIMENTAL APPROACH We used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of β-endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays. KEY RESULTS WB4-24 displaced the specific binding of exendin (9–39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60–80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, β-endorphin antiserum and a μ-opioid receptor antagonist. CONCLUSIONS AND IMPLICATIONS Our results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception. PMID:25176008

  20. NMDA receptor antagonist MK-801 blocks learning of conditioned stimulus-unconditioned stimulus contiguity but not fear of conditioned stimulus in goldfish (Carassius auratus L.).

    PubMed

    Davis, R E; Klinger, P D

    1994-10-01

    The blockade of learning of Pavlovian fear conditioning by the N-methyl-D-aspartic acid (NMDA)-receptor antagonist MK-801 was examined in 166 goldfish. In previously untrained fish, MK-801 blocked learning of a light-off or a tone conditioned stimulus (CS) paired with an electrical shock unconditioned stimulus (US). Pretraining on the light-off CS did not affect the rate of learning of the tone CS but protected the tone learning from disruption by MK-801. Switching from the light-off to the tone CS changed the identity of the CS but not its temporal contiguity with the US. Pretraining consisting of pseudoconditioning of the light-off CS did not protect subsequent tone learning from blockade by MK-801. Thus, the NMDA receptor functions are necessary for learning related to the temporal contiguity of the CS and US but not to the identity of the CS as a cue to the occurrence of the fearful effects of the US.

  1. The Adaptation of the Moth Pheromone Receptor Neuron to its Natural Stimulus

    NASA Astrophysics Data System (ADS)

    Kostal, Lubomir; Lansky, Petr; Rospars, Jean-Pierre

    2008-07-01

    We analyze the first phase of information transduction in the model of the olfactory receptor neuron of the male moth Antheraea polyphemus. We predict such stimulus characteristics that enable the system to perform optimally, i.e., to transfer as much information as possible. Few a priori constraints on the nature of stimulus and stimulus-to-signal transduction are assumed. The results are given in terms of stimulus distributions and intermittency factors which makes direct comparison with experimental data possible. Optimal stimulus is approximatelly described by exponential or log-normal probability density function which is in agreement with experiment and the predicted intermittency factors fall within the lowest range of observed values. The results are discussed with respect to electroantennogram measurements and behavioral observations.

  2. Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

    PubMed

    Reese, Jeremy N; Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2015-04-15

    This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (<50 cmH2O) and short duration (<20 s) at a smaller bladder capacity ∼80% of saline control capacity. PNS significantly (P < 0.01) increased bladder capacity from 85.5 ± 10.1 to 137.3 ± 14.1 or 148.2 ± 11.2% at 2T or 4T stimulation, respectively, where T is the threshold intensity for PNS to induce anal twitch. MTEP {3-[(2-methyl-4-thiazolyl)ethynyl]pyridine; 3 mg/kg iv, a selective mGluR5 antagonist} completely removed the PNS inhibition and significantly (P < 0.05) increased bladder capacity from 71.8 ± 9.9 to 94.0 ± 13.9% of saline control, but it did not change the bladder contraction amplitude. After propranolol (3 mg/kg iv, a β1/β2-adrenergic receptor antagonist) treatment, PNS inhibition remained but MTEP significantly (P < 0.05) reduced the bladder contraction amplitude from 18.6 ± 2.1 to 6.6 ± 1.2 cmH2O and eliminated PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the bladder contraction amplitude from 20.9 ± 3.2 to 8.1 ± 1.5 cmH2O on average demonstrating that spinal reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex.

  3. Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

    PubMed

    Reese, Jeremy N; Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2015-04-15

    This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (<50 cmH2O) and short duration (<20 s) at a smaller bladder capacity ∼80% of saline control capacity. PNS significantly (P < 0.01) increased bladder capacity from 85.5 ± 10.1 to 137.3 ± 14.1 or 148.2 ± 11.2% at 2T or 4T stimulation, respectively, where T is the threshold intensity for PNS to induce anal twitch. MTEP {3-[(2-methyl-4-thiazolyl)ethynyl]pyridine; 3 mg/kg iv, a selective mGluR5 antagonist} completely removed the PNS inhibition and significantly (P < 0.05) increased bladder capacity from 71.8 ± 9.9 to 94.0 ± 13.9% of saline control, but it did not change the bladder contraction amplitude. After propranolol (3 mg/kg iv, a β1/β2-adrenergic receptor antagonist) treatment, PNS inhibition remained but MTEP significantly (P < 0.05) reduced the bladder contraction amplitude from 18.6 ± 2.1 to 6.6 ± 1.2 cmH2O and eliminated PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the bladder contraction amplitude from 20.9 ± 3.2 to 8.1 ± 1.5 cmH2O on average demonstrating that spinal reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex. PMID:25673810

  4. Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats.

    PubMed

    Feng, Chen-Chen; Yan, Xiu-Juan; Chen, Xin; Wang, Er-Man; Liu, Qing; Zhang, Li-Yan; Chen, Jun; Fang, Jing-Yuan; Chen, Sheng-Liang

    2014-08-01

    Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2-arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.

  5. [Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

    PubMed

    Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

    2012-01-01

    On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

  6. Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors.

    PubMed

    Andreou, Anna P; Holland, Philip R; Lasalandra, Michele P; Goadsby, Peter J

    2015-03-01

    Migraine is a common and disabling neurologic disorder, with important psychiatric comorbidities. Its pathophysiology involves activation of neurons in the trigeminocervical complex (TCC). Kainate receptors carrying the glutamate receptor subunit 5 (GluK1) are present in key brain areas involved in migraine pathophysiology. To study the influence of kainate receptors on trigeminovascular neurotransmission, we determined the presence of GluK1 receptors within the trigeminal ganglion and TCC with immunohistochemistry. We performed in vivo electrophysiologic recordings from TCC neurons and investigated whether local or systemic application of GluK1 receptor antagonists modulated trigeminovascular transmission. Microiontophoretic application of a selective GluK1 receptor antagonist, but not of a nonspecific ionotropic glutamate receptor antagonist, markedly attenuated cell firing in a subpopulation of neurons activated in response to dural stimulation, consistent with selective inhibition of postsynaptic GluK1 receptor-evoked firing seen in all recorded neurons. In contrast, trigeminovascular activation was significantly facilitated in a different neuronal population. The clinically active kainate receptor antagonist LY466195 attenuated trigeminovascular activation in all neurons. In addition, LY466195 demonstrated an N-methyl-d-aspartate receptor-mediated effect. This study demonstrates a differential role of GluK1 receptors in the TCC, antagonism of which can inhibit trigeminovascular activation through postsynaptic mechanisms. Furthermore, the data suggest a novel, possibly presynaptic, modulatory role of trigeminocervical kainate receptors in vivo. Differential activation of kainate receptors suggests unique roles for this receptor in pro- and antinociceptive mechanisms in migraine pathophysiology. PMID:25679470

  7. Nociceptive behaviour upon modulation of mu-opioid receptors in the ventrobasal complex of the thalamus of rats.

    PubMed

    Pozza, Daniel Humberto; Potes, Catarina Soares; Barroso, Patrícia Araújo; Azevedo, Luís; Castro-Lopes, José Manuel; Neto, Fani Lourença

    2010-03-01

    The role of mu-opioid receptors (MORs) in the inflammatory pain processing mechanisms within the ventrobasal complex of the thalamus (VB) is not well understood. This study investigated the effect of modulating MOR activity upon nociception, by stereotaxically injecting specific ligands in the VB. Nociceptive behaviour was evaluated in two established animal models of inflammatory pain, by using the formalin (acute and tonic pain) and the ankle-bend (chronic monoarthritic pain) tests. Control (saline intra-VB injection) formalin-injected rats showed acute and tonic pain-related behaviours. In contrast, intrathalamic administration of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate (DAMGO), a MOR-specific agonist, induced a statistically significant decrease of all tonic phase pain-related behaviours assessed until 30-35min after formalin hind paw injection. In the acute phase only the number of paw-jerks was affected. In monoarthritic rats, there was a noticeable antinociceptive effect with approximately 40min of duration, as denoted by the reduced ankle-bend scores observed after DAMGO injection. Intra-VB injection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), a specific MOR antagonist, or of CTOP followed, 10min after, by DAMGO had no effects in either formalin or ankle-bend tests. Data show that DAMGO-induced MOR activation in the VB has an antinociceptive effect in the formalin test as well as in chronic pain observed in MA rats, suggesting an important and specific role for MORs in the VB processing of inflammatory pain.

  8. Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

    PubMed Central

    Qiu, Yanyan; Zhang, Yanan; Li, Jun-Xu

    2015-01-01

    Although imidazoline I2 receptor ligands have been used as discriminative stimuli, the role of efficacy of I2 receptor ligands as a critical determinant in drug discrimination has not been explored. This study characterized the discriminative stimulus effects of selective imidazoline I2 receptor ligands BU224 (a low-efficacy I2 receptor ligand) and phenyzoline (a higher efficacy I2 receptor ligand) in rats. Two groups of male Sprague-Dawley rats were trained to discriminate 5.6 mg/kg BU224 or 32 mg/kg phenyzoline (i.p.) from their vehicle in a two-lever food-reinforced drug discrimination procedure, respectively. All rats acquired the discriminations after an average of 18 (BU224) and 56 (phenyzoline) training sessions, respectively. BU224 and phenyzoline completely substituted for one another symmetrically. Several I2 receptor ligands (tracizoline, CR4056, RS45041, and idazoxan) all occasioned > 80% drug-associated lever responding in both discriminations. The I2 receptor ligand 2-BFI and a monoamine oxidase inhibitor harmane occasioned > 80% drug-associated lever responding in rats discriminating BU224. Other drugs that occasioned partial or less substitution to BU224 cue included clonidine, methamphetamine, ketamine, morphine, methadone and agmatine. Clonidine, methamphetamine and morphine also only produced partial substitution to phenyzoline cue. Naltrexone, dopamine D2 receptor antagonist haloperidol and serotonin (5-HT) 2A receptor antagonist MDL100907 failed to alter the discriminative stimulus effects of BU224 or phenyzoline. Combined, these results are the first to demonstrate that BU224 and phenyzoline can serve as discriminative stimuli and that the low-efficacy I2 receptor ligand BU224 shares similar discriminative stimulus effects with higher-efficacy I2 receptor ligands such as phenyzoline and 2-BFI. PMID:25617792

  9. Identification of spinal 5-HT sub 3 receptors and their role in the modulation of nociceptive responses in the rat

    SciTech Connect

    Glaum, S.R.

    1988-01-01

    The project consisted of two related studies: (1) the characterization of serotonin binding sites in crude and purified synaptic membranes prepared from the rat spinal cord, and (2) the association of serotonin binding sites with functional 5-HT receptor responses in the modulation of nociceptive information at the level of the spinal cord. The first series of experiments involved the preparation of membranes from the dorsal and ventral halves of the rat spinal cord and the demonstration of specific ({sup 3}H)serotonin binding to these membranes. High affinity binding sites which conformed to the 5-HT{sub 3} subtype were identified in dorsal, but not ventral spinal cord synaptic membranes. These experiments also confirmed the presence of high affinity ({sup 3}H)5-HT binding sites in dorsal spinal cord synaptic membranes of the 5-HT{sub 1} subtype. The second group of studies demonstrated the ability of selective 5-HT{sub 3} antagonists to inhibit the antinociceptive response to intrathecally administered 5-HT, as measured by a change in tail flick and hot plate latencies. Intrathecal pretreatment with the selective 5-HT{sub 3} antagonists ICS 205-930 or MDL 72222 abolished the antinociceptive effects of 5-HT. Furthermore, the selective 5-HT{sub 3} agonist 2-methyl-5-HT mimicked the antinociceptive effects of 5-HT.

  10. Improgan-induced hypothermia: a role for cannabinoid receptors in improgan-induced changes in nociceptive threshold and body temperature.

    PubMed

    Salussolia, Catherine L; Nalwalk, Julia W; Hough, Lindsay B

    2007-06-01

    Improgan, a congener of the H(2) antagonist cimetidine, produces non-opioid antinociception which is blocked by the CB(1) antagonist rimonabant, implying a cannabinoid mechanism of action. Since cannabinoids produce hypothermia as well as antinociception in rodents, the present study investigated the pharmacological activity of improgan on core body temperature and nociceptive (tail flick) responses. Improgan (60, 100 and 140 microg, intraventricular [ivt]) elicited significant decreases in core temperature 3-30 min following injection with a maximal hypothermic effect of -1.3 degrees C. Pretreatment with rimonabant (50 microg, ivt) produced a statistically significant but incomplete (29-42%) antagonism of improgan hypothermia. In control experiments, the CB(1) agonist CP-55,940 (37.9 microg, ivt) induced significant decreases in core temperature (-1.8 degrees C) 3-30 min following injection. However, unlike the case with improgan, pretreatment with rimonabant completely blocked CP-55,940 hypothermia. Furthermore, CP-55,940 and improgan elicited maximal antinociception over the same time course and dose ranges, and both effects were attenuated by rimonabant. These results show that, like cannabinoid agonists in the rat, improgan produces antinociception and hypothermia which is blocked by a CB(1) antagonist. Unlike cannabinoid agonists, however, improgan does not produce locomotor inhibition at antinociceptive doses. Additional experiments were performed to determine the effect of CC12, a recently discovered improgan antagonist which lacks affinity at CB(1) receptors. Pretreatment with CC12 (183 microg, ivt) produced complete inhibition of both the antinociception and the hypothermia produced by improgan, suggesting the possible role of an unknown improgan receptor in both of these effects.

  11. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias.

    PubMed

    Sengmany, K; Gregory, K J

    2016-10-01

    The metabotropic glutamate receptor subtype 5 (mGlu5 ) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR-based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine-tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus-bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

  12. Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons.

    PubMed

    D'Arco, Marianna; Giniatullin, Rashid; Simonetti, Manuela; Fabbro, Alessandra; Nair, Asha; Nistri, Andrea; Fabbretti, Elsa

    2007-08-01

    The molecular mechanisms of migraine pain are incompletely understood, although migraine mediators such as NGF and calcitonin gene-related peptide (CGRP) are believed to play an algogenic role. Although NGF block is proposed as a novel analgesic approach, its consequences on nociceptive purinergic P2X receptors of trigeminal ganglion neurons remain unknown. We investigated whether neutralizing NGF might change the function of P2X3 receptors natively coexpressed with NGF receptors on cultured mouse trigeminal neurons. Treatment with an NGF antibody (24 h) decreased P2X3 receptor-mediated currents and Ca2+ transients, an effect opposite to exogenously applied NGF. Recovery from receptor desensitization was delayed by anti-NGF treatment without changing desensitization onset. NGF neutralization was associated with decreased threonine phosphorylation of P2X3 subunits, presumably accounting for their reduced responses and slower recovery. Anti-NGF treatment could also increase the residual current typical of heteromeric P2X2/3 receptors, consistent with enhanced membrane location of P2X2 subunits. This possibility was confirmed with cross-linking and immunoprecipitation studies. NGF neutralization also led to increased P2X2e splicing variant at mRNA and membrane protein levels. These data suggest that NGF controlled plasticity of P2X3 subunits and their membrane assembly with P2X2 subunits. Despite anti-NGF treatment, CGRP could still enhance P2X3 receptor activity, indicating separate NGF- or CGRP-mediated mechanisms to upregulate P2X3 receptors. In an in vivo model of mouse trigeminal pain, anti-NGF pretreatment suppressed responses evoked by P2X3 receptor activation. Our findings outline the important contribution by NGF signaling to nociception of trigeminal sensory neurons, which could be counteracted by anti-NGF pretreatment.

  13. Capsaicin, Nociception and Pain.

    PubMed

    Frias, Bárbara; Merighi, Adalberto

    2016-01-01

    Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations. PMID:27322240

  14. Capsaicin, Nociception and Pain.

    PubMed

    Frias, Bárbara; Merighi, Adalberto

    2016-01-01

    Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.

  15. Peripheral μ-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals.

    PubMed

    Baillie, Landon D; Schmidhammer, Helmut; Mulligan, Sean J

    2015-06-01

    While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects. PMID:25721395

  16. Mineralocorticoid receptors guide spatial and stimulus-response learning in mice.

    PubMed

    Arp, J Marit; ter Horst, Judith P; Kanatsou, Sofia; Fernández, Guillén; Joëls, Marian; Krugers, Harm J; Oitzl, Melly S

    2014-01-01

    Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum-dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR-overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR-deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning.

  17. The 5-HT1A receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT2 receptor antagonists.

    PubMed

    Herremans, A H; van der Heyden, J A; van Drimmelen, M; Olivier, B

    1999-10-01

    Ten homing pigeons were trained to discriminate the selective 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed-ratio (FR) 30 two-key operant drug discrimination procedure. The 5-HT2 receptor antagonist mianserin (ED50 = 4.8 mg/kg) fully substituted for flesinoxan, whereas ketanserin, ritanserin, mesulergine, and SB200646A substituted only partially, suggesting an interaction between 5-HT1A and 5-HT2 receptors. However, the 5-HT2 receptor agonists [DOI (0.6 mg/kg), TFMPP (10 mg/kg), mCPP (4 mg/kg)] were unable to antagonize the flesinoxan cue. The 5-HT1A receptor antagonists DU125530 (0.5-13 mg/kg) and WAY100,635 (0.1-1 mg/kg) partially antagonized the generalization of mianserin to flesinoxan. Taken together, these results are in accordance with the hypothesis that 5-HT1A receptor activation exerts an inhibitory effect on activation of 5-HT2 receptors. These results are in broad agreement with existing theories on 5-HT1A and 5-HT2 receptor interaction. Furthermore, it is argued that the discriminative stimulus properties of a drug may undergo qualitative changes with prolonged training.

  18. Sensory receptor diversity establishes a peripheral population code for stimulus duration at low intensities.

    PubMed

    Lyons-Warren, Ariel M; Hollmann, Michael; Carlson, Bruce A

    2012-08-01

    Peripheral filtering is a fundamental mechanism for establishing frequency tuning in sensory systems. By contrast, detection of temporal features, such as duration, is generally thought to result from temporal coding in the periphery, followed by an analysis of peripheral response times within the central nervous system. We investigated how peripheral filtering properties affect the coding of stimulus duration in the electrosensory system of mormyrid fishes using behavioral and electrophysiological measures of duration tuning. We recorded from individual knollenorgans, the electrosensory receptors that mediate communication, and found correlated variation in frequency tuning and duration tuning, as predicted by a simple circuit model. In response to relatively high intensity stimuli, knollenorgans responded reliably with fixed latency spikes, consistent with a temporal code for stimulus duration. At near-threshold intensities, however, both the reliability and the temporal precision of responses decreased. Evoked potential recordings from the midbrain, as well as behavioral responses to electrosensory stimulation, revealed changes in sensitivity across the range of durations associated with the greatest variability in receptor sensitivity. Further, this range overlapped with the natural range of variation in species-specific communication signals, suggesting that peripheral duration tuning affects the coding of behaviorally relevant stimuli. We measured knollenorgan, midbrain and behavioral responses to natural communication signals and found that each of them were duration dependent. We conclude that at relatively low intensities for which temporal coding is ineffective, diversity among sensory receptors establishes a population code, in which duration is reflected in the population of responding knollenorgans.

  19. GABAB receptors in the NTS mediate the inhibitory effect of trigeminal nociceptive inputs on parasympathetic reflex vasodilation in the rat masseter muscle.

    PubMed

    Ishii, Hisayoshi; Izumi, Hiroshi

    2012-03-15

    The present study was designed to examine whether trigeminal nociceptive inputs are involved in the modulation of parasympathetic reflex vasodilation in the jaw muscles. This was accomplished by investigating the effects of noxious stimulation to the orofacial area with capsaicin, and by microinjecting GABA(A) and GABA(B) receptor agonists or antagonists into the nucleus of the solitary tract (NTS), on masseter hemodynamics in urethane-anesthetized rats. Electrical stimulation of the central cut end of the cervical vagus nerve (cVN) in sympathectomized animals bilaterally increased blood flow in the masseter muscle (MBF). Increases in MBF evoked by cVN stimulation were markedly reduced following injection of capsaicin into the anterior tongue in the distribution of the lingual nerve or lower lip, but not when injected into the skin of the dorsum of the foot. Intravenous administration of either phentolamine or propranolol had no effect on the inhibitory effects of capsaicin injection on the increases of MBF evoked by cVN stimulation, which were largely abolished by microinjecting the GABA(B) receptor agonist baclofen into the NTS. Microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS markedly attenuated the capsaicin-induced inhibition of MBF increase evoked by cVN stimulation, while microinjection of the GABA(A) receptor antagonist bicuculline did not. Our results indicate that trigeminal nociceptive inputs inhibit vagal-parasympathetic reflex vasodilation in the masseter muscle and suggest that the activation of GABA(B) rather than GABA(A) receptors underlies the observed inhibition in the NTS.

  20. Effects of the nicotinic acetylcholine receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in male rhesus monkeys.

    PubMed

    Banks, Matthew L

    2014-06-01

    Preclinical drug discrimination procedures have been useful in understanding the pharmacological mechanisms of the subjective-like effects of abused drugs. Converging lines of evidence from neurochemical and behavioral studies implicate a potential role of nicotinic acetylcholine (nACh) receptors in the abuse-related effects of cocaine. The aim of the present study was to determine the effects of the nACh receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in nonhuman primates. The effects of mecamylamine on the cocaine-like discriminative stimulus effects of nicotine were also examined. Male rhesus monkeys (n = 5) were trained to discriminate 0.32 mg/kg, IM cocaine from saline in a 2-key, food-reinforced discrimination procedure. Initially, potency and time course of cocaine-like discriminative stimulus effects were determined for nicotine and mecamylamine alone. Test sessions were then conducted examining the effects of mecamylamine on cocaine or the cocaine-like discriminative stimulus effects of nicotine. Curiously, mecamylamine produced partial cocaine-like discriminative stimulus effects. Mecamylamine did not significantly alter the discriminative stimulus effects of cocaine up to doses that significantly decreased rates of operant responding. Mecamylamine and nicotine combinations were not different than saline. These results confirm previous nonhuman primate studies of partial substitution with nicotine and extend these findings with mecamylamine. Furthermore, these results extend previous results in rats suggesting cocaine may have nACh receptor antagonist properties. PMID:24548245

  1. Daily rhythm of nociception in rats.

    PubMed

    Christina, AJM; Merlin, NJ; Vijaya, C; Jayaprakash, S; Murugesh, N

    2004-03-25

    BACKGROUND: Many behavioral and physiological variables exhibit daily rhythmicity. Few investigations of the daily rhythmicity in nociception have been conducted, and conflicting results have been obtained. The present study evaluated the daily rhythmicity in nociception in Wistar rats. METHODS: Nociception was investigated by Eddy's hot plate method, tail immersion method, and tail clip method. The latency between the noxious stimulus and the animal's response was recorded as reaction time. Separate groups of rats were tested in 4-hour intervals for 24 hours. RESULTS: There was clear daily variation in response latency. Reaction time was shortest a few hours before lights-on and longest at the light-dark transition. CONCLUSION: Nociception exhibits robust daily rhythmicity in rats. Sensitivity to pain is highest late in the dark phase of the light-dark cycle and lowest at the light-dark transition.

  2. Daily rhythm of nociception in rats

    PubMed Central

    Christina, AJM; Merlin, NJ; Vijaya, C; Jayaprakash, S; Murugesh, N

    2004-01-01

    Background Many behavioral and physiological variables exhibit daily rhythmicity. Few investigations of the daily rhythmicity in nociception have been conducted, and conflicting results have been obtained. The present study evaluated the daily rhythmicity in nociception in Wistar rats. Methods Nociception was investigated by Eddy's hot plate method, tail immersion method, and tail clip method. The latency between the noxious stimulus and the animal's response was recorded as reaction time. Separate groups of rats were tested in 4-hour intervals for 24 hours. Results There was clear daily variation in response latency. Reaction time was shortest a few hours before lights-on and longest at the light-dark transition. Conclusion Nociception exhibits robust daily rhythmicity in rats. Sensitivity to pain is highest late in the dark phase of the light-dark cycle and lowest at the light-dark transition. PMID:15043763

  3. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys.

    PubMed

    Saccone, Phillip A; Zelenock, Kathy A; Lindsey, Angela M; Sulima, Agnieszka; Rice, Kenner C; Prinssen, Eric P; Wichmann, Jürgen; Woods, James H

    2016-04-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  4. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

    PubMed Central

    Zelenock, Kathy A.; Lindsey, Angela M.; Sulima, Agnieszka; Rice, Kenner C.; Prinssen, Eric P.; Wichmann, Jürgen; Woods, James H.

    2016-01-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  5. Evidence for the participation of peripheral α5 subunit-containing GABAA receptors in GABAA agonists-induced nociception in rats.

    PubMed

    Bravo-Hernández, Mariana; Feria-Morales, Luis Alberto; Torres-López, Jorge Elías; Cervantes-Durán, Claudia; Delgado-Lezama, Rodolfo; Granados-Soto, Vinicio; Rocha-González, Héctor Isaac

    2014-07-01

    The activation of GABAA receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have suggested that in inflammatory pain, GABA shifts its signaling from inhibition to excitation by an increased GABA-induced depolarization. The contribution of peripheral α5 subunit-containing GABAA receptors to the inflammatory pain is unknown. The purpose of this study was to investigate the possible pronociceptive role of peripheral α5 subunit-containing GABAA receptors in the formalin test. Formalin (0.5%) injection into the dorsum of the right hind paw produced flinching behavior in rats. Ipsilateral local peripheral pre-treatment (-10min) with exogenous GABA (0.003-0.03µg/paw) or common GABAA receptor agonists muscimol (0.003-0.03µg/paw), diazepam (0.017-0.056µg/paw) or phenobarbital (1-100µg/paw) significantly increased 0.5% formalin-induced nociceptive behavior. The pronociceptive effects of GABA (0.03µg/paw), muscimol (0.03µg/paw), diazepam (0.056µg/paw) and phenobarbital (100µg/paw) were prevented by either the GABAA receptor antagonist bicuculline (0.01-0.1µg/paw) or selective α5 subunit-containing GABAA receptor inverse agonist L-655,708 (0.017-0.17µg/paw). The α5 subunit-containing GABAA receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naïve rats. The formalin injection did not modify α5 subunit-containing GABAA receptor expression. Overall, these results suggest that peripheral α5 subunit-containing GABAA receptors play a pronociceptive role in the rat formalin test. PMID:24726872

  6. Involvement of dopamine D2 receptor signal transduction in the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats.

    PubMed

    Mori, Tomohisa; Yoshizawa, Kazumi; Ueno, Tamami; Nishiwaki, Mizuki; Shimizu, Norifumi; Shibasaki, Masahiro; Narita, Minoru; Suzuki, Tsutomu

    2013-08-01

    We have reported previously that the inhibition of both dopaminergic and psychotomimetic/hallucinogenic components plays a role in the discriminative stimulus effects of U-50,488H. However, the mechanisms that underlie the discriminative stimulus effects of U-50,488H, and especially the component that plays a significant role, have not yet been clarified. The present study was designed to further investigate the mechanism(s) of the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats that had been trained to discriminate between 3.0 mg/kg U-50,488H and saline. The dopamine D2 receptor antagonist sulpiride, but not the D1 receptor antagonist SCH23390, generalized to the discriminative stimulus effects of U-50,488H. The mood-stabilizing agents lithium chloride and valproic acid, which have attenuating effects on the Akt/GSK3 pathway, also partially generalized to the discriminative stimulus effects of U-50,488H. In contrast, the 5-HT-related compound racemic 3,4-methylenedioxymethamphetamine, the cannabinoid receptor agonist WIN55,212-2, and the μ-opioid receptor agonist morphine failed to generalize to the discriminative stimulus effects of U-50,488H. These results suggest that the inhibition of the dopaminergic activity mediated by the postsynaptic D2 receptor, followed by suppression of the Akt/GSK3 pathway may be critical for the induction of the discriminative stimulus effects induced by U-50,488H.

  7. Muscarinic preferential M(1) receptor antagonists enhance the discriminative-stimulus effects of cocaine in rats.

    PubMed

    Tanda, Gianluigi; Katz, Jonathan L

    2007-10-01

    Previous studies of benztropine analogues have found them to inhibit dopamine uptake like cocaine, but with less effectiveness than cocaine in producing behavioral effects related to drug abuse. Studies have assessed whether nonselective muscarinic antagonists decrease the effects of cocaine because many of the benztropine analogues are also muscarinic antagonists. As previous studies were conducted with nonselective muscarinic antagonists and the benztropine analogues show preferential affinity for the M(1) muscarinic receptor subtype, the present study examined interactions of cocaine and the preferential M(1) antagonists, telenzepine (TZP) and trihexyphenidyl (TXP) on subjective effects in rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline injections. Cocaine dose-dependently increased the percentage of responses on the cocaine-appropriate lever, with full substitution at the training dose. In contrast neither TZP nor TXP produced more than 25% cocaine-appropriate responding at any dose. Both M(1) antagonists produced significant leftward shifts in the cocaine dose-effect curve, TZP at 3.0 and TXP at 0.3 and 1.0 mg/kg. The present results indicate that preferential antagonist actions at muscarinic M(1) receptors enhance rather than attenuate the discriminative-stimulus effects of cocaine, and thus those actions unlikely contribute to the reduced cocaine-like effects of BZT analogues.

  8. Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline.

    PubMed

    Appel, J B; Callahan, P M

    1989-01-01

    In order to further evaluate the extent to which particular 5-HT receptor subtypes (5-HT1, 5-HT2) might be involved in the behavioral effects of hallucinogenic drugs, rats were trained to discriminate mescaline (10 mg/kg i.p.) from saline and were given substitution (generalization) and combination (antagonism) tests with putatively selective serotonergic and related neuroactive compounds. The mescaline cue generalized to relatively high doses of the 5-HT2 agonists, 2,5-dimethoxy-4-methylamphetamine (DOM), LSD and psilocybin; the extent of generalization to 5-HT1 agonists (8-hydroxy-2-[diethylamino]tetralin (8-OHDPAT), RU-24969 and 8-hydroxy-2-[di-n-propylamino]tetralin (TFMPP] was unclear. Combinations of the training drug and sufficiently high doses of 5-HT2 antagonists (ketanserin, LY-53857, pirenperone) were followed by saline-lever responding; less selective central 5-HT (metergoline), and DA (SCH-23390, haloperidol) antagonists, did not block the mescaline cue. These data suggest that 5-HT2 receptors are involved in the stimulus properties of mescaline.

  9. Dual Modulation of Nociception and Cardiovascular Reflexes during Peripheral Ischemia through P2Y1 Receptor-Dependent Sensitization of Muscle Afferents

    PubMed Central

    Queme, Luis F.; Ross, Jessica L.; Lu, Peilin; Hudgins, Renita C.

    2016-01-01

    Numerous musculoskeletal pain disorders are based in dysfunction of peripheral perfusion and are often comorbid with altered cardiovascular responses to muscle contraction/exercise. We have recently found in mice that 24 h peripheral ischemia induced by a surgical occlusion of the brachial artery (BAO) induces increased paw-guarding behaviors, mechanical hypersensitivity, and decreased grip strength. These behavioral changes corresponded to increased heat sensitivity as well as an increase in the numbers of chemosensitive group III/IV muscle afferents as assessed by an ex vivo forepaw muscles/median and ulnar nerves/dorsal root ganglion (DRG)/spinal cord (SC) recording preparation. Behaviors also corresponded to specific upregulation of the ADP-responsive P2Y1 receptor in the DRGs. Since group III/IV muscle afferents have separately been associated with regulating muscle nociception and exercise pressor reflexes (EPRs), and P2Y1 has been linked to heat responsiveness and phenotypic switching in cutaneous afferents, we sought to determine whether upregulation of P2Y1 was responsible for the observed alterations in muscle afferent function, leading to modulation of muscle pain-related behaviors and EPRs after BAO. Using an afferent-specific siRNA knockdown strategy, we found that inhibition of P2Y1 during BAO not only prevented the increased mean blood pressure after forced exercise, but also significantly reduced alterations in pain-related behaviors. Selective P2Y1 knockdown also prevented the increased firing to heat stimuli and the BAO-induced phenotypic switch in chemosensitive muscle afferents, potentially through regulating membrane expression of acid sensing ion channel 3. These results suggest that enhanced P2Y1 in muscle afferents during ischemic-like conditions may dually regulate muscle nociception and cardiovascular reflexes. SIGNIFICANCE STATEMENT Our current results suggest that P2Y1 modulates heat responsiveness and chemosensation in muscle afferents

  10. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect.

    PubMed

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-01-01

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID:26487082

  11. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect

    PubMed Central

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-01-01

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID:26487082

  12. Attenuation of Cocaine's Reinforcing and Discriminative Stimulus Effects via Muscarinic M1 Acetylcholine Receptor StimulationS⃞

    PubMed Central

    Conn, P. Jeffrey; Lindsley, Craig; Wess, Jürgen; Boon, Joon Y.; Fulton, Brian S.; Fink-Jensen, Anders; Caine, S. Barak

    2010-01-01

    Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M1 and/or M4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M1/M4-preferring agonist xanomeline, the putative M1-selective agonist (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novel M1-selective agonist 1-(1-2-methylbenzyl)-1,4-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-one (TBPB) were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M1 subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M1 and M4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M1 receptor activation attenuates cocaine's abuse-related effects, whereas non-M1/M4 receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine

  13. N-Methyl-d-Aspartate Receptor Channel Blocker–Like Discriminative Stimulus Effects of Nitrous Oxide Gas

    PubMed Central

    Richardson, Kellianne J.

    2015-01-01

    Nitrous oxide (N2O) gas is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. Studies have shown that N2O alters the function of the N-methyl-d-aspartate (NMDA), GABAA, opioid, and serotonin receptors among others. However, the receptors systems underlying the abuse-related central nervous system effects of N2O are unclear. The present study explores the receptor systems responsible for producing the discriminative stimulus effects of N2O. B6SJLF1/J male mice trained to discriminate 10 minutes of exposure to 60% N2O + 40% oxygen versus 100% oxygen served as subjects. Both the high-affinity NMDA receptor channel blocker (+)-MK-801 maleate [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] and the low-affinity blocker memantine partially mimicked the stimulus effects of N2O. Neither the competitive NMDA antagonist, CGS-19755 (cis-4-[phosphomethyl]-piperidine-2-carboxylic acid), nor the NMDA glycine-site antagonist, L701-324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone], produced N2O-like stimulus effects. A range of GABAA agonists and positive modulators, including midazolam, pentobarbital, muscimol, and gaboxadol (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol), all failed to produce N2O-like stimulus effects. The μ-, κ-, and δ-opioid agonists, as well as 5-hydroxytryptamine (serotonin) 1B/2C (5-HT1B/2C) and 5-HT1A agonists, also failed to produce N2O-like stimulus effects. Ethanol partially substituted for N2O. Both (+)-MK-801 and ethanol but not midazolam pretreatment also significantly enhanced the discriminative stimulus effects of N2O. Our results support the hypothesis that the discriminative stimulus effects of N2O are at least partially mediated by NMDA antagonist effects similar to those produced by channel blockers. However, as none of the drugs tested fully mimicked the stimulus effects of N2O, other mechanisms may also be involved. PMID:25368340

  14. Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats

    PubMed Central

    Baladi, Michelle G; Newman, Amy H; France, Charles P

    2013-01-01

    Rationale The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. Objective This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. Method Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. Result Apomorphine, quinpirole, and lisuride occasioned >90% responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90% responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. Conclusion These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures. PMID:24030470

  15. NMDA Receptors Mediate Stimulus-Timing-Dependent Plasticity and Neural Synchrony in the Dorsal Cochlear Nucleus

    PubMed Central

    Stefanescu, Roxana A.; Shore, Susan E.

    2015-01-01

    Auditory information relayed by auditory nerve fibers and somatosensory information relayed by granule cell parallel fibers converge on the fusiform cells (FCs) of the dorsal cochlear nucleus, the first brain station of the auditory pathway. In vitro, parallel fiber synapses on FCs exhibit spike-timing-dependent plasticity with Hebbian learning rules, partially mediated by the NMDA receptor (NMDAr). Well-timed bimodal auditory-somatosensory stimulation, in vivo equivalent of spike-timing-dependent plasticity, can induce stimulus-timing-dependent plasticity (StTDP) of the FCs spontaneous and tone-evoked firing rates. In healthy guinea pigs, the resulting distribution of StTDP learning rules across a FC neural population is dominated by a Hebbian profile while anti-Hebbian, suppressive and enhancing LRs are less frequent. In this study, we investigate in vivo, the NMDAr contribution to FC baseline activity and long term plasticity. We find that blocking the NMDAr decreases the synchronization of FC- spontaneous activity and mediates differential modulation of FC rate-level functions such that low, and high threshold units are more likely to increase, and decrease, respectively, their maximum amplitudes. Three significant alterations in mean learning-rule profiles were identified: transitions from an initial Hebbian profile towards (1) an anti-Hebbian; (2) a suppressive profile; and (3) transitions from an anti-Hebbian to a Hebbian profile. FC units preserving their learning rules showed instead, NMDAr-dependent plasticity to unimodal acoustic stimulation, with persistent depression of tone-evoked responses changing to persistent enhancement following the NMDAr antagonist. These results reveal a crucial role of the NMDAr in mediating FC baseline activity and long-term plasticity which have important implications for signal processing and auditory pathologies related to maladaptive plasticity of dorsal cochlear nucleus circuitry. PMID:26622224

  16. Nociceptive and reflexive responses recorded from the human nasal mucosa.

    PubMed

    Thürauf, N; Hummel, T; Kettenmann, B; Kobal, G

    1993-12-01

    Slow electrical responses after painful stimulation with carbon dioxide, which is known to specifically activate nociceptors, were recorded from the nasal respiratory epithelium in human volunteers. The negative component of these potentials (negative mucosal potential NMP) has been hypothesized to be a summated receptor potential. The aim of the present study was to characterize the stimulus-response relationship and to demonstrate that the NMP is restricted to the site of stimulation, i.e., to the area of activated nociceptors. Eight healthy volunteers participated in the experiments. The NMP was recorded from the nasal septum and intensity ratings were obtained for each of the applied stimuli. To control for autonomic reflexes, blood flow changes were additionally recorded using a laser Doppler flow meter. Both increasing stimulus duration and increasing concentration produced a significant increase in the subjects' intensity estimates, in the NMP's amplitudes and areas under the curve, but did not change the local blood flow in a dose-related manner. The odorant hydrogen sulphide, which was used as a non-painful control stimulus, did not elicit mucosal potentials or produce blood flow changes. By recording both ipsi- and contralaterally it was also demonstrated that the NMP could only be obtained at the stimulated site, thus supporting the hypothesis that the NMP is a specific peripheral nociceptive correlate.

  17. Transcranial low-level laser therapy (810 nm) temporarily inhibits peripheral nociception: photoneuromodulation of glutamate receptors, prostatic acid phophatase, and adenosine triphosphate.

    PubMed

    Pires de Sousa, Marcelo Victor; Ferraresi, Cleber; Kawakubo, Masayoshi; Kaippert, Beatriz; Yoshimura, Elisabeth Mateus; Hamblin, Michael R

    2016-01-01

    Photobiomodulation or low-level light therapy has been shown to attenuate both acute and chronic pain, but the mechanism of action is not well understood. In most cases, the light is applied to the painful area, but in the present study we applied light to the head. We found that transcranial laser therapy (TLT) applied to mouse head with specific parameters (810 nm laser, [Formula: see text], 7.2 or [Formula: see text]) decreased the reaction to pain in the foot evoked either by pressure (von Frey filaments), cold, or inflammation (formalin injection) or in the tail (evoked by heat). The pain threshold increasing is maximum around 2 h after TLT, remains up to 6 h, and is finished 24 h after TLT. The mechanisms were investigated by quantification of adenosine triphosphate (ATP), immunofluorescence, and hematoxylin and eosin (H&E) staining of brain tissues. TLT increased ATP and prostatic acid phosphatase (an endogenous analgesic) and reduced the amount of glutamate receptor (mediating a neurotransmitter responsible for conducting nociceptive information). There was no change in the concentration of tubulin, a constituent of the cytoskeleton, and the H&E staining revealed no tissue damage. This is the first study to show inhibition of peripheral pain due to photobiomodulation of the central nervous system. PMID:26835486

  18. The expression of functional IL-2 receptor on activated macrophages depends on the stimulus applied.

    PubMed Central

    Valitutti, S; Carbone, A; Castellino, F; Maggiano, N; Ricci, R; Larocca, L M; Musiani, P

    1989-01-01

    Human peripheral blood monocytes (Mo) synthesize prostaglandin E2 (PGE2) when activated with lipopolysaccharide (LPS). This production is strongly enhanced by the addition of supernatant from phytohaemagglutinin (PHA)-activated T cells. To evaluate the factor(s) responsible for this enhancement we studied the effect of several cytokines on the PGE2 metabolism. Recombinant interleukin-1 (IL-1) or recombinant IL-2 strongly enhanced PGE2 synthesis in LPS-stimulated Mo cultures, whereas recombinant interferon-gamma (IFN-gamma) partially inhibited its production. To see whether the effect of IL-2 on Mo was due to the presence of IL-2 receptor (IL-2R) on the cell surface, flow cytometric analysis and electron microscopy were used to investigate IL-2R expression in unstimulated and stimulated Mo. Stimulated, but not resting, Mo displayed the p55 IL-2R chain on their cellular surface and associated with the polyribosomes of the rough endoplasmic reticulum in the cytoplasm. This finding strongly suggested that the p55 chain of the IL-2R was synthesized by activated Mo. To confirm this result, 125I-labelled IL-2 was bound under high- and low-affinity conditions and cross-linked to Mo cultured in the presence of LPS, IFN-gamma or IL-1. The cross-linked 125I-IL-2/IL-2R complexes were analysed by SDS-PAGE. Mo cultured with LPS, IFN-gamma and IL-1 expressed the p55 protein detected by low-affinity cross-linking, whereas only LPS-stimulated Mo displayed a barely detectable band with an apparent MW of 70,000 under high-affinity binding conditions. In addition, stimulated Mo were found capable of producing the soluble form of IL-2R. Finally, LPS-activated Mo only responded to the addition of IL-2 by an increase in PGE2 production, suggesting that the function of IL-2R on activated Mo is linked to the stimulus applied. Images Figure 2 Figure 3 PMID:2661416

  19. Nociception attenuates parasympathetic but not sympathetic baroreflex via NK1 receptors in the rat nucleus tractus solitarii.

    PubMed

    Pickering, Anthony E; Boscan, Pedro; Paton, Julian F R

    2003-09-01

    Somatic noxious stimulation can evoke profound cardiovascular responses by altering activity in the autonomic nervous system. This noxious stimulation attenuates the cardiac vagal baroreflex, a key cardiovascular homeostatic reflex. This attenuation is mediated via NK1 receptors expressed on GABAergic interneurones within the nucleus of the solitary tract (NTS). We have investigated the effect of noxious stimulation and exogenous substance P (SP) on the sympathetic component of the baroreflex. We recorded from the sympathetic chain in a decerebrate, artificially perfused rat preparation. Noxious hindlimb pinch was without effect on the sympathetic baroreflex although the cardiac vagal baroreflex gain was decreased (56 %, P < 0.01). Bilateral NTS microinjection of SP (500 fmol) produced a similar selective attenuation of the cardiac vagal baroreflex gain (62 %, P < 0.005) without effect on the sympathetic baroreflex. Recordings from the cardiac sympathetic and vagal nerves confirmed the selectivity of the SP inhibition. Control experiments using a GABAA receptor agonist, isoguvacine, indicated that both components of the baroreflex (parasympathetic and sympathetic) could be blocked from the NTS injection site. The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch. Our data suggest that noxious pinch releases SP within the NTS to selectively attenuate the cardiac vagal, but not the sympathetic, component of the baroreflex. This selective withdrawal of the cardiac vagal baroreflex seems to underlie the pinch-evoked tachycardia seen in vivo. Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS.

  20. Nociception attenuates parasympathetic but not sympathetic baroreflex via NK1 receptors in the rat nucleus tractus solitarii

    PubMed Central

    Pickering, Anthony E; Boscan, Pedro; Paton, Julian F R

    2003-01-01

    Somatic noxious stimulation can evoke profound cardiovascular responses by altering activity in the autonomic nervous system. This noxious stimulation attenuates the cardiac vagal baroreflex, a key cardiovascular homeostatic reflex. This attenuation is mediated via NK1 receptors expressed on GABAergic interneurones within the nucleus of the solitary tract (NTS). We have investigated the effect of noxious stimulation and exogenous substance P (SP) on the sympathetic component of the baroreflex. We recorded from the sympathetic chain in a decerebrate, artificially perfused rat preparation. Noxious hindlimb pinch was without effect on the sympathetic baroreflex although the cardiac vagal baroreflex gain was decreased (56%, P < 0.01). Bilateral NTS microinjection of SP (500 fmol) produced a similar selective attenuation of the cardiac vagal baroreflex gain (62%, P < 0.005) without effect on the sympathetic baroreflex. Recordings from the cardiac sympathetic and vagal nerves confirmed the selectivity of the SP inhibition. Control experiments using a GABAA receptor agonist, isoguvacine, indicated that both components of the baroreflex (parasympathetic and sympathetic) could be blocked from the NTS injection site. The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch. Our data suggest that noxious pinch releases SP within the NTS to selectively attenuate the cardiac vagal, but not the sympathetic, component of the baroreflex. This selective withdrawal of the cardiac vagal baroreflex seems to underlie the pinch-evoked tachycardia seen in vivo. Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS. PMID:12813142

  1. Nociception attenuates parasympathetic but not sympathetic baroreflex via NK1 receptors in the rat nucleus tractus solitarii.

    PubMed

    Pickering, Anthony E; Boscan, Pedro; Paton, Julian F R

    2003-09-01

    Somatic noxious stimulation can evoke profound cardiovascular responses by altering activity in the autonomic nervous system. This noxious stimulation attenuates the cardiac vagal baroreflex, a key cardiovascular homeostatic reflex. This attenuation is mediated via NK1 receptors expressed on GABAergic interneurones within the nucleus of the solitary tract (NTS). We have investigated the effect of noxious stimulation and exogenous substance P (SP) on the sympathetic component of the baroreflex. We recorded from the sympathetic chain in a decerebrate, artificially perfused rat preparation. Noxious hindlimb pinch was without effect on the sympathetic baroreflex although the cardiac vagal baroreflex gain was decreased (56 %, P < 0.01). Bilateral NTS microinjection of SP (500 fmol) produced a similar selective attenuation of the cardiac vagal baroreflex gain (62 %, P < 0.005) without effect on the sympathetic baroreflex. Recordings from the cardiac sympathetic and vagal nerves confirmed the selectivity of the SP inhibition. Control experiments using a GABAA receptor agonist, isoguvacine, indicated that both components of the baroreflex (parasympathetic and sympathetic) could be blocked from the NTS injection site. The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch. Our data suggest that noxious pinch releases SP within the NTS to selectively attenuate the cardiac vagal, but not the sympathetic, component of the baroreflex. This selective withdrawal of the cardiac vagal baroreflex seems to underlie the pinch-evoked tachycardia seen in vivo. Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS. PMID:12813142

  2. Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers.

    PubMed

    Bossard, Anne-Elisabeth; Guirimand, Frédéric; Fletcher, Dominique; Gaude-Joindreau, Valérie; Chauvin, Marcel; Bouhassira, Didier

    2002-07-01

    Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents. PMID:12098616

  3. Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.

    PubMed

    St-Jacques, Bruno; Ma, Weiya

    2014-11-01

    Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor

  4. The anoctamin family channel subdued mediates thermal nociception in Drosophila.

    PubMed

    Jang, Wijeong; Kim, Ji Young; Cui, Shanyu; Jo, Juyeon; Lee, Byoung-Cheol; Lee, Yeonwoo; Kwon, Ki-Sun; Park, Chul-Seung; Kim, Changsoo

    2015-01-23

    Calcium-permeable and thermosensitive transient receptor potential (TRP) channels mediate the nociceptive transduction of noxious temperature in Drosophila nociceptors. However, the underlying molecular mechanisms are not completely understood. Here we find that Subdued, a calcium-activated chloride channel of the Drosophila anoctamin family, functions in conjunction with the thermo-TRPs in thermal nociception. Genetic analysis with deletion and the RNAi-mediated reduction of subdued show that subdued is required for thermal nociception in nociceptors. Further genetic analysis of subdued mutant and thermo-TRP mutants show that they interact functionally in thermal nociception. We find that Subdued expressed in heterologous cells mediates a strong chloride conductance in the presence of both heat and calcium ions. Therefore, our analysis suggests that Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli.

  5. The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. III: The mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion.

    PubMed

    Fiorella, D; Helsley, S; Lorrain, D S; Rabin, R A; Winter, J C

    1995-10-01

    The present study was designed to determine the effects of p-chlorophenylalanine (PCPA) and p-chloroamphetamine (PCA) administration on (1) the levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, (2) the sensitivity of LSD-trained rats to the stimulus effects of LSD, and (3) the maximal levels of 5-HT2A and 5-HT2C receptor mediated phosphoinositide (PI) hydrolysis in rat brain. PCA and PCPA both produced a significant depletion of whole brain 5-HT and 5-HIAA concentrations. The depletion of serotonin with PCPA, but not PCA, resulted in supersensitivity of LSD-trained subjects to the stimulus effects of LSD. Neither PCPA nor PCA treatment altered the maximal level of 5-HT2A receptor-mediated PI hydrolysis. However, PCPA, but not PCA, treatment resulted in a significant upregulation (46%, P < 0.05) of the maximal level of 5-HT2C receptor mediated PI hydrolysis. These data suggest that upregulation of the 5-HT2C receptor mediates the supersensitivity to LSD discriminative stimulus which follows the depletion of central nervous system serotonin by PCPA.

  6. The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis.

    PubMed

    Fiorella, D; Rabin, R A; Winter, J C

    1995-10-01

    Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT2A and 5-HT2C subtypes, play an important role in the behavioral effects of hallucinogenic compounds. The present study was designed to determine the respective significance of these two receptors in the stimulus effects of LSD and (-)DOM in the rat. Specifically, the interactions of a series of serotonergic antagonists (risperidone, pirenpirone, metergoline, ketanserin, loxapine, LY53857, pizotyline, spiperone, cyprohepatadine, mesulergine, promethazine, and thioridazine) with the LSD stimulus and the (-)DOM stimulus in LSD-trained subjects was defined. From these data, IC50 values were determined for the inhibition of the LSD-appropriate responding elicited by either 0.1 mg/kg LSD (15-min pretreatment time) or 0.4 mg/kg (-)DOM (75-min pretreatment). In addition, the affinities of these antagonists for 5-HT2A and 5-HT2C receptors were determined in radioligand competition studies, 5-HT2A affinity correlated significantly with IC50 values for the blockade of the LSD (r = +0.75, P < 0.05) and (-)DOM (r = +0.95, P < 0.001) stimuli in the LSD trained subjects. 5-HT2C affinity did not correlate significantly with either series of IC50 values. These data indicate that (1) the stimulus effects of LSD, and (2) the substitution of (-)DOM for the LSD stimulus are mediated by agonist activity at 5-HT2A receptors.

  7. The role of Drosophila Piezo in mechanical nociception.

    PubMed

    Kim, Sung Eun; Coste, Bertrand; Chadha, Abhishek; Cook, Boaz; Patapoutian, Ardem

    2012-02-19

    Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo

  8. Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation.

    PubMed

    Juif, Pierre-Eric; Salio, Chiara; Zell, Vivien; Melchior, Meggane; Lacaud, Adrien; Petit-Demouliere, Nathalie; Ferrini, Francesco; Darbon, Pascal; Hanesch, Ulrike; Anton, Fernand; Merighi, Adalberto; Lelièvre, Vincent; Poisbeau, Pierrick

    2016-08-01

    The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats. NMD was associated with a strong alteration in the expression of growth factors controlling C nociceptor maturation as well as two-pore domain K+ channels known to set nociceptive thresholds. In good agreement, C-type sensory neurons from NMD animals appeared to be hypoexcitable but functionally connected to spinal neurons, especially those expressing TRPV1 receptors. In vivo and in vitro recordings of lamina II spinal neurons at P14 revealed that the NMD-related lack of C fiber-evoked responses resulted from an inhibitory barrage in the spinal cord dorsal horn. Eventually, C-type sensory-spinal processing could be recovered after a delay of about 10 days in NMD animals. However, animals remained hypersensitive to noxious stimulus up to P100 and this might be due to an excessive expression of Nav1.8 transcripts in DRG neurons. Together, our data provide evidence for a deleterious impact of perinatal stress exposure on the maturation of the sensory-spinal nociceptive system that may contribute to the nociceptive hypersensitivity in early adulthood. PMID:27285721

  9. Quantitative analysis of receptor tyrosine kinase-effector coupling at functionally relevant stimulus levels.

    PubMed

    Li, Simin; Bhave, Devayani; Chow, Jennifer M; Riera, Thomas V; Schlee, Sandra; Rauch, Simone; Atanasova, Mariya; Cate, Richard L; Whitty, Adrian

    2015-04-17

    A major goal of current signaling research is to develop a quantitative understanding of how receptor activation is coupled to downstream signaling events and to functional cellular responses. Here, we measure how activation of the RET receptor tyrosine kinase on mouse neuroblastoma cells by the neurotrophin artemin (ART) is quantitatively coupled to key downstream effectors. We show that the efficiency of RET coupling to ERK and Akt depends strongly on ART concentration, and it is highest at the low (∼100 pM) ART levels required for neurite outgrowth. Quantitative discrimination between ERK and Akt pathway signaling similarly is highest at this low ART concentration. Stimulation of the cells with 100 pM ART activated RET at the rate of ∼10 molecules/cell/min, leading at 5-10 min to a transient peak of ∼150 phospho-ERK (pERK) molecules and ∼50 pAkt molecules per pRET, after which time the levels of these two signaling effectors fell by 25-50% while the pRET levels continued to slowly rise. Kinetic experiments showed that signaling effectors in different pathways respond to RET activation with different lag times, such that the balance of signal flux among the different pathways evolves over time. Our results illustrate that measurements using high, super-physiological growth factor levels can be misleading about quantitative features of receptor signaling. We propose a quantitative model describing how receptor-effector coupling efficiency links signal amplification to signal sensitization between receptor and effector, thereby providing insight into design principles underlying how receptors and their associated signaling machinery decode an extracellular signal to trigger a functional cellular outcome.

  10. Selective depression of nociceptive responses of dorsal horn neurones by SNC 80 in a perfused hindquarter preparation of adult mouse.

    PubMed

    Cao, C Q; Hong, Y G; Dray, A; Perkins, M N

    2001-01-01

    Detailed electrophysiological characterisation of spinal opioid receptors in the mouse has been limited due to various technical difficulties. In this study, extracellular single unit recordings were made from dorsal horn neurones in a perfused spinal cord with attached trunk-hindquarter to investigate the role of delta-opioid receptor in mediating nociceptive and non-nociceptive transmission in mouse. Noxious electrical shock, pinch and heat stimuli evoked a mean response of 20.8+/-2.5 (n=10, P<0.005), 30.1+/-5.4 (n=58, P<0.005) and 40.9+/-6.3 (n=29, P<0.005) spikes per stimulus respectively. In 5 of 22 cells, repetitive noxious electrical stimuli applied to the hindpaw for 20 s produced a progressive increase in spike number, the phenomenon known as 'wind-up' and/or hyperactivity. When the selective delta-opioid receptor agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) was perfused for 8-10 min, these evoked nociceptive responses were reversibly depressed. SNC 80 (2 microM) depressed the nociceptive responses evoked by electrical shock, pinch and heat by 74.0+/-13.7% (n=8, P<0.01), 66.5+/-16.6% (n=10, P<0.01) and 74.1+/-17.0% (n=10, P<0.01) respectively. The maximum depression by 5 microM SNC 80 was 92.6+/-6.8% (n=3). SNC 80 at 5 microM also completely abolished the wind-up and/or hypersensitivity (n=5). The depressant effects of SNC 80 on the nociceptive responses were completely blocked by 10 microM naloxone (n=5) and 3 microM 17-(cyclopropylmethyl)-6,7-dehydro-4,5 alpha-epoxy-14 beta-ethoxy-5 beta-methylindolo [2',3':6',7'] morphinan-3-ol hydrochloride (HS 378, n=8), a novel highly selective delta-opioid receptor antagonist. Interestingly, HS 378 (3 microM) itself potentiated the background activity and evoked responses to pinch and heat by 151.8+/-38.4% (P<0.05, n=8), 34.2+/-6.1% (P<0.01, n=7) and 45.5+/-11.8% (P<0.05, n=5) respectively. In contrast, the responses of non-nociceptive

  11. Muscarinic Preferential M1 Receptor Antagonists Minimally Alter the Discriminative-Stimulus Effects of Cocaine in Rats

    PubMed Central

    Tanda, Gianluigi; Katz, Jonathan L.

    2009-01-01

    Previous studies of benztropine analogues have found them to inhibit dopamine uptake like cocaine, but with less effectiveness than cocaine in producing behavioral effects related to drug abuse. Studies have assessed whether nonselective muscarinic antagonists decrease the effects of cocaine because many of the benztropine analogues are also muscarinic antagonists. As previous studies were conducted with nonselective muscarinic antagonists and the benztropine analogues show preferential affinity for the M1 muscarinic receptor subtype, the present study examined interactions of cocaine and the preferential M1 antagonists, telenzepine (TZP) and trihexyphenidyl (TXP) on subjective effects in rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline injections. Cocaine dose-dependently increased the percentage of responses on the cocaine-appropriate lever, with full substitution at the training dose. In contrast neither TZP nor TXP produced more than 25% cocaine-appropriate responding at any dose. Both M1 antagonists produced significant leftward shifts in the cocaine dose-effect curve, TZP at 3.0 and TXP at 0.3 and 1.0 mg/kg. The present results indicate that preferential antagonist actions at muscarinic M1 receptors enhance rather than attenuate the discriminative-stimulus effects of cocaine, and thus those actions unlikely contribute to the reduced cocaine-like effects of BZT analogues. PMID:17631384

  12. What’s Coming Near? The Influence of Dynamical Visual Stimuli on Nociceptive Processing

    PubMed Central

    De Paepe, Annick L.; Crombez, Geert; Legrain, Valéry

    2016-01-01

    Objects approaching us may pose a threat, and signal the need to initiate defensive behavior. Detecting these objects early is crucial to either avoid the object or prepare for contact most efficiently. This requires the construction of a coherent representation of our body, and the space closely surrounding our body, i.e. the peripersonal space. This study, with 27 healthy volunteers, investigated how the processing of nociceptive stimuli applied to the hand is influenced by dynamical visual stimuli either approaching or receding from the hand. On each trial a visual stimulus was either approaching or receding the participant’s left or right hand. At different temporal delays from the onset of the visual stimulus, a nociceptive stimulus was applied either at the same or the opposite hand, so that it was presented when the visual stimulus was perceived at varying distances from the hand. Participants were asked to respond as fast as possible at which side they perceived a nociceptive stimulus. We found that reaction times were fastest when the visual stimulus appeared near the stimulated hand. Moreover, investigating the influence of the visual stimuli along the continuous spatial range (from near to far) showed that approaching lights had a stronger spatially dependent effect on nociceptive processing, compared to receding lights. These results suggest that the coding of nociceptive information in a peripersonal frame of reference may constitute a safety margin around the body that is designed to protect it from potential physical threat. PMID:27224421

  13. What's Coming Near? The Influence of Dynamical Visual Stimuli on Nociceptive Processing.

    PubMed

    De Paepe, Annick L; Crombez, Geert; Legrain, Valéry

    2016-01-01

    Objects approaching us may pose a threat, and signal the need to initiate defensive behavior. Detecting these objects early is crucial to either avoid the object or prepare for contact most efficiently. This requires the construction of a coherent representation of our body, and the space closely surrounding our body, i.e. the peripersonal space. This study, with 27 healthy volunteers, investigated how the processing of nociceptive stimuli applied to the hand is influenced by dynamical visual stimuli either approaching or receding from the hand. On each trial a visual stimulus was either approaching or receding the participant's left or right hand. At different temporal delays from the onset of the visual stimulus, a nociceptive stimulus was applied either at the same or the opposite hand, so that it was presented when the visual stimulus was perceived at varying distances from the hand. Participants were asked to respond as fast as possible at which side they perceived a nociceptive stimulus. We found that reaction times were fastest when the visual stimulus appeared near the stimulated hand. Moreover, investigating the influence of the visual stimuli along the continuous spatial range (from near to far) showed that approaching lights had a stronger spatially dependent effect on nociceptive processing, compared to receding lights. These results suggest that the coding of nociceptive information in a peripersonal frame of reference may constitute a safety margin around the body that is designed to protect it from potential physical threat. PMID:27224421

  14. Does the histaminergic system play a role in spinal nociception?

    PubMed

    Harasawa, K

    2000-07-01

    The author studied whether the histaminergic system is involved in spinal nociception or not. A nociception-related, slow ventral root potential of rats, which is an integrated output of motoneurons, was recorded as an index of the intensity of nociception when an electric stimulation was applied to the dorsal root. Histamine dissolved in an artificial cerebrospinal fluid caused small reduction in the potential; however, mepyramine (10 nM to 10 microM, as an H1 receptor antagonist), ranitidine (1 nM to 1 microM, as an H2 receptor antagonist), R(-)-alpha-methylhistamine (2 pM to 200 nM, as an H3 receptor agonist), and thioperamide (1 nM to 10 microM, as an H3 receptor antagonist) dose-dependently reduced the potential down to around a half of each control level. These results indicate that the histaminergic system may affect the spinal withdrawal reflex.

  15. Thermosensitive transient receptor potential (TRP) channel agonists and their role in mechanical, thermal and nociceptive sensations as assessed using animal models

    PubMed Central

    Klein, AH; Trannyguen, Minh; Joe, Christopher L.; Iodi, Carstens M.; Carstens, E

    2015-01-01

    Introduction The present paper summarizes research using animal models to investigate the roles of thermosensitive transient receptor potential (TRP) channels in somatosensory functions including touch, temperature and pain. We present new data assessing the effects of eugenol and carvacrol, agonists of the warmth-sensitive TRPV3, on thermal, mechanical and pain sensitivity in rats. Methods Thermal sensitivity was assessed using a thermal preference test, which measured the amount of time the animal occupied one of two adjacent thermoelectric plates set at different temperatures. Pain sensitivity was assessed as an increase in latency of hindpaw withdrawal away from a noxious thermal stimulus directed to the plantar hindpaw (Hargreaves test). Mechanical sensitivity was assessed by measuring the force exerted by an electronic von Frey filament pressed against the plantar surface that elicited withdrawal. Results Topical application of eugenol and carvacrol did not significantly affect thermal preference, although there was a trend toward avoidance of the hotter surface in a 30 vs. 45°C preference test for rats treated with 1 or 10% eugenol and carvacrol. Both eugenol and carvacrol induced a concentration-dependent increase in thermal withdrawal latency (analgesia), with no significant effect on mechanosensitivity. Conclusions The analgesic effect of eugenol and carvacrol is consistent with previous studies. The tendency for these chemicals to increase the avoidance of warmer temperatures suggests a possible role for TRPV3 in warmth detection, also consistent with previous studies. Additional roles of other thermosensitive TRP channels (TRPM8 TRPV1, TRPV2, TRPV4, TRPM3, TRPM8, TRPA1, TRPC5) in touch, temperature and pain are reviewed. PMID:26388966

  16. Working range of stimulus flux transduction determines dendrite size and relative number of pheromone component receptor neurons in moths.

    PubMed

    Baker, T C; Domingue, M J; Myrick, A J

    2012-05-01

    We are proposing that the "relative" abundances of the differently tuned pheromone-component-responsive olfactory receptor neurons (ORNs) on insect antennae are not a result of natural selection working to maximize absolute sensitivity to individual pheromone components. Rather, relative abundances are a result of specifically tuned sensillum-plus-ORN units having been selected to accurately transduce and report to the antennal lobe the maximal ranges of molecular flux imparted by each pheromone component in every plume strand. To not reach saturating stimulus flux levels from the most concentrated plume strands of a pheromone blend, the dendritic surface area of the ORN type that is tuned to the most abundant component of a pheromone blend is increased in dendritic diameter in order to express a greater number of major pheromone component-specific odorant receptors. The increased ability of these enlarged dendrite, major component-tuned ORNs to accurately report very high flux of its component results in a larger working range of stimulus flux able to be accurately transduced by that type of ORN. However, the larger dendrite size and possibly other high-flux adjustments in titers of pheromone-binding proteins and degrading enzymes cause a decrease in absolute sensitivity to lower flux levels of the major component in lower concentration strands of the pheromone blend. In order to restore the ability of the whole-antenna major pheromone component-specific channel to accurately report to its glomerulus the abundance of the major component in lower concentration strands, the number of major component ORNs over the entire antenna is adjusted upward, creating a greater proportion of major component-tuned ORNs than those tuned to minor components. Pheromone blend balance reported by the whole-antennal major and minor component channels in low plume-flux strands is now restored, and the relative fluxes of the 2 components occurring in both low- and high-flux strands are

  17. Roles of phosphotase 2A in nociceptive signal processing

    PubMed Central

    2013-01-01

    Multiple protein kinases affect the responses of dorsal horn neurons through phosphorylation of synaptic receptors and proteins involved in intracellular signal transduction pathways, and the consequences of this modulation may be spinal central sensitization. In contrast, the phosphatases catalyze an opposing reaction of de-phosphorylation, which may also modulate the functions of crucial proteins in signaling nociception. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. Accumulated evidence has shown that phosphatase 2A (PP2A), a serine/threonine specific phosphatase, is implicated in synaptic plasticity of the central nervous system and central sensitization of nociception. Therefore, targeting protein phosphotase 2A may provide an effective and novel strategy for the treatment of clinical pain. This review will characterize the structure and functional regulation of neuronal PP2A and bring together recent advances on the modulation of PP2A in targeted downstream substrates and relevant multiple nociceptive signaling molecules. PMID:24010880

  18. Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors.

    PubMed

    Prus, Adam J; Wise, Laura E; Pehrson, Alan L; Philibin, Scott D; Bang-Andersen, Benny; Arnt, Jørn; Porter, Joseph H

    2016-10-01

    The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus. PMID:27502027

  19. Role of 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. II: Reassessment of LSD false positives.

    PubMed

    Fiorella, D; Rabin, R A; Winter, J C

    1995-10-01

    In the context of animal studies of hallucinogens, an LSD-false positive is defined as a drug known to be devoid of hallucinogenic activity in humans but which nonetheless fully mimics LSD in animals. Quipazine, MK-212, lisuride, and yohimbine have all been reported to be LSD false positives. The present study was designed to determine whether these compounds also substitute for the stimulus effects of the more pharmacologically selective hallucinogen (-)DOM (0.56 mg/kg, 75-min pretreatment time). The LSD and (-)DOM stimuli fully generalized to quipazine (3.0 mg/kg) and lisuride (0.2 mg/kg), but only partially generalized to MK-212 (0.1-1.0 mg/kg) and yohimbine (2-20 mg/kg). In combination tests, pirenpirone (0.08 mg/kg), a compound with both D2 and 5-HT2A affinity, blocked the substitution of quipazine and lisuride for the (-)DOM stimulus. Ketanserin (2.5 mg/kg), an antagonist with greater than 1 order of magnitude higher affinity for 5-HT2A receptors than either 5-HT2C or D2 receptors, also fully blocked the substitution of these compounds for the (-)DOM stimulus, while the selective D2 antagonist thiothixene (0.1-1.0 mg/kg) failed to block the substitution of lisuride for the (-)DOM stimulus. These results suggest that quipazine and lisuride substitute for the stimulus properties of the phenylalkglamine hallucinogen (-)DOM via agonist activity at 5-HT2A receptors. In addition, these results suggest that 5-HT2A agonist activity may be required, but is not in itself sufficient, for indolamine and phenylalkglamine compounds to elicit hallucinations in humans. Finally, it is concluded that MK-212 and yohimbine are neither LSD nor (-)DOM false positives.

  20. Tachykinin acts upstream of autocrine Hedgehog signaling during nociceptive sensitization in Drosophila

    PubMed Central

    Im, Seol Hee; Takle, Kendra; Jo, Juyeon; Babcock, Daniel T; Ma, Zhiguo; Xiang, Yang; Galko, Michael J

    2015-01-01

    Pain signaling in vertebrates is modulated by neuropeptides like Substance P (SP). To determine whether such modulation is conserved and potentially uncover novel interactions between nociceptive signaling pathways we examined SP/Tachykinin signaling in a Drosophila model of tissue damage-induced nociceptive hypersensitivity. Tissue-specific knockdowns and genetic mutant analyses revealed that both Tachykinin and Tachykinin-like receptor (DTKR99D) are required for damage-induced thermal nociceptive sensitization. Electrophysiological recording showed that DTKR99D is required in nociceptive sensory neurons for temperature-dependent increases in firing frequency upon tissue damage. DTKR overexpression caused both behavioral and electrophysiological thermal nociceptive hypersensitivity. Hedgehog, another key regulator of nociceptive sensitization, was produced by nociceptive sensory neurons following tissue damage. Surprisingly, genetic epistasis analysis revealed that DTKR function was upstream of Hedgehog-dependent sensitization in nociceptive sensory neurons. Our results highlight a conserved role for Tachykinin signaling in regulating nociception and the power of Drosophila for genetic dissection of nociception. DOI: http://dx.doi.org/10.7554/eLife.10735.001 PMID:26575288

  1. Tachykinin acts upstream of autocrine Hedgehog signaling during nociceptive sensitization in Drosophila.

    PubMed

    Im, Seol Hee; Takle, Kendra; Jo, Juyeon; Babcock, Daniel T; Ma, Zhiguo; Xiang, Yang; Galko, Michael J

    2015-11-17

    Pain signaling in vertebrates is modulated by neuropeptides like Substance P (SP). To determine whether such modulation is conserved and potentially uncover novel interactions between nociceptive signaling pathways we examined SP/Tachykinin signaling in a Drosophila model of tissue damage-induced nociceptive hypersensitivity. Tissue-specific knockdowns and genetic mutant analyses revealed that both Tachykinin and Tachykinin-like receptor (DTKR99D) are required for damage-induced thermal nociceptive sensitization. Electrophysiological recording showed that DTKR99D is required in nociceptive sensory neurons for temperature-dependent increases in firing frequency upon tissue damage. DTKR overexpression caused both behavioral and electrophysiological thermal nociceptive hypersensitivity. Hedgehog, another key regulator of nociceptive sensitization, was produced by nociceptive sensory neurons following tissue damage. Surprisingly, genetic epistasis analysis revealed that DTKR function was upstream of Hedgehog-dependent sensitization in nociceptive sensory neurons. Our results highlight a conserved role for Tachykinin signaling in regulating nociception and the power of Drosophila for genetic dissection of nociception.

  2. Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses.

    PubMed

    Wang, Y; Summers, T; Peterson, W; Miiller, E; Burrell, B D

    2015-07-01

    GABA (γ-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Cl(-) current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Cl(-) efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Cl(-) homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Cl(-) exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non-nociceptive afferent while bumetanide (BUM), an inhibitor of the Cl(-) importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness

  3. Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state

    PubMed Central

    de Tommaso, Marina; Navarro, Jorge; Lanzillotti, Crocifissa; Ricci, Katia; Buonocunto, Francesca; Livrea, Paolo; Lancioni, Giulio E.

    2015-01-01

    Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor

  4. 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

    PubMed

    Gresch, Paul J; Barrett, Robert J; Sanders-Bush, Elaine; Smith, Randy L

    2007-02-01

    d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

  5. The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants.

    PubMed

    Hartley, Caroline; Goksan, Sezgi; Poorun, Ravi; Brotherhood, Kelly; Mellado, Gabriela Schmidt; Moultrie, Fiona; Rogers, Richard; Adams, Eleri; Slater, Rebeccah

    2015-07-31

    Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures.

  6. The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants.

    PubMed

    Hartley, Caroline; Goksan, Sezgi; Poorun, Ravi; Brotherhood, Kelly; Mellado, Gabriela Schmidt; Moultrie, Fiona; Rogers, Richard; Adams, Eleri; Slater, Rebeccah

    2015-01-01

    Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures. PMID:26228435

  7. Neural coding of nociceptive stimuli-from rat spinal neurones to human perception.

    PubMed

    Sikandar, Shafaq; Ronga, Irene; Iannetti, Gian Domenico; Dickenson, Anthony H

    2013-08-01

    Translational studies are key to furthering our understanding of nociceptive signalling and bridging the gaps between molecules and pathways to the patients. This requires use of appropriate preclinical models that accurately depict outcome measures used in humans. Whereas behavioural animal studies classically involve reports related to nociceptive thresholds of, for example, withdrawal, electrophysiological recordings of spinal neurones that receive convergent input from primary afferents permits investigation of suprathreshold events and exploration of the full-range coding of different stimuli. We explored the central processing of nociceptive inputs in a novel parallel investigation between rats and humans. Using radiant laser pulses, we first compared the electrophysiological responses of deep wide dynamic range and superficial nociceptive-specific neurones in the rat dorsal horn with human psychophysics and cortical responses. Secondly, we explored the effects of spatial summation using laser pulses of identical energy and different size. We observed 3 main findings. Firstly, both rodent and human data confirmed that neodymium-yttrium aluminium perovskite laser stimulation is a nociceptive-selective stimulus that never activates Aβ afferents. Secondly, graded laser stimulation elicited similarly graded electrophysiological and behavioural responses in both species. Thirdly, there was a significant degree of spatial summation of laser nociceptive input. The remarkable similarity in rodent and human coding indicates that responses of rat dorsal horn neurones can translate to human nociceptive processing. These findings suggest that recordings of spinal neuronal activity elicited by laser stimuli could be a valuable predictive measure of human pain perception. PMID:23719576

  8. Neural coding of nociceptive stimuli-from rat spinal neurones to human perception.

    PubMed

    Sikandar, Shafaq; Ronga, Irene; Iannetti, Gian Domenico; Dickenson, Anthony H

    2013-08-01

    Translational studies are key to furthering our understanding of nociceptive signalling and bridging the gaps between molecules and pathways to the patients. This requires use of appropriate preclinical models that accurately depict outcome measures used in humans. Whereas behavioural animal studies classically involve reports related to nociceptive thresholds of, for example, withdrawal, electrophysiological recordings of spinal neurones that receive convergent input from primary afferents permits investigation of suprathreshold events and exploration of the full-range coding of different stimuli. We explored the central processing of nociceptive inputs in a novel parallel investigation between rats and humans. Using radiant laser pulses, we first compared the electrophysiological responses of deep wide dynamic range and superficial nociceptive-specific neurones in the rat dorsal horn with human psychophysics and cortical responses. Secondly, we explored the effects of spatial summation using laser pulses of identical energy and different size. We observed 3 main findings. Firstly, both rodent and human data confirmed that neodymium-yttrium aluminium perovskite laser stimulation is a nociceptive-selective stimulus that never activates Aβ afferents. Secondly, graded laser stimulation elicited similarly graded electrophysiological and behavioural responses in both species. Thirdly, there was a significant degree of spatial summation of laser nociceptive input. The remarkable similarity in rodent and human coding indicates that responses of rat dorsal horn neurones can translate to human nociceptive processing. These findings suggest that recordings of spinal neuronal activity elicited by laser stimuli could be a valuable predictive measure of human pain perception.

  9. Response entropy changes after noxius stimulus.

    PubMed

    Guerrero, Jose L; Matute, E; Alsina, E; Del Blanco, B; Gilsanz, F

    2012-06-01

    Small changes in the frequency of the electromyography could reflect an inadequate anesthetic or analgesic level, and it could be more specific than the hemodynamic monitors. The Datex-Ohmeda S/5 Entropy Module includes information about the electromyographic activity of the face muscles (response entropy--RE). The aim of our study is compare entropy and BIS ability to detect a nociceptive stimulus during a sevoflurane anesthesia. We designed an observational, prospective and descriptive study that included 20 patients. We performed sevoflurane anaesthesia induction, the end-tidal was kept at 3 and 4 %, during 15 min at each concentration, with no analgesic drug and no neuromuscular blocking agent, and we applied a nociceptive stimulus: tetanus 100 Hz, during 5 s. We set the standard monitorization, BIS, RE, and state entropy (SE) along the study. There was a significant difference between RE and SE post-noxious stimulus values at 3 and 4 % end-tidal sevoflurane (p < 0.05). Only RE changed significantly at the moment of the noxious stimulation at both sevoflurane concentrations studied (p < 0.05). In patients under general anesthesia only carried out with sevoflurane at concentrations that inhibit the movement to painful stimuli, the RE is a single parameter able to detect variations after the nociceptive stimulation.

  10. Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia.

    PubMed

    Nyilas, Rita; Gregg, Laura C; Mackie, Ken; Watanabe, Masahiko; Zimmer, Andreas; Hohmann, Andrea G; Katona, István

    2009-05-01

    Cannabinoid administration suppresses pain by acting at spinal, supraspinal and peripheral levels. Intrinsic analgesic pathways also exploit endocannabinoids; however, the underlying neurobiological substrates of endocannabinoid-mediated analgesia have remained largely unknown. Compelling evidence shows that, upon exposure to a painful environmental stressor, an endocannabinoid molecule called 2-arachidonoylglycerol (2-AG) is mobilized in the lumbar spinal cord in temporal correlation with stress-induced antinociception. We therefore characterized the precise molecular architecture of 2-AG signaling and its involvement in nociception in the rodent spinal cord. Nonradioactive in situ hybridization revealed that dorsal horn neurons widely expressed the mRNA of diacylglycerol lipase-alpha (DGL-alpha), the synthesizing enzyme of 2-AG. Peroxidase-based immunocytochemistry demonstrated high levels of DGL-alpha protein and CB(1) cannabinoid receptor, a receptor for 2-AG, in the superficial dorsal horn, at the first site of modulation of the ascending pain pathway. High-resolution electron microscopy uncovered postsynaptic localization of DGL-alpha at nociceptive synapses formed by primary afferents, and revealed presynaptic positioning of CB(1) on excitatory axon terminals. Furthermore, DGL-alpha in postsynaptic elements receiving nociceptive input was colocalized with metabotropic glutamate receptor 5 (mGluR(5)), whose activation induces 2-AG biosynthesis. Finally, intrathecal activation of mGluR(5) at the lumbar level evoked endocannabinoid-mediated stress-induced analgesia through the DGL-2-AG-CB(1) pathway. Taken together, these findings suggest a key role for 2-AG-mediated retrograde suppression of nociceptive transmission at the spinal level. The striking positioning of the molecular players of 2-AG synthesis and action at nociceptive excitatory synapses suggests that pharmacological manipulation of spinal 2-AG levels may be an efficacious way to regulate pain

  11. Stimulus Response

    ERIC Educational Resources Information Center

    Kennedy, Mike

    2010-01-01

    Stimulus funds unquestionably have helped many schools keep going through tough times, but for many institutions, the tough times aren't going away anytime soon. That is why, a little more than a year after Congress passed the American Recovery and Reinvestment Act and began allocating billions of dollars in aid across the nation, the so-called…

  12. Subject-level differences in reported locations of cutaneous tactile and nociceptive stimuli

    PubMed Central

    Steenbergen, Peter; Buitenweg, Jan R.; Trojan, Jörg; Klaassen, Bart; Veltink, Peter H.

    2012-01-01

    Recent theoretical advances on the topic of body representations have raised the question whether spatial perception of touch and nociception involve the same representations. Various authors have established that subjective localizations of touch and nociception are displaced in a systematic manner. The relation between veridical stimulus locations and localizations can be described in the form of a perceptual map; these maps differ between subjects. Recently, evidence was found for a common set of body representations to underlie spatial perception of touch and slow and fast pain, which receive information from modality specific primary representations. There are neurophysiological clues that the various cutaneous senses may not share the same primary representation. If this is the case, then differences in primary representations between touch and nociception may cause subject-dependent differences in perceptual maps of these modalities. We studied localization of tactile and nociceptive sensations on the forearm using electrocutaneous stimulation. The perceptual maps of these modalities differed at the group level. When assessed for individual subjects, the differences localization varied in nature between subjects. The agreement of perceptual maps of the two modalities was moderate. These findings are consistent with a common internal body representation underlying spatial perception of touch and nociception. The subject level differences suggest that in addition to these representations other aspects, possibly differences in primary representation and/or the influence of stimulus parameters, lead to differences in perceptual maps in individuals. PMID:23226126

  13. Nociception at the diabetic foot, an uncharted territory

    PubMed Central

    Chantelau, Ernst A

    2015-01-01

    The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy. PMID:25897350

  14. Nociception at the diabetic foot, an uncharted territory.

    PubMed

    Chantelau, Ernst A

    2015-04-15

    The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy.

  15. A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor gene expression

    NASA Astrophysics Data System (ADS)

    Falvo, James V.; Brinkman, Brigitta M. N.; Tsytsykova, Alla V.; Tsai, Eunice Y.; Yao, Tso-Pang; Kung, Andrew L.; Goldfeld, Anne E.

    2000-04-01

    The cAMP response element binding protein (CREB)-binding protein (CBP)/p300 family of coactivator proteins regulates gene transcription through the integration of multiple signal transduction pathways. Here, we show that induction of tumor necrosis factor (TNF-) gene expression in T cells stimulated by engagement of the T cell receptor (TCR) or by virus infection requires CBP/p300. Strikingly, in mice lacking one copy of the CBP gene, TNF- gene induction by TCR activation is inhibited, whereas virus induction of the TNF- gene is not affected. Consistent with these findings, the transcriptional activity of CBP is strongly potentiated by TCR activation but not by virus infection of T cells. Thus, CBP gene dosage and transcriptional activity are critical in TCR-dependent TNF-α gene expression, demonstrating a stimulus-specific requirement for CBP in the regulation of a specific gene.

  16. Rise of the Sensors: Nociception and Pruritus

    PubMed Central

    2014-01-01

    Once there was a day when all type C nonmyelinated neurons were indistinguishable. That time of histologic analysis has passed, and we have entered an era of unparalleled technological insight into the mechanisms of pain and pruritus. Since the description of the capsaicin receptor, transient receptor protein vanilloid 1 (TRPV1), in 1997, we have seen the number of related sensor ion channels, G protein–coupled receptors, and signaling proteins explode. Specific nociceptive pathways have been identified based on their sensitivity to mechanical, heat, chemical, and cold stimuli. Pruritus is now recognized to have both histamine-sensitive and histamine-independent afferent arcs. Cross-talk between C-fibre systems and myelinated neural pathways has become more complex, but through complexity, a new reality of sensory coding is emerging. A multitude of novel therapeutics have been and are in planning and production stages. These will almost certainly revolutionize our understanding and treatment of pain and itch by the end of this decade. PMID:22367178

  17. An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.

    PubMed

    Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

    2016-11-01

    Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT(-/-) cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT(-/-) cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response. PMID:27544824

  18. Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider Phoneutria nigriventer

    PubMed Central

    Gewehr, Camila; Oliveira, Sara Marchesan; Rossato, Mateus Fortes; Trevisan, Gabriela; Dalmolin, Gerusa Duarte; Rigo, Flávia Karine; de Castro Júnior, Célio José; Cordeiro, Marta Nascimento; Ferreira, Juliano; Gomez, Marcus V.

    2013-01-01

    Background The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). Methodology/Principal Findings Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na+ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. Conclusion/Significance Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for

  19. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors

    SciTech Connect

    Hynes, M.D.; Lochner, M.A.; Bemis, K.G.; Hymson, D.L.

    1985-06-17

    The analgesic effect of morphine in the rat tail jerk assay was enhanced by the serotonin uptake inhibitor, fluoxetine. Tail jerk latency was not affected by fluoxetine alone. Morphine's affinity for opioid receptors labeled in vitro with /sup 3/H-naloxone or /sup 3/H-D-Ala/sup 2/-D-Leu/sup 5/-enkephalin was not altered by fluoxetine, which has no affinity for these sites at concentrations as high as 1000 nM. In rats trained to discriminate morphine from saline, fluoxetine at doses of 5 or 10 mg/kg were recognized as saline. Increasing the fluoxetine dose to 20 mg/kg did not result in generalization to either saline or morphine. The dose response curve for morphine generalization was not significantly altered by fluoxetine doses of 5 or 10 mg/kg. Those rats treated with the combination of morphine and 20 mg/kg of fluoxetine did not exhibit saline or morphine appropriate responding. Fluoxetine potentiates the analgesic properties of morphine without enhancing its affinity for opioid receptors or its discriminative stimulus properties. 30 references, 2 figures, 2 tables.

  20. Novelty is not enough: laser-evoked potentials are determined by stimulus saliency, not absolute novelty.

    PubMed

    Ronga, I; Valentini, E; Mouraux, A; Iannetti, G D

    2013-02-01

    Event-related potentials (ERPs) elicited by transient nociceptive stimuli in humans are largely sensitive to bottom-up novelty induced, for example, by changes in stimulus attributes (e.g., modality or spatial location) within a stream of repeated stimuli. Here we aimed 1) to test the contribution of a selective change of the intensity of a repeated stimulus in determining the magnitude of nociceptive ERPs, and 2) to dissect the effect of this change of intensity in terms of "novelty" and "saliency" (an increase of stimulus intensity is more salient than a decrease of stimulus intensity). Nociceptive ERPs were elicited by trains of three consecutive laser stimuli (S1-S2-S3) delivered to the hand dorsum at a constant 1-s interstimulus interval. Three, equally spaced intensities were used: low (L), medium (M), and high (H). While the intensities of S1 and S2 were always identical (L, M, or H), the intensity of S3 was either identical (e.g., HHH) or different (e.g., MMH) from the intensity of S1 and S2. Introducing a selective change in stimulus intensity elicited significantly larger N1 and N2 waves of the S3-ERP but only when the change consisted in an increase in stimulus intensity. This observation indicates that nociceptive ERPs do not simply reflect processes involved in the detection of novelty but, instead, are mainly determined by stimulus saliency. PMID:23136349

  1. The C. elegans D2-Like Dopamine Receptor DOP-3 Decreases Behavioral Sensitivity to the Olfactory Stimulus 1-Octanol

    PubMed Central

    Ezak, Meredith J.; Ferkey, Denise M.

    2010-01-01

    We previously found that dopamine signaling modulates the sensitivity of wild-type C. elegans to the aversive odorant 1-octanol. C. elegans lacking the CAT-2 tyrosine hydroxylase enzyme, which is required for dopamine biosynthesis, are hypersensitive in their behavioral avoidance of dilute concentrations of octanol. Dopamine can also modulate the context-dependent response of C. elegans lacking RGS-3 function, a negative regulator of Gα signaling. rgs-3 mutant animals are defective in their avoidance of 100% octanol when they are assayed in the absence of food (E. coli bacterial lawn), but their response is restored when they are assayed in the presence of food or exogenous dopamine. However, it is not known which receptor might be mediating dopamine's effects on octanol avoidance. Herein we describe a role for the C. elegans D2-like receptor DOP-3 in the regulation of olfactory sensitivity. We show that DOP-3 is required for the ability of food and exogenous dopamine to rescue the octanol avoidance defect of rgs-3 mutant animals. In addition, otherwise wild-type animals lacking DOP-3 function are hypersensitive to dilute octanol, reminiscent of cat-2 mutants. Furthermore, we demonstrate that DOP-3 function in the ASH sensory neurons is sufficient to rescue the hypersensitivity of dop-3 mutant animals, while dop-3 RNAi knockdown in ASH results in octanol hypersensitivity. Taken together, our data suggest that dopaminergic signaling through DOP-3 normally acts to dampen ASH signaling and behavioral sensitivity to octanol. PMID:20209143

  2. Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

    PubMed

    Kadow, Brian T; Lyon, Timothy D; Zhang, Zhaocun; Lamm, Vladimir; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2016-07-01

    This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition. PMID:27170683

  3. Alfaxalone Anaesthesia Facilitates Electrophysiological Recordings of Nociceptive Withdrawal Reflexes in Dogs (Canis familiaris).

    PubMed

    Hunt, James; Murrell, Jo; Knazovicky, David; Harris, John; Kelly, Sara; Knowles, Toby G; Lascelles, B Duncan X

    2016-01-01

    Naturally occurring canine osteoarthritis represents a welfare issue for affected dogs (Canis familiaris), but is also considered very similar to human osteoarthritis and has therefore been proposed as a model of disease in humans. Central sensitisation is recognized in human osteoarthritis sufferers but identification in dogs is challenging. Electromyographic measurement of responses to nociceptive stimulation represents a potential means of investigating alterations in central nociceptive processing, and has been evaluated in conscious experimental dogs, but is likely to be aversive. Development of a suitable anaesthetic protocol in experimental dogs, which facilitated electrophysiological nociceptive withdrawal reflex assessment, may increase the acceptability of using the technique in owned dogs with naturally occurring osteoarthritis. Seven purpose bred male hound dogs underwent electromyographic recording sessions in each of three states: acepromazine sedation, alfaxalone sedation, and alfaxalone anaesthesia. Electromyographic responses to escalating mechanical and electrical, and repeated electrical, stimuli were recorded. Subsequently the integral of both early and late rectified responses was calculated. Natural logarithms of the integral values were analysed within and between the three states using multi level modeling. Alfaxalone increased nociceptive thresholds and decreased the magnitude of recorded responses, but characteristics of increasing responses with increasing stimulus magnitude were preserved. Behavioural signs of anxiety were noted in two out of seven dogs during recordings in the acepromazine sedated state. There were few significant differences in response magnitude or nociceptive threshold between the two alfaxalone states. Following acepromazine premedication, induction of anaesthesia with 1-2 mg kg-1 alfaxalone, followed by a continuous rate infusion in the range 0.075-0.1 mg kg-1 min-1 produced suitable conditions to enable assessment

  4. Alfaxalone Anaesthesia Facilitates Electrophysiological Recordings of Nociceptive Withdrawal Reflexes in Dogs (Canis familiaris)

    PubMed Central

    Hunt, James; Murrell, Jo; Knazovicky, David; Harris, John; Kelly, Sara; Knowles, Toby G.; Lascelles, B. Duncan X.

    2016-01-01

    Naturally occurring canine osteoarthritis represents a welfare issue for affected dogs (Canis familiaris), but is also considered very similar to human osteoarthritis and has therefore been proposed as a model of disease in humans. Central sensitisation is recognized in human osteoarthritis sufferers but identification in dogs is challenging. Electromyographic measurement of responses to nociceptive stimulation represents a potential means of investigating alterations in central nociceptive processing, and has been evaluated in conscious experimental dogs, but is likely to be aversive. Development of a suitable anaesthetic protocol in experimental dogs, which facilitated electrophysiological nociceptive withdrawal reflex assessment, may increase the acceptability of using the technique in owned dogs with naturally occurring osteoarthritis. Seven purpose bred male hound dogs underwent electromyographic recording sessions in each of three states: acepromazine sedation, alfaxalone sedation, and alfaxalone anaesthesia. Electromyographic responses to escalating mechanical and electrical, and repeated electrical, stimuli were recorded. Subsequently the integral of both early and late rectified responses was calculated. Natural logarithms of the integral values were analysed within and between the three states using multi level modeling. Alfaxalone increased nociceptive thresholds and decreased the magnitude of recorded responses, but characteristics of increasing responses with increasing stimulus magnitude were preserved. Behavioural signs of anxiety were noted in two out of seven dogs during recordings in the acepromazine sedated state. There were few significant differences in response magnitude or nociceptive threshold between the two alfaxalone states. Following acepromazine premedication, induction of anaesthesia with 1–2 mg kg-1 alfaxalone, followed by a continuous rate infusion in the range 0.075–0.1 mg kg-1 min-1 produced suitable conditions to enable

  5. Rapid Determination of the Thermal Nociceptive Threshold in Diabetic Rats

    PubMed Central

    Alshahrani, Saeed; Fernandez-Conti, Filipe; Araujo, Amanda; DiFulvio, Mauricio

    2012-01-01

    Painful diabetic neuropathy (PDN) is characterized by hyperalgesia i.e., increased sensitivity to noxious stimulus, and allodynia i.e., hypersensitivity to normally innocuous stimuli1. Hyperalgesia and allodynia have been studied in many different rodent models of diabetes mellitus2. However, as stated by Bölcskei et al, determination of "pain" in animal models is challenging due to its subjective nature3. Moreover, the traditional methods used to determine behavioral responses to noxious thermal stimuli usually lack reproducibility and pharmacological sensitivity3. For instance, by using the hot-plate method of Ankier4, flinch, withdrawal and/or licking of either hind- and/or fore-paws is quantified as reflex latencies at constant high thermal stimuli (52-55 °C). However, animals that are hyperalgesic to thermal stimulus do not reproducibly show differences in reflex latencies using those supra-threshold temperatures3,5. As the recently described method of Bölcskei et al.6, the procedures described here allows for the rapid, sensitive and reproducible determination of thermal nociceptive thresholds (TNTs) in mice and rats. The method uses slowly increasing thermal stimulus applied mostly to the skin of mouse/rat plantar surface. The method is particularly sensitive to study anti-nociception during hyperalgesic states such as PDN. The procedures described bellow are based on the ones published in detail by Almási et al5 and Bölcskei et al3. The procedures described here have been approved the Laboratory Animal Care and Use Committee (LACUC), Wright State University. PMID:22643870

  6. Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception.

    PubMed

    Dimitrov, Eugene L; Petrus, Emily; Usdin, Ted B

    2010-11-01

    Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55°C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icv, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CB1 and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions.

  7. Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception

    PubMed Central

    Dimitrov, Eugene L.; Petrus, Emily; Usdin, Ted B.

    2010-01-01

    Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55 °C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icv, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CB1 and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions. PMID:20696160

  8. Is temporal summation of pain and spinal nociception altered during normal aging?

    PubMed

    Marouf, Rafik; Piché, Mathieu; Rainville, Pierre

    2015-10-01

    This study examines the effect of normal aging on temporal summation (TS) of pain and the nociceptive flexion reflex (RIII). Two groups of healthy volunteers, young and elderly, received transcutaneous electrical stimulation applied to the right sural nerve to assess pain and the nociceptive flexion reflex (RIII-reflex). Stimulus intensity was adjusted individually to 120% of RIII-reflex threshold, and shocks were delivered as a single stimulus or as a series of 5 stimuli to assess TS at 5 different frequencies (0.17, 0.33, 0.66, 1, and 2 Hz). This study shows that robust TS of pain and RIII-reflex is observable in individuals aged between 18 and 75 years and indicates that these effects are comparable between young and older individuals. These results contrast with some previous findings and imply that at least some pain regulatory processes, including TS, may not be affected by normal aging, although this may vary depending on the method.

  9. Pharmacological Properties and Discriminative Stimulus Effects of a Novel and Selective 5-HT2 Receptor Agonist AL-38022A [(S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine

    PubMed Central

    May, Jesse A.; Sharif, Najam A.; Chen, Hwang-Hsing; Liao, John C.; Kelly, Curtis R.; Glennon, Richard A.; Young, Richard; Li, Jun-Xu; Rice, Kenner C.; France, Charles P.

    2013-01-01

    AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki ≤ 2.2 nM), but a significantly lower (>100-fold less) affinity for other 5-HT receptors. In addition, AL-38022A displayed a very low affinity for a broad array of other receptors, neurotransmitter transport sites, ion channels, and second messenger elements, making it a relatively selective agent. AL-38022A potently stimulated functional responses via native and cloned rat (EC50 range: 1.9 – 22.5 nM) and human (EC50 range: 0.5 – 2.2 nM) 5-HT2 receptor subtypes including [Ca2+]i mobilization and tissue contractions with apparently similar potencies and intrinsic activities and was a full agonist at all 5-HT2 receptor subtypes. The CNS activity of AL-38022A was assessed by evaluating its discriminative stimulus effects in both a rat and a monkey drug discrimination paradigm using DOM as the training drug. AL-38022A fully generalized to the DOM stimulus in each of these studies; in monkeys MDL 100907 antagonized both DOM and AL-38022A. The pharmacological profile of AL-38022A suggests that it could be a useful tool in defining 5-HT2 receptor signaling and receptor characterization where 5-HT may function as a neurotransmitter. PMID:18718483

  10. Transcranial magnetic stimulation reduces nociceptive threshold in rats.

    PubMed

    Ambriz-Tututi, Mónica; Sánchez-González, Violeta; Drucker-Colín, René

    2012-05-01

    Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate or inhibit nerve cells in the brain noninvasively. TMS induces an electromagnetic current in the underlying cortical neurons. Varying frequencies and intensities of TMS increase or decrease excitability in the cortical area directly targeted. It has been suggested that TMS has potential in the treatment of some neurological disorders such as Parkinson's disease, stroke, and depression. Initial case reports and open label trials reported by several groups support the use of TMS in pain treatment. In the present study, we evaluated the effect of TMS on the nociceptive threshold in the rat. The parameters used were a frequency of 60 Hz and an intensity of 2 and 6 mT for 2 hr twice per day. After 5 days of TMS treatment, rats were evaluated for mechanical, chemical, and cold stimulation. We observed a significant reduction in the nociceptive threshold in TMS-treated rats but not in sham-treated rats in all behavioral tests evaluated. When TMS treatment was stopped, a slow recovery to normal mechanic threshold was observed. Interestingly, i.c.v. MK-801 or CNQX administration reverted the TMS-induced pronociception. The results suggest that high-frequency TMS can alter the nociceptive threshold and produce allodynia in the rats; results suggest the involvement of NMDA and AMPA/KA receptors on TMS-induced allodynia in the rat. PMID:22315163

  11. Quantification of Nociceptive Escape Response in C.elegans

    NASA Astrophysics Data System (ADS)

    Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

    2013-03-01

    Animals cannot rank and communicate their pain consciously. Thus in pain studies on animal models, one must infer the pain level from high precision experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. Here we explore the feasibility of C.elegans as a model for pain transduction. The nematode has a robust neurally mediated noxious escape response, which we show to be partially decoupled from other sensory behaviors. We develop a nociceptive behavioral response assay that allows us to apply controlled levels of pain by locally heating worms with an IR laser. The worms' motions are captured by machine vision programming with high spatiotemporal resolution. The resulting behavioral quantification allows us to build a statistical model for inference of the experienced pain level from the behavioral response. Based on the measured nociceptive escape of over 400 worms, we conclude that none of the simple characteristics of the response are reliable indicators of the laser pulse strength. Nonetheless, a more reliable statistical inference of the pain stimulus level from the measured behavior is possible based on a complexity-controlled regression model that takes into account the entire worm behavioral output. This work was partially supported by NSF grant No. IOS/1208126 and HFSP grant No. RGY0084/2011.

  12. Parsing pain perception between nociceptive representation and magnitude estimation.

    PubMed

    Baliki, M N; Geha, P Y; Apkarian, A V

    2009-02-01

    Assessing the size of objects rapidly and accurately clearly has survival value. A central multisensory module for subjective magnitude assessment is therefore highly likely, suggested by psychophysical studies, and proposed on theoretical grounds. Given that pain perception is fundamentally an assessment of stimulus intensity, it must necessarily engage such a central module. Accordingly, we compared functional magnetic resonance imaging (fMRI) activity of pain magnitude ratings to matched visual magnitude ratings in 14 subjects. We show that brain activations segregate into two groups, one preferentially activated for pain and another equally activated for both visual and pain magnitude ratings. The properties of regions in the first group were consistent with encoding nociception, whereas those in the second group with attention and task control. Insular cortex responses similarly segregated to a pain-specific area and an area (extending to the lateral prefrontal cortex) conjointly representing perceived magnitudes for pain and vision. These two insular areas were differentiated by their relationship to task variance, ability to encode perceived magnitudes for each stimulus epoch, temporal delay differences, and brain intrinsic functional connectivity. In a second group of subjects (n=11) we contrasted diffusion tensor imaging-based white matter connectivity for these two insular areas and observed anatomical connectivity closely corresponding to the functional connectivity identified with fMRI. These results demonstrate that pain perception is due to the transformation of nociceptive representation into subjective magnitude assessment within the insula. Moreover, we argue that we have identified a multisensory cortical area for "how much" complementary and analogous to the "where" and "what" as described for central visual processing.

  13. Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

    NASA Astrophysics Data System (ADS)

    Casey, Kenneth L.

    1999-07-01

    Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

  14. Inhibitory control of nociceptive responses of trigeminal spinal nucleus cells by somatosensory corticofugal projection in rat.

    PubMed

    Malmierca, E; Martin, Y B; Nuñez, A

    2012-09-27

    The caudal division of the trigeminal spinal nucleus (Sp5C) is an important brainstem relay station of orofacial pain transmission. The aim of the present study was to examine the effect of cortical electrical stimulation on nociceptive responses in Sp5C neurons. Extracellular recordings were performed in the Sp5C nucleus by tungsten microelectrodes in urethane-anesthetized Sprague-Dawley rats. Nociceptive stimulation was produced by application of capsaicin cream on the whisker pad or by constriction of the infraorbital nerve. Capsaicin application evoked a long-lasting increase in the spontaneous firing rate from 1.4±0.2 to 3.4±0.6 spikes/s. Non-noxious tactile responses from stimuli delivered to the receptive field (RF) center decreased 5 min. after capsaicin application (from 2.3±0.1 to 1.6±0.1 spikes/stimulus) while responses from the whisker located at the RF periphery increased (from 1.3±0.2 to 2.0±0.1 spikes/stimulus under capsaicin). Electrical train stimulation of the primary (S1) or secondary (S2) somatosensory cortical areas reduced the increase in the firing rate evoked by capsaicin. Also, S1, but not S2, cortical stimulation reduced the increase in non-noxious tactile responses from the RF periphery. Inhibitory cortical effects were mediated by the activation of GABAergic and glycinergic neurons because they were blocked by bicuculline or strychnine. The S1 and S2 cortical stimulation also inhibited Sp5C neurons in animals with constriction of the infraorbital nerve. Consequently, the corticofugal projection from S1 and S2 cortical areas modulates nociceptive responses of Sp5C neurons and may control the transmission of nociceptive sensory stimulus.

  15. Caloric vestibular stimulation modulates nociceptive evoked potentials.

    PubMed

    Ferrè, Elisa Raffaella; Haggard, Patrick; Bottini, Gabriella; Iannetti, Gian Domenico

    2015-12-01

    Vestibular stimulation has been reported to alleviate central pain. Clinical and physiological studies confirm pervasive interactions between vestibular signals and somatosensory circuits, including nociception. However, the neural mechanisms underlying vestibular-induced analgesia remain unclear, and previous clinical studies cannot rule out explanations based on alternative, non-specific effects such as distraction or placebo. To investigate how vestibular inputs influence nociception, we combined caloric vestibular stimulation (CVS) with psychophysical and electrocortical responses elicited by nociceptive-specific laser stimulation in humans (laser-evoked potentials, LEPs). Cold water CVS applied to the left ear resulted in significantly lower subjective pain intensity for experimental laser pain to the left hand immediately after CVS, relative both to before CVS and to 1 h after CVS. This transient reduction in pain perception was associated with reduced amplitude of all LEP components, including the early N1 wave reflecting the first arrival of nociceptive input to primary somatosensory cortex. We conclude that cold left ear CVS elicits a modulation of both nociceptive processing and pain perception. The analgesic effect induced by CVS could be mediated either by subcortical gating of the ascending nociceptive input, or by direct modulation of the primary somatosensory cortex.

  16. Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology.

    PubMed

    Legrain, V; Mancini, F; Sambo, C F; Torta, D M; Ronga, I; Valentini, E

    2012-10-01

    The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes.

  17. Nociception-related somatosensory evoked potentials in awake dogs recorded after intra epidermal electrical stimulation.

    PubMed

    van Oostrom, Hugo; Stienen, Peter J; Doornenbal, Arie; Hellebrekers, Ludo J

    2009-02-01

    At present, the specific neurophysiologic methodology of recording pain-related evoked potentials is considered a most promising approach to objectively quantify pain in man. This study was designed to characterise and evaluate the use of somatosensory evoked potentials to study nociception in a canine model. To this aim, somatosensory evoked potentials were evoked by intra-epidermal electrical stimulation and recorded from the scalp in 8 beagle dogs. Characteristics determined were: (1) the conduction velocities of the peripheral nerve fibres involved, (2) the stimulus intensity response characteristics and (3) the evaluation of possible disturbance of the signals by muscular activity from the hind paw withdrawal reflex (EMG artefact). The results showed (1) the conduction velocities to be in the A-delta fibre range (i.e. fibres involved in nociception), (2) an increase in amplitude and a decrease in latency of the evoked potential following increasing stimulus intensities and (3) the absence of EMG artefact in the signals. These data indicate that the evoked potentials recorded, are related to nociception and thus are suited to quantitatively characterise the perception of noxious stimuli making this model useful for pain- and analgesia-related research.

  18. Neuronal NTPDase3 Mediates Extracellular ATP Degradation in Trigeminal Nociceptive Pathway

    PubMed Central

    Ma, Lihua; Trinh, Thu; Ren, Yanfang; Dirksen, Robert T.; Liu, Xiuxin

    2016-01-01

    ATP induces pain via activation of purinergic receptors in nociceptive sensory nerves. ATP signaling is terminated by ATP hydrolysis mediated by cell surface-localized ecto-nucleotidases. Using enzymatic histochemical staining, we show that ecto-ATPase activity is present in mouse trigeminal nerves. Using immunofluorescence staining, we found that ecto-NTPDase3 is expressed in trigeminal nociceptive neurons and their projections to the brainstem. In addition, ecto-ATPase activity and ecto-NTPDase3 are also detected in the nociceptive outermost layer of the trigeminal subnucleus caudalis. Furthermore, we demonstrate that incubation with anti-NTPDase3 serum reduces extracellular ATP degradation in the nociceptive lamina of both the trigeminal subnucleus caudalis and the spinal cord dorsal horn. These results are consistent with neuronal NTPDase3 activity modulating pain signal transduction and transmission by affecting extracellular ATP hydrolysis within the trigeminal nociceptive pathway. Thus, disruption of trigeminal neuronal NTPDase3 expression and localization to presynaptic terminals during chronic inflammation, local constriction and injury may contribute to the pathogenesis of orofacial neuropathic pain. PMID:27706204

  19. Anti-nociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation.

    PubMed

    Vale, Mariana L; Cunha, Fernando Q; Brito, Gerly A C; Benevides, Verônica M; Ferreira, Sérgio H; Poole, Stephen; Ribeiro, Ronaldo A

    2006-05-01

    The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.

  20. A pro-nociceptive role of neuromedin U in adult mice.

    PubMed

    Cao, Chang Qing; Yu, Xiao Hong; Dray, Andy; Filosa, Angelo; Perkins, Martin N

    2003-08-01

    Although the neuropeptide neuromedin U (NMU) was first isolated from the spinal cord, its actions in this site are unknown. The recent identification of the NMU receptor subtype 2 (NMU2R) in the spinal cord has increased the interest in investigating the role of NMU in this part of the central nervous system. Here, we report a novel function for NMU in spinal nociception in the mouse. Systemic perfusion of NMU (rat, NMU-23) dose-dependently (0.2, 0.5, 1, and 2.5 microM) potentiated both the background activity and noxious pinch-evoked response of nociceptive or wide dynamic range, but not non-nociceptive, dorsal horn neurons. At 2.5 microM, NMU-23 increased the total background activity from 154+/-34 to 1374+/-260 spikes/160 s (P<0.005, n=28) and increased the evoked nociceptive response by 185+/-50% (P<0.01, n=13). Intrathecal administration of NMU-23 (0.4, 1.1, and 3.8 nmol/10 microl) dose-dependently decreased thermal withdrawal latencies and produced a morphine-sensitive behavioral response. These electrophysiological and behavioral results suggest that NMU may be a novel physiological regulator in spinal nociceptive transmission and processing. PMID:12927633

  1. Inhibition of M current in sensory neurons by exogenous proteases: a signaling pathway mediating inflammatory nociception.

    PubMed

    Linley, John E; Rose, Kirstin; Patil, Mayur; Robertson, Brian; Akopian, Armen N; Gamper, Nikita

    2008-10-29

    Inflammatory pain is thought to be mediated in part through the action of inflammatory mediators on membrane receptors of peripheral nerve terminals, however, the downstream signaling events which lead to pain are poorly understood. In this study we investigated the nociceptive pathways induced by activation of protease-activated receptor 2 (PAR-2) in damage-sensing (nociceptive) neurons from rat dorsal root ganglion (DRG). We found that activation of PAR-2 in these cells strongly inhibited M-type potassium currents (conducted by Kv7 potassium channels). Such inhibition caused depolarization of the neuronal resting membrane potential leading, ultimately, to nociception. Consistent with this mechanism, injection of the specific M channel blocker XE991 into rat paw induced nociception in a concentration-dependent manner. Injection of a PAR-2 agonist peptide also induced nociception but coinjection of XE991 and the PAR-2 agonist did not result in summation of nociception, suggesting that the action of both agents may share a similar mechanism. We also studied the signaling pathway of M current inhibition by PAR-2 using patch-clamp and fluorescence imaging of DRG neurons. These experiments revealed that the PAR-2 effect was mediated by phospholipase C (PLC). Further experiments demonstrated that M current inhibition required concurrent rises in cytosolic Ca(2+) concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We propose that PLC- and Ca(2+)/PIP(2)-mediated inhibition of M current in sensory neurons may represent one of the general mechanisms underlying pain produced by inflammatory mediators, and may therefore open up a new therapeutic window for treatment of this major clinical problem. PMID:18971466

  2. Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to post-fracture nociceptive sensitization

    PubMed Central

    Shi, Xiaoyou; Guo, Tian-zhi; Wei, Tzuping; Li, Wen-wu; Clark, David J; Kingery, Wade S

    2015-01-01

    Tibia fracture induces exaggerated substance P (SP) and CGRP signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hindlimbs of rats similar to those seen in complex regional pain syndrome (CRPS). Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture induced exaggerated neuropeptide signaling up-regulates spinal inflammatory mediator expression, leading to post-fracture hindlimb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hindlimb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on post-fracture pain behavior and spinal inflammatory mediator expression. Hindlimb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, NGF) were observed at 4 weeks after fracture in rats. Fracture induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor and these mice had attenuated post-fracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or NGF each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling up-regulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of CRPS. PMID:25932690

  3. Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.

    PubMed

    Shi, Xiaoyou; Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-Wu; Clark, David J; Kingery, Wade S

    2015-10-01

    Tibia fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome. PMID:25932690

  4. Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.

    PubMed

    Shi, Xiaoyou; Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-Wu; Clark, David J; Kingery, Wade S

    2015-10-01

    Tibia fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome.

  5. Touch inhibits subcortical and cortical nociceptive responses

    PubMed Central

    Mancini, Flavia; Beaumont, Anne-Lise; Hu, Li; Haggard, Patrick; Iannetti, Gian Domenico D.

    2015-01-01

    Abstract The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiologic studies in anaesthetized spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supraspinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiologic markers of nociceptive function at both subcortical and cortical levels in humans. Aδ and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the laser blink reflex, which is generated by brainstem circuits before the arrival of nociceptive signals at the cortex, and laser-evoked potentials, which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the laser blink reflex, and inhibited both Aδ-fibre and C-fibre laser-evoked potentials. Thus, we conclude that touch-induced analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supraspinal mechanisms alone are not sufficient to mediate touch-induced analgesia. PMID:26058037

  6. Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2015-02-01

    Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six μ-agonists that varied in efficacy at μ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All μ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All μ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy μ-agonist nalbuphine, but not the high-efficacy μ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective μ-opioid analgesics and reveal distinctions between opioids based on efficacy at the μ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

  7. Endogenous inhibition of pain and spinal nociception in women with premenstrual dysphoric disorder

    PubMed Central

    Palit, Shreela; Bartley, Emily J; Kuhn, Bethany L; Kerr, Kara L; DelVentura, Jennifer L; Terry, Ellen L; Rhudy, Jamie L

    2016-01-01

    Purpose Premenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle. Methods Participants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM. Results Compared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR. Conclusion Endogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase. PMID:26929663

  8. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans

    PubMed Central

    Ezcurra, Marina; Walker, Denise S.; Beets, Isabel; Swoboda, Peter

    2016-01-01

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways. PMID:26985027

  9. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

    PubMed

    Ezcurra, Marina; Walker, Denise S; Beets, Isabel; Swoboda, Peter; Schafer, William R

    2016-03-16

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.

  10. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

    PubMed

    Ezcurra, Marina; Walker, Denise S; Beets, Isabel; Swoboda, Peter; Schafer, William R

    2016-03-16

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways. PMID:26985027

  11. Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception.

    PubMed

    Liberati, Giulia; Klöcker, Anne; Safronova, Marta M; Ferrão Santos, Susana; Ribeiro Vaz, Jose-Geraldo; Raftopoulos, Christian; Mouraux, André

    2016-01-01

    The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation. PMID:26734726

  12. Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans.

    PubMed

    Hapiak, Vera; Summers, Philip; Ortega, Amanda; Law, Wen Jing; Stein, Andrew; Komuniecki, Richard

    2013-08-28

    Monoamines and neuropeptides interact to modulate most behaviors. To better understand these interactions, we have defined the roles of tyramine (TA), octopamine, and neuropeptides in the inhibition of aversive behavior in Caenorhabditis elegans. TA abolishes the serotonergic sensitization of aversive behavior mediated by the two nociceptive ASH sensory neurons and requires the expression of the adrenergic-like, Gαq-coupled, TA receptor TYRA-3 on inhibitory monoaminergic and peptidergic neurons. For example, TA inhibition requires Gαq and Gαs signaling in the peptidergic ASI sensory neurons, with an array of ASI neuropeptides activating neuropeptide receptors on additional neurons involved in locomotory decision-making. The ASI neuropeptides required for tyraminergic inhibition are distinct from those required for octopaminergic inhibition, suggesting that individual monoamines stimulate the release of different subsets of ASI neuropeptides. Together, these results demonstrate that a complex humoral mix of monoamines is focused by more local, synaptic, neuropeptide release to modulate nociception and highlight the similarities between the tyraminergic/octopaminergic inhibition of nociception in C. elegans and the noradrenergic inhibition of nociception in mammals that also involves inhibitory peptidergic signaling.

  13. Nociception, pain, negative moods and behavior selection

    PubMed Central

    Baliki, Marwan N.; Apkarian, A. Vania

    2015-01-01

    Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury; while acute pain as failure of avoidant behavior; and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms; and outline current state of knowledge regarding these mechanisms: The limbic brain imparting risk, while mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats. PMID:26247858

  14. Central effects of acetylsalicylic acid on trigeminal-nociceptive stimuli

    PubMed Central

    2014-01-01

    Background Acetylsalicylic acid is one of the most used analgesics to treat an acute migraine attack. Next to the inhibitory effects on peripheral prostaglandin synthesis, central mechanisms of action have also been discussed. Methods Using a standardized model for trigeminal-nociceptive stimulation during fMRI scanning, we investigated the effect of acetylsalicylic acid on acute pain compared to saline in 22 healthy volunteers in a double-blind within-subject design. Painful stimulation was applied using gaseous ammonia and presented in a pseudo-randomized order with several control stimuli. All participants were instructed to rate the intensity and unpleasantness of every stimulus on a VAS scale. Based on previous results, we hypothesized to find an effect of ASA on central pain processing structures like the ACC, SI and SII as well as the trigeminal nuclei and the hypothalamus. Results Even though we did not find any differences in pain ratings between saline and ASA, we observed decreased BOLD signal changes in response to trigemino-nociceptive stimulation in the ACC and SII after administration of ASA compared to saline. This finding is in line with earlier imaging results investigating the effect of ASA on acute pain. Contrary to earlier findings from animal studies, we could not find an effect of ASA on the trigeminal nuclei in the brainstem or within the hypothalamic area. Conclusion Taken together our study replicates earlier findings of an attenuating effect of ASA on pain processing structures, which adds further evidence to a possibly central mechanism of action of ASA. PMID:25201152

  15. Monitoring depth of anesthesia: from consciousness to nociception. A window on subcortical brain activity.

    PubMed

    Constant, Isabelle; Sabourdin, Nada

    2015-01-01

    Anesthesia results from several inhibitor processes, which interact to lead to loss of consciousness, amnesia, immobility, and analgesia. The anesthetic agents act on the whole brain, the cortical and subcortical areas according to their receptor targets. The conscious processes are rather integrated at the level of the cortical neuronal network, while the nonconscious processes such as the nociception or implicit memory require subcortical processing. A reliable and meaningful monitoring of depth of anesthesia should provide assessment of these different processes. Besides the EEG monitoring which gives mainly information on cortical anesthetic effects, it would be relevant to have also a subcortical feedback allowing an assessment of nociception. Several devices have been proposed in this last decade, to give us an idea of the analgesia/nociception balance. Up to now, most of them are based on the assessment of the autonomic response to noxious stimulation. Among the emerging clinical devices, we can mention those which assess vascular sympathetic response (skin conductance), cardiac and vascular sympathetic response (surgical pleth index), parasympathetic cardiac response (analgesia nociception index), and finally the pupillometry which is based on the assessment of the pupillary reflex dilatation induced by nociceptive stimulations. Basically, the skin conductance might be the most adapted to assess the stress in the awake or sedated neonate, while the performances of this method appear disappointing under anesthesia. The surgical pleth index is still poorly investigated in children. The analgesia nociception index showed promising results in adults, which have to be confirmed, especially in children and in infants, and lastly pupillometry, which can be considered as reliable and reactive in children as in adults, but which is still sometimes complicated in its use. PMID:25410376

  16. NEUROTROPHIN SELECTIVITY IN ORGANIZING TOPOGRAPHIC REGENERATION OF NOCICEPTIVE AFFERENTS

    PubMed Central

    Kelamangalath, Lakshmi; Tang, Xiaoqing; Bezik, Kathleen; Sterling, Noelle; Son, Young-Jin; Smith, George M.

    2015-01-01

    Neurotrophins represent some of the best candidates to enhance regeneration. In the current study, we investigated the effects of artemin, a member of the glial derived neurotrophic factor (GDNF) family, on sensory axon regeneration following a lumbar dorsal root injury and compared these effects with that observed after either NGF or GDNF expression in the rat spinal cord. Unlike previously published data, artemin failed to induce regeneration of large-diameter myelinated sensory afferents when expressed within either the spinal cord or DRG. However, artemin or NGF induced regeneration of calcitonin gene related peptide positive (CGRP+) axons only when expressed within the spinal cord. Accordingly, artemin or NGF enhanced recovery of only nociceptive behavior and showed a cFos distribution similar to the topography of regenerating axons. Artemin and GDNF signaling requires binding to different co-receptors (GFRα3 or GFRα1, respectively) prior to binding to the signaling receptor, cRet. Approximately 70% of DRG neurons express cRet, but only 35% express either co-receptor. To enhance artemin-induced regeneration, we co-expressed artemin with either GFRα3 or GDNF. Co-expression of artemin and GFRα3 only slightly enhanced regeneration of IB4+ non-peptidergic nociceptive axons, but not myelinated axons. Interestingly, this co-expression also disrupted the ability of artemin to produce topographic targeting and lead to significant increases in cFos immunoreactivity within the deep dorsal laminae. This study failed to demonstrate artemin-induced regeneration of myelinated axons, even with co-expression of GFR-α3, which only promoted mistargeted regeneration. PMID:26054884

  17. Processing of nociceptive mechanical and thermal information in central amygdala neurons with knee-joint input.

    PubMed

    Neugebauer, Volker; Li, Weidong

    2002-01-01

    Pain has a strong emotional dimension, and the amygdala plays a key role in emotionality. The processing of nociceptive mechanical and thermal information was studied in individual neurons of the central nucleus of the amygdala, the target of the spino-parabrachio-amygdaloid pain pathway and a major output nucleus of the amygdala. This study is the first to characterize nociceptive amygdala neurons with input from deep tissue, particularly the knee joint. In 46 anesthetized rats, extracellular single-unit recordings were made from 119 central amygdala neurons that were activated orthodromically by electrical stimulation in the lateral pontine parabrachial area and were tested for receptive fields in the knee joints. Responses to brief mechanical stimulation of joints, muscles, and skin and to cutaneous thermal stimuli were recorded. Receptive-field sizes and thresholds were mapped and stimulus-response functions constructed. Neurons in the central nucleus of the amygdala with excitatory input from the knee joint (n = 62) typically had large symmetrical receptive fields in both hindlimbs or in all four extremities and responded exclusively or preferentially to noxious mechanical stimulation of deep tissue (n = 58). Noxious mechanical stimulation of the skin excited 30 of these neurons; noxious heat activated 21 neurons. Stimulus-response data were best fitted by a sigmoid nonlinear regression model rather than by a monotonically increasing linear function. Another 15 neurons were inhibited by noxious mechanical stimulation of the knee joint and other deep tissue. Fifteen neurons had no receptive field in the knee but responded to noxious stimulation of other body areas; 27 nonresponsive neurons were not activated by natural somesthetic stimulation. Our data suggest that excitation is the predominant effect of brief painful stimulation of somatic tissue on the population of central amygdala neurons with knee joint input. Their large symmetrical receptive fields and

  18. Role of peripheral purinoceptors in the development of bee venom-induced nociception: a behavioural and electrophysiological study in rats.

    PubMed

    Li, Li; Luo, Rong; Fan, Pei; Guo, Yuan; Wang, Hui-Sheng; Ma, Shao-Jie; Zhao, Yan

    2014-11-01

    Colocalization of purinergic P2X and P2Y receptors in dorsal root ganglion sensory neurons implies that these receptors play an integrative role in the nociceptive transmission process under inflammatory conditions. In the present study, behavioural and in vivo electrophysiological methods were used to examine the peripheral role of P2 receptors in the persistent nociceptive responses induced by subcutaneous bee venom injection (2 mg/mL) in. Sprague-Dawley rats Local pretreatment with the wide-spectrum P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 1 mmol/L, 50 μL) 10 min prior to s.c. bee venom injection significantly suppressed the duration of spontaneous nociceptive lifting/licking behaviour, inhibited mechanical hyperalgesia and decreased the firing of spinal dorsal horn wide dynamic range neurons in response to bee venom, without affecting primary thermal and mirror-image hyperalgesia. The localized antinociceptive action of PPADS was not due to a systemic effect, because application of the same dose of PPADS to the contralateral side was not effective. The results suggest that activation of peripheral P2 receptors is involved in the induction of nociceptive responses, mechanical hyperalgesia and the excitation of sensory spinal neurons. PMID:25115823

  19. Fos, nociception and the dorsal horn.

    PubMed

    Coggeshall, Richard E

    2005-12-01

    The protooncogene c-fos is rapidly activated after noxious stimuli to express the protein Fos in spinal dorsal horn neurons that are in the 'correct' locations for nociceptive information transfer. As such, therefore, mapping Fos expression in these neurons is at present the best global marker for efficiently locating populations of neurons in the awake animal that respond to nociceptive input. This allows, among other things, precise behavioral measurements to be correlated with Fos expression. Two arenas where mapping dorsal horn Fos expression has made a major impact are in the anatomy of nociceptive systems and as a useful assay for the analgesic properties of various therapeutic regimens. Also Fos expression is the only way to map populations of neurons that are responding to non-localized input such as withdrawal after addiction and vascular occlusion. Another insight is that it shows a clear activation of neurons in superficial 'pain-processing' laminae by innocuous stimuli after nerve lesions, a finding that presumably bears on the allodynia that often accompanies these lesions. It is to be understood, however, that the Fos localizations are not sufficient unto themselves, but the major function of these studies is to efficiently locate populations of cells in nociceptive pathways so that powerful anatomic and physiologic techniques can be brought to bear efficiently. Thus, the purpose of this review is to summarize the studies whose numbers are geometrically expanding that deal with Fos in the dorsal horn and the conclusions therefrom.

  20. TRPV1 expression level in isolectin B₄-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity.

    PubMed

    Ono, Kentaro; Ye, Yi; Viet, Chi T; Dang, Dongmin; Schmidt, Brian L

    2015-05-01

    Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor transient receptor potential vanilloid 1 (TRPV1); however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4)-positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4-negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, which were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw, and whisker pad). The TRPV1-selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4-conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6 but not in BALB/c. These results suggest that TRPV1 expression levels in IB4-positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared with BALB/c.

  1. Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene.

    PubMed

    Laird, J M; Olivar, T; Roza, C; De Felipe, C; Hunt, S P; Cervero, F

    2000-01-01

    Studies in mice lacking genes encoding for substance P or its receptor (NK1), or with NK1 antagonists, have shown that this system contributes to nociception, but the data are complex. Here, we have further examined the role of NK1 receptors in pain and hyperalgesia by comparing nociceptive responses to mechanical and chemical stimulation of viscera and the resulting hyperalgesia and inflammation in NK1 knockout (-/-) and wild-type (+/+) mice. We concentrated on visceral nociception because substance P is expressed by a much greater proportion of visceral than cutaneous afferents. NK1 -/- mice showed normal responses to visceral mechanical stimuli, measured as behavioural responses to intraperitoneal acetylcholine or hypertonic saline or reflex responses to colon distension in anaesthetized mice, although -/- mice failed to encode the intensity of noxious colon distensions. In contrast, NK1 -/- mice showed profound deficits in spontaneous behavioural reactions to an acute visceral chemical stimulus (intracolonic capsaicin) and failed to develop referred hyperalgesia or tissue oedema. However, in an identical procedure, intracolonic mustard oil evoked normal spontaneous behaviour, referred hyperalgesia and oedema in -/- mice. The inflammatory effects of capsaicin were abolished by denervation of the extrinsic innervation of the colon in rats, whereas those of mustard oil were unchanged, showing that intracolonic capsaicin evokes neurogenic inflammation, but mustard oil does not. Tests of other neurogenic inflammatory stimuli in NK1 -/- mice revealed impaired behavioural responses to cyclophosphamide cystitis and no acute reflex responses or primary hyperalgesia to intracolonic acetic acid. We conclude that NK1 receptors have an essential role mediating central nociceptive and peripheral inflammatory responses to noxious stimuli that evoke neurogenic inflammation, and modulating responses to noxious mechanical stimuli. We propose that two separate hyperalgesia

  2. Effects of chlorpheniramine and ranitidine on the visceral nociception induced by acetic acid in rats: role of opioid system.

    PubMed

    Zanboori, A; Tamaddonfard, E; Mojtahedein, A

    2008-10-15

    In this study, effects of chlorpheniramine (H1-receptor blocker), ranitidine (H2-receptor blocker), morphine (an opioid agonist) and naloxone (an opioid antagonist) in separate and combined treatments were investigated on the visceral nociception in rats. Visceral nociception was induced by intraperitoneal injection of acetic acid (1 mL, 1%). The latency time to the beginning of the first abdominal wall contraction (first writhe) was measured and the numbers of writhes were counted for 1 h after acetic acid injection. Intraperitoneal injections of chlorpheniramine and ranitidine significantly (p < 0.05) increased the latency time to the beginning of the first writhe and also significantly (p < 0.05) decreased the numbers of writhes. The same results were obtained after subcutaneous injection of morphine. Subcutaneous injection of naloxone did not change the intensity of visceral nociception, but significantly (p < 0.05) prevented the morphine-induced antinociception. Intraperitoneal injection of chlorpheniramine significantly (p < 0.05) enhanced the morphine-induced analgesia, but did not reverse the effect of naloxone on nociceptive responses. Intraperitoneal injection of ranitidine, with no effect on the morphine-induced antinociception, significantly (p < 0.05) reversed the effect of naloxone on pain responses. These results suggest that both chlorpheniramine and ranitidine exert antinociceptive effect in the visceral nociception. In addition, morphine through a naloxone-dependent mechanism produces visceral antinociception. Moreover, the endogenous opioid system may participate in the chlorpheniramine- but not in the ranitidine-induced antinociception.

  3. Experimental evidence for alleviating nociceptive hypersensitivity by single application of capsaicin.

    PubMed

    Ma, Xiao-Li; Zhang, Fang-Xiong; Dong, Fei; Bao, Lan; Zhang, Xu

    2015-04-22

    The single application of high-concentration of capsaicin has been used as an analgesic therapy of persistent pain. However, its effectiveness and underlying mechanisms remain to be further evaluated with experimental approaches. The present study provided evidence showing that the single application of capsaicin dose-dependently alleviated nociceptive hypersensitivity, and reduced the action potential firing in small-diameter neurons of the dorsal root ganglia (DRG) in rats and mice. Pre-treatment with capsaicin reduced formalin-induced acute nocifensive behavior after a brief hyperalgesia in rats and mice. The inhibitory effects of capsaicin were calcium-dependent, and mediated by the capsaicin receptor (transient receptor potential vanilloid type-1). We further found that capsaicin exerted inhibitory effects on the persistent nociceptive hypersensitivity induced by peripheral inflammation and nerve injury. Thus, these results support the long-lasting and inhibitory effects of topical capsaicin on persistent pain, and the clinic use of capsaicin as a pain therapy.

  4. Nociceptor-Enriched Genes Required for Normal Thermal Nociception.

    PubMed

    Honjo, Ken; Mauthner, Stephanie E; Wang, Yu; Skene, J H Pate; Tracey, W Daniel

    2016-07-12

    Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals.

  5. Nociceptor-Enriched Genes Required for Normal Thermal Nociception.

    PubMed

    Honjo, Ken; Mauthner, Stephanie E; Wang, Yu; Skene, J H Pate; Tracey, W Daniel

    2016-07-12

    Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals. PMID:27346357

  6. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.

  7. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality. PMID:25485642

  8. Pruritic and Nociceptive Sensations and Dysesthesias From a Spicule of Cowhage

    PubMed Central

    LaMotte, R. H.; Shimada, S. G.; Green, B. G.; Zelterman, D.

    2009-01-01

    Although the trichomes (spicules) of a pod of cowhage (Mucuna pruriens) are known to evoke a histamine-independent itch that is mediated by a cysteine protease, little is known of the itch and accompanying nociceptive sensations evoked by a single spicule and the enhanced itch and pain that can occur in the surrounding skin. The tip of a single spicule applied to the forearm of 45 subjects typically evoked 1) itch accompanied by nociceptive sensations (NS) of pricking/stinging and, to a lesser extent, burning, and 2) one or more areas of cutaneous dysesthesia characterized by hyperknesis (enhanced itch to pricking) with or without alloknesis (itch to stroking) and/or hyperalgesia (enhanced pricking pain). Itch could occur in the absence of NS or one or more dysesthesias but very rarely the reverse. The peak magnitude of sensation was positively correlated for itch and NS and increased (exhibited spatial summation) as the number of spicules was increased within a spatial extent of 6 cm but not 1 cm. The areas of dysesthesia did not exhibit spatial summation. We conclude that itch evoked by a punctate chemical stimulus can co-exist with NS and cutaneous dysesthesias as may occur in clinical pruritus. However, cowhage itch was not always accompanied by NS or dysesthesia nor was a momentary change in itch necessarily accompanied by a similar change in NS or vice versa. Thus there may be separate neural coding mechanisms for itch, nociceptive sensations, and each type of dysesthesia. PMID:19144738

  9. Membrane Cholesterol Affects Stimulus-Activity Coupling in Type 1, but not Type 2, CCK Receptors: Use of Cell Lines with Elevated Cholesterol

    PubMed Central

    Harikumar, Kaleeckal G.; Potter, Ross M.; Patil, Achyut; Echeveste, Valerie

    2013-01-01

    The lipid microenvironment of membrane proteins can affect their structure, function, and regulation. We recently described differential effects of acute modification of membrane cholesterol on the function of type 1 and 2 cholecystokinin (CCK) receptors. We now explore the regulatory impact of chronic cholesterol modification on these receptors using novel receptor-bearing cell lines with elevated membrane cholesterol. Stable CCK1R and CCK2R expression was established in clonal lines of 25RA cells having gain-of-function in SCAP [sterol regulatory element binding protein (SREBP) cleavage-activating protein] and SRD15 cells having deficiencies in Insig-1 and Insig-2 enzymes affecting HMG CoA reductase and SREBP. Increased cholesterol in the plasma membrane of these cells was directly demonstrated, and receptor binding and signaling characteristics were shown to reflect predicted effects on receptor function. In both environments, both types of CCK receptors were internalized and recycled normally in response to agonist occupation. No differences in receptor distribution within the membrane were appreciated at the light microscopic level in these CHO-derived cell lines. Fluorescence anisotropy was studied for these receptors occupied by fluorescent agonist and antagonist, as well as when tagged with YFP. These studies demonstrated increased anisotropy of the agonist ligand occupying the active state of the CCK1R in a cholesterol-enriched environment, mimicking fluorescence of the uncoupled, inactive state of this receptor, while there was no effect of increasing cholesterol on fluorescence at the CCK2R. These cell lines should be quite useful for examining the functional characteristics of potential drugs that might be used in an abnormal lipid environment. PMID:23306829

  10. Changes in nociceptive reflex facilitation during carrageenan-induced arthritis.

    PubMed

    Herrero, J F; Cervero, F

    1996-04-22

    Facilitation of neuronal responses induced by repetitive electrical stimulation of C-fibres (wind-up) is thought to be a substrate of hyperalgesia. There is little information on how these responses are in turn modified during hyperalgesia, and the extent to which hyperalgesic states also induce a facilitation of the neuronal responses mediated by A-fibres. The current study was undertaken in order to evaluate the effects of peripheral inflammation and stimulus presentation on the facilitation of nociceptive reflexes. Flexor reflexes, recorded as single motor units, were evoked in rats by cycles of low and high frequency electrical stimulation with pulse durations of 0.2, 0.5 and 2 ms. Responses were studied in control and inflammatory conditions, using the carrageenan-induced mono-arthritis model. The results show that the facilitation of late (C-fibre mediated) responses was proportional to the pulse duration of stimulation, as well as to the stimulation frequency. Facilitation was always higher when animals were subjected to inflammation. In inflammatory conditions, facilitation of reflexes was observed not only for late (C-fibre mediated) but also for early (A-fibre mediated) reflex responses. However, the facilitation of these early responses was not proportional to the intensity of stimulation. Thus, in arthritic animals, late (C-fibre mediated) flexion reflexes elicited from the skin, are facilitated and early (A-fibre mediated) reflexes are not only facilitated but, in addition, show a novel wind-up phenomenon.

  11. Stimulus Reporting Advances

    ERIC Educational Resources Information Center

    McNeil, Michele

    2009-01-01

    Faced with their first reporting deadlines for economic-stimulus aid to education, school districts are toiling over how every stimulus penny has been spent so far and how many jobs have been saved--numbers that will be scrutinized not just by the public, but by government auditors as well. The American Recovery and Reinvestment Act, passed by…

  12. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase

    PubMed Central

    Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma; Cornett, Ben; Mackie, Ken; Bradshaw, Heather

    2016-01-01

    Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic

  13. Is temporal summation of pain and spinal nociception altered during normal aging?

    PubMed Central

    Marouf, Rafik; Piché, Mathieu; Rainville, Pierre

    2015-01-01

    Abstract This study examines the effect of normal aging on temporal summation (TS) of pain and the nociceptive flexion reflex (RIII). Two groups of healthy volunteers, young and elderly, received transcutaneous electrical stimulation applied to the right sural nerve to assess pain and the nociceptive flexion reflex (RIII-reflex). Stimulus intensity was adjusted individually to 120% of RIII-reflex threshold, and shocks were delivered as a single stimulus or as a series of 5 stimuli to assess TS at 5 different frequencies (0.17, 0.33, 0.66, 1, and 2 Hz). This study shows that robust TS of pain and RIII-reflex is observable in individuals aged between 18 and 75 years and indicates that these effects are comparable between young and older individuals. These results contrast with some previous findings and imply that at least some pain regulatory processes, including TS, may not be affected by normal aging, although this may vary depending on the method. PMID:26058038

  14. Hypergravity modulates behavioral nociceptive responses in rats

    NASA Astrophysics Data System (ADS)

    Kumei, Y.; Shimokawa, R.; Toda, K.; Kawauchi, Y.; Makita, K.; Terasawa, M.; Ohya, K.; Shimokawa, H.

    Hypergravity (2G) exposure elevated the nociceptive threshold (pain suppression) concomitantly with evoked neuronal activity in the hypothalamus. Young Wistar male rats were exposed to 2G by centrifugal rotation for 10 min. Before and after 2G exposure, the nociceptive threshold was measured as the withdrawal reflex by using the von Frey type needle at a total of 8 sites of each rat (nose, four quarters, upper and lower back, tail), and then rats were sacrificed. Fos expression was examined immunohistochemically in the hypothalamic slices of the 2G-treated rats. When rats were exposed to 2G hypergravity, the nociceptive threshold was significantly elevated to approximately 150 to 250% of the 1G baseline control levels in all the examination sites. The 2G hypergravity remarkably induced Fos expression in the paraventricular and arcuate nuclei of the hypothalamus. The analgesic effects of 2G hypergravity were attenuated by naloxone pretreatment. Data indicate that hypergravity induces analgesic effects in rats, mediated through hypothalamic neuronal activity in the endogenous opioid system and hypothalamo-pituitary-adrenal axis.

  15. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity.

    PubMed

    Mannion, R J; Costigan, M; Decosterd, I; Amaya, F; Ma, Q P; Holstege, J C; Ji, R R; Acheson, A; Lindsay, R M; Wilkinson, G A; Woolf, C J

    1999-08-01

    Brain-derived neurotrophic factor (BDNF) is expressed in nociceptive sensory neurons and transported anterogradely to the dorsal horn of the spinal cord where it is located in dense core vesicles in C-fiber terminals. Peripheral inflammation substantially up-regulates BDNF mRNA and protein in the dorsal root ganglion (DRG) in a nerve growth factor-dependent fashion and results in novel expression of BDNF by DRG neurons with myelinated axons. C-fiber electrical activity also increases BDNF expression in the DRG, and both inflammation and activity increase full-length TrkB receptor levels in the dorsal horn. Sequestration of endogenous BDNF/neurotrophin 4 by intraspinal TrkB-Fc fusion protein administration does not, in noninflamed animals, change basal pain sensitivity nor the mechanical hypersensitivity induced by peripheral capsaicin administration, a measure of C fiber-mediated central sensitization. TrkB-Fc administration also does not modify basal inflammatory pain hypersensitivity, but does block the progressive hypersensitivity elicited by low-intensity tactile stimulation of inflamed tissue. BDNF, by virtue of its nerve growth factor regulation in sensory neurons including novel expression in A fibers, has a role as a central modulator of tactile stimulus-induced inflammatory pain hypersensitivity.

  16. Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling

    PubMed Central

    Kollert, Sina; Dombert, Benjamin; Döring, Frank; Wischmeyer, Erhard

    2015-01-01

    In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K+ currents upon LPA application. In DRG neurons nociception can result from TRPV1 activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV1 and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IKSO after application of LPA whereas under these conditions IKSO in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders. PMID:26224542

  17. Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling.

    PubMed

    Kollert, Sina; Dombert, Benjamin; Döring, Frank; Wischmeyer, Erhard

    2015-07-30

    In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K(+) currents upon LPA application. In DRG neurons nociception can result from TRPV1 activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV1 and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IKSO after application of LPA whereas under these conditions IKSO in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders.

  18. Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling.

    PubMed

    Kollert, Sina; Dombert, Benjamin; Döring, Frank; Wischmeyer, Erhard

    2015-01-01

    In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K(+) currents upon LPA application. In DRG neurons nociception can result from TRPV1 activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV1 and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IKSO after application of LPA whereas under these conditions IKSO in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders. PMID:26224542

  19. Infusion of Gabrα6 siRNA into the trigeminal ganglia increased the myogenic orofacial nociceptive response of ovariectomized rats treated with 17β-estradiol

    PubMed Central

    Kramer, Phillip R.; Bellinger, Larry L.

    2014-01-01

    High levels of 17β-estradiol (E2) have been found to reduce inflammatory temporomandibular joint (TMJ) pain. A search for genes effected by a high concentration of estradiol showed an increase in GABAA receptor subunit α6 (Gabrα6) in the trigeminal ganglia (TG). Blockade of Gabrα6 expression in the TG increases masseter muscle nociception in male rats, but the relationship between estradiol’s effect on nociception and Gabrα6 expression remains unclear in females. To address this knowledge gap we hypothesized that reducing Gabrα6 expression in the TG will increase the orofacial nociceptive response of ovariectomized female rats treated with estradiol. To administer hormone osmotic pumps were placed in rats that dispensed a low diestrus plasma concentration of 17β-estradiol, in addition, 17β-estradiol was injected to produce a high proestrus plasma concentration of estradiol. A ligature was then placed around the masseter tendon to induce a nociceptive response; a model for TMJ muscle pain. Gabrα6 siRNA was later infused into the TG and the nociceptive response was measured using von Frey filaments and a meal duration assay. GABAA receptor expression was measured in the TG and trigeminal nucleus caudalis and upper cervical region (Vc-C1). Ligature significantly increased the nociceptive response but a high proestrus concentration of 17β-estradiol attenuated this response. Gabrα6 siRNA infusion decreased Gabrα6 expression in the TG and Vc-C1 but increased the nociceptive response after 17β-estradiol treatment. The results suggest estradiol decreased the orofacial nociceptive response, in part, by causing an increase in Gabrα6 expression. PMID:25128322

  20. NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

    PubMed Central

    Feltenstein, Matthew W.; See, Ronald E.

    2007-01-01

    Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague-Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single 1-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light+tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 μl/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug-CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse. PMID:17613253

  1. Stimulus control: Part I

    PubMed Central

    Dinsmoor, James A.

    1995-01-01

    In his effort to distinguish operant from respondent conditioning, Skinner stressed the lack of an eliciting stimulus and rejected the prevailing stereotype of Pavlovian “stimulus—response” psychology. But control by antecedent stimuli, whether classified as conditional or discriminative, is ubiquitous in the natural setting. With both respondent and operant behavior, symmetrical gradients of generalization along unrelated dimensions may be obtained following differential reinforcement in the presence and the absence of the stimulus. The slopes of these gradients serve as measures of stimulus control, and they can be steepened without applying differential reinforcement to any two points along the test dimension. Increases and decreases in stimulus control occur under the same conditions as those leading to increases and decreases in observing responses, indicating that it is the increasing frequency and duration of observation (and perhaps also of attention) that produces the separation in performances during discrimination learning. PMID:22478204

  2. Stimulus responsive nanoparticles

    NASA Technical Reports Server (NTRS)

    Cairns, Darren Robert (Inventor); Huebsch, Wade W. (Inventor); Sierros, Konstantinos A. (Inventor); Shafran, Matthew S. (Inventor)

    2013-01-01

    Disclosed are various embodiments of methods and systems related to stimulus responsive nanoparticles. In one embodiment includes a stimulus responsive nanoparticle system, the system includes a first electrode, a second electrode, and a plurality of elongated electro-responsive nanoparticles dispersed between the first and second electrodes, the plurality of electro-responsive nanorods configured to respond to an electric field established between the first and second electrodes.

  3. Stimulus Responsive Nanoparticles

    NASA Technical Reports Server (NTRS)

    Cairns, Darran Robert (Inventor); Huebsch, Wade W. (Inventor); Sierros, Konstantinos A. (Inventor); Shafran, Matthew S. (Inventor)

    2015-01-01

    Disclosed are various embodiments of methods and systems related to stimulus responsive nanoparticles. In one embodiment includes a stimulus responsive nanoparticle system, the system includes a first electrode, a second electrode, and a plurality of elongated electro-responsive nanoparticles dispersed between the first and second electrodes, the plurality of electro-responsive nanorods configured to respond to an electric field established between the first and second electrodes.

  4. Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions.

    PubMed

    Yegutkin, Gennady G; Guerrero-Toro, Cindy; Kilinc, Erkan; Koroleva, Kseniya; Ishchenko, Yevheniia; Abushik, Polina; Giniatullina, Raisa; Fayuk, Dmitriy; Giniatullin, Rashid

    2016-09-01

    Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

  5. Midbrain control of spinal nociception discriminates between responses evoked by myelinated and unmyelinated heat nociceptors in the rat.

    PubMed

    McMullan, Simon; Lumb, Bridget M

    2006-09-01

    Descending control of spinal nociception is a major determinant of normal and chronic pain. Myelinated (A-fibre) and unmyelinated (C-fibre) nociceptors convey different qualities of the pain signal (first and second pain, respectively), and they play different roles in the development and maintenance of chronic pain states. It is of considerable importance, therefore, to determine whether descending control has differential effects on the central processing of A- vs. C-nociceptive input. In anaesthetised rats, biceps femoris EMG was recorded to monitor the thresholds and encoding properties of responses evoked by fast (7.5 degrees Cs(-1)) or slow (2.5 degrees Cs(-1)) rates of skin heating of the dorsal surface of a hindpaw to preferentially activate myelinated or unmyelinated heat nociceptors, respectively. Activation of neurones in the periaqueductal grey (PAG) by microinjection of dl-homocysteic acid (DLH) or bicuculline (BIC) significantly increased response thresholds to slow rates of heating (P<0.001), but not those to fast rates of heating (P>0.05). The ability of the EMG to encode the stimulus intensity of fast rates of skin heating remained intact and unaltered (r2=0.99, P<0.001) following BIC but not DLH injection. In contrast, encoding of the stimulus intensity of slow rates of skin heating was abolished following BIC and DLH injection. The functional significance of differential descending control of the central processing of C- and A-nociceptive inputs is discussed with respect to role of the PAG in mediating antinociception as part of active coping strategies in emergency situations and the role of C- and A-nociceptive inputs in animal models of chronic pain. PMID:16650581

  6. The primary somatosensory cortex and the insula contribute differently to the processing of transient and sustained nociceptive and non-nociceptive somatosensory inputs.

    PubMed

    Hu, Li; Zhang, Li; Chen, Rui; Yu, Hongbo; Li, Hong; Mouraux, André

    2015-11-01

    Transient nociceptive stimuli elicit consistent brain responses in the primary and secondary somatosensory cortices (S1, S2), the insula and the anterior and mid-cingulate cortex (ACC/MCC). However, the functional significance of these responses, especially their relationship with sustained pain perception, remains largely unknown. Here, using functional magnetic resonance imaging, we characterize the differential involvement of these brain regions in the processing of sustained nociceptive and non-nociceptive somatosensory input. By comparing the spatial patterns of activity elicited by transient (0.5 ms) and long-lasting (15 and 30 s) stimuli selectively activating nociceptive or non-nociceptive afferents, we found that the contralateral S1 responded more strongly to the onset of non-nociceptive stimulation as compared to the onset of nociceptive stimulation and the sustained phases of nociceptive and non-nociceptive stimulation. Similarly, the anterior insula responded more strongly to the onset of nociceptive stimulation as compared to the onset of non-nociceptive stimulation and the sustained phases of nociceptive and non-nociceptive stimulation. This suggests that S1 is specifically sensitive to changes in incoming non-nociceptive input, whereas the anterior insula is specifically sensitive to changes in incoming nociceptive input. Second, we found that the MCC responded more strongly to the onsets as compared to the sustained phases of both nociceptive and non-nociceptive stimulation, suggesting that it could be involved in the detection of change regardless of sensory modality. Finally, the posterior insula and S2 responded maximally during the sustained phase of non-nociceptive stimulation but not nociceptive stimulation, suggesting that these regions are preferentially involved in processing non-nociceptive somatosensory input. PMID:26252509

  7. Fine-grained nociceptive maps in primary somatosensory cortex

    PubMed Central

    Mancini, Flavia; Haggard, Patrick; Iannetti, Gian Domenico; Longo, Matthew R.; Sereno, Martin I.

    2012-01-01

    Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded fMRI analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the timecourse and the spatial pattern of plastic changes in cortical organization involved in chronic pain. PMID:23197708

  8. Regulation of Granulocyte Colony-Stimulating Factor and Its Receptor in Skeletal Muscle is Dependent Upon the Type of Inflammatory Stimulus.

    PubMed

    Wright, Craig Robert; Brown, Erin Louise; Della Gatta, Paul A; Fatouros, Ioannis G; Karagounis, Leonidas G; Terzis, Gerasimos; Mastorakos, Georgios; Michailidis, Yannis; Mandalidis, Dimitris; Spengos, Kontantinos; Chatzinikolaou, Athanasios; Methenitis, Spiros; Draganidis, Dimitrios; Jamurtas, Athanasios Z; Russell, Aaron Paul

    2015-09-01

    The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G

  9. Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system.

    PubMed

    Shatillo, A; Koroleva, K; Giniatullina, R; Naumenko, N; Slastnikova, A A; Aliev, R R; Bart, G; Atalay, M; Gu, C; Khazipov, R; Davletov, B; Grohn, O; Giniatullin, R

    2013-12-01

    Indirect evidence suggests the increased production of reactive oxygen species (ROS) in migraine pathophysiology. In the current study we measured lipid peroxidation product in the rat cortex, trigeminal ganglia and meninges after the induction of cortical spreading depression (CSD), a phenomenon known to be associated with migraine aura, and tested nociceptive firing triggered by ROS in trigeminal nerves ex vivo. Application of KCl to dura mater in anesthetized rats induced several waves of CSD recorded by an extracellular electrode in the cortex. Following CSD, samples of cortex (affected regions were identified with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI)), meninges from left and right hemispheres and trigeminal ganglia were taken for biochemical analysis. We found that CSD increased the level of the lipid peroxidation product malondialdehyde (MDA) in the ipsilateral cerebral cortex and meninges, but also in both ipsi- and contralateral trigeminal ganglia. In order to test the pro-nociceptive action of ROS, we applied the mild oxidant hydrogen peroxide to isolated rat hemiskull preparations including preserved trigeminal innervations. Application of hydrogen peroxide to meninges transiently enhanced electrical spiking activity of trigeminal nerves showing a pro-nociceptive action of ROS. In the presence of hydrogen peroxide trigeminal nerves still responded to capsaicin by burst of spiking activity indicating integrity of neuronal structures. The action of hydrogen peroxide was mediated by TRPA1 receptors as it was abolished by the specific TRPA1 antagonist TCS-5861528. Using dorsal root ganglion sensory neurons as test system we found that hydrogen peroxide promoted the release of the migraine mediator calcitonin gene-related peptide (CGRP), which we previously identified as a trigger of delayed sensitization of trigeminal neurons. Our data suggest that, after CSD, oxidative stress spreads downstream within the

  10. Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture.

    PubMed

    Li, W-W; Guo, T-Z; Shi, X; Sun, Y; Wei, T; Clark, D J; Kingery, W S

    2015-12-01

    Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glial activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (L-2-aminoadipic acid (LAA)) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglial and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 h after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglial activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS. PMID:26386297

  11. Steady-state evoked potentials to tag specific components of nociceptive cortical processing.

    PubMed

    Colon, Elisabeth; Nozaradan, Sylvie; Legrain, Valery; Mouraux, André

    2012-03-01

    Studies have shown that the periodic repetition of a stimulus induces, at certain stimulation frequencies, a sustained electro-cortical response of corresponding frequency, referred to as steady-state evoked potential (SSEP). Using infrared laser stimulation, we recently showed that SSEPs can be used to explore nociceptive cortical processing. Here, we implemented a novel approach to elicit such responses, using a periodic intra-epidermal electrical stimulation of cutaneous Aδ-nociceptors (Aδ-SSEPs). Using a wide range of frequencies (3-43 Hz), we compared the scalp topographies and temporal dynamics of these Aδ-SSEPs to the Aβ-SSEPs elicited by non-nociceptive transcutaneous electrical stimulation, as well as to the transient ERPs elicited by the onsets of the 10-s stimulation trains, applied to the left and right hand. At 3 Hz, we found that the topographies of Aβ- and Aδ-SSEPs were both maximal at the scalp vertex, and resembled closely that of the late P2 wave of transient ERPs, suggesting activity originating from the same neuronal populations. The responses also showed marked habituation, suggesting that they were mainly related to unspecific, attention-related processes. In contrast, at frequencies >3 Hz, the topographies of Aβ- and Aδ-SSEPs were markedly different. Aβ-SSEPs were maximal over the contralateral parietal region, whereas Aδ-SSEPs were maximal over midline frontal regions, thus indicating an entrainment of distinct neuronal populations. Furthermore, the responses showed no habituation, suggesting more obligatory and specific stages of sensory processing. Taken together, our results indicate that Aβ- and Aδ-SSEPs offer a unique opportunity to study the cortical representation of nociception and touch. PMID:22197788

  12. Interests and Stimulus Seeking

    ERIC Educational Resources Information Center

    Kish, George B.; Donnenwerth, Gregory V.

    1969-01-01

    Examines relationships between Sensation-Seeking Scale (SSS) and vocational interests measured by the Kuder and Strong Vocational Interest Blank, among alcoholics and undergraduates. Results support construct validity of the SSS and provide further evidence of modes of expression of stimulus-seeking needs in personality. (Author/CJ)

  13. Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing.

    PubMed

    Hsu, David T; Mickey, Brian J; Langenecker, Scott A; Heitzeg, Mary M; Love, Tiffany M; Wang, Heng; Kennedy, Susan E; Peciña, Marta; Shafir, Tal; Hodgkinson, Colin A; Enoch, Mary-Anne; Goldman, David; Zubieta, Jon-Kar

    2012-02-29

    The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and a preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation level-dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) in the right middle temporal/angular gyrus while subjects were viewing negative versus neutral words. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared with controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared with controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 single nucleotide polymorphism rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD. PMID:22378896

  14. An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression.

    PubMed

    Rodríguez-Gaztelumendi, Antonio; Rojo, María Luisa; Pazos, Angel; Díaz, Alvaro

    2014-06-01

    The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

  15. An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression.

    PubMed

    Rodríguez-Gaztelumendi, Antonio; Rojo, María Luisa; Pazos, Angel; Díaz, Alvaro

    2014-06-01

    The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression. PMID:24584836

  16. Activity-dependent dephosphorylation of paxillin contributed to nociceptive plasticity in spinal cord dorsal horn.

    PubMed

    Wang, Xin-Tai; Zheng, Rui; Suo, Zhan-Wei; Liu, Yan-Ni; Zhang, Zi-Yang; Ma, Zheng-An; Xue, Ye; Xue, Man; Yang, Xian; Hu, Xiao-Dong

    2016-03-01

    The enzymatic activity of protein tyrosine kinase Src is subjected to the regulation by C-terminal Src kinase (CSK) and protein tyrosine phosphatases (PTPs). Aberrant Src activation in the spinal cord dorsal horn is pivotal for the induction and development of nociceptive behavioral sensitization. In this study, we found that paxillin, one of the well-characterized cell adhesion components involved in cell migration and survival, integrated CSK and PTPs' signaling to regulate Src-dependent nociceptive plasticity. Paxillin localized at excitatory glutamatergic synapses in the spinal dorsal horn of mice, and the phosphorylation of Tyr118 on paxillin was necessary to associate with and target CSK at synapses. After peripheral tissue injury, the enhanced neuronal activity stimulated N-methyl-D-aspartate (NMDA) subtype glutamate receptors, which initiated PTPs' signaling to catalyze Tyr118 dephosphorylation. The reduced Tyr118 phosphorylation disrupted paxillin interaction with CSK, leading to the dispersal of CSK out of synapses. With the loss of CSK-mediated inhibition, Src activity was persistently increased. The active Src potentiated the synaptic transmission specifically mediated by GluN2B subunit-containing NMDA receptors. The active Src also facilitated the induction of long-term potentiation of C fiber-evoked field potentials and exaggerated painful responses. In complete Freund's adjuvant-injected mice, viral expression of phosphomimicking paxillin mutant to resume CSK synaptic localization repressed Src hyperactivity. Meanwhile, this phosphomimicking paxillin mutant blunted NMDA receptor-mediated synaptic transmission and alleviated chronic inflammatory pain. These data showed that PTPs-mediated dephosphorylation of paxillin at Tyr118 was involved in the modification of nociceptive plasticity through CSK-Src signaling.

  17. Distinct Brain Systems Mediate the Effects of Nociceptive Input and Self-Regulation on Pain

    PubMed Central

    Woo, Choong-Wan; Roy, Mathieu; Buhle, Jason T.; Wager, Tor D.

    2015-01-01

    Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system. PMID:25562688

  18. Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

    PubMed

    Woo, Choong-Wan; Roy, Mathieu; Buhle, Jason T; Wager, Tor D

    2015-01-01

    Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.

  19. Mast Cell-Mediated Mechanisms of Nociception

    PubMed Central

    Aich, Anupam; Afrin, Lawrence B.; Gupta, Kalpna

    2015-01-01

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. PMID:26690128

  20. Spinal modulation of nociception by music.

    PubMed

    Roy, M; Lebuis, A; Hugueville, L; Peretz, I; Rainville, P

    2012-07-01

    Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant-stimulating, pleasant-relaxing, unpleasant-stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain-modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant-stimulating and pleasant-relaxing musical condition, indicating that the arousal of music had little influence on pain processing.

  1. Steady-state evoked potentials to study the processing of tactile and nociceptive somatosensory input in the human brain.

    PubMed

    Colon, E; Legrain, V; Mouraux, A

    2012-10-01

    The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response of corresponding frequency, known as steady-state evoked potentials (SS-EP). In visual, auditory and vibrotactile modalities, studies have shown that SS-EP reflect mainly activity originating from early, modality-specific sensory cortices. Furthermore, it has been shown that SS-EP have several advantages over the recording of transient event-related brain potentials (ERP), such as a high signal-to-noise ratio, a shorter time to obtain reliable signals, and the capacity to frequency-tag the cortical activity elicited by concurrently presented sensory stimuli. Recently, we showed that SS-EP can be elicited by the selective activation of skin nociceptors and that nociceptive SS-EP reflect the activity of a population of neurons that is spatially distinct from the somatotopically-organized population of neurons underlying vibrotactile SS-EP. Hence, the recording of SS-EP offers a unique opportunity to study the cortical representation of nociception and touch in humans, and to explore their potential crossmodal interactions. Here, (1) we review available methods to achieve the rapid periodic stimulation of somatosensory afferents required to elicit SS-EP, (2) review previous studies that have characterized vibrotactile and nociceptive SS-EP, (3) discuss the nature of the recorded signals and their relationship with transient event-related potentials and (4) outline future perspectives and potential clinical applications of this technique.

  2. Peripheral and Central Determinants of a Nociceptive Reaction: An Approach to Psychophysics in the Rat

    PubMed Central

    Ballantyne, Kay; Plaghki, Léon; Le Bars, Daniel

    2008-01-01

    Background The quantitative end-point for many behavioral tests of nociception is the reaction time, i.e. the time lapse between the beginning of the application of a stimulus, e.g. heat, and the evoked response. Since it is technically impossible to heat the skin instantaneously by conventional means, the question of the significance of the reaction time to radiant heat remains open. We developed a theoretical framework, a related experimental paradigm and a model to analyze in psychophysical terms the “tail-flick” responses of rats to random variations of noxious radiant heat. Methodology/Principal Findings A CO2 laser was used to avoid the drawbacks associated with standard methods of thermal stimulation. Heating of the skin was recorded with an infrared camera and was stopped by the reaction of the animal. For the first time, we define and determine two key descriptors of the behavioral response, namely the behavioral threshold (Tβ) and the behavioral latency (Lβ). By employing more than one site of stimulation, the paradigm allows determination of the conduction velocity of the peripheral fibers that trigger the response (V) and an estimation of the latency (Ld) of the central decision-making process. Ld (∼130 ms) is unaffected by ambient or skin temperature changes that affect the behavioral threshold (∼42.2–44.9°C in the 20–30°C range), behavioral latency (<500 ms), and the conduction velocity of the peripheral fibers that trigger the response (∼0.35–0.76 m/s in the 20–30°C range). We propose a simple model that is verified experimentally and that computes the variations in the so-called “tail-flick latency” (TFL) caused by changes in either the power of the radiant heat source, the initial temperature of the skin, or the site of stimulation along the tail. Conclusions/Significance This approach enables the behavioral determinations of latent psychophysical (Tβ, Lβ, Ld) and neurophysiological (V) variables that have been

  3. Learned control over spinal nociception reduces supraspinal nociception as quantified by late somatosensory evoked potentials.

    PubMed

    Ruscheweyh, Ruth; Bäumler, Maximilian; Feller, Moritz; Krafft, Stefanie; Sommer, Jens; Straube, Andreas

    2015-12-01

    We have recently shown that subjects can learn to use cognitive-emotional strategies to suppress their spinal nociceptive flexor reflex (RIII reflex) under visual RIII feedback and proposed that this reflects learned activation of descending pain inhibition. Here, we investigated whether learned RIII suppression also affects supraspinal nociception and whether previous relaxation training increases success. Subjects were trained over 3 sessions to reduce their RIII size by self-selected cognitive-emotional strategies. Two groups received true RIII feedback (with or without previous relaxation training) and a sham group received false feedback (15 subjects per group). RIII reflexes, late somatosensory evoked potentials (SEPs), and F-waves were recorded and pain intensity ratings collected. Both true feedback groups achieved significant (P < 0.01) but similar RIII suppression (to 79% ± 21% and 70% ± 17% of control). Somatosensory evoked potential amplitude (100-150 milliseconds after stimulation) was reduced in parallel with the RIII size (r = 0.57, P < 0.01). In the sham group, neither RIII size nor SEP amplitude was significantly reduced during feedback training. Pain intensity was significantly reduced in all 3 groups and also correlated with RIII reduction (r = 0.44, P < 0.01). F-wave parameters were not affected during RIII suppression. The present results show that learned RIII suppression also affects supraspinal nociception as quantified by SEPs, although effects on pain ratings were less clear. Lower motor neuron excitability as quantified by F-waves was not affected. Previous relaxation training did not significantly improve RIII feedback training success. PMID:26270584

  4. Disentangling the nature of the nicotine stimulus.

    PubMed

    Bevins, Rick A; Barrett, Scott T; Polewan, Robert J; Pittenger, Steven T; Swalve, Natashia; Charntikov, Sergios

    2012-05-01

    Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

  5. The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)

    PubMed Central

    Morales-Lázaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

    2013-01-01

    Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with

  6. The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1).

    PubMed

    Morales-Lázaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

    2013-07-01

    Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with

  7. Effects of anethole in nociception experimental models.

    PubMed

    Ritter, Alessandra Mileni Versuti; Ames, Franciele Queiroz; Otani, Fernando; de Oliveira, Rubia Maria Weffort; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2014-01-01

    This study investigated the antinociceptive activity of anethole (anethole 1-methoxy-4-benzene (1-propenyl)), major compound of the essential oil of star anise (Illicium verum), in different experimental models of nociception. The animals were pretreated with anethole (62.5, 125, 250, and 500 mg/kg) one hour before the experiments. To eliminate a possible sedative effect of anethole, the open field test was conducted. Anethole (62.5, 125, 250, and 500 mg/kg) showed an antinociceptive effect in the writhing model induced by acetic acid, in the second phase of the formalin test (125 and 250 mg/kg) in the test of glutamate (62.5, 125, and 250 mg/kg), and expresses pain induced by ACF (250 mg/kg). In contrast, anethole was not able to increase the latency time on the hot plate and decrease the number of flinches during the initial phase of the formalin test in any of the doses tested. It was also demonstrated that anethole has no association with sedative effects. Therefore, these data showed that anethole, at all used doses, has no sedative effect and has an antinociceptive effect. This effect may be due to a decrease in the production/release of inflammatory mediators. PMID:25506382

  8. Bright light activates a trigeminal nociceptive pathway

    PubMed Central

    Okamoto, Keiichiro; Tashiro, Akimasa; Chang, Zheng; Bereiter, David A.

    2010-01-01

    Bright light can cause ocular discomfort and/or pain; however, the mechanism linking luminance to trigeminal nerve activity is not known. In this study we identify a novel reflex circuit necessary for bright light to excite nociceptive neurons in superficial laminae of trigeminal subnucleus caudalis (Vc/C1). Vc/C1 neurons encoded light intensity and displayed a long delay (>10 s) for activation. Microinjection of lidocaine into the eye or trigeminal root ganglion (TRG) inhibited light responses completely, whereas topical application onto the ocular surface had no effect. These findings indicated that light-evoked Vc/C1 activity was mediated by an intraocular mechanism and transmission through the TRG. Disrupting local vasomotor activity by intraocular microinjection of the vasoconstrictive agents, norepinephrine or phenylephrine, blocked light-evoked neural activity, whereas ocular surface or intra-TRG microinjection of norepinephrine had no effect. Pupillary muscle activity did not contribute since light-evoked responses were not altered by atropine. Microinjection of lidocaine into the superior salivatory nucleus diminished light-evoked Vc/C1 activity and lacrimation suggesting that increased parasympathetic outflow was critical for light-evoked responses. The reflex circuit also required input through accessory visual pathways since both Vc/C1 activity and lacrimation were prevented by local blockade of the olivary pretectal nucleus. These findings support the hypothesis that bright light activates trigeminal nerve activity through an intraocular mechanism driven by a luminance-responsive circuit and increased parasympathetic outflow to the eye. PMID:20206444

  9. Effects of Anethole in Nociception Experimental Models

    PubMed Central

    Ritter, Alessandra Mileni Versuti; Ames, Franciele Queiroz; Otani, Fernando; de Oliveira, Rubia Maria Weffort; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2014-01-01

    This study investigated the antinociceptive activity of anethole (anethole 1-methoxy-4-benzene (1-propenyl)), major compound of the essential oil of star anise (Illicium verum), in different experimental models of nociception. The animals were pretreated with anethole (62.5, 125, 250, and 500 mg/kg) one hour before the experiments. To eliminate a possible sedative effect of anethole, the open field test was conducted. Anethole (62.5, 125, 250, and 500 mg/kg) showed an antinociceptive effect in the writhing model induced by acetic acid, in the second phase of the formalin test (125 and 250 mg/kg) in the test of glutamate (62.5, 125, and 250 mg/kg), and expresses pain induced by ACF (250 mg/kg). In contrast, anethole was not able to increase the latency time on the hot plate and decrease the number of flinches during the initial phase of the formalin test in any of the doses tested. It was also demonstrated that anethole has no association with sedative effects. Therefore, these data showed that anethole, at all used doses, has no sedative effect and has an antinociceptive effect. This effect may be due to a decrease in the production/release of inflammatory mediators. PMID:25506382

  10. Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions

    PubMed Central

    Liu, Chien-Cheng; Gao, Yong-Jing; Luo, Hao; Berta, Temugin; Xu, Zhen-Zhong; Ji, Ru-Rong; Tan, Ping-Heng

    2016-01-01

    It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord. PMID:27670299

  11. Cycloheximide: No Ordinary Bitter Stimulus

    PubMed Central

    Hettinger, Thomas P.; Formaker, Bradley K.; Frank, Marion E.

    2007-01-01

    Cycloheximide (CyX), a toxic antibiotic with a unique chemical structure generated by the actinomycete, Streptomyces griseus, has emerged as a primary focus of studies on mammalian bitter taste. Rats and mice avoid it at concentrations well below the thresholds for most bitter stimuli and T2R G-protein-coupled receptors specific for CyX with appropriate sensitivity are identified for those species. Like mouse and rat, golden hamsters, Mesocricetus auratus, also detected and rejected micromolar levels of CyX, although 1 mM CyX failed to activate the hamster chorda tympani nerve. Hamsters showed an initial tolerance for 500 μM CyX, but after that, avoidance of CyX dramatically increased, plasticity not reported for rat or mouse. As the hamster lineage branches well before division of the mouse-rat lineage in evolutionary time, differences between hamster and mouse-rat reactions to CyX are not surprising. Furthermore, unlike hamster LiCl-induced learned aversions, the induced CyX aversion neither specifically nor robustly generalized to other non-ionic bitter stimuli; and unlike adverse reactions to other chemosensory stimuli, aversions to CyX were not mollified by adding a sweetener. Thus, CyX is unlike other bitter stimuli. The gene for the high-affinity CyX receptor is a member of a cluster of 5 orthologous T2R genes that are likely rodent specific; this “CyX clade” is found in the mouse, rat and probably hamster, but not in the human or rabbit genome. The rodent CyX-T2R interaction may be one of multiple lineage-specific stimulus-receptor interactions reflecting a response to a particular environmental toxin. The combination of T2R multiplicity, species divergence and gene duplication results in diverse ligands for multiple species-specific T2R receptors, which confounds definition of ‘bitter’ stimuli across species. PMID:17400304

  12. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi-anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52μmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine.

  13. Larval defense against attack from parasitoid wasps requires nociceptive neurons.

    PubMed

    Robertson, Jessica L; Tsubouchi, Asako; Tracey, W Daniel

    2013-01-01

    Parasitoid wasps are a fierce predator of Drosophila larvae. Female Leptopilina boulardi (LB) wasps use a sharp ovipositor to inject eggs into the bodies of Drosophila melanogaster larvae. The wasp then eats the Drosophila larva alive from the inside, and an adult wasp ecloses from the Drosophila pupal case instead of a fly. However, the Drosophila larvae are not defenseless as they may resist the attack of the wasps through somatosensory-triggered behavioral responses. Here we describe the full range of behaviors performed by the larval prey in immediate response to attacks by the wasps. Our results suggest that Drosophila larvae primarily sense the wasps using their mechanosensory systems. The range of behavioral responses included both "gentle touch" like responses as well as nociceptive responses. We found that the precise larval response depended on both the somatotopic location of the attack, and whether or not the larval cuticle was successfully penetrated during the course of the attack. Interestingly, nociceptive responses are more likely to be triggered by attacks in which the cuticle had been successfully penetrated by the wasp. Finally, we found that the class IV neurons, which are necessary for mechanical nociception, were also necessary for a nociceptive response to wasp attacks. Thus, the class IV neurons allow for a nociceptive behavioral response to a naturally occurring predator of Drosophila.

  14. Larval Defense against Attack from Parasitoid Wasps Requires Nociceptive Neurons

    PubMed Central

    Robertson, Jessica L.; Tsubouchi, Asako; Tracey, W. Daniel

    2013-01-01

    Parasitoid wasps are a fierce predator of Drosophila larvae. Female Leptopilina boulardi (LB) wasps use a sharp ovipositor to inject eggs into the bodies of Drosophila melanogaster larvae. The wasp then eats the Drosophila larva alive from the inside, and an adult wasp ecloses from the Drosophila pupal case instead of a fly. However, the Drosophila larvae are not defenseless as they may resist the attack of the wasps through somatosensory-triggered behavioral responses. Here we describe the full range of behaviors performed by the larval prey in immediate response to attacks by the wasps. Our results suggest that Drosophila larvae primarily sense the wasps using their mechanosensory systems. The range of behavioral responses included both “gentle touch” like responses as well as nociceptive responses. We found that the precise larval response depended on both the somatotopic location of the attack, and whether or not the larval cuticle was successfully penetrated during the course of the attack. Interestingly, nociceptive responses are more likely to be triggered by attacks in which the cuticle had been successfully penetrated by the wasp. Finally, we found that the class IV neurons, which are necessary for mechanical nociception, were also necessary for a nociceptive response to wasp attacks. Thus, the class IV neurons allow for a nociceptive behavioral response to a naturally occurring predator of Drosophila. PMID:24205297

  15. Are tender point injections beneficial: the role of tonic nociception in fibromyalgia.

    PubMed

    Staud, Roland

    2006-01-01

    Characteristic symptoms of fibromyalgia syndrome (FM) include widespread pain, fatigue, sleep abnormalities, and distress. FM patients show psychophysical evidence for mechanical, thermal, and electrical hyperalgesia. To fulfill FM criteria, the mechanical hyperalgesia needs to be widespread and present in at least 11 out of 18 well-defined body areas (tender points). Peripheral and central abnormalities of nociception have been described in FM and these changes may be relevant for the increased pain experienced by these patients. Important nociceptor systems in the skin and muscle seem to undergo profound changes in FM patients by yet unknown mechanisms. These changes may result from the release of algesic substances after muscle or other soft tissue injury. These pain mediators can sensitize important nociceptor systems, including the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1), acid sensing ion channel (ASIC) receptors, and purino-receptors (P2X3). Subsequently, tissue mediators of inflammation and nerve growth factors can excite these receptors and cause substantial changes in pain sensitivity. FM pain is widespread and does not seem to be restricted to tender points (TP). It frequently comprises multiple areas of deep tissue pain (trigger points) with adjacent much larger areas of referred pain. Analgesia of areas of extensive nociceptive input has been found to provide often long lasting local as well as general pain relief. Thus interventions aimed at reducing local FM pain seem to be effective but need to focus less on tender points but more on trigger points (TrP) and other body areas of heightened pain and inflammation. PMID:16454721

  16. Are tender point injections beneficial: the role of tonic nociception in fibromyalgia.

    PubMed

    Staud, Roland

    2006-01-01

    Characteristic symptoms of fibromyalgia syndrome (FM) include widespread pain, fatigue, sleep abnormalities, and distress. FM patients show psychophysical evidence for mechanical, thermal, and electrical hyperalgesia. To fulfill FM criteria, the mechanical hyperalgesia needs to be widespread and present in at least 11 out of 18 well-defined body areas (tender points). Peripheral and central abnormalities of nociception have been described in FM and these changes may be relevant for the increased pain experienced by these patients. Important nociceptor systems in the skin and muscle seem to undergo profound changes in FM patients by yet unknown mechanisms. These changes may result from the release of algesic substances after muscle or other soft tissue injury. These pain mediators can sensitize important nociceptor systems, including the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1), acid sensing ion channel (ASIC) receptors, and purino-receptors (P2X3). Subsequently, tissue mediators of inflammation and nerve growth factors can excite these receptors and cause substantial changes in pain sensitivity. FM pain is widespread and does not seem to be restricted to tender points (TP). It frequently comprises multiple areas of deep tissue pain (trigger points) with adjacent much larger areas of referred pain. Analgesia of areas of extensive nociceptive input has been found to provide often long lasting local as well as general pain relief. Thus interventions aimed at reducing local FM pain seem to be effective but need to focus less on tender points but more on trigger points (TrP) and other body areas of heightened pain and inflammation.

  17. De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion.

    PubMed

    Saeed, Abeer W; Ribeiro-da-Silva, Alfredo

    2013-06-01

    Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons that express the SP receptor, also known as the neurokinin-1 receptor (NK-1r). Three types of lamina I projection neurons have been described: multipolar, fusiform, and pyramidal. Most neurons of the first two types are thought to be nociceptive and express the NK-1r, whereas most pyramidal neurons are nonnociceptive and do not express the NK-1r. In this immunocytochemical and behavioral study, we induced a neuropathic pain-like condition in the rat by means of a polyethylene cuff placed around in the sciatic nerve. We document that this lesion led to a de novo expression of NK-1r on pyramidal neurons as well as a significant increase in SP-immunoreactive innervation onto these neurons. These phenotypic changes were evident at the time of onset of neuropathic pain-related behavior. Additionally, we show that, after a noxious stimulus (intradermal capsaicin injection), these NK-1r on pyramidal neurons were internalized, providing evidence that these neurons become responsive to peripheral noxious stimulation. We suggest that the changes following nerve lesion in the phenotype and innervation pattern of pyramidal neurons are of significance for neuropathic pain and/or limb temperature regulation.

  18. Is the cutaneous silent period an opiate-sensitive nociceptive reflex?

    PubMed

    Inghilleri, Maurizio; Conte, Antonella; Frasca, Vittorio; Berardelli, Alfredo; Manfredi, Mario; Cruccu, Giorgio

    2002-05-01

    In humans, high-intensity electrical stimuli delivered to the fingers induce an inhibitory effect on C7-T1 motoneurons. This inhibitory reflex, called the cutaneous silent period (CSP) is considered a defense response specific for the human upper limbs. It is not clear whether the CSP-like other defense responses such as the corneal reflex and the R III reflex-is an opiate-sensitive nociceptive reflex. Because opiates suppress some, but not all, nociceptive reflexes, we studied the effect of the narcotic-analgesic drug fentanyl on the CSP and the R III reflex. The CSP was recorded from the first dorsal interosseous (FDI) muscle in seven normal subjects during voluntary contraction, before and 10 and 20 min after fentanyl injection. To assess possible fentanyl-induced changes, we also tested the effect of finger stimulation on motor evoked potentials (MEPs) elicited in the FDI muscle by transcranial magnetic stimulation before and after fentanyl injection. Fentanyl-induced changes were also studied on the R III reflex recorded from the biceps femoris muscle. Fentanyl, as expected, suppressed the R III reflex but failed to change the inhibitory effect of finger stimulation on FDI motoneurons. Finger stimulation reduced the size of MEPs in the FDI, and fentanyl injection left this inhibitory effect unchanged. The differential fentanyl-induced modulation of the CSP and R III reflex provides evidence that the CSP circuit is devoid of mu-opiate receptors and is therefore an opiate-insensitive nociceptive reflex, which may be useful in the assessment of central-acting, non-opioid drugs.

  19. Knockdown of FcγRIII in an arthritic temporomandibular joint reduced the nociceptive response

    PubMed Central

    Kramer, Phillip R.; Puri, Jyoti; Bellinger, Larry L.

    2010-01-01

    FcγRIII (CD16) is a receptor expressed on immune cells that selectively binds immmunoglobulin G (IgG) molecules, IgG binding results in cellular activation and cytokine release. IgG is an important factor in arthritis and can be found in arthritic temporomandibular joints (TMJ). We hypothesize that a reduction in FcγRIII expression in the TMJ tissues will reduce the nociceptive and inflammatory response in an inflamed joint. To test this hypothesis siRNA, either naked or complexed with linear polyethylenimine (PEI) was injected into the superior joint space of the TMJ. After administration of siRNA the joint was injected with saline or with complete Freund’s adjuvant (CFA) to induce arthritis. Nociceptive responses were quantitated in the rat by measuring the animal’s meal duration. FcγRIII expression in the TMJ tissue was assayed by immunocytochemistry or western. Cleavage of FcγRIII transcript was then assayed by 5′ rapid amplification of cDNA ends method (5′ RACE). Interleukin-1β (IL-1β) and IgG content was measured in the TMJ tissue by ELISA. The results indicate that injection of FcγRIII siRNA reduced the amount of FcγRIII in the TMJ tissues and that the transcript was cleaved in a manner consistent with a RNA interference mechanism. Moreover, injection of FcγRIII siRNA reduced the nociceptive response of rats with an arthritic TMJ and reduced the amount of pro-inflammatory cytokine IL-1β. We conclude that FcγRIII contributes to the pain resulting from inflammatory arthritis of the TMJ and that siRNA has the potential to be an effective treatment for this disorder. PMID:20589683

  20. Involvement of histaminergic system in the discriminative stimulus effects of morphine.

    PubMed

    Mori, Tomohisa; Narita, Minoru; Onodera, Kenji; Suzuki, Tsutomu

    2004-05-01

    The interactions between morphine and the histaminergic system are not yet fully clarified. More especially, the involvement of the histaminergic system in the discriminative stimulus effects of morphine has not been determined. Therefore, the effects of histamine-related compounds on the discriminative stimulus effects of morphine were examined in rats. Combination tests using histamine-related compounds with morphine were initiated in rats trained to discriminate between 3.0 mg/kg morphine and saline. Zolantidine (central histamine H2-receptor antagonist), but not pyrilamine (central histamine H1-receptor antagonist) or ranitidine (peripheral histamine H2-receptor antagonist), significantly attenuated the discriminative stimulus effects of morphine. The histamine precursor L-histidine significantly potentiated the discriminative stimulus effects of morphine. These results suggest that the discriminative stimulus effects of morphine are, at least in part, mediated through the central activation of histamine H2-receptors in rats.

  1. Modulation of Visceral Nociception, Inflammation and Gastric Mucosal Injury by Cinnarizine

    PubMed Central

    Abdel-Salam, Omar M.E.

    2007-01-01

    The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25–20 mg/kg, s.c.) caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7–99.4%. This effect of cinnarizine (2.5 mg/kg) was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (KATP) blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt’s forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-inflammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and KATP channels. PMID:21901060

  2. Modulation of visceral nociception, inflammation and gastric mucosal injury by cinnarizine.

    PubMed

    Abdel-Salam, Omar M E

    2007-01-01

    The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25-20 mg/kg, s.c.) caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7-99.4%. This effect of cinnarizine (2.5 mg/kg) was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (K(ATP)) blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt's forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-inflammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and K(ATP) channels. PMID:21901060

  3. Correlations among stimuli affect stimulus matching and stimulus liking.

    PubMed

    Pimenta, Dióghenes; Tonneau, François

    2016-09-01

    Human subjects were exposed to AB, AC stimulus pairs and then to matching-to-sample tests of stimulus equivalence (B-A, C-A, B-C, C-B) or to a task in which stimulus compounds (BA, CA, BC, CB) were rated for attractiveness. Matching-to-sample tests revealed emergent B-A, C-A, B-C, and C-B choices, replicating previous results in the literature. The mean proportion of correct, emergent choices increased as a function of exposure to the AB, AC pairs. On the rating task, the liking scores of all stimulus compounds also increased as a function of exposure to the AB, AC pairs. After limited exposure to these pairs, however, the liking scores of the BC and CB compounds were negative. These findings are discussed in relation to perceptual and associative perspectives on the behavioral effects of stimulus correlations.

  4. Correlations among stimuli affect stimulus matching and stimulus liking.

    PubMed

    Pimenta, Dióghenes; Tonneau, François

    2016-09-01

    Human subjects were exposed to AB, AC stimulus pairs and then to matching-to-sample tests of stimulus equivalence (B-A, C-A, B-C, C-B) or to a task in which stimulus compounds (BA, CA, BC, CB) were rated for attractiveness. Matching-to-sample tests revealed emergent B-A, C-A, B-C, and C-B choices, replicating previous results in the literature. The mean proportion of correct, emergent choices increased as a function of exposure to the AB, AC pairs. On the rating task, the liking scores of all stimulus compounds also increased as a function of exposure to the AB, AC pairs. After limited exposure to these pairs, however, the liking scores of the BC and CB compounds were negative. These findings are discussed in relation to perceptual and associative perspectives on the behavioral effects of stimulus correlations. PMID:27397574

  5. Pro-neurotrophins, sortilin, and nociception

    PubMed Central

    Lewin, Gary R; Nykjaer, Anders

    2014-01-01

    Nerve growth factor (NGF) signaling is important in the development and functional maintenance of nociceptors, but it also plays a central role in initiating and sustaining heat and mechanical hyperalgesia following inflammation. NGF signaling in pain has traditionally been thought of as primarily engaging the classic high-affinity receptor tyrosine kinase receptor TrkA to initiate sensitization events. However, the discovery that secreted proforms of nerve NGF have biological functions distinct from the processed mature factors raised the possibility that these proneurotrophins (proNTs) may have distinct function in painful conditions. ProNTs engage a novel receptor system that is distinct from that of mature neurotrophins, consisting of sortilin, a type I membrane protein belonging to the VPS10p family, and its co-receptor, the classic low-affinity neurotrophin receptor p75NTR. Here, we review how this new receptor system may itself function with or independently of the classic TrkA system in regulating inflammatory or neuropathic pain. PMID:24494677

  6. Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

    PubMed Central

    Takeda, Mamoru; Takehana, Shiori; Sekiguchi, Kenta; Kubota, Yoshiko; Shimazu, Yoshihito

    2016-01-01

    Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM) candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM. PMID:27727178

  7. Psilocybin-induced stimulus control in the rat.

    PubMed

    Winter, J C; Rice, K C; Amorosi, D J; Rabin, R A

    2007-10-01

    Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following treatment with the 5-HT(2A) receptor antagonist, M100907. In contrast, no significant antagonism was observed following treatment with the 5-HT(1A/7) receptor antagonist, WAY-100635, or the DA D(2) antagonist, remoxipride. Psilocybin generalized fully to DOM, LSD, psilocin, and, in the presence of WAY-100635, DMT while partial generalization was seen to 2C-T-7 and mescaline. LSD and MDMA partially generalized to psilocybin and these effects were completely blocked by M-100907; no generalization of PCP to psilocybin was seen. The present data suggest that psilocybin induces a compound stimulus in which activity at the 5-HT(2A) receptor plays a prominent but incomplete role. In addition, psilocybin differs from closely related hallucinogens such as 5-MeO-DMT in that agonism at 5-HT(1A) receptors appears to play no role in psilocybin-induced stimulus control.

  8. Inflammatory nociception responses do not vary with age, but diminish with the pain history

    PubMed Central

    Simón-Arceo, Karina; Contreras, Bernardo; León-Olea, Martha; Coffeen, Ulises; Jaimes, Orlando; Pellicer, Francisco

    2014-01-01

    Some of the relevant factors that must be considered when dealing with old age include its growing numbers in the general population and pain contention in this age group. In this sense, it is important to study whether antinociceptive responses change with age. To elucidate this point, persistent pain in animals is the preferred model. In addition, the response to inflammatory pain in the same individual must be explored along its lifetime. Male Wistar rats were infiltrated with carrageenan (50 μl intraplantar) and tested 3 h and 24 h after injection using thermal (plantar test) and mechanociceptive tests (von Frey). The rats were divided into the following groups: (a) young rats infiltrated for the first time at 12 weeks of age and re-infiltrated at 15 and 17 weeks; (b) adult rats infiltrated for the first time at 28 weeks of age and re-infiltrated at 44 and 56 weeks; and (c) old rats infiltrated for the first time at 56 weeks of age and re-infiltrated at 72 weeks. The rats tested for the first time at 12 and 56 weeks of age showed hyperalgesia due to carrageenan infiltration at 3 h and 24 h after injection. This result showed that old rats maintain the same antialgesic response due to inflammation. However, when the injection was repeated in the three age groups, the latency to the thermal and mechanociceptive responses at 3 h is increased when compared to animals exposed for the first time to inflammation. The response to thermal and mechanociception in old rats is the same as in young animals as long as the nociceptive stimulus is not repeated. The repetition of the stimulus produces changes compatible with desensitization of the response and evidences the significance of algesic stimulus repetition in the same individual rather than the age of the individual. PMID:25120479

  9. Evidence for a peripheral origin of the tonic nociceptive response to subcutaneous formalin.

    PubMed

    Dallel, R; Raboisson, P; Clavelou, P; Saade, M; Woda, A

    1995-04-01

    The orofacial formalin test in the rat is a valid and reliable model of nociception and is sensitive to various classes of analgesic drugs. The noxious stimulus consists in an injection of diluted formalin (2.5% in saline) into the upper lip. The behavioural nociceptive response is measured in terms of the amount of time the animal spends rubbing the injected area. Two distinct periods of intense rubbing activity can be identified, a first phase occurring in the first 3 min and a second phase lasting from 12 to 39 min after formalin injection. The present study verified the peripheral origin of the first phase of the formalin response and examined whether the second phase is produced by peripheral activation of afferent fibres and/or by a phenomenon of central facilitation induced by the neural activity that occurs during the first phase. This was determined by assessing the effect of a local anaesthetic agent (lidocaine) administered into the formalin injection site, before or after the first phase of the formalin response. Local injection of 50 microliters of lidocaine prior to formalin completely abolished the first phase of the formalin response but this blockade did not significantly influence the appearance and development of the second phase. Thus, the primary afferent activity that normally occurs during the first phase of the formalin response is not a prerequisite for the expression of the second phase. A higher dose of lidocaine (150 microliters) induced, in addition, inhibition of the first part of the second phase.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Effects of juvenile exposure to predator odor on adolescent and adult anxiety and pain nociception

    PubMed Central

    Post, Ryan J.; Dahlborg, Kaitlyn M.; O’Loughlin, Lauren E.; Bloom, Christopher M.

    2014-01-01

    Clinical researchers have tracked patients with early life trauma and noted generalized anxiety disorder, unipolar depression, and risk-taking behaviors developing in late adolescence and into early adulthood. Animal models provide an opportunity to investigate the neural and developmental processes that underlie the relationship between early stress and later abnormal behavior. The present model used repeated exposure to 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as an unconditioned fear-eliciting stimulus in order to induce stress in juvenile rats aged postnatal day (PND) 23 through 27. After further physical maturation characteristic of the adolescent stage (PND 42), animals were tested using an elevated plus maze (EPM) for anxiety and plantar test (Hargreaves method) for pain to assess any lingering effects of the juvenile stress. To assess how an additional stress later in life affects anxiety and pain nociception, PND 43 rats were exposed to inescapable shock (0.8 mA) and again tested on EPM and plantar test. A final testing period was conducted in the adult (PND 63) rats to assess resulting changes in adult behaviors. TMT-exposed rats were significantly more anxious in adolescence than controls, but this difference disappeared after exposure to the secondary stressor. In adulthood, but not in adolescence, TMT-exposed rats demonstrated lower pain sensitivity than controls. These results suggest that early life stress can play a significant role in later anxiety and pain nociception, and offer insight into the development and manifestation of anxiety- and trauma-related disorders. PMID:24732419

  11. Effects of juvenile exposure to predator odor on adolescent and adult anxiety and pain nociception.

    PubMed

    Post, Ryan J; Dahlborg, Kaitlyn M; O'Loughlin, Lauren E; Bloom, Christopher M

    2014-05-28

    Clinical researchers have tracked patients with early life trauma and noted generalized anxiety disorder, unipolar depression, and risk-taking behaviors developing in late adolescence and into early adulthood. Animal models provide an opportunity to investigate the neural and developmental processes that underlie the relationship between early stress and later abnormal behavior. The present model used repeated exposure to 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as an unconditioned fear-eliciting stimulus in order to induce stress in juvenile rats aged postnatal day (PND) 23 through 27. After further physical maturation characteristic of the adolescent stage (PND 42), animals were tested using an elevated plus maze (EPM) for anxiety and plantar test (Hargreaves method) for pain to assess any lingering effects of the juvenile stress. To assess how an additional stress later in life affects anxiety and pain nociception, PND 43 rats were exposed to inescapable shock (0.8mA) and again tested on EPM and plantar test. A final testing period was conducted in the adult (PND 63) rats to assess resulting changes in adult behaviors. TMT-exposed rats were significantly more anxious in adolescence than controls, but this difference disappeared after exposure to the secondary stressor. In adulthood, but not in adolescence, TMT-exposed rats demonstrated lower pain sensitivity than controls. These results suggest that early life stress can play a significant role in later anxiety and pain nociception, and offer insight into the development and manifestation of anxiety- and trauma-related disorders.

  12. Quantitative objective assessment of peripheral nociceptive C fibre function.

    PubMed Central

    Parkhouse, N; Le Quesne, P M

    1988-01-01

    A technique is described for the quantitative assessment of peripheral nociceptive C fibre function by measurement of the axon reflex flare. Acetylcholine, introduced by electrophoresis, is used to stimulate a ring of nociceptive C fibre endings at the centre of which the increase in blood flow is measured with a laser Doppler flowmeter. This flare (neurogenic vasodilatation) has been compared with mechanically or chemically stimulated non-neurogenic cutaneous vasodilation. The flare is abolished by local anaesthetic and is absent in denervated skin. The flare has been measured on the sole of the foot of 96 healthy subjects; its size decreases with age in males, but not in females. Images PMID:3351528

  13. Age Trends in Stimulus Overselectivity

    ERIC Educational Resources Information Center

    McHugh, Louise; Reed, Phil

    2007-01-01

    Stimulus overselectivity refers to the phenomenon whereby stimulus control over behavior is exerted only by a limited subset of the total number of stimuli present during discrimination learning. It often is displayed by individuals with autistic spectrum disorders or learning disabilities, but is not exclusive to those groups. The present studies…

  14. Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain.

    PubMed

    Nishijima, Catarine M; Ganev, Ellen G; Mazzardo-Martins, Leidiane; Martins, Daniel F; Rocha, Lúcia R M; Santos, Adair R S; Hiruma-Lima, Clelia A

    2014-08-01

    Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain.

  15. Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

    PubMed

    Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor. PMID:27302204

  16. Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

    PubMed

    Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor.

  17. Stimulus control and associative learning.

    PubMed Central

    Williams, B A

    1984-01-01

    Interest in operant research on stimulus control has declined at the same time that much interest has burgeoned in nonoperant areas. Several examples of this shift toward traditional learning theory are considered, all of which have sponsored theoretical approaches that attempt to characterize the underlying associative units. These theoretical approaches are defended on the grounds that they have generated a deeper understanding of a variety of often puzzling phenomena. My projection is that future research will be determined even more strongly by theories about the structure of associations. Particular issues for which such discussion will have major impact include (1) whether conditional stimulus control is qualitatively different than simpler forms of stimulus control, (2) whether stimulus control is organized hierarchically, and (3) the origin of categories of stimulus equivalence. PMID:6520579

  18. Understanding smell--the olfactory stimulus problem.

    PubMed

    Auffarth, Benjamin

    2013-09-01

    The main problem with sensory processing is the difficulty in relating sensory input to physiological responses and perception. This is especially problematic at higher levels of processing, where complex cues elicit highly specific responses. In olfaction, this relationship is particularly obfuscated by the difficulty of characterizing stimulus statistics and perception. The core questions in olfaction are hence the so-called stimulus problem, which refers to the understanding of the stimulus, and the structure-activity and structure-odor relationships, which refer to the molecular basis of smell. It is widely accepted that the recognition of odorants by receptors is governed by the detection of physico-chemical properties and that the physical space is highly complex. Not surprisingly, ideas differ about how odor stimuli should be classified and about the very nature of information that the brain extracts from odors. Even though there are many measures for smell, there is none that accurately describes all aspects of it. Here, we summarize recent developments in the understanding of olfaction. We argue that an approach to olfactory function where information processing is emphasized could contribute to a high degree to our understanding of smell as a perceptual phenomenon emerging from neural computations. Further, we argue that combined analysis of the stimulus, biology, physiology, and behavior and perception can provide new insights into olfactory function. We hope that the reader can use this review as a competent guide and overview of research activities in olfactory physiology, psychophysics, computation, and psychology. We propose avenues for research, particularly in the systematic characterization of receptive fields and of perception.

  19. The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man.

    PubMed

    Price, D D; Mao, J; Frenk, H; Mayer, D J

    1994-11-01

    Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up. PMID:7892014

  20. Nociceptive behavior and physiology of molluscs: animal welfare implications.

    PubMed

    Crook, Robyn J; Walters, Edgar T

    2011-01-01

    Molluscs have proven to be invaluable models for basic neuroscience research, yielding fundamental insights into a range of biological processes involved in action potential generation, synaptic transmission, learning, memory, and, more recently, nociceptive biology. Evidence suggests that nociceptive processes in primary nociceptors are highly conserved across diverse taxa, making molluscs attractive models for biomedical studies of mechanisms that may contribute to pain in humans but also exposing them to procedures that might produce painlike sensations. We review the physiology of nociceptors and behavioral responses to noxious stimulation in several molluscan taxa, and discuss the possibility that nociception may result in painlike states in at least some molluscs that possess more complex nervous systems. Few studies have directly addressed possible emotionlike concomitants of nociceptive responses in molluscs. Because the definition of pain includes a subjective component that may be impossible to gauge in animals quite different from humans, firm conclusions about the possible existence of pain in molluscs may be unattainable. Evolutionary divergence and differences in lifestyle, physiology, and neuroanatomy suggest that painlike experiences in molluscs, if they exist, should differ from those in mammals. But reports indicate that some molluscs exhibit motivational states and cognitive capabilities that may be consistent with a capacity for states with functional parallels to pain. We therefore recommend that investigators attempt to minimize the potential for nociceptor activation and painlike sensations in experimental invertebrates by reducing the number of animals subjected to stressful manipulations and by administering appropriate anesthetic agents whenever practicable, welfare practices similar to those for vertebrate subjects.

  1. Impact of Behavioral Control on the Processing of Nociceptive Stimulation

    PubMed Central

    Grau, James W.; Huie, J. Russell; Garraway, Sandra M.; Hook, Michelle A.; Crown, Eric D.; Baumbauer, Kyle M.; Lee, Kuan H.; Hoy, Kevin C.; Ferguson, Adam R.

    2012-01-01

    How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID:22934018

  2. Emotional modulation of pain and spinal nociception in fibromyalgia.

    PubMed

    Rhudy, Jamie L; DelVentura, Jennifer L; Terry, Ellen L; Bartley, Emily J; Olech, Ewa; Palit, Shreela; Kerr, Kara L

    2013-07-01

    Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes. PMID:23622762

  3. Oxidation Sensitive Nociception Involved in Endometriosis Associated Pain

    PubMed Central

    Ray, Kristeena; Fahrmann, Johannes; Mitchell, Brenda; Paul, Dennis; King, Holly; Crain, Courtney; Cook, Carla; Golovko, Mikhail; Brose, Stephen; Golovko, Svetlana; Santanam, Nalini

    2015-01-01

    Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu, rich in inflammatory markers and pain-inducing prostaglandins PGE2/PGF2α and lipid peroxides, and the endometriotic tissue is innervated with nociceptors. Our clinical study showed the abundance of oxidatively-modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively-modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (i) the detection of lipoprotein derived oxidation-sensitive pain molecules, (ii) the ability of such molecules to induce nociception, and (iii) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins similar to that seen in the PF. The oxidatively-modified lipoproteins induced hypothermia (intra-cerebroventricular) in CD-1 mice and nociception in the Hargreaves paw-withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin-E and N-acetylcysteine and the NSAID, indomethacin suppressed the pain inducing ability of oxidatively-modified lipoproteins. Treatment of human endometrial cells with oxidatively-modified lipoproteins or PF from women with endometriosis showed up-regulation of similar genes belonging to the opioid and inflammatory pathways. Our finding that oxidatively-modified lipoproteins can induce nociception has a broader impact not only in the treatment of endometriosis-associated pain but also in other diseases associated with chronic pain. PMID:25599233

  4. Central Sensitization of Mechanical Nociceptive Pathways Is Associated with a Long-Lasting Increase of Pinprick-Evoked Brain Potentials

    PubMed Central

    van den Broeke, Emanuel N.; Lambert, Julien; Huang, Gan; Mouraux, André

    2016-01-01

    Intense or sustained nociceptor activation, occurring, for example, after skin injury, can induce “central sensitization,” i.e., an increased responsiveness of nociceptive neurons in the central nervous system. A hallmark of central sensitization is increased mechanical pinprick sensitivity in the area surrounding the injured skin. The aim of the present study was to identify changes in brain activity related to this increased pinprick sensitivity. In 20 healthy volunteers, increased pinprick sensitivity was induced using high frequency electrical stimulation of the forearm skin (HFS). Mechanical pinprick stimulation (64 and 90 mN) was used to elicit event-related brain potentials (ERPs). The recordings were performed before, 20 min after and 45 min after applying HFS. The contralateral non-sensitized arm served as control. Pinprick stimulation of 64 mN, but not 90 mN, applied in the area of increased pinprick sensitivity elicited a significant increase of a late-latency positive wave, between 300 and 1100 ms after stimulus onset and was maximal at midline posterior electrodes. Most importantly, this increase in EEG activity followed the time course of the increase in pinprick perception, both being present 20 and 45 min after applying HFS. Our results show that the central sensitization of mechanical nociceptive pathways, manifested behaviorally as increased pinprick sensitivity, is associated with a long-lasting increase in pinprick-evoked brain potentials provided that a 64 mN stimulation intensity is used. PMID:27812331

  5. Bak Foong Pills induce an analgesic effect by inhibiting nociception via the somatostatin pathway in mice.

    PubMed

    Rowlands, Dewi Kenneth; Cui, Yu Gui; So, Siu Cheung; Tsang, Lai Ling; Chung, Yiu Wa; Chan, Hsiao Chang

    2012-01-01

    Dysmenorrhoea, defined as cramping pain in the lower abdomen occurring before or during menstruation, affects, to varying degrees, up to 90% of women of child-bearing age. We investigated whether BFP (Bak Foong Pills), a traditional Chinese medicine treatment for dysmenorrhoea, possesses analgesic properties. Results showed that BFP was able to significantly reduce pain responses following subchronic treatment for 3 days, but not following acute (1 h) treatment in response to acetic acid-induced writhing in C57/B6 mice. The analgesic effect was not due to inhibition of COX (cyclo-oxygenase) activity, evidenced by the lack of inhibition of prostacyclin and PGE2 (prostaglandin E2) production. Molecular analysis revealed that BFP treatment modulated the expression of a number of genes in the spinal cord of mice subjected to acetic acid writhing. RT-PCR (reverse transcription-PCR) analysis of spinal cord samples showed that both sst4 (somatostatin receptor 4) and sst2 receptor mRNA, but not μOR (μ-opiate receptor) and NK1 (neurokinin-1) receptor mRNA, were down-regulated following BFP treatment, thus implicating somatostatin involvement in BFP-induced analgesia. Administration of c-som (cyclo-somatostatin), a somatostatin antagonist, prior to acetic acid-induced writhing inhibited the analgesic effect. Thus subchronic treatment with BFP has anti-nociceptive qualities mediated via the somatostatin pathway. PMID:21980955

  6. Stimulus Structure, Discrimination, and Interference

    ERIC Educational Resources Information Center

    Runquist, Willard N.

    1975-01-01

    The general purpose of this experiment was to determine whether differences in stimulus discrimination, as determined by the MIR (missing-item recognition) test, are correlated with interference in recall, as demanded by the discriminative coding hypothesis. (Author/RK)

  7. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    PubMed

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-01

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.

  8. Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice.

    PubMed

    Katsuyama, Soh; Otowa, Akira; Kamio, Satomi; Sato, Kazuma; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Bagetta, Giacinto; Sakurada, Tsukasa; Nakamura, Hitoshi

    2015-01-01

    This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalin-induced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.

  9. A small, silent, low friction, linear actuator for mechanical nociceptive testing in veterinary research.

    PubMed

    Dixon, M J; Taylor, P M; Slingsby, L; Hoffmann, M V; Kästner, S B R; Murrell, J

    2010-07-01

    Air pressure is commonly used to drive a mechanical stimulus for nociceptive threshold testing. This may be bulky, noisy, non-linear and suffer from friction, hence development of a better system is described. A novel, light (14 g) rolling diaphragm actuator was constructed, which supplied 20 N force via a constant actuation area irrespective of the pressure and position in the stroke. Three round-ended pins, 2.5 mm diameter, mounted in a triangle on the piston, provided the stimulus. Pressure was increased manually using a syringe with the rate of rise of force controlled at 0.8 N/s by warning lights. The pressure/force relationship was calibrated using a static force transducer and mercury column. Data were collected with the actuator attached to the antero-medial radius of 12 cats and four dogs. Mechanical threshold was recorded when the animal withdrew the limb and/or turned towards the actuator. Safety cut-off was 20 N. The pressure/force relationship was linear and independent of the start point in the actuator stroke. Baseline feline thresholds were 10.0 +/- 2.5 N (mean +/- SD), which increased significantly 30 min after butorphanol administration. Baseline canine thresholds were 5.5 +/- 1.4 N and increased significantly between 15 and 45 min after administration of fentanyl or butorphanol. The system overcame the problems of earlier devices and detected an opioid-induced increase in threshold. It has considerable advantages over previous systems for research in analgesia. PMID:20457825

  10. Carving Executive Control at Its Joints: Working Memory Capacity Predicts Stimulus-Stimulus, but Not Stimulus-Response, Conflict

    ERIC Educational Resources Information Center

    Meier, Matt E.; Kane, Michael J.

    2015-01-01

    Three experiments examined the relation between working memory capacity (WMC) and 2 different forms of cognitive conflict: stimulus-stimulus (S-S) and stimulus-response (S-R) interference. Our goal was to test whether WMC's relation to conflict-task performance is mediated by stimulus-identification processes (captured by S-S conflict),…

  11. Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception

    NASA Astrophysics Data System (ADS)

    Reimann, Henning Matthias; Hentschel, Jan; Marek, Jaroslav; Huelnhagen, Till; Todiras, Mihail; Kox, Stefanie; Waiczies, Sonia; Hodge, Russ; Bader, Michael; Pohlmann, Andreas; Niendorf, Thoralf

    2016-01-01

    Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.

  12. Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception

    PubMed Central

    Reimann, Henning Matthias; Hentschel, Jan; Marek, Jaroslav; Huelnhagen, Till; Todiras, Mihail; Kox, Stefanie; Waiczies, Sonia; Hodge, Russ; Bader, Michael; Pohlmann, Andreas; Niendorf, Thoralf

    2016-01-01

    Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus. PMID:26821826

  13. Nociceptive temporalis inhibitory reflexes evoked by CO2-laser stimulation in tension-type headache.

    PubMed

    de Tommaso, M; Guido, M; Libro, G; Losito, L; Sciruicchio, V; Specchio, L M; Puca, F

    2003-06-01

    The aim of the study was to evaluate the laser-induced suppression periods of the temporalis muscle in patients with tension-type headache, compared with the pattern of temporalis activity suppression induced by electrical stimulation. Fifteen patients with chronic and 10 with episodic tension-type headaches were selected. Suppression periods were recorded simultaneously from both temporalis muscles using both electrical stimuli and CO2-laser stimuli. A significant reduction in the later electrically induced suppression period was found in both tension-type headache groups. Laser stimulation induced a first suppression period (LSP1) with a latency of about 50 ms in all patients. The features of LSP1 were similar across groups. The LSP1 should correspond to the first suppression period induced by electrical stimulus, which is partly a nociceptive response, whereas the second period seemed negligibly linked with the activation of pain-related afferents, though probably their activation may contribute to increase the reflex duration and to emphasize abnormalities in tension-type headache. PMID:12780766

  14. Nociceptive temporalis inhibitory reflexes evoked by CO2-laser stimulation in tension-type headache.

    PubMed

    de Tommaso, M; Guido, M; Libro, G; Losito, L; Sciruicchio, V; Specchio, L M; Puca, F

    2003-06-01

    The aim of the study was to evaluate the laser-induced suppression periods of the temporalis muscle in patients with tension-type headache, compared with the pattern of temporalis activity suppression induced by electrical stimulation. Fifteen patients with chronic and 10 with episodic tension-type headaches were selected. Suppression periods were recorded simultaneously from both temporalis muscles using both electrical stimuli and CO2-laser stimuli. A significant reduction in the later electrically induced suppression period was found in both tension-type headache groups. Laser stimulation induced a first suppression period (LSP1) with a latency of about 50 ms in all patients. The features of LSP1 were similar across groups. The LSP1 should correspond to the first suppression period induced by electrical stimulus, which is partly a nociceptive response, whereas the second period seemed negligibly linked with the activation of pain-related afferents, though probably their activation may contribute to increase the reflex duration and to emphasize abnormalities in tension-type headache.

  15. Attention effects on vicarious modulation of nociception and pain.

    PubMed

    Khatibi, Ali; Vachon-Presseau, Etienne; Schrooten, Martien; Vlaeyen, Johan; Rainville, Pierre

    2014-10-01

    The observation of others' facial expressions of pain has been shown to facilitate the observer's nociceptive responses and to increase pain perception. We investigated how this vicarious facilitation effect is modulated by directing the observer's attention toward the meaning of pain expression or the facial movements. In separate trials, participants were instructed to assess the "intensity of the pain expression"(meaning) or to "discriminate the facial movements" in the upper vs lower part of the face shown in 1-second dynamic clips displaying mild, moderate, or strong pain expressions or a neutral control. In 50% of the trials, participants received a painful electrical stimulation to the sural nerve immediately after the presentation of the expression. Low-level nociceptive reactivity was measured with the RIII-response, and pain perception was assessed using pain ratings. Pain induced by the electrical stimulation increased after viewing stronger pain expressions in both tasks, but the RIII-response showed this vicarious facilitation effect only in the movement discrimination task at the strongest expression intensity. These findings are consistent with the notion that vicarious processes facilitate self-pain and may prime automatic nociceptive responses. However, this priming effect is influenced by top-down attentional processes. These results provide another case of dissociation between reflexive and perceptual processes, consistent with the involvement of partly separate brain networks in the regulation of cortical and lower-level nociceptive responses. Combined with previous results, these findings suggest that vicarious pain facilitation is an automatic process that may be diminished by top-down attentional processes directed at the meaning of the expression.

  16. Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in central amygdala neurons.

    PubMed

    Li, Weidong; Neugebauer, Volker

    2004-01-01

    The laterocapsular division of the central nucleus of the amygdala (CeA) is now defined as the "nociceptive amygdala" because of its high content of neurons that respond to painful stimuli. The majority of these neurons become sensitized in a model of arthritis pain. Here we address the role of G protein-coupled group I metabotropic glutamate receptor subtypes mGluR1 and mGluR5 in nociceptive processing under normal conditions and in pain-related sensitization. Extracellular single-unit recordings were made from 65 CeA neurons in anesthetized rats. Each neuron's responses to brief mechanical stimuli, background activity, receptive field size, and threshold were measured before and after induction of the kaolin/carrageenan mono-arthritis in one knee and before and during applications of agonists and antagonists into the CeA by microdialysis. All neurons received excitatory input from the knee(s) and responded most strongly to noxious stimuli. Before arthritis, a group I mGluR1 and mGluR5 agonist (DHPG, n = 10) potentiated the responses to innocuous and noxious stimuli. This effect was mimicked by an mGluR5 agonist (CHPG, n = 15). In the arthritis pain state (>6 h after induction), the facilitatory effects of DHPG (n = 9), but not CHPG (n = 7), increased. An mGluR1 antagonist (CPCCOEt) had no effect before arthritis (n = 12) but inhibited the responses of sensitized neurons in the arthritis pain state (n = 8). An mGluR5 antagonist (MPEP) inhibited brief nociceptive responses under normal conditions (n = 19) and prolonged nociception in arthritis (n = 8). These data suggest a change of mGluR1 function and activation in the amygdala in pain-related sensitization, whereas mGluR5 is involved in brief as well as prolonged nociception.

  17. Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Lin, Heng-Teng; Chen, Yu-Wen; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-04-01

    This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine.

  18. Quantification of a contact stimulus by diapers

    NASA Astrophysics Data System (ADS)

    Nomata, Takuya; Okuyama, Takeshi; Teraoka, Hiromi; Murakami, Yasuo; Miyazawa, Kiyoshi; Tanaka, Mami

    2009-12-01

    This paper describes a development of a sensor system for measurement of a contact stimulus which diapers give to infants. A polyvinyliden fluoride (PVDF) film and a strain gauge are used as the sensor receptors. The PVDF is a kind of piezoelectric material. The sensor consists of a surface contact layer, a PVDF film, a strain gauge and an aluminum plate. First, in order to investigate the sensor performance, the sensor was located on a silicone plate and the upper part of the sensor was rubbed with an acrylic artificial finger. The finger enabled the measurement to carry out at a constant speed and force. Next, the sensor was attached on an infant dummy and the sensor outputs were measured under conditions with and without diapers. By comparison of the output under two different conditions, it was confirmed that there is a clearly difference between the two conditions. It was found that the developed sensor system has the possibility to quantify a contact stimulus which diapers give infants.

  19. Quantification of a contact stimulus by diapers

    NASA Astrophysics Data System (ADS)

    Nomata, Takuya; Okuyama, Takeshi; Teraoka, Hiromi; Murakami, Yasuo; Miyazawa, Kiyoshi; Tanaka, Mami

    2010-01-01

    This paper describes a development of a sensor system for measurement of a contact stimulus which diapers give to infants. A polyvinyliden fluoride (PVDF) film and a strain gauge are used as the sensor receptors. The PVDF is a kind of piezoelectric material. The sensor consists of a surface contact layer, a PVDF film, a strain gauge and an aluminum plate. First, in order to investigate the sensor performance, the sensor was located on a silicone plate and the upper part of the sensor was rubbed with an acrylic artificial finger. The finger enabled the measurement to carry out at a constant speed and force. Next, the sensor was attached on an infant dummy and the sensor outputs were measured under conditions with and without diapers. By comparison of the output under two different conditions, it was confirmed that there is a clearly difference between the two conditions. It was found that the developed sensor system has the possibility to quantify a contact stimulus which diapers give infants.

  20. Nociception and escape behavior in planarians

    NASA Astrophysics Data System (ADS)

    Schoetz Collins, Eva-Maria

    2015-03-01

    Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

  1. N2pc is modulated by stimulus-stimulus, but not by stimulus-response incompatibilities.

    PubMed

    Cespón, J; Galdo-Álvarez, S; Díaz, F

    2013-04-01

    Studies of the N2pc in Simon-type tasks have revealed inconsistent results. That is, N2pc was only modulated when a stimulus-stimulus (S-S) overlap covaries with the stimulus-response (S-R) overlap. The present study aimed to establish whether N2pc is modulated by the S-R or by the S-S overlap. Therefore, we designed a Simon task requiring response to a colour stimulus (an arrow) with two irrelevant dimensions (position and direction). The following conditions were thus generated: compatible direction-compatible position (CDCP); incompatible direction-compatible position (IDCP); compatible direction-incompatible position (CDIP); and incompatible direction-incompatible position (IDIP). In IDCP and CDIP, both irrelevant dimensions conveyed contradictory spatial information (S-S incompatibility), while compatibility between both irrelevant dimensions occurred in CDCP and IDIP (the direction indicated was compatible with stimulus position). The N2pc amplitude was smaller in IDCP and CDIP than in CDCP and IDIP, what suggests that N2pc was modulated by S-S incompatibility and not by S-R incompatibilities. PMID:23380335

  2. Independent processing of stimulus-stimulus and stimulus-response conflicts.

    PubMed

    Li, Qi; Nan, Weizhi; Wang, Kai; Liu, Xun

    2014-01-01

    The dimensional overlap (DO) model proposes distinct mechanisms for stimulus-stimulus (S-S) and stimulus-response (S-R) conflict effects. Many studies have examined the independence of S-S and S-R conflict effects in the color-word Stroop and Simon tasks. However, confounds exist between the distinction of DO (i.e., S-S dimensional overlap compared with S-R dimensional overlap) and the distinction of stimulus attributes (e.g., color compared with spatial location; semantic compared with nonsemantic information), which may hinder interpretation of the independence of S-S and S-R conflicts. A spatial Stroop (word) task and a spatial Stroop (arrow) task were combined with a Simon task in Experiments 1 and 2, respectively to eliminate these confounds of stimulus attributes. The results showed that S-S and S-R conflicts affected performance additively. There was no significant correlation across participants. These findings lend further support to independent processing of S-S and S-R conflicts as it is outlined in the taxonomy of DO.

  3. Benzodiazepine-like discriminative stimulus effects of toluene vapor

    PubMed Central

    Shelton, Keith L.; Nicholson, Katherine L.

    2013-01-01

    In vitro studies show that the abused inhalant toluene affects a number of ligand-gated ion channels. The two most consistently implicated of these are γ-aminobutyric acid type A (GABAA) receptors which are positively modulated by toluene and N-methyl-D-aspartate (NMDA) receptors which are negatively modulated by toluene. Behavioral studies also suggest an interaction of toluene with GABAA and/or NMDA receptors but it is unclear if these receptors underlie the abuse-related intoxicating effects of toluene. Seventeen B6SJLF1/J mice were trained using a two-choice operant drug discrimination procedure to discriminate 10 min of exposure to 2000 ppm toluene vapor from 10 min of exposure to air. The discrimination was acquired in a mean of 65 training sessions. The stimulus effects of 2000 ppm toluene vapor were exposure concentration-dependent but rapidly diminished following the cessation of vapor exposure. The stimulus effects of toluene generalized to the chlorinated hydrocarbon vapor perchloroethylene but not 1,1,2-trichloroethane nor the volatile anesthetic isoflurane. The competitive NMDA antagonist CGS-17955, the uncompetitive antagonist dizocilpine and the glycine-site antagonist L701,324 all failed to substitute for toluene. The classical nonselective benzodiazepines midazolam and chlordiazepoxide produced toluene-like stimulus effects but the alpha 1 subunit preferring positive GABAA modulator zaleplon failed to substitute for toluene. The barbiturates pentobarbital and methohexital and the GABAA-positive modulator neurosteroid allopregnanolone did not substitute for toluene. These data suggest that the stimulus effects of toluene may be at least partially mediated by benzodiazepine-like positive allosteric modulation of GABAA receptors containing alpha 2, 3 or 5 subunits. PMID:24436974

  4. Nociceptive sensitization by complement C5a and C3a in mouse

    PubMed Central

    Jang, Jun Ho; Clark, J. David; Li, Xiangqi; Yorek, Matthew S.; Usachev, Yuriy M.; Brennan, Timothy J.

    2009-01-01

    Activation of the complement system by injury increases inflammation by producing complement fragments C5a and C3a which are able to recruit and activate immune cells. Complement activation may contribute to pain after inflammation and injury. In the present study, we examined whether C5a and C3a elicit nociception when injected into mouse hind paws in vivo, and whether C5a and C3a activate and/or sensitize mechanosensitive nociceptors when applied on peripheral terminals in vitro. We also examined the dorsal root ganglia (DRG) for C5a receptor (C5aR) mRNA and effects of C5a and C3a on intracellular Ca2+ concentration ([Ca2+]i) using Ca2+ imaging. Heat hyperalgesia was elicited by intraplantar injection of C5a, and mechanical hyperalgesia by C5a and C3a. After exposure to either C5a or C3a, C-nociceptors were sensitized to heat as evidenced by an increased proportion of heat responsive fibers, lowered response threshold to heat and increased action potentials during and after heat stimulation. A-nociceptors were activated by complement. However, no change was observed in mechanical responses of A- and C- nociceptors after C5a and C3a application. The presence of C5aR mRNA was detected in DRG. C5a and C3a application elevated [Ca2+]i and facilitated capsaicin-induced [Ca2+]i responses in DRG neurons. The results suggest a potential role for complement fragments C5a and C3a in nociception by activating and sensitizing cutaneous nociceptors. PMID:20031321

  5. Is blood glucose associated with descending modulation of spinal nociception as measured by the nociceptive flexion reflex?

    PubMed Central

    Terry, Ellen L; Güereca, Yvette M; Martin, Satin L; Rhudy, Jamie L

    2016-01-01

    Objectives Prior research has shown a relationship between blood glucose levels and some forms of self-regulation (eg, executive function), with low blood glucose levels associated with impaired self-regulation. Further, engagement in self-regulation tasks depletes blood glucose. Given these relationships, the present study examined whether blood glucose is associated with another form of self-regulation, ie, descending pain modulatory processes. Methods Forty-seven (32 female) pain-free participants were recruited and completed testing. Blood glucose was measured from finger sticks and a digital meter before and after experimental pain tests. Pain tests included the nociceptive flexion reflex (NFR) threshold to assess descending modulation of spinal nociception, but also electric pain threshold to assess perceptual pain detection. The Stroop color word naming test was also assessed before and after pain testing to examine changes in executive function. Results Results indicated that mean blood glucose levels decreased after pain testing, but Stroop performance did not significantly change. Importantly, changes in blood glucose were correlated with NFR threshold, such that decreases in blood glucose were associated with lower NFR thresholds (reduced descending inhibition). Changes in blood glucose were unrelated to pain threshold or executive function. Conclusion This study suggests that glucose depletion may impair performance of descending inhibitory processes, without impacting the perceptual detection of pain (pain threshold). Although findings need to be replicated, maintaining adequate glucose levels may be necessary to support inhibition of spinal nociception. PMID:27110138

  6. Modulation of the discriminative stimulus effects of cocaine and methamphetamine by the histaminergic system.

    PubMed

    Mori, Tomohisa; Narita, Minoru; Onodera, Kenji; Suzuki, Tsutomu

    2002-06-01

    The role of the histaminergic system in the discriminative stimulus effects of cocaine and methamphetamine was examined in rats trained to discriminate between saline and cocaine (10 mg/kg) or methamphetamine (1.0 mg/kg). L-histidine (400 mg/kg), a precursor of histamine, significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. Previous studies have revealed the existence of several histamine receptor types, H1-, H2-, and H3-receptors. These enhancing effects of L-histidine on the discriminative stimulus effects of cocaine and methamphetamine were attenuated by 5.0 mg/kg of pyrilamine (an H1-receptor antagonist), but not by 1.0 mg/kg of zolantidine (an H2-receptor antagonist), suggesting that these enhancing effects of L-histidine were mediated through the activation of H1-receptors. Thioperamide (7.5 mg/kg), an H3-receptor antagonist, also significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. However, neither pyrilamine nor zolantidine affected the enhancing effects of thioperamide, unlike the results attained with L-histidine. Therefore our findings suggest that the histaminergic system may modify the discriminative stimulus effects of cocaine and methamphetamine mediated through H1- and H3-receptors.

  7. Enhancement of spontaneous and heat-evoked activity in spinal nociceptive neurons by the endovanilloid/endocannabinoid N-arachidonoyldopamine (NADA).

    PubMed

    Huang, Susan M; Walker, J Michael

    2006-02-01

    N-arachidonoyldopamine (NADA) is an endogenous molecule found in the nervous system that is capable of acting as a vanilloid agonist via the TRPV1 receptor and as a cannabinoid agonist via the CB1 receptor. Using anesthetized rats, we investigated the neural correlates of behavioral thermal hyperalgesia produced by NADA. Extracellular single cell electrophysiology was conducted to assess the effects of peripheral administration of NADA (i.pl.) on nociceptive neurons in the dorsal horn of the spinal cord. Injection of NADA in the hindpaw caused increased spontaneous discharge of spinal nociceptive neurons compared with injection of vehicle. The neurons also displayed magnified responses to application of thermal stimuli ranging from 34 to 52 degrees C. NADA-induced neural hypersensitivity was dose dependent (EC50 = 1.55 microg) and TRPV1 dependent, as the effect was abolished by co-administration of the TRPV1 antagonist 5'-iodoresiniferatoxin (I-RTX). In contrast, co-administration of the CB1 antagonist SR 141716A did not attenuate this effect. These results suggest that the enhanced responses of spinal nociceptive neurons likely underlie the behavioral thermal hyperalgesia and implicate a possible pain-sensitizing role of endogenous NADA mediated by TRPV1 in the periphery.

  8. Stimulus Effects on Local Preference: Stimulus-Response Contingencies, Stimulus-Food Pairing, and Stimulus-Food Correlation

    ERIC Educational Resources Information Center

    Davison, Michael; Baum, William M.

    2010-01-01

    Four pigeons were trained in a procedure in which concurrent-schedule food ratios changed unpredictably across seven unsignaled components after 10 food deliveries. Additional green-key stimulus presentations also occurred on the two alternatives, sometimes in the same ratio as the component food ratio, and sometimes in the inverse ratio. In eight…

  9. Defining the Stimulus - A Memoir

    PubMed Central

    Terrace, Herbert

    2010-01-01

    The eminent psychophysicist, S. S. Stevens, once remarked that, “the basic problem of psychology was the definition of the stimulus” (Stevens, 1951, p. 46). By expanding the traditional definition of the stimulus, the study of animal learning has metamorphosed into animal cognition. The main impetus for that change was the recognition that it is often necessary to postulate a representation between the traditional S and R of learning theory. Representations allow a subject to re-present a stimulus it learned previously that is currently absent. Thus, in delayed-matching-to-sample, one has to assume that a subject responds to a representation of the sample during test if it responds correctly. Other examples, to name but a few, include concept formation, spatial memory, serial memory, learning a numerical rule, imitation and metacognition. Whereas a representation used to be regarded as a mentalistic phenomenon that was unworthy of scientific inquiry, it can now be operationally defined. To accommodate representations, the traditional discriminative stimulus has to be expanded to allow for the role of representations. The resulting composite can account for a significantly larger portion of the variance of performance measures than the exteroceptive stimulus could by itself. PMID:19969047

  10. Age trends in stimulus overselectivity.

    PubMed

    McHugh, Louise; Reed, Phil

    2007-11-01

    Stimulus overselectivity refers to the phenomenon whereby stimulus control over behavior is exerted only by a limited subset of the total number of stimuli present during discrimination learning. It often is displayed by individuals with autistic spectrum disorders or learning disabilities, but is not exclusive to those groups. The present studies investigated the impact of aging on stimulus control and overselectivity. Three age groups--18-22, 47-55, and 70-80 year olds-were studied in two experiments. All participants were trained on a simple discrimination task, randomly assigned to one of two conditions (either with or without a distractor task), and then tested for the emergence of overselectivity (Experiment 1). In Experiment 2 responding controlled by the overselected stimulus elements was reduced by introducing a verbal punisher. In subsequent tests, control of behavior by the previously underselected elements from Experiment 1 was enhanced across the two younger age groups but not the oldest group of participants. The results are discussed in relation to the attention-deficit and overshadowing accounts of overselectivity. PMID:18047227

  11. Acquired Equivalence Changes Stimulus Representations

    ERIC Educational Resources Information Center

    Meeter, M.; Shohamy, D.; Myers, C. E.

    2009-01-01

    Acquired equivalence is a paradigm in which generalization is increased between two superficially dissimilar stimuli (or antecedents) that have previously been associated with similar outcomes (or consequents). Several possible mechanisms have been proposed, including changes in stimulus representations, either in the form of added associations or…

  12. Effects of hot and cold stimulus combinations on the thermal preference of rats.

    PubMed

    Rossi, Heather L; Neubert, John K

    2009-11-01

    Traditional evaluation of pain in animals has primarily used reflexive withdrawal or nocifensive response from singly presented stimulation. However, daily experience of thermal sensation involves situations in which rapid temperature changes from cold to hot can occur. Therefore, in order to better understand integration of competing stimuli and their role in the motivational character of pain perception, behavioral tasks have been adapted to evaluate treatment-driven changes in hindpaws when exposed to two or more stimuli. However, such assessments of craniofacial sensitivity are lacking. In this study, we sought to characterize thermal preference for facial stimulation when rats are given the option of experiencing a hot or cold stimulus to obtain a milk reward, or abstaining from stimulation. We found that when both cold and hot stimuli were either non-noxious or where both stimuli were noxious the hot stimulus was preferred. When the hot stimulus was noxious, non-noxious cold was preferred. Unstimulated time was dependent on the combined aversiveness of the two stimuli, such that unstimulated time was the greatest with a highly aversive stimulus pair (-4 and 48 degrees C). We also found that pairing stimuli modulated successful task completion for each stimulus, but for nociceptive heat, this was not solely a consequence of thermal preference. Finally, we found that previous preference could both induce and abolish subsequent thermode preference independent of stimulus cues. The findings in this study will allow us to evaluate experimental pain states and analgesic treatments in a manner more relatable to the experience of the patient.

  13. Sodium butyrate and its synthetic amide derivative modulate nociceptive behaviors in mice.

    PubMed

    Russo, Roberto; De Caro, Carmen; Avagliano, Carmen; Cristiano, Claudia; La Rana, Giovanna; Mattace Raso, Giuseppina; Berni Canani, Roberto; Meli, Rosaria; Calignano, Antonio

    2016-01-01

    In the present study we investigated the role of sodium butyrate (butyrate), and its more palatable derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), in animal models of acute and chronic pain. We found that oral administrations of butyrate (10-200mg/Kg) or equimolecular FBA (21.2-424mg/Kg) reduced visceral pain in a dose- and time-dependent manner. Both drugs were also effective in the formalin test, showing an antinociceptive effect. This analgesic effect was blocked by glibenclamide, suggesting the involvement of ATP-dependent K(+) channels. Moreover, following repeated administration butyrate (100-200mg/Kg) and FBA (212-424mg/Kg) retained their analgesic properties in a model of neuropathic pain, reducing mechanical and thermal hyperalgesia in the chronic constriction injury (CCI) model. The involvement of peroxisome proliferator-activated receptor (PPAR) -α and -γ for the analgesic effect of butyrate was also investigated by using PPAR-α null mice or the PPAR-γ antagonist GW9662. Western blot analysis, confirmed the role of peroxisome receptors in butyrate effects, evidencing the increase of PPAR-α and -γ expression, associated to the reduction of inflammatory markers (COX-2, iNOS, TNF-α and cFOS). In conclusion, we describe the role of butyrate-based drugs in pain, identifying different and converging non-genomic and genomic mechanisms of action, which cooperate in nociception maintenance.

  14. Reactive oxygen species are involved in group I mGluR-mediated facilitation of nociceptive processing in amygdala neurons.

    PubMed

    Ji, Guangchen; Neugebauer, Volker

    2010-07-01

    Recent biochemical and behavioral data implicate reactive oxygen species (ROS) in peripheral and spinal pain mechanisms. However, pain-related functions of ROS in the brain and mechanisms of pain-related ROS activation remain to be determined. Our previous studies showed that the amygdala plays a key role in emotional-affective pain responses and pain modulation. Hyperactivity of amygdala neurons in an animal pain model depends on group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5), but their signaling pathway remains to be determined. Here we tested the hypothesis that activation of group I mGluRs increases nociceptive processing in amygdala neurons through a mechanism that involves ROS. Extracellular single-unit recordings were made from neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC) in anesthetized adult male rats. Administration of a group I mGluR agonist (DHPG) into the CeLC by microdialysis increased the responses to innocuous and noxious somatosensory (knee joint compression) and visceral (colorectal distention [CRD]) stimuli. A ROS scavenger (PBN) and a superoxide dismutase mimetic (TEMPOL) reversed the facilitatory effects of DHPG. An mGluR5 antagonist (MPEP) also inhibited the effects of DHPG on the responses to innocuous and noxious somatosensory and visceral stimuli, whereas an mGluR1 antagonist (LY367385) decreased only the responses to visceral stimulation. The results show for the first time that ROS mediate group I mGluR-induced facilitation of nociceptive processing in amygdala neurons. The antagonist data may suggest differential contributions of subtypes mGluR1 and mGluR5 to the processing of somatosensory and visceral nociceptive information in the amygdala.

  15. The Specification and Maturation of Nociceptive Neurons from Human Embryonic Stem Cells

    PubMed Central

    Boisvert, Erin M.; Engle, Sandra J.; Hallowell, Shawn E.; Liu, Ping; Wang, Zhao-Wen; Li, Xue-Jun

    2015-01-01

    Nociceptive neurons play an essential role in pain sensation by transmitting painful stimuli to the central nervous system. However, investigations of nociceptive neuron biology have been hampered by the lack of accessibility of human nociceptive neurons. Here, we describe a system for efficiently guiding human embryonic stem cells into nociceptive neurons by first inducing these cells to the neural lineage. Subsequent addition of retinoic acid and BMP4 at specific time points and concentrations yielded a high population of neural crest progenitor cells (AP2α+, P75+), which further differentiated into nociceptive neurons (TRKA+, Nav1.7+, P2X3+). The overexpression of Neurogenin 1 (Neurog1) promoted the neurons to express genes related to sensory neurons (Peripherin, TrkA) and to further mature into TRPV1+ nociceptive neurons. Importantly, the overexpression of Neurog1 increased the response of these neurons to capsaicin stimulation, a hallmark of mature functional nociceptive neurons. Taken together, this study reveals the important role that Neurog1 plays in generating functional human nociceptive neurons. PMID:26581770

  16. The Specification and Maturation of Nociceptive Neurons from Human Embryonic Stem Cells.

    PubMed

    Boisvert, Erin M; Engle, Sandra J; Hallowell, Shawn E; Liu, Ping; Wang, Zhao-Wen; Li, Xue-Jun

    2015-11-19

    Nociceptive neurons play an essential role in pain sensation by transmitting painful stimuli to the central nervous system. However, investigations of nociceptive neuron biology have been hampered by the lack of accessibility of human nociceptive neurons. Here, we describe a system for efficiently guiding human embryonic stem cells into nociceptive neurons by first inducing these cells to the neural lineage. Subsequent addition of retinoic acid and BMP4 at specific time points and concentrations yielded a high population of neural crest progenitor cells (AP2α(+), P75(+)), which further differentiated into nociceptive neurons (TRKA(+), Nav1.7(+), P2X3(+)). The overexpression of Neurogenin 1 (Neurog1) promoted the neurons to express genes related to sensory neurons (Peripherin, TrkA) and to further mature into TRPV1(+) nociceptive neurons. Importantly, the overexpression of Neurog1 increased the response of these neurons to capsaicin stimulation, a hallmark of mature functional nociceptive neurons. Taken together, this study reveals the important role that Neurog1 plays in generating functional human nociceptive neurons.

  17. Inference of pain stimulus level from stereotypical behavioral response of C.elegans allows quantification of effects of anesthesia and mutation

    NASA Astrophysics Data System (ADS)

    Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

    In animals, we must infer the pain level from experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. To establish C.elegans as a model for pain research, we propose for the first time a quantitative model that allows inference of a thermal nociceptive stimulus level from the behavior of an individual worm. We apply controlled levels of pain by locally heating worms with an infrared laser and capturing the subsequent behavior. We discover that the behavioral response is a product of stereotypical behavior and a nonlinear function of the strength of stimulus. The same stereotypical behavior is observed in normal, anesthetized and mutated worms. From this result we build a Bayesian model to infer the strength of laser stimulus from the behavior. This model allows us to measure the efficacy of anaesthetization and mutation by comparing the inferred strength of stimulus. Based on the measured nociceptive escape of over 200 worms, our model is able to significantly differentiate normal, anaesthetized and mutated worms with 40 worm samples. This work was partially supported by NSF Grant No. IOS/1208126 and HFSP Grant No. RGY0084/.

  18. Observing Behavior and Atypically Restricted Stimulus Control

    ERIC Educational Resources Information Center

    Dube, William V.; Dickson, Chata A.; Balsamo, Lyn M.; O'Donnell, Kristin Lombard; Tomanari, Gerson Y.; Farren, Kevin M.; Wheeler, Emily E.; McIlvane, William J.

    2010-01-01

    Restricted stimulus control refers to discrimination learning with atypical limitations in the range of controlling stimuli or stimulus features. In the study reported here, 4 normally capable individuals and 10 individuals with intellectual disabilities (ID) performed two-sample delayed matching to sample. Sample-stimulus observing was recorded…

  19. D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

    PubMed Central

    Boccella, Serena; Vacca, Valentina; Errico, Francesco; Marinelli, Sara; Squillace, Marta; Di Maio, Anna; Vitucci, Daniela; Palazzo, Enza; De Novellis, Vito; Maione, Sabatino; Pavone, Flaminia; Usiello, Alessandro

    2015-01-01

    D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. PMID:25629055

  20. Comparison of operant escape and reflex tests of nociceptive sensitivity.

    PubMed

    Vierck, Charles J; Yezierski, Robert P

    2015-04-01

    Testing of reflexes such as flexion/withdrawal or licking/guarding is well established as the standard for evaluating nociceptive sensitivity and its modulation in preclinical investigations of laboratory animals. Concerns about this approach have been dismissed for practical reasons - reflex testing requires no training of the animals; it is simple to instrument; and responses are characterized by observers as latencies or thresholds for evocation. In order to evaluate this method, the present review summarizes a series of experiments in which reflex and operant escape responding are compared in normal animals and following surgical models of neuropathic pain or pharmacological intervention for pain. Particular attention is paid to relationships between reflex and escape responding and information on the pain sensitivity of normal human subjects or patients with pain. Numerous disparities between results for reflex and operant escape measures are described, but the results of operant testing are consistent with evidence from humans. Objective reasons are given for experimenters to choose between these and other methods of evaluating the nociceptive sensitivity of laboratory animals.

  1. Temporal and spectral profiles of stimulus-stimulus and stimulus-response conflict processing.

    PubMed

    Wang, Kai; Li, Qi; Zheng, Ya; Wang, Hongbin; Liu, Xun

    2014-04-01

    The ability to detect and resolve conflict is an essential function of cognitive control. Laboratory studies often use stimulus-response-compatibility (SRC) tasks to examine conflict processing in order to elucidate the mechanism and modular organization of cognitive control. Inspired by two influential theories regarding cognitive control, the conflict monitoring theory (Botvinick, Braver, Barch, Carter, & Cohen, 2001) and dimensional overlap taxonomy (Kornblum, Hasbroucq, & Osman, 1990), we explored the temporal and spectral similarities and differences between processing of stimulus-stimulus (S-S) and stimulus-response (S-R) conflicts with event related potential (ERP) and time-frequency measures. We predicted that processing of S-S conflict starts earlier than that of S-R conflict and that the two types of conflict may involve different frequency bands. Participants were asked to perform two parallel SRC tasks, both combining the Stroop task (involving S-S conflict) and Simon task (involving S-R conflict). ERP results showed pronounced SRC effects (incongruent vs. congruent) on N2 and P3 components for both S-S and S-R conflicts. In both tasks, SRC effects of S-S conflict took place earlier than those of S-R conflict. Time-frequency analysis revealed that both types of SRC effects modulated theta and alpha bands, while S-R conflict effects additionally modulated power in the beta band. These results indicated that although S-S and S-R conflict processing shared considerable ERP and time-frequency properties, they differed in temporal and spectral dynamics. We suggest that the modular organization of cognitive control should take both commonality and distinction of S-S and S-R conflict processing into consideration.

  2. Multiple Sensory Inputs Are Extensively Integrated to Modulate Nociception in C. elegans

    PubMed Central

    Summers, Philip J.; Layne, Robert M.; Ortega, Amanda C.; Harris, Gareth P.; Bamber, Bruce A.

    2015-01-01

    Sensory inputs are integrated extensively before decision making, with altered multisensory integration being associated with disorders such as autism. We demonstrate that the two C. elegans AIB interneurons function as a biphasic switch, integrating antagonistic, tonic, and acute inputs from three distinct pairs of sensory neurons to modulate nociception. Off food, animals reverse away from a noxious stimulus. In contrast, on food or serotonin, AIB signaling is inhibited and, although animals initiate an aversive response more rapidly, they continue forward after the initial backward locomotion is complete. That is, animals continue to move forward and feed even when presented with a noxious repellant, with AIB inhibition decreasing the repellant concentration evoking a maximal response. These studies demonstrate that the AIBs serve as an integrating hub, receiving inputs from different sensory neurons to modulate locomotory decision making differentially, and highlight the utility of this model to analyze the complexities of multisensory integration. SIGNIFICANCE STATEMENT Dysfunctional sensory signaling and perception are associated with a number of disease states, including autism spectrum disorders, schizophrenia, and anxiety. We have used the C. elegans model to examine multisensory integration at the interneuron level to better understand the modulation of this complex, multicomponent process. C. elegans responds to a repulsive odorant by first backing up and then either continuing forward or turning and moving away from the odorant. This decision-making process is modulated extensively by the activity state of the two AIB interneurons, with the AIBs integrating an array of synergistic and antagonistic glutamatergic inputs, from sensory neurons responding directly to the odorant to others responding to a host of additional environmental variables to ultimately fine tune aversive behaviors. PMID:26180208

  3. Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A.

    PubMed

    Mustafa, Golam; Anderson, Ethan M; Bokrand-Donatelli, Yvonne; Neubert, John K; Caudle, Robert M

    2013-11-01

    Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain-processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin-neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons' activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice, we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R-expressing neurons and also cleaves the target of botulinum toxin, a component-docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a murine model of Taxol-induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods, and that BoNT/A-LC:SP may be a useful agent for treating chronic pain.

  4. Physiological Signal Processing for Individualized Anti-nociception Management During General Anesthesia: A Review

    PubMed Central

    Bonhomme, V.; Jeanne, M.; Boselli, E.; Gruenewald, M.; Logier, R.; Richebé, P.

    2015-01-01

    Summary Objective The aim of this paper is to review existing technologies for the nociception / anti-nociception balance evaluation during surgery under general anesthesia. Methods General anesthesia combines the use of analgesic, hypnotic and muscle-relaxant drugs in order to obtain a correct level of patient non-responsiveness during surgery. During the last decade, great efforts have been deployed in order to find adequate ways to measure how anesthetic drugs affect a patient’s response to surgical nociception. Nowadays, though some monitoring devices allow obtaining information about hypnosis and muscle relaxation, no gold standard exists for the nociception / anti-nociception balance evaluation. Articles from the PubMed literature search engine were reviewed. As this paper focused on surgery under general anesthesia, articles about nociception monitoring on conscious patients, in post-anesthesia care unit or in intensive care unit were not considered. Results In this article, we present a review of existing technologies for the nociception / anti-nociception balance evaluation, which is based in all cases on the analysis of the autonomous nervous system activity. Presented systems, based on sensors and physiological signals processing algorithms, allow studying the patients’ reaction regarding anesthesia and surgery. Conclusion Some technological solutions for nociception / antinociception balance monitoring were described. Though presented devices could constitute efficient solutions for individualized anti-nociception management during general anesthesia, this review of current literature emphasizes the fact that the choice to use one or the other mainly relies on the clinical context and the general purpose of the monitoring. PMID:26293855

  5. Redox-Dependent Modulation of T-Type Ca2+ Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P

    PubMed Central

    Huang, Dongyang; Huang, Sha; Gao, Haixia; Liu, Yani; Qi, Jinlong; Chen, Pingping; Wang, Caixue; Scragg, Jason L.; Vakurov, Alexander; Peers, Chris; Du, Xiaona

    2016-01-01

    Abstract Aims: Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms. Results: SP acutely inhibited T-type voltage-gated Ca2+ channels in nociceptors. The effect was mediated by neurokinin 1 (NK1) receptor-induced stimulation of intracellular release of reactive oxygen species (ROS), as it can be prevented or reversed by the reducing agent dithiothreitol and mimicked by exogenous or endogenous ROS. This redox-mediated T-type Ca2+ channel inhibition operated through the modulation of CaV3.2 channel sensitivity to ambient zinc, as it can be prevented or reversed by zinc chelation and mimicked by exogenous zinc. Elimination of the zinc-binding site in CaV3.2 rendered the channel insensitive to SP-mediated inhibition. Importantly, peripherally applied SP significantly reduced bradykinin-induced nociception in rats in vivo; knock-down of CaV3.2 significantly reduced this anti-nociceptive effect. This atypical signaling cascade shared the initial steps with the SP-mediated augmentation of M-type K+ channels described earlier. Innovation: Our study established a mechanism underlying the peripheral anti-nociceptive effect of SP whereby this neuropeptide produces ROS-dependent inhibition of pro-algesic T-type Ca2+ current and concurrent enhancement of anti-algesic M-type K+ current. These findings will lead to a better understanding of mechanisms of endogenous analgesia. Conclusion: SP modulates T-type channel activity in nociceptors by a redox-dependent tuning of channel sensitivity to zinc; this novel modulatory pathway contributes to the peripheral anti-nociceptive effect of SP. Antioxid. Redox Signal. 25, 233–251. PMID:27306612

  6. Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.

    PubMed

    Jennings, Elaine M; Okine, Bright N; Olango, Weredeselam M; Roche, Michelle; Finn, David P

    2016-01-01

    Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences.

  7. Discriminative stimulus properties of indorenate, a serotonin agonist.

    PubMed Central

    Velázquez-Martínez, D N; López Cabrera, M; Sánchez, H; Ramírez, J I; Hong, E

    1999-01-01

    OBJECTIVE: To determine whether indorenate, a serotonin-receptor agonist, can exert discriminative control over operant responses, to establish the temporal course of discriminative control and to compare its stimulus properties to a (5-HT)IA receptor agonist. [3H]-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). DESIGN: Prospective animal study. ANIMALS: Ten male Wistar rats. INTERVENTIONS: Rats were trained to press either of 2 levers for sucrose solution according to a fixed ratio schedule, which was gradually increased. Rats were given injections of either indorenate or saline solution during discrimination training. Once they had achieved an 83% accuracy rate, rats underwent generalization tests after having received a different dose of indorenate, the training dose of indorenate at various intervals before the test, various doses of 8-OH-DPT, or NAN-190 administered before indorenate or 8-OH-DPAT. OUTCOME MEASURES: Distribution of responses between the 2 levers before the first reinforcer of the session, response rate for all the responses in the session, and a discrimination index that expressed the drug-appropriate responses as a proportion of the total responses. RESULTS: Indorenate administration resulted in discriminative control over operant responses, maintained at fixed ratio 10, at a dose of 10.0 mg/kg (but not 3.0 mg/kg). When the interval between the administration of indorenate and the start of the session was varied, the time course of its cue properties followed that of its described effects on 5-HT turnover. In generalization tests, the discrimination index was a function of the dose of indorenate employed; moreover, administration of 8-OH-DPAT (from 0.1 to 1.0 mg/kg) fully mimicked the stimulus properties of indorenate in a dose-dependent way. The (5-HT)IA antagonist NAN-190 prevented the stimulus generalization from indorenate to 8-OH-DPAT. Also, NAN-190 antagonized the stimulus control of indorenate when administered 45 minutes before

  8. Stimulus conflict triggers behavioral avoidance.

    PubMed

    Dignath, David; Eder, Andreas B

    2015-12-01

    According to a recent extension of the conflict-monitoring theory, conflict between two competing response tendencies is registered as an aversive event and triggers a motivation to avoid the source of conflict. In the present study, we tested this assumption. Over five experiments, we examined whether conflict is associated with an avoidance motivation and whether stimulus conflict or response conflict triggers an avoidance tendency. Participants first performed a color Stroop task. In a subsequent motivation test, participants responded to Stroop stimuli with approach- and avoidance-related lever movements. These results showed that Stroop-conflict stimuli increased the frequency of avoidance responses in a free-choice motivation test, and also increased the speed of avoidance relative to approach responses in a forced-choice test. High and low proportions of response conflict in the Stroop task had no effect on avoidance in the motivation test. Avoidance of conflict was, however, obtained even with new conflict stimuli that had not been presented before in a Stroop task, and when the Stroop task was replaced with an unrelated filler task. Taken together, these results suggest that stimulus conflict is sufficient to trigger avoidance.

  9. Stimulus conflict triggers behavioral avoidance.

    PubMed

    Dignath, David; Eder, Andreas B

    2015-12-01

    According to a recent extension of the conflict-monitoring theory, conflict between two competing response tendencies is registered as an aversive event and triggers a motivation to avoid the source of conflict. In the present study, we tested this assumption. Over five experiments, we examined whether conflict is associated with an avoidance motivation and whether stimulus conflict or response conflict triggers an avoidance tendency. Participants first performed a color Stroop task. In a subsequent motivation test, participants responded to Stroop stimuli with approach- and avoidance-related lever movements. These results showed that Stroop-conflict stimuli increased the frequency of avoidance responses in a free-choice motivation test, and also increased the speed of avoidance relative to approach responses in a forced-choice test. High and low proportions of response conflict in the Stroop task had no effect on avoidance in the motivation test. Avoidance of conflict was, however, obtained even with new conflict stimuli that had not been presented before in a Stroop task, and when the Stroop task was replaced with an unrelated filler task. Taken together, these results suggest that stimulus conflict is sufficient to trigger avoidance. PMID:25931151

  10. Stimulus properties of conspecific behavior

    PubMed Central

    Millard, W. J.

    1979-01-01

    Two experiments identified the conditions in which the behavior of one bird acquired discriminative control of the behavior of a second bird. The schedule-controlled behaviors of the “stimulus” bird were differentially correlated with the components of a multiple schedule according to which the pecking of an “experimental” bird produced food. In Experiment 1, three pairs of pigeons acquired a successive discrimination and two reversals with the conspecific stimuli. Experiment 2 included a control condition in which no systematic relationship existed between the conspecific stimuli and the component schedules. While differential responding during the components of the multiple schedule was again found when the conspecific stimuli were available, differential responding did not occur in the control condition. Test conditions included in the experiments indicated that (a) the differential responding was not dependent on the discriminative properties of reinforcement, (b) the pecking of the stimulus and experimental birds was temporally interrelated, (c) the visual conspecific stimuli were critical to the maintenance of the discrimination, and (d) the observed stimulus control immediately generalized to an unfamiliar conspecific. PMID:16812151

  11. Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats.

    PubMed

    Carpenter, Jessica M; Criddle, Catherine A; Craig, Helaina K; Ali, Zulfiqar; Zhang, Zhihao; Khan, Ikhlas A; Sufka, Kenneth J

    2016-03-01

    This study sought to compare the effects of Mitragyna speciosa (Korth.) Havil. extract, alkaloids fraction, and mitragynine, a μ-opioid receptor agonist, to that of morphine and oxycodone in a test of thermal nociception. In Experiment 1, male Sprague-Dawley rats were administered test articles intraperitoneally (IP) 30 min prior to testing to compare the effects of M. speciosa articles to opioid reference compounds on the hotplate assay. Test articles were vehicle, 10 mg/kg morphine, 3 mg/kg oxycodone, 300 mg/kg M. speciosa extract, 75 mg/kg M. speciosa alkaloids fraction, or 30 mg/kg mitragynine. To mirror consumer usage, Experiment 2 sought to determine whether M. speciosa articles retained their biological activity when given orally (PO). Test articles were vehicle, 6 mg/kg oxycodone, 300 mg/kg M. speciosa extract, or 100mg/kg mitragynine with hotplate tests conducted 30 and 60 min after administration. Mitragynine produced antinociceptive effects similar to the reference opioid agonists when administered IP and PO routes. These data suggest that M. speciosa extracts containing significant quantities of mitragynine may warrant consideration for further studies in primate self-administration models to yield insight into the abuse liability of this commercially available product. PMID:26688378

  12. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis.

    PubMed

    Wen, Z-H; Chang, Y-C; Jean, Y-H

    2015-11-01

    Although a large proportion of patients with osteoarthritis (OA) show inflammation in their affected joints, the pathological role of inflammation in the development and progression of OA has yet to be clarified. Glutamate is considered an excitatory amino acid (EAA) neurotransmitter in the mammalian central nervous system (CNS). There are cellular membrane glutamate receptors and transporters for signal input modulation and termination as well as vesicular glutamate transporters (VGLUTs) for signal output through exocytotic release. Glutamate been shown to mediate intercellular communications in bone cells in a manner similar to synaptic transmission within the CNS. Glutamate-mediated events may also contribute to the pathogenesis and ongoing processes of peripheral nociceptive transduction and inflammation of experimental arthritis models as well as human arthritic conditions. This review will discuss the differential roles of glutamate signaling and blockade in peripheral neuronal and non-neuronal joint tissues, including bone remodeling systems and their potentials to impact OA-related inflammation and progression. This will serve to identify several potential targets to direct novel therapies for OA. Future studies will further elucidate the role of glutamate in the development and progression of OA, as well as its association with the clinical features of the disease.

  13. Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior

    PubMed Central

    Harte, Steven E.; Meyers, Jessica B.; Donahue, Renee R.; Taylor, Bradley K.; Morrow, Thomas J.

    2016-01-01

    A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents. PMID:26915030

  14. Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior.

    PubMed

    Harte, Steven E; Meyers, Jessica B; Donahue, Renee R; Taylor, Bradley K; Morrow, Thomas J

    2016-01-01

    A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents.

  15. Congenital taurine deficiency in mice is associated with reduced sensitivity to nociceptive chemical stimulation.

    PubMed

    Lötsch, J; Hummel, T; Warskulat, U; Coste, O; Häussinger, D; Geisslinger, G; Tegeder, I

    2014-02-14

    The amino acid taurine is required for development and functioning of the central and peripheral nervous system where it exerts osmoregulatory, neuromodulatory and anti-apoptotic actions. It is subject to cellular import by the taurine transporter slc6a6. Absence of the transporter and consequently, absence of taurine leads to several neurologic deficits and sensory losses. In a slc6a6 knock-out mouse model, consequences of congenital taurine deficiency were assessed in nociceptive sensory processes. The formalin assay, hot plate assay, and summated generator potentials in response to local nociceptive stimulation with gaseous CO2 were applied. Reduced responsiveness of slc6a6(-/-) mice to nociceptive stimulation was observed in particular to chemical nociceptive stimuli. Scl6a6 knock-out mice spent significantly less time licking the formalin injected paw and displayed smaller amplitudes of the nociceptive nasal mucosa potentials than wild-type mice (p=0.002 and 0.01 respectively). In contrast, withdrawal latencies on a hot plate did not significantly differ, suggesting that intracellular taurine deficits lead in particular to a hyposensitivity of nociceptive sensory neurons sensitive to noxious chemical stimulation. As hereditary absence of taurine affects biological processes of anatomical structure development, the altered nociceptive responses likely reflect consequences of compromised peripheral nervous system development.

  16. A Conus regularis Conotoxin with a Novel Eight-Cysteine Framework Inhibits CaV2.2 Channels and Displays an Anti-Nociceptive Activity

    PubMed Central

    Bernáldez, Johanna; Román-González, Sergio A.; Martínez, Oscar; Jiménez, Samanta; Vivas, Oscar; Arenas, Isabel; Corzo, Gerardo; Arreguín, Roberto; García, David E.; Possani, Lourival D.; Licea, Alexei

    2013-01-01

    A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40 amino acids and exhibits a novel arrangement of eight cysteine residues (C-C-C-C-CC-CC). Surprisingly, two loops of the novel peptide are highly identical to the amino acids sequence of ω-MVIIA. The total length and disulfide pairing of both peptides are quite different, although the two most important residues for the described function of ω-MVIIA (Lys2 and Tyr13) are also present in the peptide reported here. Electrophysiological analysis using superior cervical ganglion (SCG) neurons indicates that RsXXIVA inhibits CaV2.2 channel current in a dose-dependent manner with an EC50 of 2.8 μM, whose effect is partially reversed after washing. Furthermore, RsXXIVA was tested in hot-plate assays to measure the potential anti-nociceptive effect to an acute thermal stimulus, showing an analgesic effect in acute thermal pain at 30 and 45 min post-injection. Also, the toxin shows an anti-nociceptive effect in a formalin chronic pain test. However, the low affinity for CaV2.2 suggests that the primary target of the peptide could be different from that of ω-MVIIA. PMID:23567319

  17. Specific activation of the paralemniscal pathway during nociception.

    PubMed

    Frangeul, Laura; Porrero, Cesar; Garcia-Amado, Maria; Maimone, Benedetta; Maniglier, Madlyne; Clascá, Francisco; Jabaudon, Denis

    2014-05-01

    Two main neuronal pathways connect facial whiskers to the somatosensory cortex in rodents: (i) the lemniscal pathway, which originates in the brainstem principal trigeminal nucleus and is relayed in the ventroposterior thalamic nucleus and (ii) the paralemniscal pathway, originating in the spinal trigeminal nucleus and relayed in the posterior thalamic nucleus. While lemniscal neurons are readily activated by whisker contacts, the contribution of paralemniscal neurons to perception is less clear. Here, we functionally investigated these pathways by manipulating input from the whisker pad in freely moving mice. We report that while lemniscal neurons readily respond to neonatal infraorbital nerve sectioning or whisker contacts in vivo, paralemniscal neurons do not detectably respond to these environmental changes. However, the paralemniscal pathway is specifically activated upon noxious stimulation of the whisker pad. These findings reveal a nociceptive function for paralemniscal neurons in vivo that may critically inform context-specific behaviour during environmental exploration.

  18. Mechanical signalling in tissues and its possible role in nociception.

    PubMed

    Traverso, Silvano

    2011-01-01

    Mechanotransduction is known to play a key role in physiological as well as pathological processes. In the present work, the possibility is discussed that even weak mechanical signals travelling through the extracellular matrix can elicit significant cellular responses, by causing gel/sol transitions and actomyosin contractions. Such mechanical cues can result from both physiological activities, such as the heartbeat, and noxious stimuli to which tissues respond by rearranging the cells' cytoskeleton and remodelling the extracellular matrix. The possibility is explored that such viscoelastic modifications also affect the function of nociceptors, thus modulating pain transmission. Growing evidence indicates that the rearrangement of the axonal cytoskeleton represents a key step in nociception. Hyperalgesia is suggested to result from an exceedingly dynamical state of the nociceptor's cytoskeleton, which would lead to enhanced electrical conduction and synaptic facilitation.

  19. Sertraline inhibits formalin-induced nociception and cardiovascular responses

    PubMed Central

    Santuzzi, C.H.; Futuro Neto, H.A.; Pires, J.G.P.; Gonçalves, W.L.S.; Tiradentes, R.V.; Gouvea, S.A.; Abreu, G.R.

    2011-01-01

    The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8 per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg−1·day−1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5% (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7%), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9%, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism. PMID:22086464

  20. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks.

    PubMed

    Stankewitz, Anne; Aderjan, David; Eippert, Falk; May, Arne

    2011-02-01

    Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.

  1. A role for nociceptive, myelinated nerve fibers in itch sensation.

    PubMed

    Ringkamp, Matthias; Schepers, Raf J; Shimada, Steven G; Johanek, Lisa M; Hartke, Timothy V; Borzan, Jasenka; Shim, Beom; LaMotte, Robert H; Meyer, Richard A

    2011-10-19

    Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of nonhistaminergic mechanisms. To investigate the role of small myelinated afferents in nonhistaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: (1) a selective conduction block in myelinated fibers substantially reduces itch in a subgroup of subjects with A-fiber-dominated itch, (2) the time course of itch sensation differs between subjects with A-fiber- versus C-fiber-dominated itch, (3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, (4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, (5) the time of peak itch sensation for subjects with A-fiber-dominated itch matches the time for peak response in myelinated fibers, and (6) the time for peak itch sensation for subjects with C-fiber-dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that nonhistaminergic itch is mediated through activity in both unmyelinated and myelinated afferents. PMID:22016517

  2. Alternatives to mammalian pain models 2: using Drosophila to identify novel genes involved in nociception.

    PubMed

    Caldwell, Jason C; Tracey, W Daniel

    2010-01-01

    Identification of the molecules involved in nociception is fundamental to our understanding of pain. Drosophila, with its short generation time, powerful genetics and capacity for rapid, genome-wide mutagenesis, represents an ideal invertebrate model organism to dissect nociception. The fly has already been used to identify factors that are involved in other sensory systems such as vision, chemosensation, and audition. Thus, the tiny fruit fly is a viable alternative to mammalian model organisms. Here we present a brief primer on techniques used in screening for thermal and/or mechanical nociception mutants using Drosophila. PMID:20336410

  3. Long-term potentiation in spinal nociceptive systems--how acute pain may become chronic.

    PubMed

    Rygh, Lars Jørgen; Svendsen, Frode; Fiskå, Atle; Haugan, Frøydis; Hole, Kjell; Tjølsen, Arne

    2005-11-01

    Chronic pain is a major problem since it is difficult to treat and the understanding of the underlying neurobiology is sparse. The mechanisms underpinning the transition of acute into chronic pain remain unclear. However, long-term potentiation (LTP) in spinal nociceptive systems may be one such mechanism. Here, we briefly review the literature regarding LTP in spinal nociceptive systems including our own data on LTP in deep convergent nociceptive neurons. Furthermore, we discuss the role of this phenomenon in understanding the neurobiology of chronic pain and the possible therapeutic implications.

  4. A new look at arthritis management: nociceptive reflex excitability as a pain biomarker.

    PubMed

    Courtney, Carol A

    2015-01-01

    Research studies have begun to identify altered neurophysiological mechanisms that develop as a consequence of chronic painful knee arthritis. Neuroplastic changes may occur in nociceptive pathways, thereby contributing to heightened chronic pain and spread of symptoms, as well as diminished quality of life. One biomarker for examining central sensitization of nociceptive pathways is the measurement of flexion reflex excitability, also called the nociceptive reflex. In a recent article in Arthritis Research & Therapy, Rice and colleagues utilize this biomarker to analyze the clinical and neurophysiological effects of a very common and typical medical intervention, joint aspiration and intra-articular corticosteroid injection.

  5. Can crayfish take the heat? Procambarus clarkii show nociceptive behaviour to high temperature stimuli, but not low temperature or chemical stimuli

    PubMed Central

    Puri, Sakshi; Faulkes, Zen

    2015-01-01

    Nociceptors are sensory neurons that are tuned to tissue damage. In many species, nociceptors are often stimulated by noxious extreme temperatures and by chemical agonists that do not damage tissue (e.g., capsaicin and isothiocyanate). We test whether crustaceans have nociceptors by examining nociceptive behaviours and neurophysiological responses to extreme temperatures and potentially nocigenic chemicals. Crayfish (Procambarus clarkii) respond quickly and strongly to high temperatures, and neurons in the antenna show increased responses to transient high temperature stimuli. Crayfish showed no difference in behavioural response to low temperature stimuli. Crayfish also showed no significant changes in behaviour when stimulated with capsaicin or isothiocyanate compared to controls, and neurons in the antenna did not change their firing rate following application of capsaicin or isothiocyanate. Noxious high temperatures appear to be a potentially ecologically relevant noxious stimulus for crayfish that can be detected by sensory neurons, which may be specialized nociceptors. PMID:25819841

  6. Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids

    PubMed Central

    Staniaszek, LE; Norris, LM; Kendall, DA; Barrett, DA; Chapman, V

    2010-01-01

    Background and purpose: Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB1) receptors was determined. Experimental approach: Effects of spinal and peripheral administration of nimesulide (1–100 µg per 50 µL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB1 receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Key results: Spinal, but not peripheral, injection of nimesulide (1–100 µg per 50 µL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB1 receptor antagonist AM251 (1 µg per 50 µL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. Conclusions and implications: Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB1 receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to

  7. Pupillary responses to chromatic stimulus

    NASA Astrophysics Data System (ADS)

    Suaste-Gomez, Ernesto; Rodriguez Guzman, M. C. Ma. Dolores A.; Druzgalski, Christopher

    2000-06-01

    Pupillary responses of the subjects under chromatic visual stimulation were filmed with video-oculography systems (VOG). Specifically, programmable chromatic visual stimuli were displayed on the monitor of a personal computer (PC) and responses tested in several normal subjects and those with ophthalmic pathologic conditions. Visual excitation utilized a reversal stimulus checkerboard pattern. Image processing techniques were applied in order to evaluate the pupil variations due to chromatic stimulation. In particular, the studies determined a relationship between pupillary response (PR) and steady-state retinal sensitivity (photopic vision). Finally, the retinal illuminance in trolands (td), as a product of the pupil area in mm2 and luminance in cd/m2 to full-field chromatic stimulation (FFCS) and checkerboard pattern reversal chromatic stimulation (CPRCS) was determined.

  8. Poverty of the stimulus revisited.

    PubMed

    Berwick, Robert C; Pietroski, Paul; Yankama, Beracah; Chomsky, Noam

    2011-01-01

    A central goal of modern generative grammar has been to discover invariant properties of human languages that reflect "the innate schematism of mind that is applied to the data of experience" and that "might reasonably be attributed to the organism itself as its contribution to the task of the acquisition of knowledge" (Chomsky, 1971). Candidates for such invariances include the structure dependence of grammatical rules, and in particular, certain constraints on question formation. Various "poverty of stimulus" (POS) arguments suggest that these invariances reflect an innate human endowment, as opposed to common experience: Such experience warrants selection of the grammars acquired only if humans assume, a priori, that selectable grammars respect substantive constraints. Recently, several researchers have tried to rebut these POS arguments. In response, we illustrate why POS arguments remain an important source of support for appeal to a priori structure-dependent constraints on the grammars that humans naturally acquire.

  9. Stimulus Coding Rules for Perceptual Learning

    PubMed Central

    Klein, Stanley A; Levi, Dennis M; Yu, Cong

    2008-01-01

    Perceptual learning of visual features occurs when multiple stimuli are presented in a fixed sequence (temporal patterning), but not when they are presented in random order (roving). This points to the need for proper stimulus coding in order for learning of multiple stimuli to occur. We examined the stimulus coding rules for learning with multiple stimuli. Our results demonstrate that: (1) stimulus rhythm is necessary for temporal patterning to take effect during practice; (2) learning consolidation is subject to disruption by roving up to 4 h after each practice session; (3) importantly, after completion of temporal-patterned learning, performance is undisrupted by extended roving training; (4) roving is ineffective if each stimulus is presented for five or more consecutive trials; and (5) roving is also ineffective if each stimulus has a distinct identity. We propose that for multi-stimulus learning to occur, the brain needs to conceptually “tag” each stimulus, in order to switch attention to the appropriate perceptual template. Stimulus temporal patterning assists in tagging stimuli and switching attention through its rhythmic stimulus sequence. PMID:18707195

  10. Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature.

    PubMed

    Boada, M Danilo; Eisenach, James C; Ririe, Douglas G

    2016-01-01

    The ability to distinguish mechanical from thermal input is a critical component of peripheral somatosensory function. Polymodal C fibers respond to both stimuli. However, mechanosensitive, modality-specific fast-conducting tactile and nociceptor afferents theoretically carry information only about mechanical forces independent of the thermal environment. We hypothesize that the thermal environment can nonetheless modulate mechanical force sensibility in fibers that do not respond directly to change in temperature. To study this, fast-conducting mechanosensitive peripheral sensory fibers in male Sprague-Dawley rats were accessed at the soma in the dorsal root ganglia from T11 or L4/L5. Neuronal identification was performed using receptive field characteristics and passive and active electrical properties. Neurons responded to mechanical stimuli but failed to generate action potentials in response to changes in temperature alone, except for the tactile mechanical and cold sensitive neurons. Heat and cold ramps were utilized to determine temperature-induced modulation of response to mechanical stimuli. Mechanically evoked electrical activity in non-nociceptive, low-threshold mechanoreceptors (tactile afferents) decreased in response to changes in temperature while mechanically induced activity was increased in nociceptive, fast-conducting, high-threshold mechanoreceptors in response to the same changes in temperature. These data suggest that mechanical activation does not occur in isolation but rather that temperature changes appear to alter mechanical afferent activity and input to the central nervous system in a dynamic fashion. Further studies to understand the psychophysiological implications of thermal modulation of fast-conducting mechanical input to the spinal cord will provide greater insight into the implications of these findings. PMID:26581873

  11. Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature.

    PubMed

    Boada, M Danilo; Eisenach, James C; Ririe, Douglas G

    2016-01-01

    The ability to distinguish mechanical from thermal input is a critical component of peripheral somatosensory function. Polymodal C fibers respond to both stimuli. However, mechanosensitive, modality-specific fast-conducting tactile and nociceptor afferents theoretically carry information only about mechanical forces independent of the thermal environment. We hypothesize that the thermal environment can nonetheless modulate mechanical force sensibility in fibers that do not respond directly to change in temperature. To study this, fast-conducting mechanosensitive peripheral sensory fibers in male Sprague-Dawley rats were accessed at the soma in the dorsal root ganglia from T11 or L4/L5. Neuronal identification was performed using receptive field characteristics and passive and active electrical properties. Neurons responded to mechanical stimuli but failed to generate action potentials in response to changes in temperature alone, except for the tactile mechanical and cold sensitive neurons. Heat and cold ramps were utilized to determine temperature-induced modulation of response to mechanical stimuli. Mechanically evoked electrical activity in non-nociceptive, low-threshold mechanoreceptors (tactile afferents) decreased in response to changes in temperature while mechanically induced activity was increased in nociceptive, fast-conducting, high-threshold mechanoreceptors in response to the same changes in temperature. These data suggest that mechanical activation does not occur in isolation but rather that temperature changes appear to alter mechanical afferent activity and input to the central nervous system in a dynamic fashion. Further studies to understand the psychophysiological implications of thermal modulation of fast-conducting mechanical input to the spinal cord will provide greater insight into the implications of these findings.

  12. Role of serotonin in the discriminative stimulus properties of mescaline.

    PubMed

    Browne, R G; Ho, B T

    1975-01-01

    Rats were trained to discriminate intraperitoneally administered mescaline from saline in a two-lever operant chamber for food reinforcement. Reward was contingent upon responses made greater than 15 sec apart (DRL-15) on the appropriate lever paired with either drug or saline administration. Following the establishment of discriminative response control by mescaline, the animals were tested for stimulus generalization produced by mescaline after: (a) blockade of periphreral and central serotonin (5-HT) receptors with cinanserin, methysergide, or cyproheptadine; (b) blockade of peripheral 5-HT receptors with xylamidine tosylate; and (c) depletion of brain 5-HT with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA). The results show that all three central 5-HT antagonists greatly reduced the discriminability of mescaline while the peripheral antagonist, xylamidine tosylate, was without effect. Furthermore, these agents at the doses employed did not effect the discriminability of saline. Depletion of 5-HT with PCPA potentiated the effects of a sub-threshold dose of mescaline and slightly reduced the discriminability of saline. The results indicate that mescaline produces its discriminative stimulus properties by directly stimulating central serotonergic receptors.

  13. The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation

    PubMed Central

    Inutsuka, Ayumu; Yamashita, Akira; Chowdhury, Srikanta; Nakai, Junichi; Ohkura, Masamichi; Taguchi, Toru; Yamanaka, Akihiro

    2016-01-01

    The level of wakefulness is one of the major factors affecting nociception and pain. Stress-induced analgesia supports an animal’s survival via prompt defensive responses against predators or competitors. Previous studies have shown the pharmacological effects of orexin peptides on analgesia. However, orexin neurons contain not only orexin but also other co-transmitters such as dynorphin, neurotensin and glutamate. Thus, the physiological importance of orexin neuronal activity in nociception is unknown. Here we show that adult-stage selective ablation of orexin neurons enhances pain-related behaviors, while pharmacogenetic activation of orexin neurons induces analgesia. Additionally, we found correlative activation of orexin neurons during nociception using fiber photometry recordings of orexin neurons in conscious animals. These findings suggest an integrative role for orexin neurons in nociceptive perception and pain regulation. PMID:27385517

  14. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons.

    PubMed

    Cho, Hawon; Yang, Young Duk; Lee, Jesun; Lee, Byeongjoon; Kim, Tahnbee; Jang, Yongwoo; Back, Seung Keun; Na, Heung Sik; Harfe, Brian D; Wang, Fan; Raouf, Ramin; Wood, John N; Oh, Uhtaek

    2012-05-27

    Nociceptors are a subset of small primary afferent neurons that respond to noxious chemical, thermal and mechanical stimuli. Ion channels in nociceptors respond differently to noxious stimuli and generate electrical signals in different ways. Anoctamin 1 (ANO1 also known as TMEM16A) is a Ca(2+)-activated chloride channel that is essential for numerous physiological functions. We found that ANO1 was activated by temperatures over 44 °C with steep heat sensitivity. ANO1 was expressed in small sensory neurons and was highly colocalized with nociceptor markers, which suggests that it may be involved in nociception. Application of heat ramps to dorsal root ganglion (DRG) neurons elicited robust ANO1-dependent depolarization. Furthermore, knockdown or deletion of ANO1 in DRG neurons substantially reduced nociceptive behavior in thermal pain models. These results indicate that ANO1 is a heat sensor that detects nociceptive thermal stimuli in sensory neurons and possibly mediates nociception.

  15. Heart rate variability analysis as an index of emotion regulation processes: interest of the Analgesia Nociception Index (ANI).

    PubMed

    De Jonckheere, J; Rommel, D; Nandrino, J L; Jeanne, M; Logier, R

    2012-01-01

    Autonomic Nervous System (ANS) variations are strongly influence by emotion regulation processes. Indeed, emotional stimuli are at the origin of an activation of the ANS and the way an individual pass from a state of alert in the case of emotional situation to a state of calm is closely coupled with the ANS flexibility. We have previously described and developed an Analgesia Nociception Index (ANI) for real time pain measurement during surgical procedure under general anesthesia. This index, based on heart rate variability analysis, constitutes a measure of parasympathetic tone and can be used in several other environments. In this paper, we hypothesized that such an index could be used as a tool to investigate the processes of emotional regulation of a human subject. To test this hypothesis, we analyzed ANI's response to a negative emotional stimulus. This analysis showed that the index decreases during the emotion induction phase and returns to its baseline after 2 minutes. This result confirms that ANI could be a good indicator of parasympathetic changes in emotional situation.

  16. Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: prevalence and associated factors.

    PubMed

    Curatolo, Michele; Müller, Monika; Ashraf, Aroosiah; Neziri, Alban Y; Streitberger, Konrad; Andersen, Ole K; Arendt-Nielsen, Lars

    2015-11-01

    Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10th percentile cutoff of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% confidence interval) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As a secondary aim, we analyzed demographic, psychosocial, and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference, and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of sociodemographic, psychological, and clinical pain-related characteristics.

  17. Distribution and Properties of Visceral Nociceptive Neurons in Rabbit Cingulate Cortex

    PubMed Central

    Sikes, Robert W.; Vogt, Leslie J.; Vogt, Brent A.

    2008-01-01

    Human imaging localizes most visceral nociceptive responses to anterior cingulate cortex (ACC), however, imaging in conscious subjects cannot completely control anticipatory and reflexive activity or resolve neuron activity. This study overcame these shortcomings by recording individual neuron responses in 12 anesthetized and paralyzed rabbits to define the visceronociceptive response pattern by region and layer. Balloon distension was applied to the colon at innocuous (15 mmHg) or noxious (60 mmHg) intensities, and innocuous and noxious mechanical, thermal and electrical stimuli were applied to the skin. Simultaneous recording from multiple regions assured differences were not due to anesthesia and neuron responses were resolved by spike sorting using principal components analysis. Of the total 346 neurons, 48% were nociceptive; responding to noxious levels of visceral or cutaneous stimulation, or both. Visceronociceptive neurons were most frequent in ACC (39%) and midcingulate cortex (MCC, 36%) and infrequent in retrosplenial cortex (RSC, 12%). In contrast, cutaneous nociceptive units were higher in MCC (MCC, 43%; ACC, 32%; RSC, 23%). Visceral-specific neurons were proportionately more frequent in ACC (37%), while cutaneous-specific units predominated in RSC (62.5%). Visceral nociceptive response durations were longer than those for cutaneous responses. Postmortem analysis of electrode tracks confirmed regional designations, and laminar analysis found inhibitory responses mainly in superficial layers and excitatory in deep layers. Thus, cingulate visceral nociception extends beyond ACC, this is the first report of nociceptive activity in RSC including nociceptive cutaneous responses, and these regional differences require a new model of cingulate nociceptive processing. PMID:18022321

  18. The peripheral pro-nociceptive state induced by repetitive inflammatory stimuli involves continuous activation of protein kinase A and protein kinase C epsilon and its Na(V)1.8 sodium channel functional regulation in the primary sensory neuron.

    PubMed

    Villarreal, Cristiane Flora; Sachs, Daniela; Funez, Mani Indiana; Parada, Carlos Amílcar; de Queiroz Cunha, Fernando; Ferreira, Sérgio Henrique

    2009-03-01

    In the present study, the participation of the Na(V)1.8 sodium channel was investigated in the development of the peripheral pro-nociceptive state induced by daily intraplantar injections of PGE(2) in rats and its regulation in vivo by protein kinase A (PKA) and protein kinase C epsilon (PKCvarepsilon) as well. In the prostaglandin E(2) (PGE(2))-induced persistent hypernociception, the Na(V)1.8 mRNA in the dorsal root ganglia (DRG) was up-regulated. The local treatment with dipyrone abolished this persistent hypernociception but did not alter the Na(V)1.8 mRNA level in the DRG. Daily intrathecal administrations of antisense Na(V)1.8 decreased the Na(V)1.8 mRNA in the DRG and reduced ongoing persistent hypernociception. Once the persistent hypernociception had been abolished by dipyrone, but not by Na(V)1.8 antisense treatment, a small dose of PGE(2) restored the hypernociceptive plateau. These data show that, after a period of recurring inflammatory stimuli, an intense and prolonged nociceptive response is elicited by a minimum inflammatory stimulus and that this pro-nociceptive state depends on Na(V)1.8 mRNA up-regulation in the DRG. In addition, during the persistent hypernociceptive state, the PKA and PKCvarepsilon expression and activity in the DRG are up-regulated and the administration of the PKA and PKCvarepsilon inhibitors reduce the hypernociception as well as the Na(V)1.8 mRNA level. In the present study, we demonstrated that the functional regulation of the Na(V)1.8 mRNA by PKA and PKCvarepsilon in the primary sensory neuron is important for the development of the peripheral pro-nociceptive state induced by repetitive inflammatory stimuli and for the maintenance of the behavioral persistent hypernociception. PMID:19073148

  19. Investigation of Stimulus-Response Compatibility Using a Startling Acoustic Stimulus

    ERIC Educational Resources Information Center

    Maslovat, Dana; Carlsen, Anthony N.; Franks, Ian M.

    2012-01-01

    We investigated the processes underlying stimulus-response compatibility by using a lateralized auditory stimulus in a simple and choice reaction time (RT) paradigm. Participants were asked to make either a left or right key lift in response to either a control (80dB) or startling (124dB) stimulus presented to either the left ear, right ear, or…

  20. An Evaluation of the Number of Presentations of Target Sounds during Stimulus-Stimulus Pairing Trials

    ERIC Educational Resources Information Center

    Miliotis, Adriane; Sidener, Tina M.; Reeve, Kenneth F.; Carbone, Vincent; Sidener, David W.; Rader, Lisa; Delmolino, Lara

    2012-01-01

    Stimulus-stimulus pairing (SSP) of vocalizations pairs the speech of others with the delivery of highly preferred items. The goal of this procedure is to produce a temporary increase in vocalizations, thus creating a larger variety of sounds that can subsequently be brought under appropriate stimulus control (Esch, Carr, & Grow, 2009). In this…

  1. Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids

    PubMed Central

    Ringel, Amit; Majchrzak-Hong, Sharon F; Yang, Jun; Blanchard, Helene; Zamora, Daisy; Loewke, James D; Rapoport, Stanley I; Hibbeln, Joseph R; Davis, John M; Hammock, Bruce D; Taha, Ameer Y

    2016-01-01

    Background Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. Results Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. Conclusions The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes. PMID:27030719

  2. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

    PubMed Central

    Zambelli, Vanessa O.; Gross, Eric R.; Chen, Che-Hong; Gutierrez, Vanessa P.; Cury, Yara; Mochly-Rosen, Daria

    2014-01-01

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase 2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R2=0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than wild-type mice. Finally, Alda-1 treatment was also beneficial when given even after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians’ apparent lower pain tolerance. PMID:25163478

  3. Antinociceptive Effects of Prim-O-Glucosylcimifugin in Inflammatory Nociception via Reducing Spinal COX-2

    PubMed Central

    Wu, Liu-Qing; Li, Yu; Li, Yuan-Yan; Xu, Shi-hao; Yang, Zong-Yong; Lin, Zheng; Li, Jun

    2016-01-01

    We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund’s adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an ED50 of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNFα, IL-1β and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 (PGE2). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression. PMID:27257008

  4. Stimulus Probability Effects in Absolute Identification

    ERIC Educational Resources Information Center

    Kent, Christopher; Lamberts, Koen

    2016-01-01

    This study investigated the effect of stimulus presentation probability on accuracy and response times in an absolute identification task. Three schedules of presentation were used to investigate the interaction between presentation probability and stimulus position within the set. Data from individual participants indicated strong effects of…

  5. Some determinants of inhibitory stimulus control.

    PubMed

    Weisman, R G

    1969-05-01

    Interspersed reinforcement and extinction during discrimination learning generate a U-shaped gradient of inhibition about the stimulus correlated with extinction. The present work showed that extinction is not a necessary determinant of inhibitory stimulus control. In Exp. I, a reduction in the rate of reinforcement, through a shift from a multiple variable-interval 1-min variable-interval 1-min schedule to a multiple variable-interval 1-min variable-interval 5-min schedule, resulted in a post-discrimination line orientation gradient of inhibition about the stimulus correlated with the variable-interval 5-min schedule. In Exp. II, the rates of reinforcement, correlated with a pair of stimuli, were held constant during a shift from a multiple variable-interval 1-min variable-interval 1-min schedule to a multiple variable-interval 1-min differential-reinforcement-of-low-rate schedule. Inhibitory stimulus control about the stimulus correlated with the differential reinforcement of low rate was obtained. In both experiments, a reduction in the rate of responding during one stimulus and behavioral contrast during the other stimulus preceded the observation of inhibitory stimulus control.

  6. Stimulus Intensity and the Perception of Duration

    ERIC Educational Resources Information Center

    Matthews, William J.; Stewart, Neil; Wearden, John H.

    2011-01-01

    This article explores the widely reported finding that the subjective duration of a stimulus is positively related to its magnitude. In Experiments 1 and 2 we show that, for both auditory and visual stimuli, the effect of stimulus magnitude on the perception of duration depends upon the background: Against a high intensity background, weak stimuli…

  7. Why Additional Presentations Help Identify a Stimulus

    ERIC Educational Resources Information Center

    Guest, Duncan; Kent, Christopher; Adelman, James S.

    2010-01-01

    Nosofsky (1983) reported that additional stimulus presentations within a trial increase discriminability in absolute identification, suggesting that each presentation creates an independent stimulus representation, but it remains unclear whether exposure duration or the formation of independent representations improves discrimination in such…

  8. Development of a canine nociceptive thermal escape model.

    PubMed

    Wegner, Kirsten; Horais, Kjersti A; Tozier, Nicolle A; Rathbun, Michael L; Shtaerman, Yuri; Yaksh, Tony L

    2008-02-15

    Acute nociceptive models which have been validated for large animal species are limited, yet nociceptive assessment in non-rodent species is important in analgesic drug development where larger animals may be necessary because of the technical requirements of the study. Here we report development and validation of a canine hind paw thermal escape model and the effect of analgesics on withdrawal latencies. Individual focused projection bulbs were used as left and right voltage-adjusted thermal stimuli placed below a glass plate in a specifically designed canine holding apparatus. After acclimation, dogs were lightly restrained in a fabric sling while standing on the glass plate. The anterior center of the metatarsal pad of the left and right hind paw was positioned on the glass over each light, and duration of stimulation tolerance timed. For every trial, the escape latency from lamp actuation to paw withdrawal was recorded twice for each hind paw. The mean population baseline withdrawal latency of 9.3+/-1.7s (mean+/-S.D., n=12 dogs) was shown to be repeatable between paws, within and between individual animals, and between test days. This latency corresponded to a glass surface temperature of 49.5 degrees C. A cut-off time of 20s (corresponding to a glass surface temperature of 56.5 degrees C) was set to prevent tissue damage. Intravenous administration (mg/kg) of morphine (1.0), hydromorphone (0.2), butorphanol (0.4), fentanyl (0.01), and dexmedetomidine (0.01) significantly (p<0.05) increased withdrawal latency from baseline within 15-30 min of administration while buprenorphine (0.03) produced a delayed, modest but significant latency increase. Rank order of opioid analgesic duration was morphine=hydromorphone>butorphanol>bupenorphine>fentanyl=saline. A dose-effect curve for hydromorphone was generated and corresponded to previously described dose-effect relationships in other species. The non-analgesic tranquilizer acepromazine (0.1mg/kg) produced mild sedation

  9. Quantitative and methodological aspects of stimulus equivalence.

    PubMed

    O'mara, H

    1991-01-01

    The number of different ways of linking stimuli in the training phase of a conditional discrimination procedure designed to teach equivalence relations has hitherto been underestimated. An algorithm from graph theory that produces the correct number of such different ways is given. The establishment of equivalence relations requires transitive stimulus control. A misconception in a previous analysis of the conditions necessary for demonstrating transitive stimulus control is indicated. This misconception concerns responding in an unreinforced test trial to a negative rather than a positive comparison stimulus. Such behavior cannot be attributed to discriminative control by degree of association with reinforcement if the negative comparison stimulus has been less associated with reinforcement than the positive comparison stimulus in an antecedent training phase.

  10. The stimulus integration area for horizontal vergence.

    PubMed

    Allison, Robert S; Howard, Ian P; Fang, Xueping

    2004-06-01

    Over what region of space are horizontal disparities integrated to form the stimulus for vergence? The vergence system might be expected to respond to disparities within a small area of interest to bring them into the range of precise stereoscopic processing. However, the literature suggests that disparities are integrated over a fairly large parafoveal area. We report the results of six experiments designed to explore the spatial characteristics of the stimulus for vergence. Binocular eye movements were recorded using magnetic search coils. Each dichoptic display consisted of a central target stimulus that the subject attempted to fuse, and a competing stimulus with conflicting disparity. In some conditions the target was stationary, providing a fixation stimulus. In other conditions, the disparity of the target changed to provide a vergence-tracking stimulus. The target and competing stimulus were combined in a variety of conditions including those in which (1) a transparent textured-disc target was superimposed on a competing textured background, (2) a textured-disc target filled the centre of a competing annular background, and (3) a small target was presented within the centre of a competing annular background of various inner diameters. In some conditions the target and competing stimulus were separated in stereoscopic depth. The results are consistent with a disparity integration area with a diameter of about 5 degrees. Stimuli beyond this integration area can drive vergence in their own right, but they do not appear to be summed or averaged with a central stimulus to form a combined disparity signal. A competing stimulus had less effect on vergence when separated from the target by a disparity pedestal. As a result, we propose that it may be more useful to think in terms of an integration volume for vergence rather than a two-dimensional retinal integration area. PMID:14985895

  11. Stimulus-response coupling in platelets

    SciTech Connect

    Huang, E.M.

    1986-01-01

    To understand the mechanism of stimulus-response coupling in platelets, the potentiating effect of succinate and lithium on platelet activation was examined. The action of succinate was immediate; preincubation with succinate did not lead to desensitization. Succinate was comparable to ADP in lowering cAMP levels previously elevated by PGl/sub 2/. Since inhibition of cAMP is not a prerequisite for platelet activation, the mechanism of potentiation of succinate remains undefined. Lithium has also been shown to inhibit adenylate cyclase in PGl/sub 2/-pretreated platelets. Lithium, however, can also inhibit inositol phosphate (InsP) phosphatase and lead to an accumulation of InsP. In human platelets, lithium also enhanced the thrombin-induced accumulation of (/sup 3/H)inositol-labelled inositol trisphosphate (InsP/sub 3/), and inositol bisphosphate (InsP/sub 2/). One hour after thrombin addition, all 3 inositol phosphates returned to near basal levels. In the presence of lithium, while labelled InsP/sub 2/ and InsP/sub 3/ returned to their respective basal levels, the InsP level remained elevated, consistent with the known inhibitory effect of lithium on InsP phosphatase. In thrombin-stimulated platelets prelabeled with (/sup 32/P)phosphate, lithium led to a decrease in labelled phosphatidylinositol 4-phosphate (PtdIns4P) as well as an enhanced production of labelled lysophosphatidylinositol, suggesting multiple effects of lithium on platelet phosphoinositide metabolism. These observed effects, however, occurred too slowly to be the mechanism by which lithium potentiated agonist-induced platelet activation. To study the agonist-receptor interaction, the effect of the specific, high affinity thrombin inhibitor, hirudin, on thrombin-induced accumulation of (/sup 3/H)inositol-labelled inositol phosphates was studied.

  12. Keratinocytes can modulate and directly initiate nociceptive responses

    PubMed Central

    Baumbauer, Kyle M; DeBerry, Jennifer J; Adelman, Peter C; Miller, Richard H; Hachisuka, Junichi; Lee, Kuan Hsien; Ross, Sarah E; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M

    2015-01-01

    How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing. DOI: http://dx.doi.org/10.7554/eLife.09674.001 PMID:26329459

  13. Thermal nociceptive properties of trigeminal afferent neurons in rats

    PubMed Central

    2010-01-01

    Background Although nociceptive afferents innervating the body have been heavily studied form many years, much less attention has been paid to trigeminal afferent biology. In particular, very little is known concerning trigeminal nociceptor responses to heat, and almost nothing in the rat. This study uses a highly controlled and reproducible diode laser stimulator to investigate the activation of trigeminal afferents to noxious skin heating. Results The results of this experiment demonstrate that trigeminal thermonociceptors are distinct from themonociceptors innervating the limbs. Trigeminal nociceptors have considerably slower action potential conduction velocities and lower temperature thresholds than somatic afferent neurons. On the other hand, nociceptors innervating both tissue areas separate into those that respond to short pulse, high rate skin heating and those that respond to long pulse, low rate skin heating. Conclusions This paper provides the first description in the literature of the in vivo properties of thermonociceptors in rats. These finding of two separate populations aligns with the separation between C and A-delta thermonociceptors innervating the paw, but have significant differences in terms of temperature threshold and average conduction velocities. An understanding of the temperature response properties of afferent neurons innervating the paw skin have been critical in many mechanistic discoveries, some leading to new pain therapies. A clear understanding of trigeminal nociceptors may be similarly useful in the investigation of trigeminal pain mechanisms and potential therapies. PMID:20609212

  14. Pregabalin modulation of spinal and brainstem visceral nociceptive processing.

    PubMed

    Sikandar, Shafaq; Dickenson, Anthony H

    2011-10-01

    Brainstem and spinal mechanisms mediating visceral nociception are investigated here using electrophysiology and immunohistochemistry techniques in a model of acute visceral pain. Colorectal distension (CRD) produced graded visceromotor responses (VMR) in normal rats, and these were facilitated by intracolonic mustard oil (MO) that generated acute visceral hyperalgesia. The neuropathic pain drug pregabalin (PGB) is thought to have state-dependent effects in attenuating neuropathic, but not acute somatic pain, likely by impairing calcium-channel trafficking. We found that systemic PGB produced antinociceptive effects on CRD-evoked VMRs in naïve rats lacking pathophysiology and in MO-pretreated rats. Systemic PGB also significantly reduced Fos labelling in lumbosacral spinal cords of rats given noxious repetitive CRD; however, PGB did not alter this measure of neural activity in the brainstem. Differential brainstem processing of noxious somatic and visceral stimuli may underlie the unique lack of state-dependent actions of PGB in this visceral pain model. Single-unit recordings in the rostral ventromedial medulla (RVM) verify that brainstem processing of somatic and visceral stimuli differs. The effects of CRD on RVM cells classed as ON, OFF, or NEUTRAL were independent of their somatic responses, with surprising changes in RVM cell activity to innocuous visceral stimulation. PGB also markedly reduced the visceral responses of RVM ON-cells to noxious CRD. These results illustrate clear differences in the central processing of visceral and somatic stimuli, yet a common role for descending modulation by brainstem activity in mediating evoked pain measures.

  15. Stimulus-dependent refractoriness in the Frankenhaeuser-Huxley model.

    PubMed

    Morse, R P; Allingham, D; Stocks, N G

    2015-10-01

    Phenomenological neural models, such as the leaky integrate-and-fire model, normally have a fixed refractory time-course that is independent of the stimulus. The recovery of threshold following an action potential is typically based on physiological experiments that use a two-pulse paradigm in which the first pulse is suprathreshold and causes excitation and the second pulse is used to determine the threshold at various intervals following the first. In such experiments, the nerve is completely unstimulated between the two pulses. This contrasts the receptor stimuli in normal physiological systems and the electrical stimuli used by cochlear implants and other neural prostheses. A numerical study of the Frankenhaeuser-Huxley conductance-based model of nerve fibre was therefore undertaken to investigate the effect of stimulation on refractoriness. We found that the application of a depolarizing stimulus during the later part of what is classically regarded as the absolute refractory period could effectively prolong the absolute refractory period, while leaving the refractory time-constants and other refractory parameters largely unaffected. Indeed, long depolarizing pulses, which would have been suprathreshold if presented to a resting nerve fibre, appeared to block excitation indefinitely. Stimulation during what is classically regarded as the absolute refractory period can therefore greatly affect the temporal response of a nerve. We conclude that the classical definition of absolute refractory period should be refined to include only the initial period following an action potential when an ongoing stimulus would not affect threshold; this period was found to be about half as long as the classical absolute refractory period. We further conclude that the stimulus-dependent nature of the relative refractory period must be considered when developing a phenomenological nerve model for complex stimuli.

  16. Stimulus-dependent refractoriness in the Frankenhaeuser-Huxley model.

    PubMed

    Morse, R P; Allingham, D; Stocks, N G

    2015-10-01

    Phenomenological neural models, such as the leaky integrate-and-fire model, normally have a fixed refractory time-course that is independent of the stimulus. The recovery of threshold following an action potential is typically based on physiological experiments that use a two-pulse paradigm in which the first pulse is suprathreshold and causes excitation and the second pulse is used to determine the threshold at various intervals following the first. In such experiments, the nerve is completely unstimulated between the two pulses. This contrasts the receptor stimuli in normal physiological systems and the electrical stimuli used by cochlear implants and other neural prostheses. A numerical study of the Frankenhaeuser-Huxley conductance-based model of nerve fibre was therefore undertaken to investigate the effect of stimulation on refractoriness. We found that the application of a depolarizing stimulus during the later part of what is classically regarded as the absolute refractory period could effectively prolong the absolute refractory period, while leaving the refractory time-constants and other refractory parameters largely unaffected. Indeed, long depolarizing pulses, which would have been suprathreshold if presented to a resting nerve fibre, appeared to block excitation indefinitely. Stimulation during what is classically regarded as the absolute refractory period can therefore greatly affect the temporal response of a nerve. We conclude that the classical definition of absolute refractory period should be refined to include only the initial period following an action potential when an ongoing stimulus would not affect threshold; this period was found to be about half as long as the classical absolute refractory period. We further conclude that the stimulus-dependent nature of the relative refractory period must be considered when developing a phenomenological nerve model for complex stimuli. PMID:26187096

  17. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury

    PubMed Central

    Stuck, Ellen D.; Irvine, Karen-Amanda; Bresnahan, Jacqueline C.

    2015-01-01

    Abstract Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity. PMID:26668821

  18. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

    PubMed

    Huie, J Russell; Stuck, Ellen D; Lee, Kuan H; Irvine, Karen-Amanda; Beattie, Michael S; Bresnahan, Jacqueline C; Grau, James W; Ferguson, Adam R

    2015-01-01

    Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.

  19. Adaptive stimulus optimization for sensory systems neuroscience.

    PubMed

    DiMattina, Christopher; Zhang, Kechen

    2013-01-01

    In this paper, we review several lines of recent work aimed at developing practical methods for adaptive on-line stimulus generation for sensory neurophysiology. We consider various experimental paradigms where on-line stimulus optimization is utilized, including the classical optimal stimulus paradigm where the goal of experiments is to identify a stimulus which maximizes neural responses, the iso-response paradigm which finds sets of stimuli giving rise to constant responses, and the system identification paradigm where the experimental goal is to estimate and possibly compare sensory processing models. We discuss various theoretical and practical aspects of adaptive firing rate optimization, including optimization with stimulus space constraints, firing rate adaptation, and possible network constraints on the optimal stimulus. We consider the problem of system identification, and show how accurate estimation of non-linear models can be highly dependent on the stimulus set used to probe the network. We suggest that optimizing stimuli for accurate model estimation may make it possible to successfully identify non-linear models which are otherwise intractable, and summarize several recent studies of this type. Finally, we present a two-stage stimulus design procedure which combines the dual goals of model estimation and model comparison and may be especially useful for system identification experiments where the appropriate model is unknown beforehand. We propose that fast, on-line stimulus optimization enabled by increasing computer power can make it practical to move sensory neuroscience away from a descriptive paradigm and toward a new paradigm of real-time model estimation and comparison.

  20. Adaptive stimulus optimization for sensory systems neuroscience

    PubMed Central

    DiMattina, Christopher; Zhang, Kechen

    2013-01-01

    In this paper, we review several lines of recent work aimed at developing practical methods for adaptive on-line stimulus generation for sensory neurophysiology. We consider various experimental paradigms where on-line stimulus optimization is utilized, including the classical optimal stimulus paradigm where the goal of experiments is to identify a stimulus which maximizes neural responses, the iso-response paradigm which finds sets of stimuli giving rise to constant responses, and the system identification paradigm where the experimental goal is to estimate and possibly compare sensory processing models. We discuss various theoretical and practical aspects of adaptive firing rate optimization, including optimization with stimulus space constraints, firing rate adaptation, and possible network constraints on the optimal stimulus. We consider the problem of system identification, and show how accurate estimation of non-linear models can be highly dependent on the stimulus set used to probe the network. We suggest that optimizing stimuli for accurate model estimation may make it possible to successfully identify non-linear models which are otherwise intractable, and summarize several recent studies of this type. Finally, we present a two-stage stimulus design procedure which combines the dual goals of model estimation and model comparison and may be especially useful for system identification experiments where the appropriate model is unknown beforehand. We propose that fast, on-line stimulus optimization enabled by increasing computer power can make it practical to move sensory neuroscience away from a descriptive paradigm and toward a new paradigm of real-time model estimation and comparison. PMID:23761737

  1. Nociception- and anxiety-like behavior in rats submitted to different periods of restraint stress.

    PubMed

    Gameiro, Gustavo Hauber; Gameiro, Paula Hauber; Andrade, Annicele da Silva; Pereira, Lígia Ferrinho; Arthuri, Mariana Trevisani; Marcondes, Fernanda Klein; Veiga, Maria Cecília Ferraz de Arruda

    2006-04-15

    The aim of this study was to evaluate the effect of acute, sub-chronic and chronic stress on nociception induced by formalin injection in rats' temporomandibular joint (TMJ). It was evaluated the relation between blood levels of adrenocorticotropin, corticosterone, the levels of anxiety and nociceptive responses recorded after different stress protocols. Animals were initially submitted to acute restraint stress (15; 30 min and 1 h), or exposed to sub-chronic (3 days-1 h/day) or chronic stress (40 days-1 h/day). Then, animals were (1) killed immediately to collect blood for hormonal determinations; or (2) submitted to the elevated plus-maze to evaluate anxiety; or (3) submitted to the TMJ formalin test to evaluate nociception. It was also evaluated the role of serotoninergic and opioid systems in nociceptive changes induced by stress. For this, the serotonin-selective reuptake inhibitor (fluoxetine 10 mg/kg) and the opioid agonist (morphine 1-5 mg/kg) were administered before the nociception test. All stress protocols significantly raised the levels of ACTH or corticosterone, as well as the anxiety behavior. In relation to nociception, the chronic stressed animals showed an increase in nociceptive responses (hyperalgesia). In this group, there was a reduction in the morphine analgesic effects, suggesting dysfunction in the endogenous opioid system. Fluoxetine had an analgesic effect in both stressed and control groups, although this effect was more evident in the stressed group. It was concluded that stress-induced hyperalgesia may result from changes in the serotoninergic and opioid systems, which can explain, at least in part, the important link between stress and orofacial pain. PMID:16488452

  2. Evaluation of mechanical and thermal nociception as objective tools to measure painful and nonpainful lameness phases in multiparous sows.

    PubMed

    Mohling, C M; Johnson, A K; Coetzee, J F; Karriker, L A; Stalder, K J; Abell, C E; Tyler, H D; Millman, S T

    2014-07-01

    The objective of this study was to quantify pain sensitivity differences using mechanical nociception threshold (MNT) and thermal nociception threshold (TNT) tests when sows were in painful and nonpainful transient lameness phases. A total of 24 mixed parity crossbred sows (220.15 ± 21.23 kg) were utilized for the MNT test, and a total of 12 sows (211.41 ± 20.21 kg) were utilized for the TNT test. On induction day (D0), all sows were anesthetized and injected with Amphotericin B (10mg/mL) in the distal interphalangeal joint space in both claws of one randomly selected hind limb to induce transient lameness. Three days were compared: (1) D-1 (sound phase, defined as 1 d before induction), (2) D+1 (most lame phase, defined as 1 d after induction), and (3) D+6 (resolution phase, defined as 6 d after induction). After completion of the first round, sows were given a 7-d rest period and then the procedures were repeated with lameness induced in the contralateral hind limb. During the MNT test, pressure was applied perpendicularly to 3 landmarks in a randomized sequence for each sow: 1) middle of cannon on the hind limb (cannon), 2) 1 cm above the coronary band on the medial hind claw (medial claw), and 3) 1 cm above the coronary band on the lateral hind claw (lateral claw). During the TNT test, a radiant heat stimulus was directed 1 cm above the coronary band. The data were analyzed using the MIXED procedure in SAS with sow as the experimental unit. Differences were analyzed between sound and lame limbs on each day. For the MNT test, pressure tolerated by the lame limb decreased for every landmark (P < 0.05) when comparing D-1 and D+1. The sound limb tolerated more pressure on D+1 and D+6 than on baseline D-1 (P < 0.05). Thermal stimulation tolerated by the sound limb did not change over the 3 d (P > 0.05). However, the sows tolerated less heat stimulation on their lame limb on D+1 compared to D-1 levels (P < 0.05). Both MNT and TNT tests indicated greater pain

  3. On the development of stimulus control.

    PubMed

    Heinemann, E G; Avin, E

    1973-09-01

    Pigeons were trained to peck one key when presented with white noise at any of five intensities lower than a reference intensity, and to peck another key when presented with white noise at any of five intensities greater than the reference intensity. The shape of the stimulus control curves (proportion of responses to one key versus stimulus intensity) changed from a horizontal line at the beginning of training to the sigmoid form of typical psychometric functions at the end of training. The development of stimulus control is described in terms of a model based on the theory of signal recognition and a concept of attention.

  4. The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword

    PubMed Central

    Chen, Jun; Lariviere, William R.

    2010-01-01

    Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study. PMID:20558236

  5. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control.

    PubMed

    Karai, Laszlo; Brown, Dorothy C; Mannes, Andrew J; Connelly, Stephen T; Brown, Jacob; Gandal, Michael; Wellisch, Ofer M; Neubert, John K; Olah, Zoltan; Iadarola, Michael J

    2004-05-01

    Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management. PMID:15124026

  6. Continuous- and Discrete-Time Stimulus Sequences for High Stimulus Rate Paradigm in Evoked Potential Studies

    PubMed Central

    Wang, Tao; Huang, Jiang-hua; Lin, Lin

    2013-01-01

    To obtain reliable transient auditory evoked potentials (AEPs) from EEGs recorded using high stimulus rate (HSR) paradigm, it is critical to design the stimulus sequences of appropriate frequency properties. Traditionally, the individual stimulus events in a stimulus sequence occur only at discrete time points dependent on the sampling frequency of the recording system and the duration of stimulus sequence. This dependency likely causes the implementation of suboptimal stimulus sequences, sacrificing the reliability of resulting AEPs. In this paper, we explicate the use of continuous-time stimulus sequence for HSR paradigm, which is independent of the discrete electroencephalogram (EEG) recording system. We employ simulation studies to examine the applicability of the continuous-time stimulus sequences and the impacts of sampling frequency on AEPs in traditional studies using discrete-time design. Results from these studies show that the continuous-time sequences can offer better frequency properties and improve the reliability of recovered AEPs. Furthermore, we find that the errors in the recovered AEPs depend critically on the sampling frequencies of experimental systems, and their relationship can be fitted using a reciprocal function. As such, our study contributes to the literature by demonstrating the applicability and advantages of continuous-time stimulus sequences for HSR paradigm and by revealing the relationship between the reliability of AEPs and sampling frequencies of the experimental systems when discrete-time stimulus sequences are used in traditional manner for the HSR paradigm. PMID:23606900

  7. Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.

    PubMed

    Baptista, Daniela; Nunes-de-Souza, Ricardo Luiz; Canto-de-Souza, Azair

    2012-11-01

    Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1 μl intra-dPAG injections of vehicle, 5.6 and 10 nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1 nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1 ml/10 g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5 min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01 nmol) enhanced it. Combined injections of ketanserin (10 nmol/0.1 μl), a 5-HT(2A/2C) receptor antagonist, and 0.01 nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01 nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice.

  8. Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys.

    PubMed

    Cunningham, Colin S; Javors, Martin A; McMahon, Lance R

    2012-06-01

    This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4β2 receptor-selective antagonist dihydro-β-erythroidine (DHβE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHβE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHβE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHβE-sensitive receptors (i.e., α4β2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has

  9. Stimulus Suffix Effects in Dichotic Memory

    ERIC Educational Resources Information Center

    Parkinson, Stanley R.; Hubbard, Lora L.

    1974-01-01

    in the present dichotic memory research, the addition of either a monaural stimulus suffix on the unattended ear or a binaural suffix was shown to selectively impair unattended-ear performance. (Editor)

  10. Sensitization of the Nociceptive System in Complex Regional Pain Syndrome

    PubMed Central

    Diedrichs, Carolina; Baron, Ralf; Gierthmühlen, Janne

    2016-01-01

    Background Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion. Objective Aims were to investigate how sensory, autonomic and motor function change in the course of the disease. Methods 19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1–33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16–53 months later). Results CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain. Conclusions The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability. PMID:27149519

  11. Spinal nociceptive transmission by mechanical stimulation of bone marrow

    PubMed Central

    Tanaka, Satoshi; Sekiguchi, Takemi; Sugiyama, Daisuke; Kawamata, Mikito

    2016-01-01

    Background Since bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin. Results Intraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation. Conclusions The results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain

  12. Antinociceptive activity of atranorin in mice orofacial nociception tests.

    PubMed

    Siqueira, Rosana S; Bonjardim, Leonardo R; Araújo, Adriano A S; Araújo, Bruno E S; Melo, Marcélia G D; Oliveira, Marília G B; Gelain, Daniel P; Silva, Francilene A; DeSantana, Josimari M; Albuquerque-Júnior, Ricardo L C; Rocha, Ricardo F; Moreira, José C F; Antoniolli, Angelo R; Quintans-Júnior, Lucindo J

    2010-01-01

    Physicochemical characterization and antinociceptive and anti-inflammatory activities of atranorin (AT) extracted from Cladina kalbii Ahti in formalin- and capsaicin-induced orofacial pain and anti-inflammatory tests in rodents were studied. Physicochemical characterization showed that AT has the general formula C19H18O8. Male Swiss mice were pretreated with AT (100, 200, and 400 mg/kg, i.p.), morphine (3 mg/kg, i.p.), or vehicle (0.9% saline with two drops of 0.2% Tween 80) before formalin (20 microl, 2%) or capsaicin (20 microl, 2.5 microg) were injected into the right vibrissa. Our results showed that i.p. treatment with AT displayed marked inhibitory effects in different orofacial pain tests in mice. AT (400 mg/kg, i.p.) was effective in reducing the nociceptive face-rubbing behavioural response in both phases of the formalin test, which was also naloxone-sensitive. Additionally, AT produced a significant antinociceptive effect at all doses in the capsaicin test. Such results were unlikely to be provoked by motor abnormality, since AT-treated mice exhibited no performance alteration on the rota rod apparatus. AT exhibited significant anti-inflammatory activity in the acute model of inflammation (leukocyte migration to the peritoneal cavity), carrageenan- and arachidonic acid-induced hind paw edema in rats. Additionally, AT exhibited a dose-dependent antioxidant activity in vitro, as assessed by total radical-trapping antioxidant parameter and total antioxidant reactivity assays. All these findings suggest that AT might represent an important tool for the management of orofacial pain and/or inflammatory disorders. PMID:21138055

  13. Forcing the issue: aromatic tuning facilitates stimulus-independent modulation of a two-component signaling circuit.

    PubMed

    Nørholm, Morten H H; von Heijne, Gunnar; Draheim, Roger R

    2015-04-17

    Two-component signaling circuits allow bacteria to detect and respond to external stimuli. Unfortunately, the input stimulus remains unidentified for the majority of these circuits. Therefore, development of a synthetic method for stimulus-independent modulation of these circuits is highly desirable because particular physiological or developmental processes could be controlled for biotechnological purposes without the need to identify the stimulus itself. Here, we demonstrate that aromatic tuning, i.e., repositioning the aromatic residues commonly found at the cytoplasmic end of the receptor (EnvZ) transmembrane domain, facilitates stimulus-independent modulation of signal output from the EnvZ/OmpR osmosensing circuit of Escherichia coli. We found that these osmosensing circuits retained the ability to respond appropriately to increased external osmolarity, suggesting that the tuned receptors were not locked in a single conformation. We also noted that circuits containing aromatically tuned variants became more sensitive to changes in the receptor concentration than their wild-type counterpart, suggesting a new way to study mechanisms underpinning receptor concentration-dependent robustness. We believe that aromatic tuning has several advantages compared to previous methods aimed at stimulus-independent modulation of receptors and that it will be generally applicable to a wide-range of two-component circuits.

  14. Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice

    PubMed Central

    Brenneis, Christian; Coste, Ovidiu; Schmidt, Ronald; Angioni, Carlo; Popp, Laura; Nusing, Rolf M; Becker, Wiebke; Scholich, Klaus; Geisslinger, Gerd

    2008-01-01

    Abstract Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice. PMID:18419601

  15. Simultaneous impairment of passive avoidance learning and nociception in rats following chronic swim stress

    PubMed Central

    Nazeri, Masoud; Shabani, Mohammad; Parsania, Shahrnaz; Golchin, Leila; Razavinasab, Moazamehosadat; Abareghi, Fatemeh; Kermani, Moein

    2016-01-01

    Background: Stress can alter response to nociception. Under certain circumstances stress enhances nociception, a phenomenon which is called stress-induced hyperalgesia (SIH). While nociception has been studied in this paradigm, possible alterations occurring in passive avoidance (PA) learning after exposing rats to this type of stress has not been studied before. Materials and Methods: In the current study, we evaluated the effect of chronic swim stress (FS) or sham swim (SS) on nociception in both spinal (tail-flick) and supraspinal (53.5°C hot-pate) levels. Furthermore, PA task was performed to see whether chronic swim stress changes PA learning or not. Mobility of rats and anxiety-like behavior were assessed using open-field test (OFT). Results: Supraspinal pain response was altered by swim stress (hot-plate test). PA learning was impaired by swim stress, rats in SS group did not show such impairments. Rats in the FS group showed increased mobility (rearing, velocity, total distant moved (TDM) and decreased anxiety-like behavior (time spent in center and grooming) compared to SS rats. Conclusions: This study demonstrated the simultaneous impairment of PA and nociception under chronic swim stress, whether this is simply a co-occurrence or not is of special interest. This finding may implicate a possible role for limbic structures, though this hypothesis should be studied by experimental lesions in different areas of rat brain to assess their possible role in the pathophysiology of SIH. PMID:27308265

  16. New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation.

    PubMed

    Colucci, Mariantonella; Maione, Francesco; Bonito, Maria Carmela; Piscopo, Alessandro; Di Giannuario, Amalia; Pieretti, Stefano

    2008-06-01

    DMSO is one of the most common solvents used experimentally to dissolve hydrophobic substances for in vivo and in vitro purposes. A wide range of pharmacological effects exerted by DMSO has been documented in both animal and human experimental models. However, only a few and sometimes contrasting data about the effects of DMSO in animal models of nociception and inflammation are presently available. In this study, we evaluated the effects induced by DMSO and a DMSO-containing saline on thermal and chemical nociception, inflammation and locomotor activity in CD1 mice. We demonstrated that centrally or orally administered DMSO displayed anti-nociceptive effects to thermal (hot plate and tail-flick test) and chemical (formalin test) stimuli. Conversely, DMSO was able to increase both nociceptive phases in the formalin test when applied subcutaneously in the dorsal surface of the mouse hind paws 10 min before formalin administration. Oral administration of DMSO produced anti-inflammatory effects on zymosan-induced edema in the mouse paw, whereas local administration potentiated the inflammatory action exerted by zymosan. Oral and central, but not local, administration of DMSO improved the mouse locomotor activity. These results suggest that DMSO displayed opposite effects on nociception and inflammation, depending on the route of administration. New and helpful evidence about DMSO laboratory applications need to be considered in the in vivo studies to assess correctly the pharmacological properties of investigated drugs.

  17. Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain.

    PubMed

    Dutra, Marcela M G B; Nascimento Júnior, Elias B; Godin, Adriana M; Brito, Ana Mercy S; Melo, Ivo S F; Augusto, Paulo S A; Rodrigues, Felipe F; Araújo, Débora P; de Fátima, Ângelo; Coelho, Márcio M; Machado, Renes R

    2015-12-01

    We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300μg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity. PMID:26522924

  18. Anti-nociceptive and anti-inflammatory activities of the extracts of Stauntonia chinensis.

    PubMed

    Ying, Chen; Ning, Wu; Ying, Liu; Hao, Gao; Hua-Jin, Dong; Rui-Bin, Su; Xin-Sheng, Yao; Jin, Li

    2014-09-01

    The aim of this investigation was to study the anti-nociceptive and anti-inflammatory activities of Stauntonia chinensis (S. chinensis) and the possible action mechanisms of effective fractions. The anti-nociceptive and anti-inflammatory activities of S. chinensis extracts, including the 60% EtOH extract (YMG), the n-BuOH extract (YMGB) and the aqueous residue (YMGW) of YMG, and the fractions from YMGB (YMGB1~YMGB7) were investigated by using the mouse acetic acid-induced writhing test and the rat formalin test. The effect of these extracts on the PGE2 production was tested as well. In the mouse acetic acid-induced writhing test and the rat formalin test, YMGW and YMGB displayed anti-nociceptive and anti-inflammatory activities, suggesting that they were the active ingredients of YMG. Among the fractions isolated from YMGB, YMGB1, YMGB3, YMGB4 and YMGB6 were the main active ingredients producing anti-nociceptive activity and YMGB3, YMGB5, YMGB6 and YMGB7 were the main active ingredients producing anti-inflammatory activity. Additionally, YMGW, YMGB and its separations reduced the production of PGE2, which might be the mechanism of them producing anti-inflammatory activity. These results demonstrated the active ingredients of S. chinensis producing anti-nociceptive and anti-inflammatory activities, which is valuable to validate the substance basis of S. chinensis's pharmacological actions.

  19. Evidence that substance P selectively modulates C-fiber-evoked discharges of dorsal horn nociceptive neurons.

    PubMed

    Kellstein, D E; Price, D D; Hayes, R L; Mayer, D J

    1990-09-01

    Previous studies suggest that the undecapeptide substance P (SP) functions as a primary afferent neurotransmitter or neuromodulator of nociception which may mediate the slow temporal summation ('windup') of discharges of dorsal horn nociceptive neurons elicited by repetitive stimulation of C-afferents. The present study tested this hypothesis by investigating the effects of local spinal application of SP and an SP antagonist. [D-Pro2,D-Trp7,9]-SP (DPDT), on A- and C-fiber-evoked firing of dorsal horn neurons in an intact, urethane-anesthetized rat preparation. Extracellular single unit recordings from both wide dynamic range and nociceptive specific neurons during controlled repetitive electrical stimulation of the ipsilateral hind paw indicated that SP enhanced C-evoked firing in an apparent dose-related manner (100 greater than 20 = 4 nmol), whereas DPDT inhibited C-evoked discharges with an apparent bell-shaped dose-response (20 greater than 100 = 4 nmol). Neither agent significantly altered either A-evoked or spontaneous activity. In agreement with previous investigators, morphine sulfate also selectively inhibited C-fiber-evoked firing without altering A-fiber-mediated activity, validating the selectivity of our system. These findings provide additional evidence that SP functions as a neuromodulator of primary afferent nociception, and further suggest that the effects of SP are selective to nociceptive transmission mediated by C-fibers. PMID:1701684

  20. Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice.

    PubMed

    Bonjardim, L R; Silva, A M; Oliveira, M G B; Guimarães, A G; Antoniolli, A R; Santana, M F; Serafini, M R; Santos, R C; Araújo, A A S; Estevam, C S; Santos, M R V; Lyra, A; Carvalho, R; Quintans-Júnior, L J; Azevedo, E G; Botelho, M A

    2011-08-01

    In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia.

  1. Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs.

    PubMed

    Winter, J C

    2008-01-01

    It has been observed that agents with agonist activity at 5-HT2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed-ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.

  2. Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms.

    PubMed

    Godin, Adriana M; Araújo, Débora P; César, Isabela C; Menezes, Raquel R; Brito, Ana Mercy S; Melo, Ivo S F; Coura, Giovanna M E; Bastos, Leandro F S; Almeida, Mariana O; Byrro, Ricardo M D; Matsui, Tamires C; Batista, Carla R A; Pianetti, Gerson A; de Fátima, Ângelo; Machado, Renes R; Coelho, Márcio M

    2015-06-01

    The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD-OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceptive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1h before intraplantar injection of formaldehyde, inhibited both phases of the nociceptive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity.

  3. Observing behavior and atypically restricted stimulus control.

    PubMed

    Dube, William V; Dickson, Chata A; Balsamo, Lyn M; O'Donnell, Kristin Lombard; Tomanari, Gerson Y; Farren, Kevin M; Wheeler, Emily E; McIlvane, William J

    2010-11-01

    Restricted stimulus control refers to discrimination learning with atypical limitations in the range of controlling stimuli or stimulus features. In the study reported here, 4 normally capable individuals and 10 individuals with intellectual disabilities (ID) performed two-sample delayed matching to sample. Sample-stimulus observing was recorded with an eye-tracking apparatus. High accuracy scores indicated stimulus control by both sample stimuli for the 4 nondisabled participants and 4 participants with ID, and eye tracking data showed reliable observing of all stimuli. Intermediate accuracy scores indicated restricted stimulus control for the remaining 6 participants. Their eye-tracking data showed that errors were related to failures to observe sample stimuli and relatively brief observing durations. Five of these participants were then given interventions designed to improve observing behavior. For 4 participants, the interventions resulted initially in elimination of observing failures, increased observing durations, and increased accuracy. For 2 of these participants, contingencies sufficient to maintain adequate observing were not always sufficient to maintain high accuracy; subsequent procedure modifications restored it, however. For the 5th participant, initial improvements in observing were not accompanied by improved accuracy, an apparent instance of observing without attending; accuracy improved only after an additional intervention that imposed contingencies on observing behavior. Thus, interventions that control observing behavior seem necessary but may not always be sufficient for the remediation of restricted stimulus control.

  4. Extinguished operant responding shows stimulus specificity.

    PubMed

    McSweeney, Frances K; Murphy, Eric S; Kowal, Benjamin P

    2004-03-31

    The experiment tested for stimulus specificity in extinguished operant responding. Eight pigeons pecked keys for food reinforcers delivered by a variable interval (VI) 60-s schedule. The key was illuminated with red light during some sessions and white light during others. Then, responding was placed on extinction. During some sessions of extinction, the color of the key light remained constant throughout the session (red or white). During other sessions the color changed at 30 min into the session (red to white or white to red). Response rate increased after the change of key color in extinction. If it is assumed that key color is part of the stimulus to which subjects habituate, then these results are consistent with McSweeney and Swindell's [J. Gen. Psychol. 129 (2002) 364] suggestion that responding declines in extinction partly because subjects habituate to the stimuli that support conditioned responding. Habituation is relatively specific to the exact nature of the stimulus presented. Therefore, changes in the stimulus violate stimulus specificity and restore habituated responding. The results are also consistent with other theories that attribute extinction to a reduction of stimulus control [e.g., Psychol. Bull. 114 (1993) 80; J. Exp. Psychol.: Anim. Behav. Process. 16 (1990) 235], but considerations such as parsimony and testability favor the habituation hypothesis over these theories.

  5. The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain.

    PubMed

    Malek, Natalia; Kostrzewa, Magdalena; Makuch, Wioletta; Pajak, Agnieszka; Kucharczyk, Mateusz; Piscitelli, Fabiana; Przewlocka, Barbara; Di Marzo, Vincenzo; Starowicz, Katarzyna

    2016-09-01

    There is considerable evidence to support the role of anandamide (AEA), an endogenous ligand of cannabinoid receptors, in neuropathic pain modulation. AEA also produces effects mediated by other biological targets, of which the transient receptor potential vanilloid type 1 (TRPV1) has been the most investigated. Both, inhibition of AEA breakdown by fatty acid amide hydrolase (FAAH) and blockage of TRPV1 have been shown to produce anti-nociceptive effects. Recent research suggests the usefulness of dual-action compounds, which may afford greater anti-allodynic efficacy. Therefore, in the present study, we examined the effect of N-arachidonoyl-serotonin (AA-5-HT), a blocker of FAAH and TRPV1, in a rat model of neuropathic pain after intrathecal administration. We found that treatment with AA-5-HT increased the pain threshold to mechanical and thermal stimuli, with highest effect at the dose of 500nM, which was most strongly attenuated by AM-630, CB2 antagonist, administration. The single action blockers PF-3845 (1000nM, for FAAH) and I-RTX (1nM, for TRPV1) showed lower efficacy than AA-5-HT. Moreover AA-5-HT (500nM) elevated AEA and palmitoylethanolamide (PEA) levels. Among the possible targets of these mediators, only the mRNA levels of CB2, GPR18 and GPR55, which are believed to be novel cannabinoid receptors, were upregulated in the spinal cord and/or DRG of CCI rats. It was previously reported that AA-5-HT acts in CB1 and TRPV1-dependent manner after systemic administration, but here for the first time we show that AA-5-HT action at the spinal level involves CB2, with potential contributions from GRP18 and/or GPR55 receptors. PMID:27326920

  6. Regulation of Nociceptive Plasticity Threshold and DARPP-32 Phosphorylation in Spinal Dorsal Horn Neurons by Convergent Dopamine and Glutamate Inputs.

    PubMed

    Buesa, Itsaso; Aira, Zigor; Azkue, Jon Jatsu

    2016-01-01

    Dopamine can influence NMDA receptor function and regulate glutamate-triggered long-term changes in synaptic strength in several regions of the CNS. In spinal cord, regulation of the threshold of synaptic plasticity may determine the proneness to undergo sensitization and hyperresponsiveness to noxious input. In the current study, we increased endogenous dopamine levels in the dorsal horn by using re-uptake inhibitor GBR 12935. During the so-induced hyperdopaminergic transmission, conditioning low-frequency (1 Hz) stimulation (LFS) to the sciatic nerve induced long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn neurons. The magnitude of LTP was attenuated by blockade of either dopamine D1-like receptors (D1LRs) by with SCH 23390 or NMDA receptor subunit NR2B with antagonist Ro25-6981. Conditioning LFS during GBR 12935 administration increased phosphorylation of dopamine- and cAMP-regulated phosphoprotein of Mr 32kDa (DARPP-32) at threonine 34 residue in synaptosomal (P3) fraction of dorsal horn homogenates, as assessed by Western blot analysis, which was partially prevented by NR2B blockade prior to conditioning stimulation. Conditioning LFS also was followed by higher co-localization of phosphorylated form of NR2B at tyrosine 1472 and pDARPP-32Thr34- with postsynaptic marker PSD-95 in transverse L5 dorsal horn sections. Such increase could be significantly attenuated by D1LR blockade with SCH 23390. The current results support that coincidental endogenous recruitment of D1LRs and NR2B in dorsal horn synapses plays a role in regulating afferent-induced nociceptive plasticity. Parallel increases in DARPP-32 phosphorylation upon LTP induction suggests a role for this phosphoprotein as intracellular detector of convergent D1L- and NMDA receptor activation. PMID:27610622

  7. Regulation of Nociceptive Plasticity Threshold and DARPP-32 Phosphorylation in Spinal Dorsal Horn Neurons by Convergent Dopamine and Glutamate Inputs

    PubMed Central

    Buesa, Itsaso; Aira, Zigor

    2016-01-01

    Dopamine can influence NMDA receptor function and regulate glutamate-triggered long-term changes in synaptic strength in several regions of the CNS. In spinal cord, regulation of the threshold of synaptic plasticity may determine the proneness to undergo sensitization and hyperresponsiveness to noxious input. In the current study, we increased endogenous dopamine levels in the dorsal horn by using re-uptake inhibitor GBR 12935. During the so-induced hyperdopaminergic transmission, conditioning low-frequency (1 Hz) stimulation (LFS) to the sciatic nerve induced long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn neurons. The magnitude of LTP was attenuated by blockade of either dopamine D1-like receptors (D1LRs) by with SCH 23390 or NMDA receptor subunit NR2B with antagonist Ro25-6981. Conditioning LFS during GBR 12935 administration increased phosphorylation of dopamine- and cAMP-regulated phosphoprotein of Mr 32kDa (DARPP-32) at threonine 34 residue in synaptosomal (P3) fraction of dorsal horn homogenates, as assessed by Western blot analysis, which was partially prevented by NR2B blockade prior to conditioning stimulation. Conditioning LFS also was followed by higher co-localization of phosphorylated form of NR2B at tyrosine 1472 and pDARPP-32Thr34- with postsynaptic marker PSD-95 in transverse L5 dorsal horn sections. Such increase could be significantly attenuated by D1LR blockade with SCH 23390. The current results support that coincidental endogenous recruitment of D1LRs and NR2B in dorsal horn synapses plays a role in regulating afferent-induced nociceptive plasticity. Parallel increases in DARPP-32 phosphorylation upon LTP induction suggests a role for this phosphoprotein as intracellular detector of convergent D1L- and NMDA receptor activation. PMID:27610622

  8. Occlusion for stimulus deprivation amblyopia

    PubMed Central

    Antonio-Santos, Aileen; Vedula, Satyanarayana S; Hatt, Sarah R; Powell, Christine

    2014-01-01

    Background Stimulus deprivation amblyopia (SDA) develops due to an obstruction to the passage of light secondary to a condition such as cataract. The obstruction prevents formation of a clear image on the retina. SDA can be resistant to treatment, leading to poor visual prognosis. SDA probably constitutes less than 3% of all amblyopia cases, although precise estimates of prevalence are unknown. In developed countries, most patients present under the age of one year; in less developed parts of the world patients are likely to be older at the time of presentation. The mainstay of treatment is removal of the cataract and then occlusion of the better-seeing eye, but regimens vary, can be difficult to execute, and traditionally are believed to lead to disappointing results. Objectives Our objective was to evaluate the effectiveness of occlusion therapy for SDA in an attempt to establish realistic treatment outcomes. Where data were available, we also planned to examine evidence of any dose response effect and to assess the effect of the duration, severity, and causative factor on the size and direction of the treatment effect. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2013), EMBASE (January 1980 to October 2013), the Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2013), PubMed (January 1946 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 October 2013. Selection criteria We planned

  9. Encoding of sound localization cues by an identified auditory interneuron: effects of stimulus temporal pattern.

    PubMed

    Samson, Annie-Hélène; Pollack, Gerald S

    2002-11-01

    An important cue for sound localization is binaural comparison of stimulus intensity. Two features of neuronal responses, response strength, i.e., spike count and/or rate, and response latency, vary with stimulus intensity, and binaural comparison of either or both might underlie localization. Previous studies at the receptor-neuron level showed that these response features are affected by the stimulus temporal pattern. When sounds are repeated rapidly, as occurs in many natural sounds, response strength decreases and latency increases, resulting in altered coding of localization cues. In this study we analyze binaural cues for sound localization at the level of an identified pair of interneurons (the left and right AN2) in the cricket auditory system, with emphasis on the effects of stimulus temporal pattern on binaural response differences. AN2 spike count decreases with rapidly repeated stimulation and latency increases. Both effects depend on stimulus intensity. Because of the difference in intensity at the two ears, binaural differences in spike count and latency change as stimulation continues. The binaural difference in spike count decreases, whereas the difference in latency increases. The proportional changes in response strength and in latency are greater at the interneuron level than at the receptor level, suggesting that factors in addition to decrement of receptor responses are involved. Intracellular recordings reveal that a slowly building, long-lasting hyperpolarization is established in AN2. At the same time, the level of depolarization reached during the excitatory postsynaptic potential (EPSP) resulting from each sound stimulus decreases. Neither these effects on membrane potential nor the changes in spiking response are accounted for by contralateral inhibition. Based on comparison of our results with earlier behavioral experiments, it is unlikely that crickets use the binaural difference in latency of AN2 responses as the main cue for

  10. Application of bifurcation analysis for determining the mechanism of coding of nociceptive signals

    NASA Astrophysics Data System (ADS)

    Dik, O. E.; Shelykh, T. N.; Plakhova, V. B.; Nozdrachev, A. D.; Podzorova, S. A.; Krylov, B. V.

    2015-10-01

    The patch clamp method is used for studying the characteristics of slow sodium channels responsible for coding of nociceptive signals. Quantitative estimates of rate constants of transitions of "normal" and pharmacologically modified activation gating mechanisms of these channels are obtained. A mathematical model of the type of Hogdkin-Huxley nociceptive neuron membrane is constructed. Cometic acid, which is a drug substance of a new nonopioid analgesic, is used as a pharmacological agent. The application of bifurcation analysis makes it possible to outline the boundaries of the region in which a periodic impulse activity is generated. This boundary separates the set of values of the model parameter for which periodic pulsation is observed from the values for which such pulsations are absent or damped. The results show that the finest effect of modulation of physical characteristic of a part of a protein molecule and its effective charge suppresses the excitability of the nociceptive neuron membrane and, hence, leads to rapid reduction of pain.

  11. Adaptation of body temperature and nociception to cold stress in preweanling rats.

    PubMed

    Hamm, R J; Knisely, J S; Lyons, C M

    1990-05-01

    In order to investigate the response of rat pups to stress, 10-day-old rats (N = 10) were exposed to cold water (14 degrees C) for 5 min or to a control treatment (N = 10) for 5 consecutive days. On the sixth day when the rats were 15 days of age, all rat pups were immersed in cold water for 5 min. Body temperature and nociceptive threshold were recorded as functional indexes of the stress response to cold water. Results revealed that the rat pups that had been previously exposed to the cold stressor demonstrated a smaller decline in body temperature and a smaller increase in nociceptive threshold following cold-water immersion than rat pups which had no prior experience with the stressor. Thus, as measured by thermoregulatory and nociceptive function, 15-day-old rat pups are capable of adapting to repeated stressful experiences.

  12. From a Somatotopic to a Spatiotopic Frame of Reference for the Localization of Nociceptive Stimuli

    PubMed Central

    De Paepe, Annick L.; Crombez, Geert; Legrain, Valéry

    2015-01-01

    To react efficiently to potentially threatening stimuli, we have to be able to localize these stimuli in space. In daily life we are constantly moving so that our limbs can be positioned at the opposite side of space. Therefore, a somatotopic frame of reference is insufficient to localize nociceptive stimuli. Here we investigated whether nociceptive stimuli are mapped into a spatiotopic frame of reference, and more specifically a peripersonal frame of reference, which takes into account the position of the body limbs in external space, as well as the occurrence of external objects presented near the body. Two temporal order judgment (TOJ) experiments were conducted, during which participants had to decide which of two nociceptive stimuli, one applied to either hand, had been presented first while their hands were either uncrossed or crossed over the body midline. The occurrence of the nociceptive stimuli was cued by uninformative visual cues. We found that the visual cues prioritized the perception of nociceptive stimuli applied to the hand laying in the cued side of space, irrespective of posture. Moreover, the influence of the cues was smaller when they were presented far in front of participants’ hands as compared to when they were presented in close proximity. Finally, participants’ temporal sensitivity was reduced by changing posture. These findings are compatible with the existence of a peripersonal frame of reference for the localization of nociceptive stimuli. This allows for the construction of a stable representation of our body and the space closely surrounding our body, enabling a quick and efficient reaction to potential physical threats. PMID:26317671

  13. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats.

    PubMed

    Dimov, Luiz Fabio; Franciosi, Adriano Cardozo; Campos, Ana Carolina Pinheiro; Brunoni, André Russowsky; Pagano, Rosana Lima

    2016-01-01

    Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment. PMID:27071073

  14. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats

    PubMed Central

    Dimov, Luiz Fabio; Franciosi, Adriano Cardozo; Campos, Ana Carolina Pinheiro; Brunoni, André Russowsky

    2016-01-01

    Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment. PMID:27071073

  15. Nociceptive stimuli induce changes in somatosensory responses of rat dorsal column nuclei neurons.

    PubMed

    Costa-García, Miguel; Nuñez, Angel

    2004-10-29

    Accumulating evidence suggest that the dorsal column nuclei (DCN) neurons play a role in nociception. To evaluate DCN neuronal responses to nociceptive stimuli, unit recordings were performed in urethane-anesthesized rats. Neurons selected for this analysis displayed a low spontaneous firing rate and some of them were antidromically activated by electrical stimulation of the ventral posterolateral thalamic nucleus. Formalin injections into receptive fields (RFs) of DCN cells, or applications of short-lasting and long-lasting thermal nociceptive stimuli were used. DCN neurons displayed smaller responses when long-lasting nociceptive thermal stimuli were applied to their RFs in comparison with values obtained from the innocuous cutaneous stimulation (5.2+/-1.0 and 4.0+/-0.6 spikes/stimuli, respectively; p=0.02). Formalin also decreased the responses to innocuous cutaneous stimuli when these stimuli were applied to the formalin injection site (2.6+/-0.3 spikes/stimuli in control conditions and 1.8+/-0.3 spikes/stimuli 20 min after formalin; p=0.002). In contrast, responses to sensory stimuli applied at the periphery of the RF after formalin injection increased (2.2+/-0.2 to 2.8+/-0.3 spikes/stimuli; p=0.005). In some cases, DCN neurons expanded their RF. Fiber input to the DCN did not modify their somatosensory responses when nociceptive stimuli were applied. Results demonstrate that thermal and formalin nociceptive stimuli modify the somatosensory responses of DCN neurons. Thus, decreasing somatosensory responses at the pain induction site or the generation of allodynia may be due to the activity of DCN neurons.

  16. Changing Balance of Spinal Cord Excitability and Nociceptive Brain Activity in Early Human Development.

    PubMed

    Hartley, Caroline; Moultrie, Fiona; Gursul, Deniz; Hoskin, Amy; Adams, Eleri; Rogers, Richard; Slater, Rebeccah

    2016-08-01

    In adults, nociceptive reflexes and behavioral responses are modulated by a network of brain regions via descending projections to the spinal dorsal horn [1]. Coordinated responses to noxious inputs manifest from a balance of descending facilitation and inhibition. In contrast, young infants display exaggerated and uncoordinated limb reflexes [2]. Our understanding of nociceptive processing in the infant brain has been advanced by the use of electrophysiological and hemodynamic imaging [3-6]. From approximately 35 weeks' gestation, nociceptive-specific patterns of brain activity emerge [7], whereas prior to this, non-specific bursts of activity occur in response to noxious, tactile, visual, and auditory stimulation [7-10]. During the preterm period, refinement of spinal cord excitability is also observed: reflex duration shortens, response threshold increases, and improved discrimination between tactile and noxious events occurs [2, 11, 12]. However, the development of descending modulation in human infants remains relatively unexplored. In 40 infants aged 28-42 weeks' gestation, we examined the relationship between nociceptive brain activity and spinal reflex withdrawal activity in response to a clinically essential noxious procedure. Nociceptive-specific brain activity increases in magnitude with gestational age, whereas reflex withdrawal activity decreases in magnitude, duration, and latency across the same developmental period. By recording brain and spinal cord activity in the same infants, we demonstrate that the maturation of nociceptive brain activity is concomitant with the refinement of noxious-evoked limb reflexes. We postulate that, consistent with studies in animals, infant reflexes are influenced by the development of top-down inhibitory modulation from maturing subcortical and cortical brain networks. PMID:27374336

  17. Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation.

    PubMed

    Pritchard, Rory A; Falk, Lovissa; Larsson, Mathilda; Leinders, Mathias; Sorkin, Linda S

    2016-01-01

    Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.

  18. Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation

    PubMed Central

    Pritchard, Rory A.; Falk, Lovissa; Larsson, Mathilda; Leinders, Mathias; Sorkin, Linda S.

    2016-01-01

    Abstract Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated. PMID:26313408

  19. Neuroactive steroids, nociception and neuropathic pain: A flashback to go forward.

    PubMed

    Coronel, María F; Labombarda, Florencia; González, Susana L

    2016-06-01

    The present review discusses the potential role of neurosteroids/neuroactive steroids in the regulation of nociceptive and neuropathic pain, and recapitulates the current knowledge on the main mechanisms involved in the reduction of pain, especially those occurring at the dorsal horn of the spinal cord, a crucial site for nociceptive processing. We will make special focus on progesterone and its derivative allopregnanolone, which have been shown to exert remarkable actions in order to prevent or reverse the maladaptive changes and pain behaviors that arise after nervous system damage in various experimental neuropathic conditions.

  20. A negative stimulus movement effect in pigeons.

    PubMed

    Daniel, Thomas A; Katz, Jeffrey S

    2016-09-01

    Rhesus monkeys and humans perform more accurately in matching-to-sample tasks when the sample stimulus moves through space (Washburn et al., 1989; Washburn, 1993). This Stimulus Movement Effect (SME) is believed to be due to movement increasing attention toward the sample stimulus, creating an easier discrimination between the sample and choice stimuli. To date, there is no evidence for this phenomenon in a non-mammalian species. In the current study, we investigate the possibility of an SME in an avian species. Across three experiments, pigeons were tested with moving and stationary sample stimuli in a non-matching- to-sample task. The area and velocity by which the sample stimulus traveled was manipulated but no advantage for moving over stationary sample trials was found within or across sessions. Even when a delay condition was implemented, there was no advantage for moving sample trials. Contrary to the results found in humans and monkeys, pigeons performed better when the sample was stationary, a negative SME, and no evidence was found that stimulus movement increases discrimination performance.

  1. Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation.

    PubMed

    Matsuta, Yosuke; Mally, Abhijith D; Zhang, Fan; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2013-07-15

    The contribution of metabotropic glutamate receptors (mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under α-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P < 0.0001) reduced bladder capacity to 26.6 ± 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 ± 8.3% at 2T (P < 0.01) and 80.8 ± 9.2% at 4T (P = 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders. PMID:23576608

  2. Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo

    PubMed Central

    2009-01-01

    Background γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. Results In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)-/- mice). Lack of the GABAB(1) subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1) expression in nociceptors. Conclusion This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly changed upon a specific

  3. Stimulus-Stimulus Pairing and Subsequent Mand Acquisition of Children with Various Levels of Verbal Repertoires

    ERIC Educational Resources Information Center

    Yoon, Soyoung; Feliciano, Gina M.

    2007-01-01

    Effects of a stimulus-stimulus pairing procedure on the subsequent acquisition of mand operants were investigated. An attempt was made to shape novel sounds that emerged through the pairing procedure into a mand. Six children, aged two to five years, with moderate to severe language and communication delays, participated. Two conditions were used…

  4. Sample Stimulus Control Shaping and Restricted Stimulus Control in Capuchin Monkeys: A Methodological Note

    ERIC Educational Resources Information Center

    Brino, Ana Leda F., Barros, Romariz S., Galvao, Ol; Garotti, M.; Da Cruz, Ilara R. N.; Santos, Jose R.; Dube, William V.; McIlvane, William J.

    2011-01-01

    This paper reports use of sample stimulus control shaping procedures to teach arbitrary matching-to-sample to 2 capuchin monkeys ("Cebus apella"). The procedures started with identity matching-to-sample. During shaping, stimulus features of the sample were altered gradually, rendering samples and comparisons increasingly physically dissimilar. The…

  5. Emergent Stimulus Relations Depend on Stimulus Correlation and Not on Reinforcement Contingencies

    ERIC Educational Resources Information Center

    Minster, Sara Tepaeru; Elliffe, Douglas; Muthukumaraswamy, Suresh D.

    2011-01-01

    We aimed to investigate whether novel stimulus relations would emerge from stimulus correlations when those relations explicitly conflicted with reinforced relations. In a symbolic matching-to-sample task using kanji characters as stimuli, we arranged class-specific incorrect comparison stimuli in each of three classes. After presenting either Ax…

  6. Stimulus design for model selection and validation in cell signaling.

    PubMed

    Apgar, Joshua F; Toettcher, Jared E; Endy, Drew; White, Forest M; Tidor, Bruce

    2008-02-01

    Mechanism-based chemical kinetic models are increasingly being used to describe biological signaling. Such models serve to encapsulate current understanding of pathways and to enable insight into complex biological processes. One challenge in model development is that, with limited experimental data, multiple models can be consistent with known mechanisms and existing data. Here, we address the problem of model ambiguity by providing a method for designing dynamic stimuli that, in stimulus-response experiments, distinguish among parameterized models with different topologies, i.e., reaction mechanisms, in which only some of the species can be measured. We develop the approach by presenting two formulations of a model-based controller that is used to design the dynamic stimulus. In both formulations, an input signal is designed for each candidate model and parameterization so as to drive the model outputs through a target trajectory. The quality of a model is then assessed by the ability of the corresponding controller, informed by that model, to drive the experimental system. We evaluated our method on models of antibody-ligand binding, mitogen-activated protein kinase (MAPK) phosphorylation and de-phosphorylation, and larger models of the epidermal growth factor receptor (EGFR) pathway. For each of these systems, the controller informed by the correct model is the most successful at designing a stimulus to produce the desired behavior. Using these stimuli we were able to distinguish between models with subtle mechanistic differences or where input and outputs were multiple reactions removed from the model differences. An advantage of this method of model discrimination is that it does not require novel reagents, or altered measurement techniques; the only change to the experiment is the time course of stimulation. Taken together, these results provide a strong basis for using designed input stimuli as a tool for the development of cell signaling models. PMID

  7. Stimulus probability effects in absolute identification.

    PubMed

    Kent, Christopher; Lamberts, Koen

    2016-05-01

    This study investigated the effect of stimulus presentation probability on accuracy and response times in an absolute identification task. Three schedules of presentation were used to investigate the interaction between presentation probability and stimulus position within the set. Data from individual participants indicated strong effects of presentation probability on both proportion correct and response times. The effects were moderated by the ubiquitous stimulus position effect. The accuracy and response time data were predicted by an exemplar-based model of perceptual cognition (Kent & Lamberts, 2005). The bow in discriminability was also attenuated when presentation probability for middle items was relatively high, an effect that will constrain future model development. The study provides evidence for item-specific learning in absolute identification. Implications for other theories of absolute identification are discussed. (PsycINFO Database Record

  8. Contributions to drug abuse research of Steven R. Goldberg's behavioral analysis of stimulus-stimulus contingencies.

    PubMed

    Katz, Jonathan L

    2016-05-01

    By the mid-1960s, the concept that drugs can function as reinforcing stimuli through response-reinforcer contingencies had created a paradigm shift in drug abuse science. Steve Goldberg's first several publications focused instead on stimulus-stimulus contingencies (respondent conditioning) in examining Abraham Wikler's two-factor hypothesis of relapse involving conditioned withdrawal and reinforcing effects of drugs. Goldberg provided a compelling demonstration that histories of contingencies among stimuli could produce lasting withdrawal reactions in primates formerly dependent on opioids. Other studies conducted by Goldberg extended the analysis of effects of stimulus-stimulus contingencies on behavior maintained by opioid reinforcing effects and showed that withdrawal-inducing antagonist administration can produce conditioned increases in self-administration. Subsequent studies of the effects of stimuli associated with cocaine injection under second-order schedules showed that the maintenance of behavior with drug injections was in most important aspects similar to the maintenance of behavior with more conventional reinforcers when the behavior-disrupting pharmacological effects of the drugs were minimized. Studies on second-order schedules demonstrated a wide array of conditions under which behavior could be maintained by drug injection and further influenced by stimulus-stimulus contingencies. These schedules present opportunities to produce in the laboratory complex situations involving response- and stimulus-stimulus contingencies, which go beyond simplistic pairings of stimuli and more closely approximate those found with human drug abusers. A focus on the response- and stimulus-stimulus contingencies, and resulting quantifiable changes in objective and quantifiable behavioral endpoints exemplified by the studies by Steve Goldberg, remains the most promising way forward for studying problems of drug dependence. PMID:26564234

  9. Discovery of Prostamide F2α and Its Role in Inflammatory Pain and Dorsal Horn Nociceptive Neuron Hyperexcitability

    PubMed Central

    Giordano, Catia; Boccella, Serena; Lichtman, Aron; Maione, Sabatino; Di Marzo, Vincenzo

    2012-01-01

    It was suggested that endocannabinoids are metabolized by cyclooxygenase (COX)-2 in the spinal cord of rats with kaolin/λ-carrageenan-induced knee inflammation, and that this mechanism contributes to the analgesic effects of COX-2 inhibitors in this experimental model. We report the development of a specific method for the identification of endocannabinoid COX-2 metabolites, its application to measure the levels of these compounds in tissues, and the finding of prostamide F2α (PMF2α) in mice with knee inflammation. Whereas the levels of spinal endocannabinoids were not significantly altered by kaolin/λ-carrageenan-induced knee inflammation, those of the COX-2 metabolite of AEA, PMF2α, were strongly elevated. The formation of PMF2α was reduced by indomethacin (a non-selective COX inhibitor), NS-398 (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor). In healthy mice, spinal application of PMF2α increased the firing of nociceptive (NS) neurons, and correspondingly reduced the threshold of paw withdrawal latency (PWL). These effects were attenuated by the PMF2α receptor antagonist AGN211336, but not by the FP receptor antagonist AL8810. Also prostaglandin F2α increased NS neuron firing and reduced the threshold of PWL in healthy mice, and these effects were antagonized by AL8810, and not by AGN211336. In mice with kaolin/λ-carrageenan-induced knee inflammation, AGN211336, but not AL8810, reduced the inflammation-induced NS neuron firing and reduction of PWL. These findings suggest that inflammation-induced, and prostanoid-mediated, enhancement of dorsal horn NS neuron firing stimulates the production of spinal PMF2α, which in turn contributes to further NS neuron firing and pain transmission by activating specific receptors. PMID:22363560

  10. Stimulus equivalence: testing Sidman's (2000) theory.

    PubMed

    Minster, Sara Tepaeru; Jones, Max; Elliffe, Douglas; Muthukumaraswamy, Suresh D

    2006-05-01

    Sidman's (2000) theory regarding the origin of equivalence relations predicts that a reinforcing stimulus common to distinct equivalence classes must drop out of the equivalence relations. This prediction was tested in the present study by arranging class-specific reinforcers, R1 and R2, following correct responding on the prerequisite conditional discriminations (Ax-Bx, Cx-Bx) for two stimulus classes, A1B1C1 and A2B2C2. A class-common reinforcer, R3, was presented following correct responding on the prerequisite conditional discriminations for a further two stimulus classes, A3B3C3 and A4B4C4. Sidman's theory predicts reinforcer inclusion within Classes 1 and 2 only, given this training arrangement. Experiment 1 tested for the emergence of four equivalence classes and of stimulus-reinforcer and reinforcer-stimulus relations in each class. Four of the 6 subjects demonstrated the reinforcer-based relations in all four equivalence classes, rather than in only those classes with a class-specific reinforcer, as Sidman's theory predicts. One of the remaining 2 subjects showed the reinforcer-based relations in three of the four classes. Experiment 2 extended these findings to document the emergence of interclass matching relations based on the common reinforcer R3, in 5 of 6 subjects, such that a Class 3 sample occasioned the selection of a Class 4 sample when the Class 3 comparison was absent, and similarly, a Class 4 sample occasioned the selection of a Class 3 comparison when the Class 4 comparison was absent. These interclass relations emerged despite the simultaneous maintenance of Class 3 and 4 baseline conditional discriminations, so that the Class 3 and 4 stimuli and reinforcer simultaneously were, and were not, part of a single larger equivalence class. These data are irreconcilable with Sidman's theory, and question the utility of the application of the equivalence relation in describing derived stimulus relations.

  11. Primary cutaneous plasmacytoma: a role for a triggering stimulus?

    PubMed

    Zendri, E; Venturi, C; Ricci, R; Giordano, G; De Panfilis, G

    2005-05-01

    Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma, characterized by clonal proliferation of plasma cells, that primarily develops in the skin. Five cases have been described to date in which a local triggering stimulus may be involved in development of this skin tumour. We describe the case of a primary cutaneous plasmacytoma localized to the lower lip. This site had been affected for 15 years with recurrent herpes simplex virus-1 infection. Neoplastic plasma cells were found to be bcl-2-positive. We hypothesize that chronic stimulation of keratinocytes by herpes simplex virus-1, possibly through toll-like receptors, may have favoured the release of cytokines (e.g. interleukin-6) able to induce plasma cell proliferation, transformation and survival. PMID:15807675

  12. Analgesic effect of indomethacin shown using the nociceptive flexion reflex in humans.

    PubMed Central

    Guieu, R; Blin, O; Pouget, J; Serratrice, G

    1992-01-01

    This study investigated whether indomethacin has an analgesic effect on the central nervous system. As analgesics which affect the central nervous system produce a correlated decrease in the subjective sensation of pain and in the nociceptive reflex in humans, the amplitude of the nociceptive flexion of the biceps femoris was studied. Eight patients (six men, two women) aged 35-70 years (mean 51) with rheumatic diseases were included in the study. Each patient was his or her own control and was given a single intramuscular injection of either 50 mg of indomethacin or a placebo. A placebo controlled, double blind experimental design was used. Patients were evaluated before and 30, 60, and 75 minutes after the injection. Seventy five minutes after injection, indomethacin gave a 54% decrease in the amplitude of the nociceptive reflex, whereas the placebo produced a decrease of only 12%. This suggests that indomethacin exerts a depressive effect on the amplitude of the nociceptive reflex and affects the central nervous system as part of its analgesic action. PMID:1575589

  13. Chronic Psychological Stress Enhances Nociceptive Processing in the Urinary Bladder in High-Anxiety Rats

    PubMed Central

    Robbins, M.T.; DeBerry, J.; Ness, T.J.

    2007-01-01

    This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC). PMID:17521683

  14. Effects of Visual Cortex Activation on the Nociceptive Blink Reflex in Healthy Subjects

    PubMed Central

    Sava, Simona L.; de Pasqua, Victor; Magis, Delphine; Schoenen, Jean

    2014-01-01

    Bright light can cause excessive visual discomfort, referred to as photophobia. The precise mechanisms linking luminance to the trigeminal nociceptive system supposed to mediate this discomfort are not known. To address this issue in healthy human subjects we modulated differentially visual cortex activity by repetitive transcranial magnetic stimulation (rTMS) or flash light stimulation, and studied the effect on supraorbital pain thresholds and the nociceptive-specific blink reflex (nBR). Low frequency rTMS that inhibits the underlying cortex, significantly decreased pain thresholds, increased the 1st nBR block ipsi- and contralaterally and potentiated habituation contralaterally. After high frequency or sham rTMS over the visual cortex, and rMS over the right greater occipital nerve we found no significant change. By contrast, excitatory flash light stimulation increased pain thresholds, decreased the 1st nBR block of ipsi- and contralaterally and increased habituation contralaterally. Our data demonstrate in healthy subjects a functional relation between the visual cortex and the trigeminal nociceptive system, as assessed by the nociceptive blink reflex. The results argue in favour of a top-down inhibitory pathway from the visual areas to trigemino-cervical nociceptors. We postulate that in normal conditions this visuo-trigeminal inhibitory pathway may avoid disturbance of vision by too frequent blinking and that hypoactivity of the visual cortex for pathological reasons may promote headache and photophobia. PMID:24936654

  15. Introduction and validation of a less painful algorithm to estimate the nociceptive flexion reflex threshold.

    PubMed

    Lichtner, Gregor; Golebiewski, Anna; Schneider, Martin H; von Dincklage, Falk

    2015-05-22

    The nociceptive flexion reflex (NFR) is a widely used tool to investigate spinal nociception for scientific and diagnostic purposes, but its clinical use is currently limited due to the painful measurement procedure, especially restricting its applicability for patients suffering from chronic pain disorders. Here we introduce a less painful algorithm to assess the NFR threshold. Application of this new algorithm leads to a reduction of subjective pain ratings by over 30% compared to the standard algorithm. We show that the reflex threshold estimates resulting from application of the new algorithm can be used interchangeably with those of the standard algorithm after adjusting for the constant difference between the algorithms. Furthermore, we show that the new algorithm can be applied at shorter interstimulus intervals than are commonly used with the standard algorithm, since reflex threshold values remain unchanged and no habituation effects occur when reducing the interstimulus interval for the new algorithm down to 3s. Finally we demonstrate the utility of the new algorithm to investigate the modulation of nociception through different states of attention. Taken together, the here presented new algorithm could increase the utility of the NFR for investigation of nociception in subjects who were previously not able to endure the measurement procedure, such as chronic pain patients.

  16. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice

    PubMed Central

    Hassani, Faezeh Vahdati; Rezaee, Ramin; Sazegara, Hasan; Hashemzaei, Mahmoud; Shirani, Kobra; Karimi, Gholamreza

    2015-01-01

    Objective(s): Based on the previous reports, silymarin can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration. Regarding the fact that inflammation plays an important role in neuropathic and formalin-induced pain, it was assumed that silymarin could reduce pain. The present study investigates the analgesic effects of silymarin in chemical nociception and a model of neuropathic pain. Materials and Methods: Chemical nociception was produced by injection of 20 µl of formalin (0.5% formaldehyde in saline) into the plantar region of the right hind paw. A sciatic-nerve ligated mouse was applied as the model of neuropathic pain and the antinociceptive response of silymarin was examined 14 days after unilateral nerve-ligation using the hot plate test. Results: The intraperitoneal administration of silymarin (25, 50, and, 100 mg/kg) 2 hr prior to the intraplantar formalin injection suppressed the nociceptive response during the late phase of the formalin test significantly, but it was not in a dose-dependent manner. Different doses of silymarin 14 days after unilateral sciatic nerve ligation in hot plate test did not induce obvious antinociception. Conclusion: Results of the present study indicated that repeated administration of silymarin prevents the formalin-induced nociceptive behavior. However, it is not effective in the treatment of sciatic neuropathic pain. PMID:26351564

  17. Exteroceptive aspects of nociception: Insights from graphesthesia and two-point discrimination

    PubMed Central

    Mørch, Carsten Dahl; Andersen, Ole K.; Quevedo, Alexandre S.; Arendt-Nielsen, Lars; Coghill, Robert C.

    2011-01-01

    The exteroceptive capabilities of the nociceptive system have long been thought to be considerably more limited than those of the tactile system. However, most investigations of spatio-temporal aspects of the nociceptive system have largely focused on intensity coding as consequence of spatial or temporal summation. Graphesthesia, the identification of numbers “written” on the skin, and assessment of the two-point discrimination thresholds were used to compare the exteroceptive capabilities of the tactile and nociceptive systems. Numbers were “written” on the forearm and the abdomen by tactile stimulation and by painful non-contact infrared laser heat stimulation. Subjects performed both graphesthesia tasks better than chance. The tactile graphesthesia tasks were performed with 89% (82–97%) correct responses on the forearm and 86% (79–94%) correct responses on the abdomen. Tactile graphesthesia tasks were significantly better than painful heat graphesthesia tasks that were performed with 31% (23–40%) and 44% (37–51%) correct responses on the forearm and abdomen, respectively. These findings demonstrate that the central nervous system is capable of assembling complex spatio-temporal patterns of nociceptive information from the body surface into unified mental objects with sufficient accuracy to enable behavioral discrimination. PMID:20541867

  18. Exteroceptive aspects of nociception: insights from graphesthesia and two-point discrimination.

    PubMed

    Mørch, Carsten Dahl; Andersen, Ole K; Quevedo, Alexandre S; Arendt-Nielsen, Lars; Coghill, Robert C

    2010-10-01

    The exteroceptive capabilities of the nociceptive system have long been thought to be considerably more limited than those of the tactile system. However, most investigations of spatio-temporal aspects of the nociceptive system have largely focused on intensity coding as consequence of spatial or temporal summation. Graphesthesia, the identification of numbers "written" on the skin, and assessment of the two-point discrimination thresholds were used to compare the exteroceptive capabilities of the tactile and nociceptive systems. Numbers were "written" on the forearm and the abdomen by tactile stimulation and by painful non-contact infrared laser heat stimulation. Subjects performed both graphesthesia tasks better than chance. The tactile graphesthesia tasks were performed with 89% (82-97%) correct responses on the forearm and 86% (79-94%) correct responses on the abdomen. Tactile graphesthesia tasks were significantly better than painful heat graphesthesia tasks that were performed with 31% (23-40%) and 44% (37-51%) correct responses on the forearm and abdomen, respectively. These findings demonstrate that the central nervous system is capable of assembling complex spatio-temporal patterns of nociceptive information from the body surface into unified mental objects with sufficient accuracy to enable behavioral discrimination.

  19. High Plasma Pentraxin 3 Levels in Diabetic Polyneuropathy Patients with Nociceptive Pain.

    PubMed

    Salcini, Celal; Atasever-Arslan, Belkis; Sunter, Gulin; Gur, Hazal; Isik, Fatma Busra; Saylan, Cemil Can; Yalcin, Ayse Destina

    2016-01-01

    Diabetic polyneuropathy is the most common neurologic complication of diabetes mellitus. Underlying mechanisms of diabetic polyneuropathy are related to various metabolic and inflammatory pathways. Pentraxin 3 (PTX3) is an acute phase protein that is produced locally at the inflammatory sites by several cell types. Thioredoxin binding protein 2 (TBP2) is a thioredoxin regulator involved in intracellular energy pathways and cell growth. We measured the plasma levels of PTX3 and TBP2 in type 2 diabetic patients (n = 27) with pain complaints and compared their levels with those of healthy age- and sex-matched subjects (n = 24). Moreover, the diabetic patients were divided into two groups using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale: patients with nociceptive pain that is caused by tissue damage and patients with neuropathic pain that is caused by nerve damage. Patients with LANSS scores of < 12 were considered to have nocicceptive pain (n = 15), while patients with LANSS scores of ≥ 12 were considered to have neuropathic pain (n = 12). We found that PTX3 levels were significantly higher in diabetic patients compared to controls (p = 0.03), but there was no significant difference in the TBP2 levels. Importantly, patients with nociceptive pain had significantly higher PTX3 levels compared to patients with neuropathic pain (p < 0.05). Thus, plasma PTX3 levels can be helpful for discrimination of nociceptive pain from neuropathic pain in diabetic patients. We propose that PTX3 may contribute to the onset of nociceptive pain.

  20. Effects of visual cortex activation on the nociceptive blink reflex in healthy subjects.

    PubMed

    Sava, Simona L; de Pasqua, Victor; Magis, Delphine; Magis, Delphine; Schoenen, Jean; Schoenen, Jean

    2014-01-01

    Bright light can cause excessive visual discomfort, referred to as photophobia. The precise mechanisms linking luminance to the trigeminal nociceptive system supposed to mediate this discomfort are not known. To address this issue in healthy human subjects we modulated differentially visual cortex activity by repetitive transcranial magnetic stimulation (rTMS) or flash light stimulation, and studied the effect on supraorbital pain thresholds and the nociceptive-specific blink reflex (nBR). Low frequency rTMS that inhibits the underlying cortex, significantly decreased pain thresholds, increased the 1st nBR block ipsi- and contralaterally and potentiated habituation contralaterally. After high frequency or sham rTMS over the visual cortex, and rMS over the right greater occipital nerve we found no significant change. By contrast, excitatory flash light stimulation increased pain thresholds, decreased the 1st nBR block of ipsi- and contralaterally and increased habituation contralaterally. Our data demonstrate in healthy subjects a functional relation between the visual cortex and the trigeminal nociceptive system, as assessed by the nociceptive blink reflex. The results argue in favour of a top-down inhibitory pathway from the visual areas to trigemino-cervical nociceptors. We postulate that in normal conditions this visuo-trigeminal inhibitory pathway may avoid disturbance of vision by too frequent blinking and that hypoactivity of the visual cortex for pathological reasons may promote headache and photophobia. PMID:24936654

  1. Carving executive control at its joints: Working memory capacity predicts stimulus-stimulus, but not stimulus-response, conflict.

    PubMed

    Meier, Matt E; Kane, Michael J

    2015-11-01

    Three experiments examined the relation between working memory capacity (WMC) and 2 different forms of cognitive conflict: stimulus-stimulus (S-S) and stimulus-response (S-R) interference. Our goal was to test whether WMC's relation to conflict-task performance is mediated by stimulus-identification processes (captured by S-S conflict), response-selection processes (captured by S-R conflict), or both. In Experiment 1, subjects completed a single task presenting both S-S and S-R conflict trials, plus trials that combined the 2 conflict types. We limited ostensible goal-maintenance contributions to performance by requiring the same goal for all trial types and by presenting frequent conflict trials that reinforced the goal. WMC predicted resolution of S-S conflict as expected: Higher WMC subjects showed reduced response time interference. Although WMC also predicted S-R interference, here, higher WMC subjects showed increased error interference. Experiment 2A replicated these results in a version of the conflict task without combined S-S/S-R trials. Experiment 2B increased the proportion of congruent (nonconflict) trials to promote reliance on goal-maintenance processes. Here, higher WMC subjects resolved both S-S and S-R conflict more successfully than did lower WMC subjects. The results were consistent with Kane and Engle's (2003) 2-factor theory of cognitive control, according to which WMC predicts executive-task performance through goal-maintenance and conflict-resolution processes. However, the present results add specificity to the account by suggesting that higher WMC subjects better resolve cognitive conflict because they more efficiently select relevant stimulus features against irrelevant, distracting ones.

  2. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

    PubMed Central

    Rodriguez, Jesse S.; McMahon, Lance R.

    2014-01-01

    SUMMARY Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50 = 0.01 mg/kg) and decreased response rate (ED50 = 0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940 = JWH-018 > Δ9-THC = WIN-55212-2 = JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and 9-THC decreased rectal temperature by 2.2 and 2.8 °C, respectively; the doses decreasing temperature by 2 °C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and 9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoid on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects. PMID:24972243

  3. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects.

    PubMed

    Rodriguez, Jesse S; McMahon, Lance R

    2014-10-01

    Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

  4. Effects of acute stressors on nociception, adrenocortical responses and behavior of dairy cows.

    PubMed

    Herskin, Mette S; Munksgaard, Lene; Ladewig, Jan

    2004-12-15

    Effects of acute stressors on behavioral, adrenocortical and nociceptive responses were examined in 24 dairy cows kept in tie stalls, using 15 min of social isolation in novel surroundings (ISOL), fixation by the head in the home stall (FIX) and the provision of novel neighbors/stall (NEIGH) as acute stressors as well as a control treatment (CON). Each cow was exposed to one treatment daily in a balanced order. All stressors led to signs of hypoalgesia as indicated by slower (P=0.01) and reduced responses (P<0.10) toward nociceptive laser stimulation after exposure to the acute stressors. ISOL, however, had stronger effects than FIX or NEIGH. ISOL or FIX led to increased plasma concentration of cortisol (P<0.001), whereas NEIGH or CON did not. The behavioral responses were affected by treatments as well, as shown by decreased rumination for all stressors (P<0.001) and a gradual increase in active avoidance from CON to NEIGH to FIX (P<0.001). Furthermore, exposure to NEIGH led to increased exploration (P<0.001), aggression (P<0.10) and self-grooming behavior (P<0.10) compared with the CON treatment. The results suggest that nociceptive changes are part of responses toward acute stress in dairy cows. The nociceptive changes, however, were not direct reflections of the adrenocortical or behavioral responses toward the acute stressors. Therefore, quantification of nociceptive changes, in combination with behavioral and physiological registrations, can be one way to broaden the range of biological systems, considered for the study of animals under stress, and thereby extend the understanding of responses toward acute stress in dairy cows. PMID:15581663

  5. Consequences of a Human TRPA1 Genetic Variant on the Perception of Nociceptive and Olfactory Stimuli

    PubMed Central

    Heimann, Dirk; Doehring, Alexandra; Walter, Carmen; Dimova, Violeta; Geisslinger, Gerd; Lötsch, Jörn

    2014-01-01

    Background TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity. Methods Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2). Results Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced. Conclusions The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants. PMID:24752136

  6. Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats.

    PubMed

    Takehana, Shiori; Sekiguchi, Kenta; Inoue, Maki; Kubota, Yoshiko; Ito, Yukihiko; Yui, Kei; Shimazu, Yoshihito; Takeda, Mamoru

    2016-01-01

    Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia. PMID:26608254

  7. Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats.

    PubMed

    Takehana, Shiori; Sekiguchi, Kenta; Inoue, Maki; Kubota, Yoshiko; Ito, Yukihiko; Yui, Kei; Shimazu, Yoshihito; Takeda, Mamoru

    2016-01-01

    Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia.

  8. Stimulus control of cocaine self-administration.

    PubMed

    Weiss, Stanley J; Kearns, David N; Cohn, Scott I; Schindler, Charles W; Panlilio, Leigh V

    2003-01-01

    Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior.

  9. Stimulus Offers Funding Support for Ed. Facilities

    ERIC Educational Resources Information Center

    Ash, Katie

    2009-01-01

    Some two months after enactment of the federal economic-stimulus package, school facilities directors are still trying to piece together how much money will be available under the measure for school construction projects, what it can be used for, and when it can be accessed. Before President Barack Obama signed the $787 billion American Recovery…

  10. Electrophysiological Correlates of Stimulus Equivalence Processes

    ERIC Educational Resources Information Center

    Haimson, Barry; Wilkinson, Krista M.; Rosenquist, Celia; Ouimet, Carolyn; McIlvane, William J.

    2009-01-01

    Research reported here concerns neural processes relating to stimulus equivalence class formation. In Experiment 1, two types of word pairs were presented successively to normally capable adults. In one type, the words had related usage in English (e.g., uncle, aunt). In the other, the two words were not typically related in their usage (e.g.,…

  11. Facilities Bonds Prove Hot Item under Stimulus

    ERIC Educational Resources Information Center

    Klein, Alyson

    2009-01-01

    Construction bonding authority--a technical, and often obscure, source of capital funding for school districts--has emerged as a hot ticket for those looking to finance school facilities work under the federal government's economic-stimulus program. School districts left out of the loop for direct funding are lining up for some of at least $24…

  12. Stimulus Picture Identification in Articulation Testing

    ERIC Educational Resources Information Center

    Mullen, Patricia A.; Whitehead, Robert L.

    1977-01-01

    Compared with 20 normal speaking and 20 articulation defective Ss (7 and 8 years old) was the percent of correct initial identification of stimulus pictures on the Goldman-Fristoe Test of Articulation with the percent correct identification on the Arizona Articulation Proficiency Scale. (Author/IM)

  13. States Hurt as Stimulus Loses Steam

    ERIC Educational Resources Information Center

    Cavanagh, Sean; Hollingsworth, Heather

    2011-01-01

    States are finally arriving at the "funding cliff"--the point where about $100 billion in federal economic-stimulus aid for education runs out. The loss seems certain to compound severe budget woes and could mean thousands of school layoffs and the elimination of popular programs and services in districts across the country. The bulk of that…

  14. Infants' Bimodal Recognition of Human Stimulus Configurations.

    ERIC Educational Resources Information Center

    Francis, Patricia L.; McCroy, George

    The major purpose of this study was to examine bimodal coordination of featural stimuli in infancy. Specifically of interest was infant sensitivity to the auditory and visual combinations that characterize male and female stimulus configurations. A total of 27 male and 27 female subjects of 3, 6, and 9 months of age participated in the study.…

  15. Stimulus control of cocaine self-administration.

    PubMed Central

    Weiss, Stanley J; Kearns, David N; Cohn, Scott I; Schindler, Charles W; Panlilio, Leigh V

    2003-01-01

    Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior. PMID:12696744

  16. Stimulus type and the list strength paradigm.

    PubMed

    Osth, Adam F; Dennis, Simon; Kinnell, Angela

    2014-01-01

    In recognition memory, increasing the strength of studied items does not reduce performance on other items, an effect dubbed the null list strength effect (LSE). While this finding has been replicated many times, it has rarely been tested using stimuli other than single words. Kinnell and Dennis ( 2012 ) recently tested for the presence of list length effects using non-word stimulus classes while controlling for the confounds that are present in list length designs. Small list length effects were found for fractal and face images. We adopted the same paradigm and stimuli used by Kinnell and Dennis to test whether these stimuli would be susceptible to list strength effects as well. We found significant LSEs for fractal images, but null LSEs for face images and natural scene photographs. Stimuli other than words do appear to be susceptible to list strength effects, but these effects are small and restricted to particular stimulus classes, as is the case in list length designs. Models of memory may be able to address differences between these stimulus classes by attributing differences in representational overlap between the stimulus classes.

  17. The Poverty of the Mayan Stimulus

    ERIC Educational Resources Information Center

    Pye, Clifton

    2012-01-01

    Poverty of the stimulus (POS) arguments have instigated considerable debate in the recent linguistics literature. This article uses the comparative method to challenge the logic of POS arguments. Rather than question the premises of POS arguments, the article demonstrates how POS arguments for individual languages lead to a "reductio ad absurdum"…

  18. Stimulus Equivalence: Testing Sidman's (2000) Theory

    ERIC Educational Resources Information Center

    Minster, Sara Tepaeru; Jones, Max; Elliffe, Douglas; Muthukumaraswamy, Suresh D.

    2006-01-01

    Sidman's (2000) theory regarding the origin of equivalence relations predicts that a reinforcing stimulus common to distinct equivalence classes must drop out of the equivalence relations. This prediction was tested in the present study by arranging class-specific reinforcers, R1 and R2, following correct responding on the prerequisite conditional…

  19. Stimulus Configuration, Classical Conditioning, and Hippocampal Function.

    ERIC Educational Resources Information Center

    Schmajuk, Nestor A.; DiCarlo, James J.

    1991-01-01

    The participation of the hippocampus in classical conditioning is described in terms of a multilayer network portraying stimulus configuration. A model of hippocampal function is presented, and computer simulations are used to study neural activity in the various brain areas mapped according to the model. (SLD)

  20. Stimulus Over-Selectivity in Rats

    ERIC Educational Resources Information Center

    Gibson, Evelyn; Reed, Phil

    2005-01-01

    The present study explored whether a similar phenomenon to stimulus over-selectivity occurred in rats, in the hope of establishing a non-human model for the autism. Rats were serially presented with two-15 seconds, two-element compound stimuli prior to the delivery of food, in an appetitive classical conditioning procedure. Each compound stimulus…

  1. Bigrams and the Richness of the Stimulus

    ERIC Educational Resources Information Center

    Kam, Xuan-Nga Cao; Stoyneshka, Iglika; Tornyova, Lidiya; Fodor, Janet D.; Sakas, William G.

    2008-01-01

    Recent challenges to Chomsky's "poverty of the stimulus" thesis for language acquisition suggest that children's primary data may carry "indirect evidence" about linguistic constructions despite containing no instances of them. Indirect evidence is claimed to suffice for grammar acquisition, without need for innate knowledge. This article reports…

  2. Evaluation of a Brief Stimulus Preference Assessment.

    ERIC Educational Resources Information Center

    Roane, Henry S.; Vollmer, Timothy R.; Ringdahl, Joel E.; Marcus, Bethany A.

    1998-01-01

    A study evaluated the utility of a five-minute stimulus preference assessment for 20 individuals with developmental disabilities. The brief assessment identified stimuli that functioned as reinforcers for a simple operant response and identified preferred stimuli that were differentially effective as reinforcers. This assessment was associated…

  3. Discriminative stimulus effects of hallucinogenic drugs: a possible relation to reinforcing and aversive effects.

    PubMed

    Mori, Tomohisa; Yoshizawa, Kazumi; Shibasaki, Masahiro; Suzuki, Tsutomu

    2012-01-01

    The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers are trying to elucidate the mechanisms that underlie the discriminative stimulus effects of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, the patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ketamine, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. However, the mechanisms of the discriminative stimulus effects of hallucinogenic drugs are not yet fully clear. This review will briefly focus on the recent findings regarding hallucinogenic/psychotomimetic drug-induced discriminative stimulus effects in animals. In summary, recent research has demonstrated that there are at least two plausible mechanisms that can explain the cue of the discriminative stimulus effects of hallucinogenic drugs; one is mediated mainly by 5-HT(2) receptors, and the other is mediated through sigma-1 (σ(1))-receptor chaperone regulated by endogenous hallucinogenic ligand.

  4. Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors

    PubMed Central

    Gintzler, Alan R; Liu, Nai-Jiang

    2013-01-01

    Estrogens have a multitude of effects on opioid systems and are thought to play a key role in sexually dimorphic nociception and opioid antinociception. Heretofore, classical genomic actions of estrogens are largely thought to be responsible for the effects of these steroids on nociception and opioid antinociception. The recent discovery that estrogens can also activate estrogen receptors that are located in the plasma membrane, the effects of which are manifest in seconds to minutes instead of hours to days has revolutionized our thinking concerning the ways in which estrogens are likely to modulate pain responsiveness and the dynamic nature of that modulation. This review summarizes parameters of opioid functionality and nociception that are subject to modulation by estrogens, underscoring the added dimensions of such modulation that accrues from rapid membrane estrogen receptor signaling. Implications of this mode of signaling regarding putative sources of estrogens and its degradation are also discussed. PMID:23036438

  5. Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors

    PubMed Central

    Mrozkova, Petra; Spicarova, Diana; Palecek, Jiri

    2016-01-01

    Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception. PMID:27755539

  6. Asymmetrical Stimulus Generalization following Differential Fear Conditioning

    PubMed Central

    Bang, Sun Jung; Allen, Timothy A.; Jones, Lauren K.; Boguszewski, Pawel; Brown, Thomas H.

    2008-01-01

    Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22 kHz USVs and 50 kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22 kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4 kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50 kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS+) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS−) was explicitly unpaired with the US. There were no significant differences among these cues in CS+-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS+ was a 22 kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS−, discrimination failed due to generalization from the CS+. Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination. PMID:18434217

  7. trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors.

    PubMed

    Fang, Xin; Djouhri, Laiche; McMullan, Simon; Berry, Carol; Okuse, Kenji; Waxman, Stephen G; Lawson, Sally N

    2005-05-11

    To test the hypothesis that trkA (the high-affinity NGF receptor) is selectively expressed in nociceptive dorsal root ganglion (DRG) neurons, we examined the intensity of trkA immunoreactivity in single dye-injected rat DRG neurons, the sensory receptor properties of which were identified in vivo with mechanical and thermal stimuli. We provide the first evidence in single identified neurons that strong trkA expression in DRGs is restricted to nociceptive neurons, probably accounting for the profound influence of NGF on these neurons. Furthermore, we demonstrate that trkA expression is as high in rapidly conducting (Aalpha/beta) as in more slowly conducting (Adelta and C) nociceptors. All Aalpha/beta low-threshold mechanoreceptors (LTMs) are trkA negative, although weak but detectable trkA is present in some C and Adelta LTMs. NGF can influence electrophysiological properties of DRG neurons, probably by binding to trkA. We found positive correlations for single identified Aalpha/beta (but not C or Adelta) nociceptors between trkA immunocytochemical intensity and electrophysiological properties typical of nociceptors, namely long action potential and afterhyperpolarization durations and large action potential amplitudes. Furthermore, for Aalpha/beta (notCorAdelta) nociceptors, trkA intensity is inversely correlated with conduction velocity. Similar relationships, again only in Aalpha/beta nociceptors, between electrophysiological properties and trkA expression exist for sodium channel Nav1.8 but not Nav1.9 immunoreactivities. These findings suggest that in Aalpha/beta nociceptors, influences of NGF on expression levels of Nav1.8 are related to, and perhaps limited by, expression levels of trkA. This view is supported by a positive correlation between immuno-intensities of trkA and Nav1.8 in A-fiber, but not C-fiber, nociceptors. PMID:15888662

  8. Distinct temporal filtering mechanisms are engaged during dynamic increases and decreases of noxious stimulus intensity

    PubMed Central

    Mørch, Carsten Dahl; Frahm, Ken Steffen; Coghill, Robert C.; Arendt-Nielsen, Lars; Andersen, Ole Kæseler

    2015-01-01

    Abstract Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1°C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1°C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1°C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity. PMID:26035254

  9. THE NEURONAL DISTRIBUTION OF CANNABINOID RECEPTOR TYPE 1 IN THE TRIGEMINAL GANGLION OF THE RAT

    PubMed Central

    PRICE, T. J.; HELESIC, G.; PARGHI, D.; HARGREAVES, K. M.; FLORES, C. M.

    2007-01-01

    Cannabinoid compounds have been shown to produce antinociception and antihyperalgesia by acting upon cannabinoid receptors located in both the CNS and the periphery. A potential mechanism by which cannabinoids could inhibit nociception in the periphery is the activation of cannabinoid receptors located on one or more classes of primary nociceptive neurons. To address this hypothesis, we evaluated the neuronal distribution of cannabinoid receptor type 1 (CB1) in the trigeminal ganglion (TG) of the adult rat through combined in situ hybridization (ISH) and immunohistochemistry (IHC). CB1 receptor mRNA was localized mainly to medium and large diameter neurons of the maxillary and mandibular branches of the TG. Consistent with this distribution, in a de facto nociceptive sensory neuron population that exhibited vanilloid receptor type 1 immunoreactivity, colocalization with CB1 mRNA was also sparse (<5%). Furthermore, very few neurons (approximately 5%) in the peptidergic (defined as calcitonin gene-related peptide- or substance P-immunoreactive) or the isolectin B4-binding sensory neuron populations contained CB1 mRNA. In contrast, and consistent with the neuron-size distribution for CB1, nearly 75% of CB1-positive neurons exhibited N52-immunoreactivity, a marker of myelinated axons. These results indicate that in the rat TG, CB1 receptors are expressed predominantly in neurons that are not thought to subserve nociceptive neurotransmission in the noninjured animal. Taken together with the absence of an above background in situ signal for CB2 mRNA in TG neurons, these findings suggest that the peripherally mediated antinociceptive effects of cannabinoids may involve either as yet unidentified receptors or interaction with afferent neuron populations that normally subserve non-nociceptive functions. PMID:12849749

  10. The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat.

    PubMed

    Price, T J; Helesic, G; Parghi, D; Hargreaves, K M; Flores, C M

    2003-01-01

    Cannabinoid compounds have been shown to produce antinociception and antihyperalgesia by acting upon cannabinoid receptors located in both the CNS and the periphery. A potential mechanism by which cannabinoids could inhibit nociception in the periphery is the activation of cannabinoid receptors located on one or more classes of primary nociceptive neurons. To address this hypothesis, we evaluated the neuronal distribution of cannabinoid receptor type 1 (CB1) in the trigeminal ganglion (TG) of the adult rat through combined in situ hybridization (ISH) and immunohistochemistry (IHC). CB1 receptor mRNA was localized mainly to medium and large diameter neurons of the maxillary and mandibular branches of the TG. Consistent with this distribution, in a de facto nociceptive sensory neuron population that exhibited vanilloid receptor type 1 immunoreactivity, colocalization with CB1 mRNA was also sparse (<5%). Furthermore, very few neurons (approximately 5%) in the peptidergic (defined as calcitonin gene-related peptide- or substance P-immunoreactive) or the isolectin B4-binding sensory neuron populations contained CB1 mRNA. In contrast, and consistent with the neuron-size distribution for CB1, nearly 75% of CB1-positive neurons exhibited N52-immunoreactivity, a marker of myelinated axons. These results indicate that in the rat TG, CB1 receptors are expressed predominantly in neurons that are not thought to subserve nociceptive neurotransmission in the noninjured animal. Taken together with the absence of an above background in situ signal for CB2 mRNA in TG neurons, these findings suggest that the peripherally mediated antinociceptive effects of cannabinoids may involve either as yet unidentified receptors or interaction with afferent neuron populations that normally subserve non-nociceptive functions.

  11. Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer.

    PubMed

    Hirata, T; Keto, Y; Nakata, M; Takeuchi, A; Funatsu, T; Akuzawa, S; Sasamata, M; Miyata, K

    2008-05-01

    In this study, we examined the effects of serotonin (5-HT)3 receptor antagonists (5-HT3RAs) including ramosetron, alosetron, and cilansetron on colonic nociceptive threshold in rats. Furthermore, we established a restraint stress-induced colonic hyperalgesia model in rats, and compared the inhibitory effects of 5-HT3RAs on restraint stress-induced colonic hyperalgesia and diarrhoea with those of loperamide, trimebutine, tiquizium and polycarbophil. The colonic nociceptive threshold was measured as the balloon pressure at the time the rat showed a nociceptive response during colonic distension by an intrarectally inserted balloon. Oral administration of ramosetron (3-30 microg kg(-1)), alosetron (30-300 microg kg(-1)), or cilansetron (30-300 microg kg(-1)) increased the colonic nociceptive threshold in a dose-dependent manner in non-stressed rats. Restraint stress for 1 h significantly decreased the colonic nociceptive threshold, but ramosetron (0.3-3 microg kg(-1)), alosetron (3-30 microg kg(-1)), cilansetron (3-30 microg kg(-1)) and trimebutine (100-1000 mg kg(-1)) significantly inhibited the decrease in the threshold. Loperamide (3-30 mg kg(-1)), tiquizium (100-1000 mg kg(-1)) and polycarbophil (1000 mg kg(-1)) did not affect the restraint stress-induced decrease in the colonic nociceptive threshold. All drugs tested in this study showed dose-dependent inhibition of restraint stress-induced diarrhoea in rats. These results indicate that, unlike existing antidiarrhoeal and spasmolytic agents, 5-HT3RAs have inhibitory effects on colonic nociception, and prevented restraint stress-induced both diarrhoea and hyperalgesia at almost the same doses in rats. This suggests that the 5-HT3RAs may be useful in ameliorating both colonic hyperalgesia and diarrhoea in patients with irritable bowel syndrome. PMID:18221252

  12. Some stimulus properties of inhalants: preliminary findings.

    PubMed

    Vila, J; Colotla, V A

    1981-01-01

    Water-deprived rats allowed access to 0.1% saccharin during 10 min followed by a 15-min (Exp. 1A) or a 30-min (Exp. 1B) exposure to lacquer thinner (6,360 ppm) failed to show a conditioned aversion to the saccharin solution. However, when the solvent odor was paired with water drinking followed by a 0.6 M LiCl injection (Exp. 2) the rats developed an aversion to water associated to lacquer thinner, drinking less than when water was presented alone. The findings suggest that whereas lacquer thinner does not appear to function as an unconditioned stimulus, it may acquire properties of conditioned stimulus in this paradigm of conditioned aversion. PMID:7335142

  13. Stimulus Contrast and Retinogeniculate Signal Processing.

    PubMed

    Rathbun, Daniel L; Alitto, Henry J; Warland, David K; Usrey, W Martin

    2016-01-01

    Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals. PMID:26924964

  14. Stimulus Contrast and Retinogeniculate Signal Processing

    PubMed Central

    Rathbun, Daniel L.; Alitto, Henry J.; Warland, David K.; Usrey, W. Martin

    2016-01-01

    Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals. PMID:26924964

  15. Stimulus Contrast and Retinogeniculate Signal Processing.

    PubMed

    Rathbun, Daniel L; Alitto, Henry J; Warland, David K; Usrey, W Martin

    2016-01-01

    Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals.

  16. Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in rhesus monkeys.

    PubMed

    Li, Jun-Xu; Rice, Kenner C; France, Charles P

    2008-02-01

    Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and related drugs have been studied extensively in rodents, although the generality of those findings across species is not known. The goals of this study were to see whether monkeys could discriminate DOM and to characterize the DOM discriminative stimulus by studying a variety of drugs, including those with hallucinogenic activity in humans. Four rhesus monkeys discriminated between 0.32 mg/kg s.c. DOM and vehicle after an average of 116 (range = 85-166) sessions while responding under a fixed ratio 5 schedule of stimulus shock termination. Increasing doses of DOM occasioned increased responding on the drug lever with the training dose occasioning DOM-lever responding for up to 2 h. The serotonin (5-HT)(2A/2C) receptor antagonists ritanserin and ketanserin, the 5-HT(2A) receptor antagonist (+)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL100907), and its (-)stereoisomer MDL100009 [(-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol], but not haloperidol, completely blocked the discriminative stimulus effects of DOM. Quipazine as well as several drugs with hallucinogenic activity in humans, including (+)lysergic acid diethylamide, (-)DOM, and 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), occasioned DOM-lever responding. The kappa-opioid receptor agonists U-50488 and salvinorin A (a hallucinogen) did not exert DOM-like effects and neither did ketamine, phencyclidine, amphetamine, methamphetamine, cocaine, morphine, yohimbine, fenfluramine, 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), or (+/-)-2-(N-phenethyl-N-1'-propyl)amino-5-hydroxytetralin hydrochloride (N-0434). These data confirm in nonhuman primates a prominent role for 5-HT(2A) receptors in the discriminative stimulus effects of some drugs with hallucinogenic activity in humans. The failure of another drug with hallucinogenic activity (salvinorin A) to substitute for DOM indicates that

  17. Stimulus control in a two-choice discrimination procedure

    NASA Technical Reports Server (NTRS)

    Galloway, W. D.

    1973-01-01

    Experimental investigation upon pigeons of the relation between performance during discriminative training and subsequently obtained stimulus control test results. The results obtained support the proposition that bias generated by training dependencies is a major determiner of stimulus control.

  18. Optimal Stimulus Shapes for Neuronal Excitation

    PubMed Central

    Forger, Daniel B.; Paydarfar, David; Clay, John R.

    2011-01-01

    An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e.g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of post-synaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks. PMID:21760759

  19. Stimulus generalization and operant context renewal.

    PubMed

    Podlesnik, Christopher A; Miranda-Dukoski, Ludmila

    2015-10-01

    Context renewal is the relapse of an extinguished response due to changing the stimulus context following extinction. Reinforcing operant responding in Context A and extinguishing in Context B results in relapse when either returning to Context A (ABA renewal) or introducing a novel Context C (ABC renewal). ABA renewal typically is greater than ABC renewal. The present study assessed whether renewal might be conceptualized through excitatory and inhibitory generalization gradients inferred from studies of stimulus generalization. We arranged one keylight-color alternation frequency for pigeons to signal reinforcement in Phase 1 and a different alternation frequency to signal extinction in Phase 2. During a subsequent test in extinction, we presented a range of keylight-alternation frequencies and found renewal to be a function of keylight-alternation frequency. Specifically, Phase-3 responding increased as keylight-alternation frequency differed from that arranged during extinction in Phase 2. Moreover, we observed a shift in the function beyond the originally reinforced keylight-alternation frequency arranged in training (i.e., peak shift). We discuss the relevance of these findings for conceptualizing stimulus-control processes governing generalization gradients for understanding the processes underlying context renewal. PMID:26241660

  20. Stimulus-responsive nanopreparations for tumor targeting.

    PubMed

    Zhu, Lin; Torchilin, Vladimir P

    2013-01-01

    Nanopreparations such as liposomes, micelles, polymeric and inorganic nanoparticles, and small molecule/nucleic acid/protein conjugates have demonstrated various advantages over "naked" therapeutic molecules. These nanopreparations can be further engineered with functional moieties to improve their performance in terms of circulation longevity, targetability, enhanced intracellular penetration, carrier-mediated enhanced visualization, and stimuli-sensitivity. The idea of application of a stimulus-sensitive drug or imaging agent delivery system for tumor targeting is based on the significant abnormalities in the tumor microenvironment and its cells, such as an acidic pH, altered redox potential, up-regulated proteins and hyperthermia. These internal conditions as well as external stimuli, such as magnetic field, ultrasound and light, can be used to modify the behavior of the nanopreparations that control drug release, improve drug internalization, control the intracellular drug fate and even allow for certain physical interactions, resulting in an enhanced tumor targeting and antitumor effect. This article provides a critical view of current stimulus-sensitive drug delivery strategies and possible future directions in tumor targeting with primary focus on the combined use of stimulus-sensitivity with other strategies in the same nanopreparation, including multifunctional nanopreparations and theranostics. PMID:22869005

  1. Stimulus-responsive nanopreparations for tumor targeting

    PubMed Central

    Zhu, Lin; Torchilin, Vladimir P.

    2012-01-01

    Nanopreparations such as liposomes, micelles, polymeric and inorganic nanoparticles, and small molecule/nucleic acid/protein conjugates have demonstrated various advantages versus “naked” therapeutic molecules. These nanopreparations can be further engineered with functional moieties to improve their performance in terms of circulation longevity, targetability, enhanced intracellular penetration; carrier-mediated enhanced visualization, and stimuli-sensitivity. The idea of application of a stimulus-sensitive drug or imaging agent delivery system for tumor targeting is based on the fact of the significant abnormalities in the tumor microenvironment and its cells, such as an acidic pH, altered redox potential, up-regulated proteins and hyperthermia. These internal conditions as well as external stimuli such as magnetic field, ultrasound and light, can be used to modify the behavior of the nanopreparations that control drug release, improve drug internalization, control the intracellular drug fate and even allow for certain physical interactions, resulting in an enhanced tumor targeting and antitumor effect. This article provides a critical view of current stimulus-sensitive drug delivery strategies and possible future directions in tumor targeting with primary focus on the combined use of stimulus-sensitivity with other strategies in the same nanopreparation, including multifunctional nanopreparations and theranostics. PMID:22869005

  2. Impact of stimulus uncanniness on speeded response

    PubMed Central

    Takahashi, Kohske; Fukuda, Haruaki; Samejima, Kazuyuki; Watanabe, Katsumi; Ueda, Kazuhiro

    2015-01-01

    In the uncanny valley phenomenon, the causes of the feeling of uncanniness as well as the impact of the uncanniness on behavioral performances still remain open. The present study investigated the behavioral effects of stimulus uncanniness, particularly with respect to speeded response. Pictures of fish were used as visual stimuli. Participants engaged in direction discrimination, spatial cueing, and dot-probe tasks. The results showed that pictures rated as strongly uncanny delayed speeded response in the discrimination of the direction of the fish. In the cueing experiment, where a fish served as a task-irrelevant and unpredictable cue for a peripheral target, we again observed that the detection of a target was slowed when the cue was an uncanny fish. Conversely, the dot-probe task suggested that uncanny fish, unlike threatening stimulus, did not capture visual spatial attention. These results suggested that stimulus uncanniness resulted in the delayed response, and importantly this modulation was not mediated by the feelings of threat. PMID:26052297

  3. Stimulus-responsive nanopreparations for tumor targeting.

    PubMed

    Zhu, Lin; Torchilin, Vladimir P

    2013-01-01

    Nanopreparations such as liposomes, micelles, polymeric and inorganic nanoparticles, and small molecule/nucleic acid/protein conjugates have demonstrated various advantages over "naked" therapeutic molecules. These nanopreparations can be further engineered with functional moieties to improve their performance in terms of circulation longevity, targetability, enhanced intracellular penetration, carrier-mediated enhanced visualization, and stimuli-sensitivity. The idea of application of a stimulus-sensitive drug or imaging agent delivery system for tumor targeting is based on the significant abnormalities in the tumor microenvironment and its cells, such as an acidic pH, altered redox potential, up-regulated proteins and hyperthermia. These internal conditions as well as external stimuli, such as magnetic field, ultrasound and light, can be used to modify the behavior of the nanopreparations that control drug release, improve drug internalization, control the intracellular drug fate and even allow for certain physical interactions, resulting in an enhanced tumor targeting and antitumor effect. This article provides a critical view of current stimulus-sensitive drug delivery strategies and possible future directions in tumor targeting with primary focus on the combined use of stimulus-sensitivity with other strategies in the same nanopreparation, including multifunctional nanopreparations and theranostics.

  4. Stimulus generalization and operant context renewal.

    PubMed

    Podlesnik, Christopher A; Miranda-Dukoski, Ludmila

    2015-10-01

    Context renewal is the relapse of an extinguished response due to changing the stimulus context following extinction. Reinforcing operant responding in Context A and extinguishing in Context B results in relapse when either returning to Context A (ABA renewal) or introducing a novel Context C (ABC renewal). ABA renewal typically is greater than ABC renewal. The present study assessed whether renewal might be conceptualized through excitatory and inhibitory generalization gradients inferred from studies of stimulus generalization. We arranged one keylight-color alternation frequency for pigeons to signal reinforcement in Phase 1 and a different alternation frequency to signal extinction in Phase 2. During a subsequent test in extinction, we presented a range of keylight-alternation frequencies and found renewal to be a function of keylight-alternation frequency. Specifically, Phase-3 responding increased as keylight-alternation frequency differed from that arranged during extinction in Phase 2. Moreover, we observed a shift in the function beyond the originally reinforced keylight-alternation frequency arranged in training (i.e., peak shift). We discuss the relevance of these findings for conceptualizing stimulus-control processes governing generalization gradients for understanding the processes underlying context renewal.

  5. Measuring Joint Stimulus Control by Complex Graph/Description Correspondences

    ERIC Educational Resources Information Center

    Fields, Lanny; Spear, Jack

    2012-01-01

    Joint stimulus control occurs when responding is determined by the correspondence of elements of a complex sample and a complex comparison stimulus. In academic settings, joint stimulus control of behavior would be evidenced by the selection of an accurate description of a complex graph in which each element of a graph corresponded to particular…

  6. Trigemino-hypoglossal somatic reflex in the pharmacological studies of nociception in orofacial area.

    PubMed

    Zubrzycki, Marek; Janecka, Anna; Zubrzycka, Maria

    2015-01-01

    Disorders involving the orofacial area represent a major medical and social problem. They are a consequence of central nociceptive processes associated with stimulation of the trigeminal nerve nucleus. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neuropeptide solutions, can be used in the pharmacological studies of nociception in orofacial area. The investigated neuropeptides diffuse through the cerebroventricular lining producing an analgesic effect either directly, through the trigemino-hypoglossal reflex arc neurons or indirectly through the periaqueductal central gray, raphe nuclei or locus coeruleus neurons. The aim of this review is to present the effect of pharmacological activity of various neuropeptides affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats. PMID:26581382

  7. Artificial nociception and motor responses to pain, for humans and robots.

    PubMed

    Bagnato, Carlo; Takagi, Atsushi; Burdet, Etienne

    2015-01-01

    This concept paper describes nociception and the role of pain in humans. Understanding the mechanisms of pain can give insight into the implementation of artificial pain for robots. Identification of noxious contacts could help robots to elicit reactions in order to avoid or minimize damage to the robot and the environment. The information processing of artificial pain can also be used to optimally regulate incoming sensory information and prevent accidents or real pain to the users of robotic systems and prostheses, improving the performance of robots and their interaction with human users. Besides the applications of artificial nociception for robotic manipulation and intelligent prostheses, the development of computational models of pain mechanisms for the discrimination of noxious stimuli from innocuous touch can find crucial clinical applications, addressing the vulnerable non-verbal population who are unable to report pain.

  8. Gravity stress elevates the nociceptive threshold level with immunohistochemical changes in the rat brain

    NASA Astrophysics Data System (ADS)

    Kumei, Yasuhiro; Shimokawa, Reiko; Kimoto, Mari; Kawauchi, Yasuko; Shimokawa, Hitoyata; Makita, Koshi; Ohya, Keiichi; Toda, Kazuo

    2001-08-01

    Young Wistar male rats were exposed to 2G hypergravity by continuous centrifugation for 15 minutes. The nociceptive threshold was measured by using the von Frey type filament on the rat skin surfaces after hypergravity exposure. Following the hypergravity exposure, rats were sacrificed with anesthesia, then perfused and fixed for immunohistochemical examination. The 2G hypergravity elevated the nociceptive threshold up to 2-fold and induced analgesic effects on rats that remained for 2 hours after termination of centrifugation. Expression of Fos-immunoreactive proteins was prominently induced by 2G hypergravity in the arcuate nucleas and the paraventricular nucleus of the hypothalamus. The 15-minute flash exposure to 2G hypergravity induced pain suppression in rats, which might be attributed to change of neuronal activity in rat hypothalamus.

  9. Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice

    PubMed Central

    Quadros, Andreza U.; Pinto, Larissa G.; Fonseca, Miriam M.; Kusuda, Ricardo; Cunha, Fernando Q.; Cunha, Thiago M.

    2015-01-01

    The assessment of articular nociception in experimental animals is a challenge because available methods are limited and subject to investigator influence. In an attempt to solve this problem, the purpose of this study was to establish the use of dynamic weight bearing (DWB) as a new device for evaluating joint nociception in an experimental model of antigen-induced arthritis (AIA) in mice. AIA was induced in Balb/c and C57BL/6 mice, and joint nociception was evaluated by DWB. Western Blotting and real-time PCR were used to determine protein and mRNA expression, respectively. DWB detected a dose- and time-dependent increase in joint nociception during AIA and was able to detect the dose-response effects of different classes of analgesics. Using DWB, it was possible to evaluate the participation of spinal glial cells (microglia and astrocytes) and cytokines (IL-1β and TNFα) for the genesis of joint nociception during AIA. In conclusion, the present results indicated that DWB is an effective, objective and predictable test to study both the pathophysiological mechanisms involved in arthritic nociception in mice and for evaluating novel analgesic drugs against arthritis. PMID:26511791

  10. Selective impact of Tau loss on nociceptive primary afferents and pain sensation.

    PubMed

    Sotiropoulos, Ioannis; Lopes, André T; Pinto, Vitor; Lopes, Sofia; Carlos, Sara; Duarte-Silva, Sara; Neves-Carvalho, Andreia; Pinto-Ribeiro, Filipa; Pinheiro, Sara; Fernandes, Rui; Almeida, Armando; Sousa, Nuno; Leite-Almeida, Hugo

    2014-11-01

    Tau protein hyperphosphorylation and consequent malfunction are hallmarks of Alzheimer's disease pathology; importantly, pain perception is diminished in these patients. In physiological conditions, Tau contributes to cytoskeletal dynamics and in this way, influences a number of cellular mechanisms including axonal trafficking, myelination and synaptic plasticity, processes that are also implicated in pain perception. However, there is no in vivo evidence clarifying the role of Tau in nociception. Thus, we tested Tau-null (Tau-/-) and Tau+/+ mice for acute thermal pain (Hargreaves' test), acute and tonic inflammatory pain (formalin test) and mechanical allodynia (Von Frey test). We report that Tau-/- animals presented a decreased response to acute noxious stimuli when compared to Tau+/+ while their pain-related behavior is augmented under tonic painful stimuli. This increased reactivity to tonic pain was accompanied by enhanced formalin-evoked c-fos staining of second order nociceptive neurons at Tau-null dorsal horn. In addition, we analyzed the primary afferents conveying nociceptive signals, estimating sciatic nerve fiber density, myelination and nerve conduction. Ultrastructural analysis revealed a decreased C-fiber density in the sciatic nerve of Tau-null mice and a hypomyelination of myelinated fibers (Aδ-fibers) - also confirmed by western blot analysis - followed by altered conduction properties of Tau-null sciatic nerves. To our knowledge, this is the first in vivo study that demonstrates that Tau depletion negatively affects the main systems conveying nociceptive information to the CNS, adding to our knowledge about Tau function(s) that might also be relevant for understanding peripheral neurological deficits in different Tauopathies.

  11. Effect of gonadotropin-releasing hormone analogue on thermal nociception in mice.

    PubMed

    Bobyntsev, I I; Sever'yanova, L A; Kryukov, A A

    2006-02-01

    Intraperitoneal treatment with an analogue of gonadotropin-releasing hormone in doses of 0.004-450 microg/kg produced an analgesic effect on male mice in the hot plate test. Castration significantly elevated the nociceptive thresholds. In castrated mice the effects of the test peptide were less pronounced and had an algesic nature. Our results indicate that these effects depend on functional activity of the hypothalamic-pituitary-gonadal axis.

  12. The roles of sodium channels in nociception: implications for mechanisms of pain

    PubMed Central

    Cummins, Theodore R; Sheets, Patrick L; Waxman, Stephen G

    2007-01-01

    Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms. Voltage-gated sodium channels are critically important for electrogenesis and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine. Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation. These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception. Experiments with transgenic mice lines have clearly implicated Nav1.7, Nav1.8 and Nav1.9 in inflammatory, and possibly neuropathic, pain. However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels has come out recently from studies on human inherited disorders of nociception. Point mutations in Nav1.7 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes. Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain. Equally exciting, a recent study has indicated that recessive mutations in Nav1.7 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain. In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception. PMID:17766042

  13. Peripheral nerve injury activates convergent nociceptive input to dorsal horn neurons from neighboring intact nerve.

    PubMed

    Terayama, Ryuji; Yamamoto, Yuya; Kishimoto, Noriko; Maruhama, Kotaro; Mizutani, Masahide; Iida, Seiji; Sugimoto, Tomosada

    2015-04-01

    Previous studies demonstrated that peripheral nerve injury induced excessive nociceptive response of spinal cord dorsal horn neurons and such change has been proposed to reflect the development of neuropathic pain state. The aim of this study was to examine the spinal dorsal horn for convergence of nociceptive input to second-order neurons deafferented by peripheral nerve injury. Double immunofluorescence labeling for c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) was performed to detect convergent synaptic input to spinal dorsal horn neurons after the saphenous nerve injury. c-Fos expression and the phosphorylation of ERK were induced by noxious heat stimulation of the hindpaw and by electrical stimulation of the injured or uninjured saphenous nerve, respectively. Within the central terminal field of the saphenous nerve, the number of c-Fos protein-like immunoreactive (c-Fos-IR) cell profiles was significantly decreased at 3 days and returned to the control level by 14 days after the injury. p-ERK immunoreactive (p-ERK-IR) cell profiles were distributed in the central terminal field of the saphenous nerve, and the topographic distribution pattern and number of such p-ERK-IR cell profiles remained unchanged after the nerve injury. The time course of changes in the number of double-labeled cell profiles was similar to that of c-Fos-IR cell profiles after the injury. These results indicate that convergent primary nociceptive input through neighboring intact nerves contributes to increased responsiveness of spinal dorsal horn nociceptive neurons.

  14. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain.

    PubMed

    Shu, Yi; Zhou, Zhaowei; Wan, Yanjie; Sanders, Robert D; Li, Min; Pac-Soo, Chen Knien; Maze, Mervyn; Ma, Daqing

    2012-02-01

    Anesthetic-induced neurodegeneration in the developing brain has been well documented. However, the experiments carried out so far do not include surgical conditions. This proof of concept study was designed to investigate the impact of nociceptive stimuli on anesthetic induced neuroapoptosis in the rat developing brain. Separate cohorts of 7-day-old Sprague-Dawley rat pups were randomly assigned to six groups: Naïve (room air); Anesthesia alone (70% nitrous oxide and 0.75% isoflurane for 6 h); Formalin injection alone (subcutaneous injection with 10 μL 5% formalin into the left hind paw); Anesthesia+formalin injection; Surgical incision (to the left hind paw) alone; Anesthesia+surgical incision. Apoptosis (Caspase-3) and neuronal activation (c-Fos) in the brain and spinal cord section, and cortical TNF-α and IL-1β were measured with in situ immunostaining and western blot respectively. Cognition was tested using Trace Fear conditioning 40 days after the insult. Prolonged anesthesia caused widespread apoptosis in the central nervous system compared to naïve animals. Nociceptive stimulation with formalin (F) or surgical incision (S) increased the injury in the brain cortex (F: 60% or S: 40% increase) and spinal cord (F: 80% vs. S: 50% increase) respectively. Both nociceptive stimuli further augmented cognitive impairment induced by the anesthetics when assessed 40 days later. The activated pain pathway and the increased expression of the pro-inflammatory cytokine, IL-1β, in the cortex may be responsible for the enhanced neuroapoptosis. Nociceptive stimulation and prolonged anesthesia produced significantly more apoptosis than prolonged anesthesia alone when administered to neonates during the synaptogenic period. PMID:22075165

  15. Failure to observe untested derived stimulus relations in extinction: implications for understanding stimulus-equivalence formation.

    PubMed

    Doughty, Adam H; Leake, Lesley W; Stoudemire, M Lee

    2014-11-01

    Wilson and Hayes (1996) and Doughty, Kastner, and Bismark (2011) observed resurgence of past equivalence relations when newer equivalence relations were punished or extinguished, respectively. Their findings support the notion that deriving stimulus relations is a form of operant behavior. Although there is consensus regarding the operant nature of deriving untrained stimulus relations, the necessary and sufficient conditions that establish these relations remain unclear. For example, in the aforementioned work, the resurgent equivalence relations were tested earlier in each study. The present research investigated whether this resurgence of equivalence relations requires their initial testing. In Experiment 1, college students received arbitrary matching-to-sample training in Phase 1. After these baseline discriminations were established, equivalence testing was omitted. In Phase 2, four 4-member equivalence classes were established that were inconsistent with the Phase-1 training. These Phase-2 relations then were extinguished to test whether the equivalence relations consistent with Phase-1 training would occur. Unlike in earlier research, these untested relations did not occur reliably. This finding was replicated in Experiment 2, and additional tests of stimulus relatedness did not reveal any evidence of derived stimulus relations consistent with the Phase-1 training. The present research extends other findings suggesting that the equivalence-testing context helps establish these stimulus classes.

  16. Failure to observe untested derived stimulus relations in extinction: implications for understanding stimulus-equivalence formation.

    PubMed

    Doughty, Adam H; Leake, Lesley W; Stoudemire, M Lee

    2014-11-01

    Wilson and Hayes (1996) and Doughty, Kastner, and Bismark (2011) observed resurgence of past equivalence relations when newer equivalence relations were punished or extinguished, respectively. Their findings support the notion that deriving stimulus relations is a form of operant behavior. Although there is consensus regarding the operant nature of deriving untrained stimulus relations, the necessary and sufficient conditions that establish these relations remain unclear. For example, in the aforementioned work, the resurgent equivalence relations were tested earlier in each study. The present research investigated whether this resurgence of equivalence relations requires their initial testing. In Experiment 1, college students received arbitrary matching-to-sample training in Phase 1. After these baseline discriminations were established, equivalence testing was omitted. In Phase 2, four 4-member equivalence classes were established that were inconsistent with the Phase-1 training. These Phase-2 relations then were extinguished to test whether the equivalence relations consistent with Phase-1 training would occur. Unlike in earlier research, these untested relations did not occur reliably. This finding was replicated in Experiment 2, and additional tests of stimulus relatedness did not reveal any evidence of derived stimulus relations consistent with the Phase-1 training. The present research extends other findings suggesting that the equivalence-testing context helps establish these stimulus classes. PMID:25306940

  17. Phytochemical Screening and Anti-nociceptive Properties of the Ethanolic Leaf Extract of Trema Cannabina Lour

    PubMed Central

    Hossain, Hemayet; Jahan, Ismet Ara; Islam, Howlader Sariful; Kanti, Dey Shubhra; Arpona, Hira; Arif, Ahmed

    2013-01-01

    Purpose: The present study was designed to investigate the anti-nociceptive activity of ethanolic leaf extract of Trema cannabina Lour (family: Cannabaceae) in experimental animal models. Methods: The anti-nociceptive action was carried out against two types of noxious stimuli, thermal (hot plate and tail immersion tests) and chemical (acetic acid-induced writhing) in mice. Results: Phytochemical analysis of crude extract indicated the presence of reducing sugar, tannins, steroid and alkaloid types of secondary metabolites. Crude extract of T. cannabina (500 mg/kg dose) showed maximum time needed for the response against thermal stimuli (6.79±0.15 seconds) which is comparable to diclofenac sodium (8.26±0.14 seconds) in the hot plate test. Hot tail immersion test also showed similar results as in hot plate test. At the dose of 250 and 500 mg/kg body weight, the extract showed significantly and in a dose-dependent (p<0.001) reduction in acetic acid induced writhing in mice with a maximum effect of 47.56% reduction at 500 mg/kg dose comparable to that of diclofenac sodium (67.07%) at 25 mg/kg. Conclusion: The obtained results tend to suggest the Anti-nociceptive activity of ethanolic leaf extract of Trema cannabina and thus provide the scientific basis for the traditional uses of this plant part as a remedy for pain. PMID:24312820

  18. New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input.

    PubMed

    Henssen, Dylan J H A; Kurt, Erkan; Kozicz, Tamas; van Dongen, Robert; Bartels, Ronald H M A; van Cappellen van Walsum, Anne-Marie

    2016-01-01

    Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called trigeminothalamic tracts have been investigated before. In these animal-based studies from the previous century, the intracerebral pathways were mapped using different retro- and anterograde tracing methods. We review the literature on the trigeminothalamic tracts focusing on these animal tracer studies. Subsequently, we related the observations of these studies to clinical findings using fMRI trials. The intracerebral trigeminal pathways can be subdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral) trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidence we hypothesize the co-existence of an ipsilateral nociceptive conduction tract to the cerebral cortex and we translate evidence from animal-based research to the human anatomy. Our hypothesis differs from the classical idea that orofacial pain arises only from nociceptive information via the contralateral, ventral trigeminothalamic pathway. Better understanding of the histology, anatomy and connectivity of the trigeminal fibers could contribute to the discovery of a more effective pain treatment in patients suffering from various orofacial pain syndromes. PMID:27242449

  19. Do sex hormones influence emotional modulation of pain and nociception in healthy women?

    PubMed

    Rhudy, Jamie L; Bartley, Emily J; Palit, Shreela; Kerr, Kara L; Kuhn, Bethany L; Martin, Satin L; Delventura, Jennifer L; Terry, Ellen L

    2013-12-01

    Sex hormones may contribute to inter- and intra-individual differences in pain by influencing emotional modulation of pain and nociception. To study this, a well-validated picture-viewing paradigm was used to assess emotional modulation of pain and the nociceptive flexion reflex (NFR; physiologic measure of nociception) during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle in healthy normally cycling women (n=40). Salivary estradiol, progesterone, and testosterone were assessed at each testing session. Emotional modulation of pain/NFR did not differ across menstrual phases, but low estradiol was associated with weaker emotional modulation of NFR (during all phases) and emotional modulation of pain (ovulatory and late-luteal phases). Given evidence that a failure to emotionally modulate pain might be a risk factor for chronic pain, low estradiol may promote chronic pain via this mechanism. However, future research is needed to extend these findings to women with disturbances of pain, emotion, and/or sex hormones.

  20. Dependence of Nociceptive Detection Thresholds on Physiological Parameters and Capsaicin-Induced Neuroplasticity: A Computational Study

    PubMed Central

    Yang, Huan; Meijer, Hil G. E.; Doll, Robert J.; Buitenweg, Jan R.; van Gils, Stephan A.

    2016-01-01

    Physiological properties of peripheral and central nociceptive subsystems can be altered over time due to medical interventions. The effective change for the whole nociceptive system can be reflected in changes of psychophysical characteristics, e.g., detection thresholds. However, it is challenging to separate contributions of distinct altered mechanisms with measurements of thresholds only. Here, we aim to understand how these alterations affect Aδ-fiber-mediated nociceptive detection of electrocutaneous stimuli. First, with a neurophysiology-based model, we study the effects of single-model parameters on detection thresholds. Second, we derive an expression of model parameters determining the functional relationship between detection thresholds and the interpulse interval for double-pulse stimuli. Third, in a case study with topica