Relative and absolute refractory periods were determined in sensory fibres of 24 median nerves and in 19 sural nerves of 30 volunteers aged 20–60 years, who had no sign of a neuromuscular disorder. The critical interval of conduction (absolute refractory period) was found to be about 0.7 msec. In median as well as in sural nerve the relative refractory periods
W. Tackmann; H. J. Lehmann
The human cutaneous sensory map has been a work in progress over the past century, depicting sensory territories supplied by both the spinal and cranial nerves. Two critical discoveries, which shaped our understanding of cutaneous innervation, were sensory dermatome overlap between contiguous spinal levels and axial lines across areas where no sensory overlap exists. These concepts define current dermatome maps. We wondered whether the overlap between contiguous sensory territories was even tighter: if neural communications were present in the peripheral nerve territories consistently connecting contiguous spinal levels? A literature search using peer-reviewed articles and established anatomy texts was performed aimed at identifying the presence of communications between sensory nerves in peripheral nerve territories and their relationship to areas of adjacent and non-adjacent spinal or cranial nerves and axial lines (lines of discontinuity) in the upper and lower limbs, trunk and perineum, and head and neck regions. Our findings demonstrate the consistent presence of sensory nerve communications between peripheral nerve territories derived from spinal nerves within areas of axial lines in the upper and lower limbs, trunk and perineum, and head and neck. We did not find examples of communications crossing axial lines in the limbs or lines of discontinuity in the face, but did find examples crossing axial lines in the trunk and perineum. Sensory nerve communications are common. They unify concepts of cutaneous innervation territories and their boundaries, and refine our understanding of the sensory map of the human skin. Clin. Anat. 27:681-690, 2014. © 2013 Wiley Periodicals, Inc. PMID:23824984
Ladak, Adil; Tubbs, R Shane; Spinner, Robert J
This study examined the effectiveness of sensory desensitization training for 12 nonverbal children with autism to facilitate participation in an electrophysiological study assessing linguistic processing. Sensory desensitization was achieved for 10 of the 12 children and thus allowed collection of usable data in a passive linguistic paradigm.…
Roesler, Cynthia P.; Flax, Judy; MacRoy-Higgins, Michelle; Fermano, Zena; Morgan-Byrne, Julie; Benasich, April A.
Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases. PMID:24692141
Lee, Lu-Yuan; Yu, Jerry
Thirty-nine patients from six families with hereditary motor and sensory neuropathy type I and control subjects were included in this study. A neurological deficit score (NDS) was derived from a neurological examination and compared with neurophysiological test findings. Further, sensory nerve conduction velocities (SNCV) were compared with the motor nerve conduction velocities (MNCV). Five patients whom peaks of N11\\/N13 complex
M. Aramideh; J. E. Hoogendijk; C. M. Aalfs; F. E. Posthumus Meyjes; M. Visser; B. W. Ongerboer De Visser
Menthol and cinnamaldehyde (CA) are plant-derived spices commonly used in oral hygiene products, chewing gum, and many other applications. However, little is known regarding their sensory interactions in the oral cavity. We used a human psychophysics approach to investigate the temporal dynamics of oral irritation elicited by sequential application of menthol and/or CA, and ratiometric calcium imaging methods to investigate activation of rat trigeminal ganglion (TG) cells by these agents. Irritancy decreased significantly with sequential oral application of menthol and CA (self-desensitization). Menthol cross-desensitized irritation elicited by CA, and vice versa, over a time course of at least 60 min. Seventeen and 19% of TG cells were activated by menthol and CA, respectively, with ?50% responding to both. TG cells exhibited significant self-desensitization to menthol applied at a 5, but not 10, min interval. They also exhibited significant self-desensitization to CA at 400 but not 200 ?M. Menthol cross-desensitized TG cell responses to CA. CA at a concentration of 400 but not 200 ?M also cross-desensitized menthol-evoked responses. The results support the argument that the perceived reductions in oral irritancy and cross-interactions between menthol and CA and menthol observed (at least at short interstimulus intervals) can be largely accounted for by the properties of trigeminal sensory neurons innervating the tongue.
Klein, Amanda H.; Zanotto, Karen L.; Sawyer, Carolyn M.; Ivanov, Margaret; Cheung, Susan
An examination of the pattern of outflow of radioactivity in sciatic nerves was made at times from 1 to 82 days in the rat and up to 132 days in the cat after injecting the L5 and L7 dorsal root ganglia, respectively, with 3H-leucine. Slow waves moving at a rate of 1-2 mm/day were looked for on the basis of their reported presence in the motor fibers of the rat. A consistent pattern of slow waves was not seen in the cat or rat sensory fibers of the sciatic nerves nor was evidence of a slow wave found in the cat dorsal columns. Irregularities in the pattern of outflow which at times appeared as waves did so in an irregular fashion, a pattern inconsistent with a steady progression of slow waves in the fibers. The decrease of radioactivity appearing first near the ganglia helps create the impression of a wave along with irregular decreases in the overall levels of radio-activity with time. The results were explained on the basis of the unitary hypothesis. The labeled components are considered to be moved down the fiber by the fast transport mechanism, those components dropping off locally in the fibers early on, constituting the slow wave. As those components turn over locally in the various organelles of fiber and are further redistributed, they may at times give rise to what appears as waves.
Stromska, D.P.; Ochs, S.
Background and Purpose Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain-inducing stimuli such as capsaicin (CAP) or bradykinin (BK) to influence intracellular calcium concentrations ([Ca2+]i) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPAR? and of TRPV1 channels in PEA-induced effects was also studied. Experimental Approach [Ca2+]i was evaluated by single-cell microfluorimetry in differentiated F11 cells. Activation of TRPV1 channels was assessed by imaging and patch-clamp techniques in CHO cells transiently-transfected with rat TRPV1 cDNA. Key Results In F11 cells, PEA (1–30 ?M) dose-dependently increased [Ca2+]i. The TRPV1 antagonists capsazepine (1 ?M) and SB-366791 (1 ?M), as well as the PPAR? antagonist GW-6471 (10 ?M), inhibited PEA-induced [Ca2+]i increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPAR?. When compared with CAP, PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub-effective PEA concentrations, closer to those found in vivo, counteracted CAP- and BK-induced [Ca2+]i transients, as well as CAP-induced TRPV1 activation. Conclusions and Implications Activation of PPAR? and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced [Ca2+]i transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences.
Ambrosino, Paolo; Soldovieri, Maria Virginia; Russo, Claudio; Taglialatela, Maurizio
Mitochondrial dysfunction and subsequent oxidative stress has been reported for a variety of cell types in inflammatory diseases. Given the abundance of mitochondria at the peripheral terminals of sensory nerves and the sensitivity of transient receptor potential (TRP) ankyrin 1 (A1) and TRP vanilloid 1 (V1) to reactive oxygen species (ROS) and their downstream products of lipid peroxidation, we investigated the effect of nerve terminal mitochondrial dysfunction on airway sensory nerve excitability. Here we show that mitochondrial dysfunction evoked by acute treatment with antimycin A (mitochondrial complex III Qi site inhibitor) preferentially activated TRPA1-expressing “nociceptor-like” mouse bronchopulmonary C-fibers. Action potential discharge was reduced by the TRPA1 antagonist HC-030031. Inhibition of TRPV1 further reduced C-fiber activation. In mouse dissociated vagal neurons, antimycin A induced Ca2+ influx that was significantly reduced by pharmacological inhibition or genetic knockout of either TRPA1 or TRPV1. Inhibition of both TRPA1 and TRPV1 was required to abolish antimycin A-induced Ca2+ influx in vagal neurons. Using an HEK293 cell expression system, antimycin A induced concentration-dependent activation of both hTRPA1 and hTRPV1 but failed to activate nontransfected cells. Myxothiazol (complex III Qo site inhibitor) inhibited antimycin A-induced TRPA1 activation, as did the reducing agent dithiothreitol. Scavenging of both superoxide and hydrogen peroxide inhibited TRPA1 activation following mitochondrial modulation. In conclusion, we present evidence that acute mitochondrial dysfunction activates airway sensory nerves preferentially via TRPA1 through the actions of mitochondrially-derived ROS. This represents a novel mechanism by which inflammation may be transduced into nociceptive electrical signaling.
Nesuashvili, Lika; Hadley, Stephen H.; Bahia, Parmvir K.
The authors study 65 cases of repair of digital nerve lesions performed in 60 patients. They evaluate the quality of sensory recovery by clinical (Dellon and Weber Tests) and electrophysiological tests (velocity, amplitude and duration of the Compound Sensory Action Potential). The results show a complete recovery in 26%, a recovery of discrimination sensitivity in 73.8% and a recovery of protective sensation in 96.9% of the cases. Age and severity of the associated trauma are the most important factors influencing the quality of the sensory recovery. PMID:7846993
Vertruyen, M F; Burgeon, M A; Dachy, B S; Ley, R E
Background Arthritis of the hand can limit a person’s ability to perform daily activities. Whether or not sensory deficits contribute to the disability in this population remains unknown. The primary purpose of this study was to determine if women with osteoarthritis (OA) or rheumatoid arthritis (RA) of the hand have sensory impairments. Methods Sensory function in the dominant hand of women with hand OA or RA and healthy women was evaluated by measuring sensory nerve action potentials (SNAPs) from the median, ulnar and radial nerves, sensory mapping (SM), and vibratory and current perception thresholds (VPT and CPT, respectively) of the second and fifth digits. Results All SNAP amplitudes were significantly lower for the hand OA and hand RA groups compared with the healthy group (p?0.05). No group differences were found for SNAP conduction velocities, SM, VPT, and CPT. Discussion We propose, based on these findings, that women with hand OA or RA may have axonal loss of sensory fibers in the median, ulnar and radial nerves. Less apparent were losses in conduction speed or sensory perception.
We investigated the involvement of primary sensory nerves in intestinal autoregulatory escape induced by postganglionic nerve stimulation (NS) in anesthetized rats. Anterior mesenteric artery (AMA) blood flow velocity (BF) was measured with a pulsed Doppler flowmeter. Periarterial NS elicited an abrupt fall in BF, which was followed by a recovery in BF toward the basal value, despite sustained NS. This recovery from NS constituted the neurogenic escape phenomenon. Vasoconstrictor responses to NS were abolished by periarterial application of tetrodotoxin. Acute, surgical interruption of proximal periarterial nerves had no effect on BF responses to distal NS, suggesting a peripheral rather than a central nervous mechanism for the escape phenomenon. Escape from NS-induced vasoconstriction was significantly inhibited by prior administration of the selective sensory neurotoxin capsaicin as either subcutaneous injection in neonatal life, acute application to periarterial nerves, or acute injection into the jejunal lumen. In rats pretreated 24 h with reserpine, NS provoked a vasodilator response that was inhibited by intrajejunal capsaicin. Increases in arterial blood pressure (BP) and heart rate observed during NS were blocked by periarterial (but not intrajejunal) application of capsaicin. Transmural electrical field stimulation elicited significantly greater nerve-induced contractions in AMA rings from control rats. Our findings support the hypothesis that postganglionic NS activates both vasoconstrictor sympathetic nerve branches and vasodilator afferent C-fibers. The latter nerves release vasodilator peptides in the periphery during continuous low frequency NS that appear to be essential for autoregulatory escaped in our model. PMID:2316694
Remak, G; Hottenstein, O D; Jacobson, E D
The superficial branch of the radial nerve was dissected using loupe magnification in 20 cadaver forearms. The nerve was found to arise between the tendons of the branchioradialis and extensor carpi radialis longus 8.6 cm proximal to the radial styloid, piercing the forearm fascia 6.0 cm from the radial styloid. An average of 5.8 branches crossed the wrist joint. Innervation to the dorsum of the digits was variable, with 45% of specimens innervating the radial 2 1/2 digits and 30% innervating the radial 3 1/2 digits. Sixteen specimens had branches directly overlying the typical transverse incision for De Quervain's release and 12 specimens had branches directly overlying the 3-4 wrist arthroscopy portal. An appreciation for the location of the superficial radial nerve in the forearm, the variation of its digital innervation, and the proximity of branches to commonly used surgical incisions is important when performing surgical procedures over the dorsum of the hand and wrist. PMID:7955689
Auerbach, D M; Collins, E D; Kunkle, K L; Monsanto, E H
Introduction: Distal sensory neuropathy is the most common form of diabetic neuropathy. We developed a novel antidromic technique for assessment of distal nerve function for early diagnosis of diabetic neuropathy. Methods: Diabetic and control groups underwent standard and more distal sensory nerve conduction studies (NCS); sensory nerve action potentials (SNAPs) of the proper digital branches of the medial plantar nerve were recorded with our method after stimulation at the sole and recording from digits I and II. Results: Comparison between controls and diabetics showed a statistically significant difference in mean SNAP amplitudes for all nerves tested. A higher percentage of abnormal SNAPs was obtained with our technique than with either conventional or more distal NCS in all patients. Conclusions: As compared with clinical evaluation and other NCS, our antidromic stimulation was the most sensitive method to detect abnormal sensory nerve conduction in symptomatic and asymptomatic diabetic patients. Muscle Nerve 50:193-199, 2014. PMID:24282067
Squintani, Giovanna; Zoppini, Giacomo; Donato, Francesco; Pineschi, Elena; Donini, Diana; Stoico, Vincenzo; Moretto, Giuseppe; Bonora, Enzo; Morini, Alberto
The paper examines electrophysiological changes associated with regeneration of a tongue sensory nerve to a different part of the tongue. Normally, the chorda tympani nerve innervates the anterior two thirds of the rat tongue and the IXth (glossopharyngea...
Skin biopsy is a valuable diagnostic tool for small-fiber-predominant neuropathy by the quantification of intra-epidermal nerve fiber density (IENFD). It has the unique advantage of being a minimally invasive procedure with the potential for longitudinal evaluation of both sensory and autonomic fibers. Unmyelinated small fibers are not otherwise quantified objectively with such a level of sensitivity as has been reported with IENFD. Recent advances include an expansion of the skin punch biopsy technique to evaluate larger myelinated fibers and mechanoreceptors, and recent work has also focused on additional methods of quantifying dermal fibers and densely innervated autonomic structures. This review discusses current work using skin biopsy for the pathologic analysis of peripheral nerve fibers in neuropathy of various causes as well as its use in clinical trials.
Myers, M. Iliza; Peltier, Amanda C.
Detection and primary processing of physical, chemical and thermal sensory stimuli by peripheral sensory nerve fibers is key to sensory perception in animals and humans. These peripheral sensory nerve fibers express a plethora of receptors and ion channel proteins which detect and initiate specific sensory stimuli. Methods are available to characterize the electrical properties of peripheral sensory nerve fibers innervating the skin, which can also be utilized to identify the functional expression of specific ion channel proteins in these fibers. However, similar electrophysiological methods are not available (and are also difficult to develop) for the detection of the functional expression of receptors and ion channel proteins in peripheral sensory nerve fibers innervating other visceral organs, including the most challenging tissues such as bone. Moreover, such electrophysiological methods cannot be utilized to determine the expression of non-excitable proteins in peripheral sensory nerve fibers. Therefore, immunostaining of peripheral/visceral tissue samples for sensory nerve fivers provides the best possible way to determine the expression of specific proteins of interest in these nerve fibers. So far, most of the protein expression studies in sensory neurons have utilized immunostaining procedures in sensory ganglia, where the information is limited to the expression of specific proteins in the cell body of specific types or subsets of sensory neurons. Here we report detailed methods/protocols for the preparation of peripheral/visceral tissue samples for immunostaining of peripheral sensory nerve fibers. We specifically detail methods for the preparation of skin or plantar punch biopsy and bone (femur) sections from mice for immunostaining of peripheral sensory nerve fibers. These methods are not only key to the qualitative determination of protein expression in peripheral sensory neurons, but also provide a quantitative assay method for determining changes in protein expression levels in specific types or subsets of sensory fibers, as well as for determining the morphological and/or anatomical changes in the number and density of sensory fibers during various pathological states. Further, these methods are not confined to the staining of only sensory nerve fibers, but can also be used for staining any types of nerve fibers in the skin, bones and other visceral tissue.
Shepherd, Andrew J.; Mohapatra, Durga P.
Functional recovery is usually poor following peripheral nerve injury when reinnervation is delayed. Early innervation by sensory nerve has been indicated to prevent atrophy of the denervated muscle. It is hypothesized that early protection with sensory axons is adequate to improve functional recovery of skeletal muscle following prolonged denervation of mixed nerve injury. In this study, four groups of rats received surgical denervation of the tibial nerve. The proximal and distal stumps of the tibial nerve were ligated in all animals except for those in the immediate repair group. The experimental groups underwent denervation with nerve protection of peroneal nerve (mixed protection) or sural nerve (sensory protection). The experimental and unprotected groups had a stage II surgery in which the trimmed proximal and distal tibial nerve stumps were sutured together. After 3 months of recovery, electrophysiological, histological and morphometric parameters were assessed. It was detected that the significant muscle atrophy and a good preserved structure of the muscle were observed in the unprotected and protective experimental groups, respectively. Significantly fewer numbers of regenerated myelinated axons were observed in the sensory-protected group. Enhanced recovery in the mixed protection group was indicated by the results of the muscle contraction force tests, regenerated myelinated fiber, and the results of the histological analysis. Our results suggest that early axons protection by mixed nerve may complement sensory axons which are required for promoting functional recovery of the denervated muscle natively innervated by mixed nerve.
Li, Qing Tian; Zhang, Pei Xun; Yin, Xiao Feng; Han, Na; Kou, Yu Hui; Deng, Jiu Xu; Jiang, Bao Guo
After peripheral nerve injury, axons often project sprouts from the node of Ranvier proximal to the damage site. It is well known that one parent axon can sprout and maintain several regenerating axons. If enough endoneurial tubes in the distal stump are present for the regenerating axons to grow along, then the number of mature myelinated nerve fibers in the distal stump will be greater than the number in the proximal stump. "Multiple regeneration" is used to describe this phenomenon in the peripheral nerve. According to previous studies, a prominent nerve containing many axons can be repaired by the multiple regenerating axons sprouting from another nerve that contains fewer axons. Most peripheral nerves contain a mixture of myelinated motor and sensory axons as well as unmyelinated sensory and autonomic axons. In this study, a multiple regeneration animal model was developed by bridging the proximal common peroneal nerve with the distal common peroneal nerve and the tibial nerve. Differences in the multiple regeneration ratio of motor and sensory nerves were evaluated using histomorphometry one month after ablating the dorsal root ganglion (DRGs) and ventral roots, respectively. The results suggest that the motor nerves have a significantly larger multiple regeneration ratio than the sensory nerves at two different time points. PMID:22409279
Jianping, Peng; Xiaofeng, Yin; Yanhua, Wang; Zhenwei, Wang; Yuhui, Kou; Chungui, Xu; Peixun, Zhang; Baoguo, Jiang
The response to nerve growth factor (NGF) of two sensory neuron populations of the trigeminal nerve was studied in chick embryos. NGF promoted neuronal survival and cellular hypertrophy in the Gasserian ganglia with minimal effect on the neuron population of the mesencephalic trigeminal nucleus. NGF induced prolific neurite outgrowth from cultured Gasserian ganglia, in contrast, cultured mesencephalic trigeminal neurons remained
Charles Straznicky; Robert A. Rush
The objectives of this study were to describe the topographical anatomy of the pudendal nerve and to develop techniques of its blocking in adult male dromedary camels. Two cadavers and 30 adult male dromedary camels were used for the description of topographical anatomy and pudendal nerve block techniques, respectively. Results revealed that the pudendal nerve arises from the ventral branches of the 2(nd) and 3(rd) sacral spinal nerves. The nerve had three divisions; dorsal, middle, and ventral. The caudal rectal nerve was a branch of the dorsal division. Three blocking techniques were developed according to the results of topographical anatomy. The first technique was 15 cm cranial to the tail base and 7 cm lateral to the midline. The second was 12 cm cranial to the tail base and 7 cm lateral to the midline. The third was about 3 cm on either sides of the anus. Details and complications of each technique were reported. In conclusion, the anatomy of the pudendal nerve was different from that of cattle and horse. The second technique (12 cm cranial to the tail base and 7 cm lateral to the midline) for pudendal nerve block was superior among the three methods. Duration of nerve blocking was suitable for examination and for performing some surgical procedures in male dromedary camels. PMID:21705059
Ahmed, A F; Al-Sobayil, F A; Al-Halag, M A
The suprascapular nerve is responsible for most of the sensory innervation to the shoulder joint and is potentially at risk during surgery. In this study, 31 shoulders in 22 cadavers were dissected to investigate the sensory innervation of the shoulder joint by the suprascapular nerve, with special reference to its sensory branches. In 27 shoulders (87.1%), a small sensory branch was observed that splits off from the main stem of the suprascapular nerve proximal (48.2%), inferior (40.7%), or distal (11.1%) to the transverse scapular ligament. This percentage is considerably higher than has been previously found. In 74.2% of the shoulders, an acromial branch was also found, originating just proximal to the scapular neck, running to the infraspinatus tendon. These cadaveric results indicate that sensory branches to the shoulder joint are more common and numerous than previously described and therefore should be considered in shoulder surgery and nerve blocks to this area. PMID:18262803
Vorster, Willie; Lange, Christopher P E; Briët, Robert J P; Labuschagne, Barend C J; du Toit, Don F; Muller, Christo J F; de Beer, Joe F
Extracellular recordings were made from single auditory afferents in the isolated half-head of the turtle, and changes in their acoustic sensitivity were examined following electrical stimulation of the efferent fibres to the basilar papilla. Short trains of efferent shocks caused a prolonged elevation of the pure tone thresholds of the auditory afferents and an abolition of their spontaneous activity. These changes could be demonstrated in a majority of recordings and without antidromic firing of the afferent. The amount of desensitization increased steeply with shock number and a train of ten closely spaced shocks could elevate the threshold at the most sensitive or characteristic frequency by four orders of magnitude. Desensitization also occurred with single efferent shocks at repetition frequencies exceeding 25/s. Discharge rate versus sound pressure functions were constructed for a number of afferents. The maximum slope of the functions, and the saturated firing rates were both reduced by efferent stimulation; there was also an over-all shift of the rate-intensity function to higher stimulus levels. Such effects would enable the afferent to signal a wider range of sound pressures. Efferent stimulation caused a broadening of the afferent frequency-threshold curves by removal of the narrowly-tuned region around the characteristic frequency. We suggest that the loss in tuning and concomitant improvement in temporal resolution may be a functionally important consequence of efferent action. Images Plate 1
Art, J J; Fettiplace, R
To study chronic catecholamine desensitization, mini-osmotic pumps were implanted subcutaneously to deliver NE, (0.5 micrograms/kg/min) or saline over 3-4 wk in dogs instrumented with left ventricular (LV) pressure gauges and arterial and left atrial pressure catheters. An acute challenge to NE (0.4 micrograms/kg/min) in intact, conscious dogs increased LV dP/dt by 1,531 +/- 208 mmHg/s before NE pumps, and by a similar amount, 1,340 +/- 166 mmHg/s, 3-4 wk after NE pumps. In contrast, an acute challenge to isoproterenol (ISO, 0.4 micrograms/kg/min) increased LV dP/dt by 5,344 +/- 532 mmHg/s before NE pumps, and significantly less (P less than 0.05; 2,425 +/- 175 mmHg/s) after NE pumps. In the presence of ganglionic and alpha 1-adrenergic blockades, NE (0.4 micrograms/kg/min) increased LV dP/dt by 3,656 +/- 468 mmHg/s before NE pumps and significantly less (P less than 0.01; 1,459 +/- 200 mmHg/s) after NE pumps. Confirming this, an acute challenge to NE (0.4 micrograms/kg/min) in dogs with arterial baroreceptor denervation increased LV dP/dt by 3,732 +/- 896 mmHg/s before NE pumps, and significantly less (P less than 0.05, 1,725 +/- 408 mmHg/s) after NE pumps. In addition, in cardiac denervated dogs, NE (0.4 micrograms/kg/min) increased LV dP/dt by 9,901 +/- 1,404 mmHg/s before NE pumps and significantly less (P less than 0.01, 2,690 +/- 306 mmHg/s) after NE pumps. Desensitization of heart rate responses to NE challenge was also more apparent in the absence of reflex mechanisms. Thus, neural reflex mechanisms play a major role in physiological expression of cardiac desensitization to catecholamines in conscious dogs.
Nejima, J; Uemura, N; Vatner, D E; Homcy, C J; Hintze, T H; Vatner, S F
Retrograde CoS-impregnation was used to trace and map the course of sensory nerves and the distribution and innervation of the various proprioceptor types in all leg segments of Cupiennius salei, a Ctenid spider.
Ernst-August Seyfarth; Wolfgang Eckweiler; Klaus Hammer
ObjectiveThe pattern of abnormal median-normal sural sensory nerve action potential (SNAP) is frequently found in acute\\/chronic inflammatory demyelinating polyneuropathy (AIDP\\/CIDP), whereas sural\\/radial SNAP amplitude ratio is sensitive to detect dying-back degeneration. To investigate whether radial SNAP and its amplitude ratio to median or sural SNAP provide additional particular patterns of sensory nerve involvement.
Noriko Tamura; Satoshi Kuwabara; Sonoko Misawa; Masahiro Mori; Miho Nakata; Takamichi Hattori
Diabetes is the most prevalent metabolic disorder in the United States, and between 50% and 70% of diabetic patients suffer from diabetes-induced neuropathy. Yet our current knowledge of the functional changes in sensory nerves and their distal terminals caused by diabetes is limited. Here, we set out to investigate the functional and morphological consequences of diabetes on specific subtypes of cutaneous sensory nerves in mice. Diabetes was induced in C57Bl/6 mice by a single intraperitoneal injection of streptozotocin. After 6–8 wk, mice were characterized for behavioral sensitivity to mechanical and heat stimuli followed by analysis of sensory function using teased nerve fiber recordings and histological assessment of nerve fiber morphology. Diabetes produced severe functional impairment of C-fibers and rapidly adapting A?-fibers, leading to behavioral hyposensitivity to both mechanical and heat stimuli. Electron microscopy images showed that diabetic nerves have axoplasm with more concentrated organelles and frequent axon-myelin separations compared with control nerves. These changes were restricted to the distal nerve segments nearing their innervation territory. Furthermore, the relative proportion of A?-fibers was reduced in diabetic skin-nerve preparations compared with nondiabetic control mice. These data identify significant deficits in sensory nerve terminal function that are associated with distal fiber loss, morphological damage, and behavioral hyposensitivity in diabetic C57Bl/6 mice. These findings suggest that diabetes damages sensory nerves, leading to functional deficits in sensory signaling that underlie the loss of tactile acuity and pain sensation associated with insensate diabetic neuropathy.
Lennertz, Richard C.; Medler, Karen A.; Bain, James L.; Wright, Douglas E.
Targeted reinnervation is a new neural-machine interface that has been developed to help improve the function of new- generation prosthetic limbs. Targeted reinnervation is a surgical procedure that takes the nerves that once innervated a severed limb and redirects them to proximal muscle and skin sites. The sensory afferents of the redirected nerves reinnervate the skin overlying the transfer site.
Paul D. Marasco; Aimee E. Schultz; Todd A. Kuiken
Teased fibers were made from 153 spontaneous A afferents ending in sciatic nerve end neuromas of 3–14 days standing, 21 A afferents from intact sensory endings in the contralateral sciatic nerve, and 50 intact A afferents from the sciatic nerve in intact rats. Ninety-two percent of the injured fibers responded to adenosine 5?-triphosphate (ATP) (i.v.). However, few fibers from the
Yong Chen; Yi-Hong Zhang; Zhi-Qi Zhao
Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median-ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies.
Macias, M. Y.; Lehman, C. T.; Sanger, J. R.; Riley, D. A.
In this study, we extracted gait-phase information from natural sensory nerve signals of primarily cutaneous origin recorded in the forelimbs of cats during walking on a motorized treadmill. Nerve signals were recorded in seven cats using nerve cuff or patch electrodes chronically implanted on the median, ulnar, and\\/or radial nerves. Features in the electroneurograms that were related to paw contact
K. D. Strange; J. A. Hoffer; J. B. Wagenaar
The spontaneous return of sensation in autologously reconstructed breasts, especially in the Transverse Rectus Abdominis Myocutaneous (TRAM) flap, generated the belief that sensory reinnervation by nerve repair of the flap would be superfluous. This study compares the sensation of the following non-reconstructed and reconstructed breasts: (1) non-operated breasts; (2) flaps of patients reconstructed with the Deep Inferior Epigastric Perforator (DIEP) flap with sensory nerve repair; (3) flaps of patients reconstructed with the Deep Inferior Epigastric Perforator (DIEP) flap without nerve repair; and (4) flaps of patients reconstructed with the free TRAM flap without nerve repair. Statistically significant lower pressure thresholds were found for DIEP flaps with nerve repair through Semmes-Weinstein testing. More segments of the DIEP flaps with nerve repair reacted to cold, warm and vibratory stimuli compared to flaps without nerve repair. Delayed but satisfactory sensory evoked potential responses were obtained for all reconstructed breasts, but in 46% of TRAM flaps no response could be registered compared with 23% and 0% for DIEP flaps without and with nerve repair, respectively. Questionnaires confirmed the objective data and showed return of erogenous sensation in 30% of the patients with DIEP flaps with nerve repair. Our data reconfirm the possibility of spontaneous return of sensation in pedicled and/or free lower abdominal flaps without nerve repair. Nerve repair in free DIEP flaps nevertheless does restore sensation earlier postoperatively, increases the quality and quantity of sensation in the flap and has a higher chance of providing erogenous sensation. The benefits obtained outweigh the disadvantages of the increased operating time. PMID:10343589
Blondeel, P N; Demuynck, M; Mete, D; Monstrey, S J; Van Landuyt, K; Matton, G; Vanderstraeten, G G
The aim of this study was to analyse the pattern of sensory nerve endings and blood vessels around the sinus tarsi. The superficial and deep parts of the fat pads at the inferior extensor retinaculum (IER) as well as the subtalar joint capsule inside the sinus tarsi from 13 cadaver feet were dissected. The distribution of the sensory nerve endings and blood vessels were analysed in the resected specimens as the number per cm(2) after staining with haematoxylin-eosin, S100 protein, low-affinity neurotrophin receptor p75, and protein gene product 9.5 using the classification of Freeman and Wyke. Free nerve endings were the predominant sensory ending (P < 0.001). Ruffini and Golgi-like endings were rarely found and no Pacini corpuscles were seen. Significantly more free nerve endings (P < 0.001) and blood vessels (P = 0.01) were observed in the subtalar joint capsule than in the superficial part of the fat pad at the IER. The deep part of the fat pad at the IER had significantly more blood vessels than the superficial part of the fat pad at the IER (P = 0.012). Significantly more blood vessels than free nerve endings were seen in all three groups (P < 0.001). No significant differences in distribution were seen in terms of right or left side, except for free nerve endings in the superficial part of the fat pad at the IER (P = 0.003). A greater number of free nerve endings correlated with a greater number of blood vessels. The presence of sensory nerve endings between individual fat cells supports the hypothesis that the fat pad has a proprioceptive role monitoring changes and that it is a source of pain in sinus tarsi syndrome due to the abundance of free nerve endings. PMID:24472004
Rein, Susanne; Manthey, Suzanne; Zwipp, Hans; Witt, Andreas
1. The time constants of motor and sensory nerve fibres were studied in normal human ulnar nerves by the method of latent addition, using threshold tracking to follow the recovery of excitability after brief conditioning current pulses. The 60 microseconds test and conditioning stimuli were applied at the wrist, and the conditioning stimuli were set to 90, 60, 30, -30, -60 and -90% of the control threshold current. Compound muscle action potentials were recorded from abductor digiti minimi, and sensory nerve action potentials from the little finger. 2. Recovery from depolarizing conditioning pulses was slower than recovery from hyperpolarizing pulses and strongly dependent on conditioning pulse amplitude. The voltage dependence of latent addition was attributed to subthreshold activation of sodium channels (local response). 3. Motor and sensory nerve excitability generally recovered from -90% hyperpolarizing pulses as the sum of two exponential components, although the slow component was negligible in some motor nerves. The fast component (time constant 43.3 +/- 2.0 microseconds, mean +/- S.E.M., n = 9) was similar between motor and sensory fibres in the same subject. It showed no consistent voltage dependence, and was attributed to a passive input time constant of the fibres. The slow component of recovery from hyperpolarizing pulses was greater in sensory than in motor fibres and was voltage dependent: it could be greatly increased in motor and sensory fibres by steady depolarization. It was attributed to a regenerative membrane current, active at the resting potential in sensory and at least some motor nerves. 4. The latent addition responses were compared with the computed responses of four theoretical models. Both motor and sensory responses were well fitted by a model in which a fraction of the sodium channels (less in motor than in sensory fibres) were activated at potentials 20 mV more negative than normal and at half the normal rate, and did not inactivate. 5. It is concluded that the differences in latent addition between motor and sensory fibres are primarily due to differences in non-classical, voltage-dependent ion channels, active close to the resting potential. These "threshold channels' may help to account for the longer strength-duration time constant of sensory fibres, for their lower rheobase, and for their greater tendency to fire repetitively.
Bostock, H; Rothwell, J C
A prior peripheral nerve injury in vivo, promotes a rapid elongated mode of sensory neurons neurite regrowth in vitro. This in vitro model of conditioned axotomy allows analysis of the cellular and molecular mechanisms leading to an improved neurite re-growth. Our differential interference contrast microscopy and immunocytochemistry results show that conditioned axotomy, induced by sciatic nerve injury, did not increase somatic size of adult lumbar sensory neurons from mice dorsal root ganglia sensory neurons but promoted the appearance of larger neurites and growth cones. Using atomic force microscopy on live neurons, we investigated whether membrane mechanical properties of growth cones of axotomized neurons were modified following sciatic nerve injury. Our data revealed that neurons having a regenerative growth were characterized by softer growth cones, compared to control neurons. The increase of the growth cone membrane elasticity suggests a modification in the ratio and the inner framework of the main structural proteins.
Szabo, Vivien; Vegh, Attila-Gergely; Lucas, Olivier; Cloitre, Thierry; Scamps, Frederique; Gergely, Csilla
A prior peripheral nerve injury in vivo, promotes a rapid elongated mode of sensory neurons neurite regrowth in vitro. This in vitro model of conditioned axotomy allows analysis of the cellular and molecular mechanisms leading to an improved neurite re-growth. Our differential interference contrast microscopy and immunocytochemistry results show that conditioned axotomy, induced by sciatic nerve injury, did not increase somatic size of adult lumbar sensory neurons from mice dorsal root ganglia sensory neurons but promoted the appearance of larger neurites and growth cones. Using atomic force microscopy on live neurons, we investigated whether membrane mechanical properties of growth cones of axotomized neurons were modified following sciatic nerve injury. Our data revealed that neurons having a regenerative growth were characterized by softer growth cones, compared to control neurons. The increase of the growth cone membrane elasticity suggests a modification in the ratio and the inner framework of the main structural proteins. PMID:23418549
Martin, Marta; Benzina, Ouafa; Szabo, Vivien; Végh, Attila-Gergely; Lucas, Olivier; Cloitre, Thierry; Scamps, Frédérique; Gergely, Csilla
The neurotransmitters\\/modulators involved in the interaction between pulmonary neuroepithelial bodies (NEBs) and the va- gal sensory component of their innervation have not yet been elucidated. Because P2X 3 purinoreceptors are known to be strongly expressed in peripheral sensory neurons, the aim of the present study was to examine the localization of nerve endings expressing P2X 3 purinoreceptors in the rat
Inge Brouns; Dirk Adriaensen; Geoff Burnstock; Jean-Pierre Timmermans
High-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss. In this study, we implanted Utah Slanted Electrode Arrays (USEAs) intrafascicularly at the elbow or shoulder in arm nerves of rhesus monkeys (n = 4) under isoflurane anesthesia. Input-output curves indicated that pulse-width-modulated single-electrode stimulation in each arm nerve could recruit single muscles with little or no recruitment of other muscles. Stimulus trains evoked specific, natural, hand movements, which could be combined via multielectrode stimulation to elicit coordinated power or pinch grasp. Stimulation also elicited short-latency evoked potentials (EPs) in primary somatosensory cortex, which might be used to provide sensory feedback from a prosthetic limb. These results demonstrate a high-resolution, high-channel-count interface to the peripheral nervous system for restoring hand function after neural injury or disruption or for examining nerve structure.
Ledbetter, Noah M.; Ethier, Christian; Oby, Emily R.; Hiatt, Scott D.; Wilder, Andrew M.; Ko, Jason H.; Agnew, Sonya P.; Miller, Lee E.
High-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss. In this study, we implanted Utah Slanted Electrode Arrays (USEAs) intrafascicularly at the elbow or shoulder in arm nerves of rhesus monkeys (n = 4) under isoflurane anesthesia. Input-output curves indicated that pulse-width-modulated single-electrode stimulation in each arm nerve could recruit single muscles with little or no recruitment of other muscles. Stimulus trains evoked specific, natural, hand movements, which could be combined via multielectrode stimulation to elicit coordinated power or pinch grasp. Stimulation also elicited short-latency evoked potentials (EPs) in primary somatosensory cortex, which might be used to provide sensory feedback from a prosthetic limb. These results demonstrate a high-resolution, high-channel-count interface to the peripheral nervous system for restoring hand function after neural injury or disruption or for examining nerve structure. PMID:23076108
Ledbetter, Noah M; Ethier, Christian; Oby, Emily R; Hiatt, Scott D; Wilder, Andrew M; Ko, Jason H; Agnew, Sonya P; Miller, Lee E; Clark, Gregory A
The purpose of this investigation was to study lateral palmar nerve (LPN) and medial palmar nerve (MPN) morphology and determine nociception and sensory nerve conduction velocity (SNCV) following placement of continuous peripheral nerve block (CPNB) catheters along LPN and MPN with subsequent bupivacaine (BUP) infusion. Myelinated nerve fiber distribution in LPN and MPN was examined after harvesting nerve specimens in 3 anesthetized horses and processing them for morphometric analysis. In 5 sedated horses, CPNB catheters were placed along each PN in both forelimbs. Horses then received in one forelimb 3 mL 0.125% BUP containing epinephrine 1:200 000 and 0.04% NaHCO3 per catheter site followed by 2 mL/h infusion over a 6-day period, while in the other forelimb equal amounts of saline (SAL) solution were administered. The hoof withdrawal response (HWR) threshold during pressure loading of the area above the dorsal coronary band was determined daily in both forelimbs. On day 6 SNCV was measured under general anesthesia of horses in each limb’s LPN and MPN to detect nerve injury, followed by CPNB catheter removal. The SNCV was also recorded in 2 anesthetized non-instrumented horses (sham controls). In both LPN and MPN myelinated fiber distributions were bimodal. The fraction of large fibers (>7 ?m) was greater in the MPN than LPN (P < 0.05). Presence of CPNB catheters and SAL administration did neither affect measured HWR thresholds nor SNCVs, whereas BUP infusion suppressed HWRs. In conclusion, CPNB with 0.125% BUP provides pronounced analgesia by inhibiting sensory nerve conduction in the distal equine forelimb.
Zarucco, Laura; Driessen, Bernd; Scandella, Massimiliano; Cozzi, Francesca; Cantile, Carlo
The purpose of this investigation was to study lateral palmar nerve (LPN) and medial palmar nerve (MPN) morphology and determine nociception and sensory nerve conduction velocity (SNCV) following placement of continuous peripheral nerve block (CPNB) catheters along LPN and MPN with subsequent bupivacaine (BUP) infusion. Myelinated nerve fiber distribution in LPN and MPN was examined after harvesting nerve specimens in 3 anesthetized horses and processing them for morphometric analysis. In 5 sedated horses, CPNB catheters were placed along each PN in both forelimbs. Horses then received in one forelimb 3 mL 0.125% BUP containing epinephrine 1:200 000 and 0.04% NaHCO(3) per catheter site followed by 2 mL/h infusion over a 6-day period, while in the other forelimb equal amounts of saline (SAL) solution were administered. The hoof withdrawal response (HWR) threshold during pressure loading of the area above the dorsal coronary band was determined daily in both forelimbs. On day 6 SNCV was measured under general anesthesia of horses in each limb's LPN and MPN to detect nerve injury, followed by CPNB catheter removal. The SNCV was also recorded in 2 anesthetized non-instrumented horses (sham controls). In both LPN and MPN myelinated fiber distributions were bimodal. The fraction of large fibers (>7 ?m) was greater in the MPN than LPN (P < 0.05). Presence of CPNB catheters and SAL administration did neither affect measured HWR thresholds nor SNCVs, whereas BUP infusion suppressed HWRs. In conclusion, CPNB with 0.125% BUP provides pronounced analgesia by inhibiting sensory nerve conduction in the distal equine forelimb. PMID:21197231
Zarucco, Laura; Driessen, Bernd; Scandella, Massimiliano; Cozzi, Francesca; Cantile, Carlo
Even though peripheral nerves regenerate well, axons are often misrouted and reinnervate inappropriate distal pathways post-injury. Misrouting most likely occurs at branch points where regenerating axons make choices. Here, we show that the accuracy of sensory axon reinnervation is enhanced by overexpression of the guidance molecule nerve growth factor (NGF) distal to the bifurcation. We used the femoral nerve as model, which contains both sensory and motor axons that intermingle in the parent trunk and distally segregate into the saphenous (SB) and motor branch (MB). Transection of the parent trunk resulted in misrouting of axon reinnervation to SB and MB. To enhance sensory axon targeting, recombinant adenovirus encoding NGF was injected along the SB close to the bifurcation one week post-injury. The accuracy of axon reinnervation was assessed by retrograde tracing at 3 or 8 weeks after nerve injury. NGF overexpression significantly increased the accuracy of SB axon reinnervation to the appropriate nerve branch, in a manner independent of enhancing axon regeneration. This novel finding provides in vivo evidence that gradient expression of neurotrophin can be used to enhance targeting of distal peripheral pathways to increase axon regeneration into the appropriate nerve branch.
Hu, Xinhua; Cai, Jie; Yang, Jun; Smith, George M.
A man with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), or Lewis-Sumner syndrome, presented with a progressive left lumbosacral plexus lesion resembling a neurofibroma. After 7 years he developed a left ulnar nerve lesion with conduction block in its upper segment. Treatment with intravenous immunoglobulin improved the symptoms and signs of both lesions. We conclude that inflammatory neuropathy must be considered in the differential diagnosis of peripheral nerve tumors, and that unifocal lesions may precede multifocal involvement in MADSAM by several years. In addition, we discuss the clinical features in 9 patients attending a specialist peripheral nerve clinic and review the literature. PMID:16609974
Allen, David C; Smallman, Clare A; Mills, Kerry R
Percutaneous electrical stimulation of the trigeminal root was performed in 18 subjects undergoing surgery for idiopathic trigeminal neuralgia or implantation of electrodes into Meckel's cave for recording of limbic epileptic activity. All subjects had normal trigeminal reflexes and evoked potentials. Sensory action potentials were recorded antidromically from the supraorbital (V1), infraorbital (V2) and mental (V3) nerves. In the awake subject,
G Cruccu; M Inghilleri; M Manfredi; M Meglio
The effects of the venoms of the spiders Latrodectus mactans tredecimguttatus (black widow) and Latrodectus mactans hasselti (red back) on sensory nerve terminals in muscle spindles were studied in the mouse. A sublethal dose of venom was injected into tibialis anterior and extensor digitorum longus muscles of one leg. After survival from 30 minutes to 6 weeks muscles were examined
L. S. Queiroz; L. W. Duchen
This protocol details methods to identify and record from cutaneous primary afferent axons in an isolated mammalian skin–saphenous nerve preparation. The method is based on extracellular recordings of propagated action potentials from single-fiber receptive fields. Cutaneous nerve endings show graded sensitivities to various stimulus modalities that are quantified by adequate and controlled stimulation of the superfused skin with heat, cold, touch, constant punctate pressure or chemicals. Responses recorded from single-fibers are comparable with those obtained in previous in vivo experiments on the same species. We describe the components and the setting-up of the basic equipment of a skin–nerve recording station (few days), the preparation of the skin and the adherent saphenous nerve in the mouse (15–45 min) and the isolation and recording of neurons (approximately 1–3 h per recording). In addition, stimulation techniques, protocols to achieve single-fiber recordings, issues of data acquisition and action potential discrimination are discussed in detail.
Zimmermann, Katharina; Hein, Alexander; Hager, Ulrich; Kaczmarek, Jan Stefan; Turnquist, Brian P; Clapham, David E; Reeh, Peter W
Peripheral nerve injury in vivo promotes a regenerative growth in vitro characterized by an improved neurite regrowth. Knowledge of the conditioning injury effects on both morphology and mechanical properties of live sensory neurons could be instrumental to understand the cellular and molecular mechanisms leading to this regenerative growth. In the present study, we use differential interference contrast microscopy, fluorescence microscopy, and atomic force microscopy (AFM) to show that conditioned axotomy, induced by sciatic nerve injury, does not increase somatic size of sensory neurons from adult mice lumbar dorsal root ganglia but promotes the appearance of longer and larger neurites and growth cones. AFM on live neurons is also employed to investigate changes in morphology and membrane mechanical properties of somas of conditioned neurons following sciatic nerve injury. Mechanical analysis of the soma allows distinguishing neurons having a regenerative growth from control ones, although they show similar shapes and sizes. PMID:24165740
Benzina, Ouafa; Szabo, Vivien; Lucas, Olivier; Saab, Mari-belle; Cloitre, Thierry; Scamps, Frédérique; Gergely, Csilla; Martin, Marta
Peripheral nerve injury in vivo promotes a regenerative growth in vitro characterized by an improved neurite regrowth. Knowledge of the conditioning injury effects on both morphology and mechanical properties of live sensory neurons could be instrumental to understand the cellular and molecular mechanisms leading to this regenerative growth. In the present study, we use differential interference contrast microscopy, fluorescence microscopy and atomic force microscopy (AFM) to show that conditioned axotomy, induced by sciatic nerve injury, does not increase somatic size of sensory neurons from adult mice lumbar dorsal root ganglia but promotes the appearance of longer and larger neurites and growth cones. AFM on live neurons is also employed to investigate changes in morphology and membrane mechanical properties of somas of conditioned neurons following sciatic nerve injury. Mechanical analysis of the soma allows distinguishing neurons having a regenerative growth from control ones, although they show similar shapes and sizes.
Benzina, Ouafa; Szabo, Vivien; Lucas, Olivier; Saab, Marie-belle; Cloitre, Thierry; Scamps, Frédérique; Gergely, Csilla; Martin, Marta
The neural pathways that relay information from cutaneous receptors to the cortex provide the somatic sensory information needed for cortical function. The last sensory relay neurons in this pathway have cell bodies in the thalamus and axons that synapse on neurons in the somatosensory cortex. After cortical lesions that damage mature thalamocortical fibers in the somatosensory cortex, we have attempted to reestablish somatosensory cortical function by grafting embryonic neocortical cells into the lesioned area. Such grafts survive in adult host animals but are not innervated by thalamic neurons, and consequently the grafted neurons show little if any spontaneous activity and no responses to cutaneous stimuli. We have reported that transection of peripheral sensory nerves prior to grafting "conditions" or "primes" the thalamic neurons in the ventrobasal complex so that they extend axons into grafts subsequently placed in the cortical domain of the cut nerve. In this report we present evidence that the ingrowth of ventrobasal fibers leads to graft neurons that become functionally integrated into the sensory circuitry of the host brain. Specifically, the conditioning lesions made prior to grafting produce graft neurons that are spontaneously active and can be driven by natural activation of cutaneous receptors or electrical stimulation of the transected nerve after it regenerates. Furthermore, oxidative metabolism in these grafts reaches levels that are comparable to normal cortex, whereas without prior nerve cut, oxidative metabolism is abnormally low in neocortical grafts. We conclude that damage to the sensory periphery transsynaptically stimulates reorganization of sensory pathways through mechanisms that include axonal elongation and functional synaptogenesis. Images
Ebner, F F; Erzurumlu, R S; Lee, S M
We have used the autoradiographic method to locate trigeminal nerve endings in monkey teeth. The nerve endings were labeled in two adult female Macaca fascicularis by 20 hours of axonal transport of radioactive protein (/sup 3/H-L-proline). We found a few labeled axons in contralateral mandibular central incisors and one mandibular canine. In ipsilateral teeth, numerous myelinated and unmyelinated axons were labeled; they formed a few terminal branches in the roots but primarily branched in the crown to form the peripheral plexus of Raschkow and to terminate as free endings in the odontoblast layer, predentin, and as far as 120 micrometers into dentinal tubules. Electron microscopic autoradiography showed that the radioactive axonally transported protein was confined to sensory axons and endings; odontoblasts and dentin matrix were not significantly labeled. Labeled free nerve endings were closely apposed to odontoblasts in dentin but did not form distinctive junctions with them. Nerve endings were most numerous in the regular tubular dentin of the crown adjacent to the tip of the pulp horn, occurring in at least half of the dentinal tubules there. Our results show tha dentinal sensory nerve endings in primate teeth can be profuse, sparse, or absent depending on the location and structure of dentin and its adjacent pulp. When dentin was innervated, the tubules were straight and contained odontoblast processes, the predentin was wide, the odontoblast cell bodies were relatively columnar, and there was an adjacent cell-free zone and pulpal nerve plexus.
Byers, M.R.; Dong, W.K.
Neuron-enriched acidic protein having a molecular mass of 22 kDa, NAP-22, is a Ca(2+)-dependent calmodulin-binding protein and is phosphorylated with protein kinase C (PKC). This protein is localized to the biological membrane via myristoylation and found in the membrane fraction of the brain and in the synaptic vesicle fraction. Recent studies showed that NAP-22 is localized in the membrane raft domain in a cholesterol-dependent manner and suggest a role for NAP-22 in maturation and/or maintenance of nerve terminals by controlling cholesterol-dependent membrane dynamics. The present study revealed the immunohistochemical distribution of NAP-22 in the peripheral nerves in rat muscles. In all examined muscles, nerve terminals in the motor endplates showed NAP-22 immunoreactivity associated with the membranes of synaptic vesicles and nerve terminals. In the muscle spindles, annulospiral endings, which made spirals around the intrafusal muscles, showed intense NAP-22 immunoreactivity. Autonomic nerve fibers around the intramuscular blood vessels also showed the immunoreactivity for NAP-22. NAP-22 immunoreactivity in these peripheral nerves was observed from birth to adulthood (100 days after birth). Though growth-associated protein-43 (GAP-43) immunoreactivity in these nerves was observed from birth, this immunoreactivity decreased from 20 days after birth. These findings suggest that NAP-22 is distributed and regulates functions in the motor, sensory and autonomic nerve terminals in the peripheral nervous system. PMID:14988044
Iino, Satoshi; Taguchi, Katsutoshi; Maekawa, Shohei; Nojyo, Yoshiaki
Intraoperative iatrogenic nerve injuries occur despite vigilance in the operating room. Most of these injuries occur as a\\u000a result of patient positioning, traction or pressure injury, hematoma, or technical error. The median nerve is especially susceptible\\u000a to injury during carpal tunnel release. A rare but devastating injury of the median nerve is complete transection. The number\\u000a of devastating injuries is
Renata V. Weber; Susan E. Mackinnon
Percutaneous electrical stimulation of the trigeminal root was performed in 18 subjects undergoing surgery for idiopathic trigeminal neuralgia or implantation of electrodes into Meckel's cave for recording of limbic epileptic activity. All subjects had normal trigeminal reflexes and evoked potentials. Sensory action potentials were recorded antidromically from the supraorbital (V1), infraorbital (V2) and mental (V3) nerves. In the awake subject, sensory potentials were usually followed by myogenic artifacts due to direct activation of masticatory muscles or reflex activation of facial muscles. In the anaesthetised and curarised subject, sensory potentials from the three nerves showed 1.4-2.2 ms onset latency, 1.9-2.7 ms peak latency and 17-29 microV amplitude. Sensory conduction velocity was computed at the onset latency (maximum CV) and at the peak latency (peak CV). On average, maximum and peak CV were 52 and 39 m/s for V1, 54 and 42 m/s for V2 and 54 and 44 m/s for V3. There was no apparent difference in CV between subjects with trigeminal neuralgia and those with epilepsy. A significant inverse correlation was found between CV and age, the overall maximum CV declining from 59 m/s (16 years) to 49 m/s (73 years). This range of CV is compatible both with histometric data and previous electrophysiological findings on trigeminal nerve conduction. Intraoperative intracranial stimulation is also proposed as a method of monitoring trigeminal function under general anaesthesia. PMID:3681311
Cruccu, G; Inghilleri, M; Manfredi, M; Meglio, M
The growth/differentiation factor-15, GDF-15, has been found to be secreted by Schwann cells in the lesioned peripheral nervous system. To investigate whether GDF-15 plays a role in peripheral nerve regeneration, we substituted exogenous GDF-15 into 10-mm sciatic nerve gaps in adult rats and compared functional and morphological regeneration to a vehicle control group. Over a period of 11 weeks, multiple functional assessments, including evaluation of pinch reflexes, the Static Sciatic Index and of electrophysiological parameters, were performed. Regenerated nerves were then morphometrically analyzed for the number and quality of regenerated myelinated axons. Substitution of GDF-15 significantly accelerated sensory recovery while the effects on motor recovery were less strong. Although the number of regenerated myelinated axons was significantly reduced after GDF-15 treatment, the regenerated axons displayed advanced maturation corroborating the results of the functional assessments. Our results suggest that GDF-15 is involved in the complex orchestration of peripheral nerve regeneration after lesion. PMID:22955564
Mensching, Leonore; Börger, Ann-Kathrin; Wang, Xialong; Charalambous, Petar; Unsicker, Klaus; Haastert-Talini, Kirsten
Sensory maximum nerve conduction velocity (MNCV) and motor MNCV were monitored in altogether 14 beagle dogs anaesthetized with pentobarbital. Sensory MNCV was determined by averaging cortically evoked potentials from somatosensory area I (SS I) in response to repeated electrical stimulation of digital paw pads, tibial nerve at calcaneus or sciatic nerve at trochanter. Sensory MNCV determined from paw to tibial nerve at calcaneus was 53 m/sec, from tibial nerve at calcaneus to sciatic nerve at trochanter 64 m/sec and from sciatic nerve at trochanter to crotex SS I 53 m/sec. Motor peripheral MNCV determined in the customary way from sciatic nerve at trochanter to tibial nerve at calcaneus was 68 m/sec and distal latency 3.6 msec. Motor central MNCV from motor cortex to the sciatic nerve at the trochanter in 5 unanaesthetized dogs was 57 m/sec. These testing procedures serve for quantitative assessment of possible impairment of impulse transmission in the central and peripheral sensory and motor pathway of beagle dogs used in routine toxicity studies. PMID:7180741
Schaeppi, U; Teste, M; Siegenthaler, U
SUMMARY. The spontaneous return of sensation in autologously reconstructed breasts, especially in the Transverse Rectus Abdominis Myocutaneous (TRAM) flap, generated the belief that sensory reinnervation by nerve repair of the flap would be superfluous.This study compares the sensation of the following non-reconstructed and reconstructed breasts: (1) non-operated breasts; (2) flaps of patients reconstructed with the Deep Inferior Epigastric Perforator (DIEP)
P. N. Blondeel; M. Demuynck; D. Mete; S. J. Monstrey; K. Van Landuyt
Sensory nerve biopsy specimens from patients with Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy\\u000a (CIDP), and controls consisting of other neuropathies, were examined in order to characterise the nature and intensity of\\u000a any inflammatory infiltrate. In order to establish whether ?? T cells were present in these infiltrates we examined the expression\\u000a of ?? and ?? T cell receptors
John Winer; Sharon Hughes; Joanne Cooper; Anne Ben-Smith; Caroline Savage
Motor and sensory regeneration was studied in a 40mm long graft interposed between the sectioned stumps of the rat median nerve. Animals were behaviorally assessed from 1 to 720 days after surgery by the grasping and modified Randall–Sellito tests. Rats recovered grasping function 43.7 (S.D.±2.6) days after surgery. Grasping strength attained 50 and 65% of the normal control group, 280
Jayme Augusto Bertelli; Adair Roberto Soares dos Santos; Madjid Taleb; João Batista Calixto; Jean Claude Mira; Marcos Flávio Ghizoni
Six New Zealand white rabbits were anesthetized with pentobarbital, and sciatic nerves were exposed and cut at the mid thigh. Both proximal and distal ends were incubated directly with Blue-SAb in a micropipe of 5 mm diameter covering the nerve trunk ends for 30 minutes at room temperature. After removal of the micropipe, the nerve ends were washed with physiological saline. Blue-stained fasciculi, i.e., sensory fasciculi were seen among unstained ones under the operating microscope. This method requires no histological sections. Neural cells of the spinal cord and ganglion were cultured in RPM11640 medium containing Bright Blue. The growth and metabolism of the neural cells were tested by MTT assay and their morphology was observed. Statistical difference between the experiment and control groups was determined, indicating that Bright Blue had no effect on the neural cells and their repairing power. This rapid immunostaining technique offers a good approach for the identification and accurate coaptation of sensory fasciculi in peripheral nerve repair. PMID:1284789
Gu, X S; Yan, Z Q; Yan, W X; Chen, C F
Spontaneous pain is difficult to measure in animals. One proposed biomarker of spontaneous pain is autotomy, a behavior frequently observed in rats with complete hindpaw denervation (the neuroma model of neuropathic pain). A large body of evidence suggests that this behavior reflects spontaneous dysesthesic sensations akin to phantom limb pain or anesthesia dolorosa. After partial paw denervation, such as in the spared nerve injury (SNI) model of neuropathic pain, autotomy is rare. Does this mean that spontaneous pain is absent? We denervated hindpaws in two stages: SNI surgery completed 7 or 28 days later by transection of the saphenous and sural nerves (SaSu). Minimal autotomy was evoked by the first stage. But it started rapidly after SaSu surgery rendered the limb numb, much more rapidly than after denervation in a single stage (neuroma model). The acceleration was proportional to the delay between the two surgeries. This "priming" effect of the first surgery indicates that the neural substrate of autotomy, spontaneous neuropathic pain, was not initiated by the onset of numbness, but rather by the first, SNI surgery. But the animal's pain experience was occult. The saphenous and sural nerves provided nociceptive sensory cover for the paw, preventing the behavioral expression of the spontaneous pain in the form of autotomy. The results support prior observations suggesting that partial nerve injury triggers spontaneous pain as well as allodynia, and illustrate the importance of nociceptive sensory cover in the prevention of self-inflicted limb injury. PMID:22548979
Koplovitch, Pini; Minert, Anne; Devor, Marshall
Growth hormone (GH) secretion is stimulated by aerobic and resistive exercise and inhibited by exposure to actual or simulated (bedrest, hindlimb suspension) microgravity. Moreover, hypothalamic growth hormone-releasing factor (GRF) and preproGRF mRNA are markedly decreased in spaceflight rats. These observations suggest that reduced sensory input from inactive muscles may contribute to the reduced secretion of GH seen in "0 G". Thus, the aim of this study was to determine the effect of muscle sensory nerve stimulation on secretion of GH. Fed male Wistar rats (304 +/- 23 g) were anesthetized (pentobarbital) and the right peroneal (Pe), tibial (T), and sural (S) nerves were cut. Electrical stimulation of the distal (D) or proximal (P) ends of the nerves was implemented for 15 min. to mimic the EMG activity patterns of ankle extensor muscles of a rat walking 1.5 mph. The rats were bled by cardiac puncture and their anterior pituitaries collected. Pituitary and plasma bioactive (BGH) and immunoactive (IGH) GH were measured by bioassay and RIA.
Grindeland, Richard E.; Roy, R. R.; Edgerton, V. R.; Gosselink, K. L.; Grossman, E. J.; Sawchenko, P. E.; Wade, Charles E. (Technical Monitor)
Extensive neurophysiological investigations consisting of different techniques to evaluate the efferents and afferents of the pudendal nerve were carried out in 27 healthy subjects. These investigations included motor evoked potential recordings from the external anal sphincter in response to magnetic stimulation of the cortex and lumbosacral roots, measurement of sacral reflex latency to magnetic and electrical stimulation, and cortical sensory evoked potential recording after stimulation of the dorso-genital nerve and anal canal. Motor latencies after transcranial magnetic stimulation to the anal sphincter were 25.1 +/- 2.9 msec at rest and 20.9 +/- 2.0 msec with voluntary sphincter contraction (facilitation). Motor latency after lumbosacral root stimulation was 3.7 +/- 1.0 msec. Mean sacral reflex latency after magnetic stimulation was 43.8 +/- 11.2 msec and was significantly longer than after electrical stimulation (37.0 +/- 7.2 msec; P < 0.05). P1 latency of the sensory evoked potentials after dorso-genital nerve stimulation was 40 +/- 3 msec and was significantly shorter than after anal stimulation 46 +/- 3 msec (P < 0.01). Evoked potential recording allows us to study both upper and lower motor neuron components to the anal sphincter. The present study paves the way for the combined application of these tests in the evaluation of disorders of the pelvic floor. PMID:7511520
Loening-Baucke, V; Read, N W; Yamada, T; Barker, A T
Introduction Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice. Methods Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting). Results At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum. Conclusions Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain.
Following traumatic peripheral nerve injury reinnervation of denervated targets may be achieved by regeneration of injured axons and by collateral sprouting of neighbor undamaged axons. Experimental models commonly use sciatic nerve injuries to assess nerve regeneration and neuropathic pain, but behavioral tests for evaluating sensory recovery often disregard the pattern of hindpaw innervation. This may lead to confounding attribution of recovery of sensory responses to improvement in sciatic nerve regeneration instead of collateral reinnervation by the undamaged saphenous nerve. We used a standardized methodology to assess the separate contribution of collateral and regenerative skin reinnervation on sensory responses. Section and suture of the sciatic nerve induced loss of sensibility in the lateral and central areas of the injured paw, but nociceptive responses rapidly recovered by expansion of the intact saphenous innervation territory. We used electronic Von Frey and Plantar test devices to measure mechanical and thermal withdrawal thresholds in specific sites of the injured paw: lateral site innervated by the sciatic nerve, medial site that remained innervated by the saphenous nerve, and central site originally innervated by the sciatic nerve but affected by saphenous sprouting. After sciatic section, signs of early hyperalgesia developed in medial and central paw areas due to saphenous sprouting and expansion. The regenerating sciatic nerve fibers reached the paw at 3-4weeks and a late mechanical hyperalgesia was observed at the lateral site. Immunohistochemical staining of sensory fibers innervating the medial and lateral areas revealed a different pattern of skin reinnervation. Hypersensitivity in the intact saphenous nerve area was paralleled by early fiber sprout growth in the subepidermal plexus, but not entering the epidermis. On the other side, late sciatic hyperalgesia was accompanied by gradual skin reinnervation after 4weeks. The standardization of algesimetry testing in sciatic nerve injury models, as proposed in this study, provides a suitable model for studying in parallel neuropathic pain and sensory nerve regeneration processes. Our results also indicate that collateral sprouting and axonal regeneration contribute differently in the initiation and maintenance of neuropathic pain. PMID:24552688
Cobianchi, Stefano; de Cruz, Julia; Navarro, Xavier
The lamellar cells of the sensory corpuscles of the pig dermis must be considered to be epithelial cells as they contain cytokeratins. The cytokeratins detected are similar to those found in simple epithelia. Moreover, lamellar cells are embedded in an extracellular matrix reminiscent of the basement membrane of epithelium since it contains laminin and collagen IV. The perineural cells surrounding the nerves of pig dermis present the same features. These results suggest that lamellar cells and perineural cells have the same origin. The nature of the lamellar and perineural cells of the rabbit or human dermis is not as clear since cytokeratins were not detected in those cells. These results, together with recent observations on Merkel cells, may indicate that epithelio-neuronal junctions are a general feature of cutaneous sensory receptors. PMID:2436379
Ortonne, J P; Verrando, P; Pautrat, G; Darmon, M
Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli. Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors. PMID:14712238
Jordt, Sven-Eric; Bautista, Diana M; Chuang, Huai-Hu; McKemy, David D; Zygmunt, Peter M; Högestätt, Edward D; Meng, Ian D; Julius, David
Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2 > 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.
Mulder, Jan; Hokfelt, Tomas; Knuepfer, Mark M.
Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.
Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.
The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation. PMID:22233379
Fernandes, E S; Fernandes, M A; Keeble, J E
Targeted reinnervation is a new neural-machine interface that has been developed to help improve the function of new-generation prosthetic limbs. Targeted reinnervation is a surgical procedure that takes the nerves that once innervated a severed limb and redirects them to proximal muscle and skin sites. The sensory afferents of the redirected nerves reinnervate the skin overlying the transfer site. This creates a sensory expression of the missing limb in the amputee's reinnervated skin. When these individuals are touched on this reinnervated skin they feel as though they are being touched on their missing limb. Targeted reinnervation takes nerves that once served the hand, a skin region of high functional importance, and redirects them to less functionally relevant skin areas adjacent to the amputation site. In an effort to better understand the sensory capacity of the reinnervated target skin following this procedure, we examined grating orientation thresholds and point localization thresholds on two amputees who had undergone the targeted reinnervation surgery. Grating orientation thresholds and point localization thresholds were also measured on the contralateral normal skin of the targeted reinnervation amputees and on analogous sites in able-bodied controls. Grating orientation thresholds for the reinnervated skin of the targeted reinnervation amputees were found to be similar to normal ranges for both the amputees’ contralateral skin and also for the control population. Point localization thresholds for these amputees were found to be lower for their reinnervated skin than for their contralateral skin. Reinnervated point localization thresholds values were also lower in comparison to homologous chest sites on the control population. Mechanisms appear to be in place to maximize re-established touch input in targeted reinnervation amputees. It seems that sound sensory function is provided to the denervated skin of the residual limb when connected to afferent pathways once serving highly functionally relevant regions of the brain. This suggests that tactile interface devices could be used to give a physiologically appropriate sense of touch to a prosthetic limb, which would likely help with better functional utilization of the prosthetic device and possibly help to more effectively integrate the device with the user's self-image.
Schultz, Aimee E.; Kuiken, Todd A.
We previously identified melanocortin receptor 4 (MC4R) in a search for genes associated with hypoglossal nerve regeneration. As melanocortins promote nerve regeneration after axonal injury, we investigated whether MC4R functions as a key receptor for peripheral nerve regeneration. In situ hybridization revealed that MC4R mRNA is induced in mouse hypoglossal motor neurons after axonal injury, whereas mRNAs for MC1R, MC2R, MC3R, and MC5R are not expressed either before or after nerve injury. This result was confirmed by RT-PCR. The level of MC4R mRNA expression increased significantly from day 3 after axotomy, reached a peak on day 5, and decreased to the control level on day 14. Similar induction of MC4R was observed in axotomized mouse dorsal root ganglia (DRGs). MC4R mRNA expression was induced exclusively among the MCR family in the L4-6 DRG after sciatic nerve injury. We further examined whether alpha-melanocortin stimulating hormone (alpha-MSH) promotes neurite elongation via MC4R. In mouse DRG neuron culture, alpha-MSH significantly promoted neurite outgrowth at a concentration of 10(-8) mol/L. This neurite-elongation effect was entirely inhibited by the addition of a selective MC4R blocker, JKC-363. Therefore, it is concluded that alpha-MSH could stimulate neurite elongation via MC4R in DRG neurons. The present results suggest that induction of MC4R is crucial for motor and sensory neurons to regenerate after axonal injury. PMID:17286587
Tanabe, Katsuhisa; Gamo, Kazushige; Aoki, Shunsuke; Wada, Keiji; Kiyama, Hiroshi
To investigate the distribution of nerve growth factor (NGF) receptors on peripheral and central axons, (/sup 125/I)NGF was injected into the sciatic nerve or spinal cord of adult rats. Accumulation of (/sup 125/I)NGF in lumbar dorsal root ganglia was monitored by gamma emission counting and radioautography. (/sup 125/I)NGF, injected endoneurially in small quantities, was taken into sensory axons by a saturable process and was transported retrogradely to their cell bodies at a maximal rate of 2.5 to 7.5 mm/hr. Because very little (/sup 125/I)NGF reached peripheral terminals, the results were interpreted to indicate that receptors for NGF are present on nonterminal segments of sensory axons. The specificity and high affinity of NGF uptake were illustrated by observations that negligible amounts of gamma activity accumulated in lumbar dorsal root ganglia after comparable intraneural injection of (/sup 125/I) cytochrome C or (/sup 125/I)oxidized NGF. Similar techniques were used to demonstrate avid internalization and retrograde transport of (/sup 125/I)NGF by intraspinal axons arising from dorsal root ganglia. Following injection of (/sup 125/I)NGF into lumbar or cervical regions of the spinal cord, neuronal perikarya were clearly labeled in radioautographs of lumbar dorsal root ganglia. Sites for NGF uptake on primary sensory neurons in the adult rat are not restricted to peripheral axon terminals but are extensively distributed along both peripheral and central axons. Receptors on axons provide a mechanism whereby NGF supplied by glia could influence neuronal maintenance or axonal regeneration.
Richardson, P.M.; Riopelle, R.J.
Hereditary sensory and autonomic neuropathy type V (HSAN V) is an autosomal recessive disorder characterized by the loss of deep pain perception. The anomalous pain and temperature sensations are due to the absence of nociceptive sensory innervation. The neurotrophin nerve growth factor (NGF), by binding to tropomyosin receptor A (TrkA) and p75NTR receptors, is essential for the development and survival of sensory neurons, and for pain perception during adulthood. Recently a homozygous missense mutation (R100W) in the NGF gene has been identified in HSAN V patients. Interestingly, alterations in NGF signalling, due to mutations in the NGF TRKA gene, have also been involved in another congenital insensitivity to pain, HSAN IV, characterized not only by absence of reaction to painful stimuli, but also anhidrosis and mental retardation. These symptoms are absent in HSAN V patients. Unravelling the mechanisms that underlie the differences between HSAN IV and V could assist in better understanding NGF biology. This review highlights the recent key findings in the understanding of HSAN V, including insights into the molecular mechanisms of the disease, derived from genetic studies of patients with this disorder. PMID:24494679
The morphology and distribution of the sensory neurones of the pudendal nerve within the spinal ganglia of rats were investigated by use of horseradish peroxidase (HRP). The labelling was visualized in diaminobenzidine (DAB) or tetramethyl-benzidine (TMB)-stained sections. Injection of HRP directly into the pudendal nerve labelled perikarya predominantly in the sixth lumbar DRG (L6). Following injection of HRP into the
D. C. M. Taylor; H.-W. Korf; Fr.-K. Pierau
Good clinical outcome after digital nerve repair is highly relevant for proper hand function and has a significant socioeconomic impact. However, level of evidence for competing surgical techniques is low. The aim is to summarize and compare the outcomes of digital nerve repair with different methods (end-to-end and end-to-side coaptations, nerve grafts, artificial conduit-, vein-, muscle, and muscle-in-vein reconstructions, and replantations) to provide an aid for choosing an individual technique of nerve reconstruction and to create reference values of standard repair for nonrandomized clinical studies. 87 publications including 2,997 nerve repairs were suitable for a precise evaluation. For digital nerve repairs there was practically no particular technique superior to another. Only end-to-side coaptation had an inferior two-point discrimination in comparison to end-to-end coaptation or nerve grafting. Furthermore, this meta-analysis showed that youth was associated with an improved sensory recovery outcome in patients who underwent digital replantation. For end-to-end coaptations, recent publications had significantly better sensory recovery outcomes than older ones. Given minor differences in outcome, the main criteria in choosing an adequate surgical technique should be gap length and donor site morbidity caused by graft material harvesting. Our clinical experience was used to provide a decision tree for digital nerve repair.
Wolf, Petra; Harder, Yves; Kern, Yasmin; Paprottka, Philipp M.; Machens, Hans-Gunther; Lohmeyer, Jorn A.
Background The spared nerve injury (SNI) model of neuropathic pain produces robust and reproducible behavioral mechanical hypersensitivity. Although this rodent model of neuropathic pain has been well established and widely used, peripheral mechanisms underlying this phenotype remain incompletely understood. Here we investigated the role of cutaneous sensory fibers in the maintenance of mechanical hyperalgesia in mice post-SNI. Findings SNI produced robust, long-lasting behavioral mechanical hypersensitivity compared to sham and naïve controls beginning by post-operative day (POD) 1 and continuing through at least POD 180. We performed teased fiber recordings on single cutaneous fibers from the spared sural nerve using ex vivo skin-nerve preparations. Recordings were made between POD 16–42 after SNI or sham surgery. A?-mechanoreceptors (AM) and C fibers, many of which are nociceptors, from SNI mice fired significantly more action potentials in response to suprathreshold mechanical stimulation than did fibers from either sham or naïve control mice. However, there was no increase in spontaneous activity. Conclusions To our knowledge, this is the first study evaluating the contribution of primary afferent fibers in the SNI model. These data suggest that enhanced suprathreshold firing in AM and C fibers may play a role in the marked, persistent mechanical hypersensitivity observed in this model. These results may provide insight into mechanisms underlying neuropathic pain in humans.
The eyes and skin are highly innervated by sensory nerves; stimulation of these nerves by irritants may give rise to neurogenic inflammation, leading to sensory irritation and pain. Few in vitro models of neurogenic inflammation have been described in conjunction with alternative skin and eye irritation methods, despite the fact that the sensory innervation of these organs is well-documented. To date, alternative approaches to the Draize skin and eye irritation tests have proved largely successful at classifying severe irritants, but are generally poor at discriminating between agents with mild to moderate irritant potential. We propose that the development of in vitro models for the prediction of sensory stimulation will assist in the re-classification of the irritant potential of agents that are under-predicted by current in vitro strategies. This review describes the range of xenobiotics known to cause inflammation and pain through the stimulation of sensory nerves, as well as the endogenous mediators and receptor types that are involved. In particular, it focuses on the vanilloid receptor, its activators and its regulation, as these receptors function as integrators of responses to numerous noxious stimuli. Cell culture models and ex vivo preparations that have the potential to serve as predictors of sensory irritation are also described. In addition, as readily available sensory neuron cell line models are few in number, stem cell lines (with the capacity to differentiate into sensory neurons) are explored. Finally, a preliminary strategy to enable assessment of whether incorporation of a sensory component will enhance the predictive power of current in vitro eye and skin testing strategies is proposed. PMID:15612874
Garle, Michael J; Fry, Jeffrey R
Sensory nerve conduction velocity (NCV) and the vibratory sense (biothesiometry) were determined in 67 children and adolescents with insulin dependent diabetes. Age at onset of diabetes varied between 1-14 years (mean +/- S.D. 6.5 +/- 3.6) and the duration of diabetes between 4-17 years (7.7 +/- 3.4). Within +/- 3 months of the nerve function tests blood was drawn for determination of C-peptide and insulin antibodies (IgG and IRI). A low NCV (less than 50 m/s) in the sural nerve and/or an abnormal vibratory sense (greater than or equal to 1.0 microns) were found in 34 patients (50.7%). Measurable fasting serum C-peptide 0.04-0.60 pmol/ml (0.17 +/- 0.15) was found in 16 patients (23.9%). All but one patients had insulin antibodies with IgG 0.130-11.029 mU/ml (2.957 +/- 2.509) and total IRI 10-9120 muU/ml (1204 +/- 1723). In multiple regression analysis we did not find any correlation between nerve function and sex, age, or age at onset of diabetes, and there was only a weak relationship between NCV and duration. However, there was a positive correlation between NCV and C-peptide (p less than 0.001). Vibration sense was also better among patients with C-peptide (p less than 0.05). The results support the view that insulin deficiency contributes to peripheral diabetic neuropathy. PMID:525341
Ludvigsson, J; Johannesson, G; Heding, L; Häger, A; Larsson, Y
As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4-month-old), middle-aged (13-month-old) and old (36-month-old) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP(+) and NF200(+) nerve fibers that innervate the bone remained remarkably unchanged as did the severity of acute skeletal fracture pain. Thus, while bone mass, quality, and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age. PMID:20947214
Jimenez-Andrade, Juan M; Mantyh, William G; Bloom, Aaron P; Freeman, Katie T; Ghilardi, Joseph R; Kuskowski, Michael A; Mantyh, Patrick W
Peripheral nerve injuries have a devastating impact on muscle function due to the distance the axons must regenerate to reinnervate the target muscle. By the time the axons reinnervate the muscle, it has strophied and lost itself receptiveness resulting in impaired function. The objective of this study was to answer the following questions: 1. Do sensory axons delay muscle atrophy
Karen Lynn Veltri
Peripheral nerve injuries have a devastating impact on muscle function due to the distance the axons must regenerate to reinnervate the target muscle. By the time the axons reinnervate the muscle, it has atrophied and lost its receptiveness resulting in impaired function. The objective of this study was to answer the following questions: (1) Do sensory axons delay muscle atrophy
Karen Lynn Veltri
As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4 month old), middle-aged (13 month) and old (36 month) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP+ and NF200+ nerve fibers that innervate the bone remained remarkably unchanged as well as the severity of acute skeletal fracture pain. Thus, while bone mass, quality and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age.
Jimenez-Andrade, Juan M.; Mantyh, William G.; Bloom, Aaron P.; Freeman, Katie T.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.
Successful assessing intestinal lumen content with ultrasound signals might lay a strong basis for the development of the artificial anal sphincter. In the present study, we utilized a modified MLU02-212 ultrasonic gas bubble detector to test the distal part of proximal colon in each rabbit, for the group of twenty healthy New Zealand rabbits. Voltage signals of solid, liquid, gas and empty content of the lumen were collected and compared. The results indicated that there were significant differences among the voltage signals in the 4 conditions (P = 0.000), respectively. Multiple comparison showed significant differences existed in any pair of the four conditions (P = 0.000). Three signal non-overlapping regions existed in these 4 conditions. Thus it seemed that ultrasound could be utilized to distinguish various contents inside the intestinal lumen and could act as "artificial sensory nerve". PMID:22616169
Li, Jianguo; Huang, Zonghai; Shi, Fujun; Chen, Fei; Zhang, Quanan
Background Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K+ channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K2P channels after peripheral axotomy in mammals. Results Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo. Conclusions In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability.
1. Sensory ganglia from 8-day-old chick embryos were incubated with a specific nerve growth factor and with insulin. 2. From the total lipid extract of the ganglia a compound with steroid characteristics was isolated. 3. The synthesis of this compound, measured spectrophotometrically, diminished after addition of the nerve growth factor and insulin to the incubation medium. 4. The incorporation of sodium [2-14C]acetate and dl-[2-14C]mevalonic acid into total lipids of the sensory ganglia was stimulated by the nerve growth factor and insulin, but the radioactivity of the sterol-like compound was slightly lower. The incorporation of labelled mevalonic acid either into total lipids or into the sterol-like compound was about 25% lower. 5. About 20% of the acetate incorporated into total lipids and about 87% of the mevalonic acid were recovered in the sterol-like compound.
Liuzzi, Antonia; Foppen, Fredrik H.
1. Electrical events in the peripheral nerve terminals of baroreceptors were investigated following isolation and identification of receptive fields innervated by single baroreceptor fibres. A slow potential change, that is a local depolarization which had the characteristics of a generator (receptor) potential, was recorded from the common carotid baroreceptor fibres at a point close to the sensory terminals. 2. The slow potential increased in amplitude with increasing stimulus strength and its time course increased with increasing duration of the mechanical stimulus. Action potentials were initiated from the slow potential when the applied mechanical stimulus was suprathreshold. 3. The slow potentials evoked by a train of subthreshold stimuli summed to evoke action potentials. 4. When a high-frequency train of suprathreshold stimuli was applied to the baroreceptors, the slow potential following a preceding one from which an action potential was initiated failed to fire the nerve fibre. 5. When the sodium content of the Ringer—Locke solution was decreased, the slow potential remained after blockage of the action potential. 6. The slow potential remained after abolishing the spike potential by application of tetrodotoxin.
Low amplitude high frequency waves (LHW) were investigated in normal and patient cervical somatosensory evoked potentials after median nerve stimulation (CSEP) in parallel to normal and patient conducted somatosensory evoked potentials (SEP) after tibial nerve stimulation. Normal recordings were obtained in five subjects undergoing dorsal root entry zone (DREZ) coagulation for pain relief. Patient recordings were obtained in 11 subjects suffering from either syringomyelia, spinal cord tumour, or both. All recordings were made intraoperatively from the dorsal spinal cord surface using the subpial recording technique. Normal CSEP showed typical triphasic potential starting with an initial P9, followed by N13 and a final positivity, P1. Numerous LHW were superimposed on slow triphasic potential. To improve the visibility of LHW, slow triphasic potential was removed from the original CSEP. Potentials thus obtained contained only high frequency components of CSEP, i.e. LHW. They were compared with conducted SEP after tibial nerve stimulation. Comparison revealed similarities in high frequency, low amplitude and general wave form, LHW thus showing characteristics of conducted potential. Duration was found to be significantly shorter than normal duration in both patient LHW (Student's t-test, P < 0.0005) and patient conducted SEP (Student's t-test, P = 0.064). A shorter duration was associated with worsening of configuration in patient LHW and patient conducted SEP. These changes of LHW could not be connected with distortion of N13 seen in patient CSEP. A shorter duration and worsening of configuration in patient LHW were most prominent in cases with a loss of vibration and posture senses, but were also observed in cases where only pain and temperature senses were affected. We therefore concluded that cuneate fascicle is the most likely generator of LHW, although the participation of other cervical long sensory tracts, e.g. spinothalamic tract, cannot be ruled out. PMID:9402889
Prestor, B; Gnidovec, B; Golob, P
Background Sensory disturbance is common following stroke and can exacerbate functional deficits, even in patients with relatively good motor function. In particular, loss of appropriate sensory feedback in severe sensory loss impairs manipulation capability. We hypothesized that task-oriented training with sensory feedback assistance would improve manipulation capability even without sensory pathway recovery. Methods We developed a system that provides sensory feedback by transcutaneous electrical nerve stimulation (SENS) for patients with sensory loss, and investigated the feasibility of the system in a stroke patient with severe sensory impairment and mild motor deficit. The electrical current was modulated by the force exerted by the fingertips so as to allow the patient to identify the intensity. The patient had severe sensory loss due to a right thalamic hemorrhage suffered 27 months prior to participation in the study. The patient first practiced a cylindrical grasp task with SENS for 1 hour daily over 29 days. Pressure information from the affected thumb was fed back to the unaffected shoulder. The same patient practiced a tip pinch task with SENS for 1 hour daily over 4 days. Pressure information from the affected thumb and index finger was fed back to the unaffected and affected shoulders, respectively. We assessed the feasibility of SENS and examined the improvement of manipulation capability after training with SENS. Results The fluctuation in fingertip force during the cylindrical grasp task gradually decreased as the training progressed. The patient was able to maintain a stable grip force after training, even without SENS. Pressure exerted by the tip pinch of the affected hand was unstable before intervention with SENS compared with that of the unaffected hand. However, they were similar to each other immediately after SENS was initiated, suggesting that the somatosensory information improved tip pinch performance. The patient’s manipulation capability assessed by the Box and Block Test score improved through SENS intervention and was partly maintained after SENS was removed, until at least 7 months after the intervention. The sensory test score, however, showed no recovery after intervention. Conclusions We conclude that the proposed system would be useful in the rehabilitation of patients with sensory loss.
We present expression of Po protein and Po mRNA on the sural nerve of a patient with hereditary motor and sensory neuropathy type III. This patient was identified with a point mutation in Po gene, which resulted in the substitution of glycine for arginine in transmembrane domain of P0 protein. An electron microscopic examination revealed very thin myelinated fibers surrounded by multilamellated onion bulbs composed with greatly proliferated Schwann cells. An immunocytochemical and immunoblot analysis is showed P0 protein normally expressed in myelin on the sural nerve. By in situ hybridization, mRNA of P0 protein was detected at normal levels in Schwann cell cytoplasm. Those observations indicated that there was no truncated myelin P0 protein in peripheral nerve of this patient. PMID:7523605
Tachi, N; Kasai, K; Chiba, S; Naganuma, M; Uyemura, K; Hayasaka, K
Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process. PMID:20932251
Touska, Filip; Marsakova, Lenka; Teisinger, Jan; Vlachova, Viktorie
Transcutaneous electrical nerve stimulation decreased early and late somatosensory evoked potential amplitudes and stimulus intensity ratings, and elevated sensory detection threshold, in normal subjects. Effects on pain threshold depended on pre-treatment threshold. These findings are relevant to treatment of clinical pain by transcutaneous electrical nerve stimulation.
Golding, J F; Ashton, H; Marsh, R; Thompson, J W
Abstract The influence of breaching the connective sheaths of the donor sural nerve on axonal sprouting into the end-to-side coapted peroneal nerve was examined in the rat. In parallel, the effect of these procedures on the donor nerve was assessed. The sheaths of the donor nerve at the coaptation site were either left completely intact (group A) or they were breached by epineurial sutures (group B), an epineurial window (group C), or a perineurial window (group D). In group A, the compound action potential (CAP) of sensory axons was detected in ?10% and 40% of the recipient nerves at 4 and 8 weeks, respectively, which was significantly less frequently than in group D at both recovery periods. In addition, the number of myelinated axons in the recipient nerve was significantly larger in group D than in other groups at 4 weeks. At 8 weeks, the number of axons in group A was only ?15% of the axon numbers in other groups (p<0.05). Focal subepineurial degenerative changes in the donor nerves were only seen after 4 weeks, but not later. The average CAP area and the total number of myelinated axons in the donor nerves were not different among the experimental groups. In conclusion, myelinated sensory axons are able to penetrate the epiperineurium of donor nerves after end-to-side nerve coaption; however, their ingrowth into recipient nerves is significantly enhanced by breaching the epiperineurial sheets at the coaptation site. Breaching does not cause permanent injury to the donor nerve.
Zele, Tilen; Tomsic, Martin; Sketelj, Janez; Bajrovic, Fajko F.
We examined the effects of cannabinoid receptor agonists on various respiratory reactions induced by the activation of capsaicin-sensitive afferent sensory nerves (C-fibers). (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited electrical field stimulation- and capsaicin-induced guinea pig bronchial smooth muscle contraction, but not the neurokinin A-induced contraction. A cannabinoid CB2 receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR 144528), reduced the inhibitory effect of WIN 55212-2, but not a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A). A cannabinoid CB2 agonist, JWH 133, also inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction and its inhibitory effect was blocked by SR 144528. The inhibitory effect of WIN 55212-2 on electrical field stimulation-induced bronchial contraction was reduced by the pretreatment of large conductance Ca(2+)-activated K+ channel (Maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not other K+ channel blockers, dendrotoxin or glibenclamide. A Maxi-K+ channel opener, 1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimidazolone (NS1619), inhibited bronchial contraction induced by electrical field stimulation. WIN 55212-2 and JWH 133 blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. These findings suggest that WIN 55212-2 inhibit the activation of C-fibers via cannabinoid CB2 receptors and Maxi-K+ channels in guinea pig airways. PMID:15306537
Yoshihara, Shigemi; Morimoto, Hiroshi; Yamada, Yumi; Abe, Toshio; Arisaka, Osamu
This article addresses the proximal sensory neuropathies of the leg, concentrating on those nerves that are purely sensory or have a predominately sensory onset. These include the lateral femoral cutaneous nerve, the ilioinguinal nerve, the genitofemoral nerve, and the posterior femoral cutaneous nerve. The obturator and femoral nerves are also summarily mentioned with respect to their sensory symptoms. PMID:10393758
Reid, V; Cros, D
[A case of acute autonomic, sensory and motor neuropathy with swelling and gadolinium enhancement of bilateral trigeminal nerve on MRI and dissociation between superficial and deep sensation disturbance].
We report a case of a 46-year old man with acute autonomic, sensory and motor neuropathy (AASMN). He developed severe orthostatic hypotension, anuria,anhydrosis, tonic pupil with dysarthria, dysphagia, jaw claudication, and dysesthesia and sharp pain several days after symptom of upper respiratory infection. Neurological examination revealed severely decreased superficial sensation with normal deep sensation. Brain MRI findings showed bilateral trigeminal nerve swelling with gadolinium (Gd) enhancement. His motor and sensory symptoms and MRI abnormality were improved after the administration of intravenous immunoglobulin and intravenous methylprednisolone therapy; however his autonomic symptoms scarcely reacted to these immunotherapies. As long as we investigated in AASMN cases, bilateral trigeminal nerve swelling with Gd enhancement and dissociation between superficial and deep sensation disturbance have not reported, suggesting that the present case mainly disrupted C nerve fibers distributing postganglionic autonomic and temperature-pain sensory nerves. PMID:23470893
Naito, Hiroyuki; Doi, Hikaru; Inamizu, Saeko; Ito, Hijiri; Araki, Takehisa
Chronic neuropathic pain affects millions of individuals worldwide, is typically long-lasting, and remains poorly treated with existing therapies. Neuropathic pain arising from peripheral nerve lesions is known to be dependent on the emergence of spontaneous and evoked hyperexcitability in damaged nerves. Here, we report that the potassium channel subunit Kv9.1 is expressed in myelinated sensory neurons, but is absent from small unmyelinated neurons. Kv9.1 expression was strongly and rapidly downregulated following axotomy, with a time course that matches the development of spontaneous activity and pain hypersensitivity in animal models. Interestingly, siRNA-mediated knock-down of Kv9.1 in naive rats led to neuropathic pain behaviors. Diminished Kv9.1 function also augmented myelinated sensory neuron excitability, manifested as spontaneous firing, hyper-responsiveness to stimulation, and persistent after-discharge. Intracellular recordings from ex vivo dorsal root ganglion preparations revealed that Kv9.1 knock-down was linked to lowered firing thresholds and increased firing rates under physiologically relevant conditions of extracellular potassium accumulation during prolonged activity. Similar neurophysiological changes were detected in animals subjected to traumatic nerve injury and provide an explanation for neuropathic pain symptoms, including poorly understood conditions such as hyperpathia and paresthesias. In summary, our results demonstrate that Kv9.1 dysfunction leads to spontaneous and evoked neuronal hyperexcitability in myelinated fibers, coupled with development of neuropathic pain behaviors.
Tsantoulas, Christoforos; Zhu, Lan; Shaifta, Yasin; Grist, John; Ward, Jeremy P. T.; Raouf, Ramin; Michael, Gregory J.; McMahon, Stephen B.
Background During a continuous femoral nerve block, the influence of catheter tip position relative to the femoral nerve on infusion characteristics remains unknown. Methods We inserted bilateral femoral perineural catheters in volunteers (ultrasound-guided, needle in-plane). Subjects’ dominant side was randomized to have the catheter tip placed either anterior or posterior to the femoral nerve. The contralateral limb received the alternative position. Ropivacaine 0.1% was administered through both catheters concurrently for 6 hours (4 mL/h). Outcome measures included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current over to the distal quadriceps tendon. Measurements were performed at Hour 0 (baseline), and on the hour until Hour 9, as well as Hour 22. The primary endpoint was the MVIC of the quadriceps at Hour 6. Results As a percentage of the baseline measurement, quadriceps MVIC for limbs with anterior (n=16) and posterior (n=16) catheter tip placement did not differ to a statistically significant degree at Hour 6 (mean [SD] 29%  vs. 30% , respectively; 95% CI: ?22% to 20%; p=0.931), or at any other time point. However, the maximum tolerance to cutaneous electrical current was higher in limbs with anterior compared to posterior catheter tip placement at Hour 6 (20  vs. 6  mA, respectively; 95% CI: 1 mA to 27 mA; p=0.035), as well as at Hours 1, 7, 8, and 9 (p<0.04). Conclusions This study documents the significant (70–80%) quadriceps femoris weakness induced by a continuous femoral nerve block infusion at a relatively low dose of ropivacaine (4 mg/h) delivered through a perineural catheter located both anterior and posterior to the femoral nerve. In contrast, an anterior placement increases cutaneous sensory block compared with a posterior insertion, without a concurrent relative increase in motor block.
Ilfeld, Brian M.; Loland, Vanessa J.; Sandhu, NavParkash S.; Suresh, Preetham J.; Bishop, Michael J.; Donohue, Michael C.; Ferguson, Eliza J.; Madison, Sarah J.
Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.
Jimenez-Andrade, Juan M; Herrera, Monica B; Ghilardi, Joseph R; Vardanyan, Marina; Melemedjian, Ohannes K; Mantyh, Patrick W
Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses. In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D(2/3) agonist), ropinirole (D(2/3/4) agonist), SKF 38393 (D(1/5) agonist), AR-C68397AA (Viozan) (dual D(2)/B(2) agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus. The quinagolide response was blocked by sulpiride (D(2/3) antagonist) but not SCH 23390 (D(1/5) antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner. In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease. PMID:12055141
Birrell, Mark A; Crispino, Natascia; Hele, David J; Patel, Hema J; Yacoub, Magdi H; Barnes, Peter J; Belvisi, Maria G
Peripheral neuropathy is the most frequent neurological complication of HIV infection, affecting more than one-third of infected patients, including patients treated with antiretroviral therapy. Although emerging noninvasive techniques for corneal nerve assessments are increasingly being used to diagnose and monitor peripheral neuropathies, corneal nerve alterations have not been characterized in HIV. Here, to determine whether SIV infection leads to corneal nerve fiber loss, we immunostained corneas for the nerve fiber marker ?III tubulin. We developed and applied both manual and automated methods to measure nerves in the corneal subbasal plexus. These counting methods independently indicated significantly lower subbasal corneal nerve fiber density among SIV-infected animals that rapidly progressed to AIDS compared with slow progressors. Concomitant with decreased corneal nerve fiber density, rapid progressors had increased levels of SIV RNA and CD68-positive macrophages and expression of glial fibrillary acidic protein by glial satellite cells in the trigeminal ganglia, the location of the neuronal cell bodies of corneal sensory nerve fibers. In addition, corneal nerve fiber density was directly correlated with epidermal nerve fiber length. These findings indicate that corneal nerve assessment has great potential to diagnose and monitor HIV-induced peripheral neuropathy and to set the stage for introducing noninvasive techniques to measure corneal nerve fiber density in HIV clinical settings. PMID:24828391
Dorsey, Jamie L; Mangus, Lisa M; Oakley, Jonathan D; Beck, Sarah E; Kelly, Kathleen M; Queen, Suzanne E; Metcalf Pate, Kelly A; Adams, Robert J; Marfurt, Carl F; Mankowski, Joseph L
Rheumatoid arthritis (RA) and rat models of RA exhibit symmetrical mirror-image spread. Many studies have sought to understand the underlying mechanisms and have reported contralateral effects that are manifested in many different forms. It is now well accepted that neurogenic mechanisms contribute to the symmetrical spread of inflammation. However, very few investigators have directly assessed changes in contralateral nerve function and there is a paucity of data. In the present study our aim was to investigate whether there are changes, in particular in the nervous system but also in the vascular system contralateral to an inflamed rat knee joint, that might precede overt inflammation and symmetrical spread. Three to five days following Complete Freund's Adjuvant (CFA) injection we found spontaneous antidromic (away from the CNS) activity in the homologous sensory nerve contralateral to the inflamed joint. Antidromic activity of this nature is known to result in the peripheral release of pro-inflammatory and vasoactive neuropeptides. Importantly, this activity was modulated by systemic analgesic treatment. Furthermore, levels of Evans blue dye extravasation were significantly increased in the joint contralateral to inflammation, indicating altered vascular function. These data suggest that contralateral increases in sensory neural activity and vascular function may account for the symmetrical spread of RA, and that early analgesic treatment may prevent or delay the spread of this debilitating disease.
Kelly, Sara; Dunham, James Philip; Donaldson, Lucy Frances
Background Bilateral sagittal split ramus osteotomy (BSSRO) is a common orthognatic surgical procedure. Sensory disturbances in the inferior alveolar nerve, including hypoesthesia and dysesthesia, are frequently observed after BSSRO, even without distinct nerve injury. The mechanisms that underlie individual differences in the vulnerability to sensory disturbances have not yet been elucidated. Methods The present study investigated the relationships between genetic polymorphisms and the vulnerability to sensory disturbances after BSSRO in a genome-wide association study (GWAS). A total of 304 and 303 patients who underwent BSSRO were included in the analyses of hypoesthesia and dysesthesia, respectively. Hypoesthesia was evaluated using the tactile test 1 week after surgery. Dysesthesia was evaluated by interview 4 weeks after surgery. Whole-genome genotyping was conducted using Illumina BeadChips including approximately 300,000 polymorphism markers. Results Hypoesthesia and dysesthesia occurred in 51 (16.8%) and 149 (49.2%) subjects, respectively. Significant associations were not observed between the clinical data (i.e., age, sex, body weight, body height, loss of blood volume, migration length of bone fragments, nerve exposure, duration of anesthesia, and duration of surgery) and the frequencies of hypoesthesia and dysesthesia. Significant associations were found between hypoesthesia and the rs502281 polymorphism (recessive model: combined ?2 = 24.72, nominal P = 6.633 × 10-7), between hypoesthesia and the rs2063640 polymorphism (recessive model: combined ?2 = 23.07, nominal P = 1.563 × 10-6), and between dysesthesia and the nonsynonymous rs2677879 polymorphism (trend model: combined ?2 = 16.56, nominal P = 4.722 × 10-5; dominant model: combined ?2 = 16.31, nominal P = 5.369 × 10-5). The rs502281 and rs2063640 polymorphisms were located in the flanking region of the ARID1B and ZPLD1 genes on chromosomes 6 and 3, whose official names are “AT rich interactive domain 1B (SWI1-like)” and “zona pellucida-like domain containing 1”, respectively. The rs2677879 polymorphism is located in the METTL4 gene on chromosome 18, whose official name is “methyltransferase like 4”. Conclusions The GWAS of sensory disturbances after BSSRO revealed associations between genetic polymorphisms located in the flanking region of the ARID1B and ZPLD1 genes and hypoesthesia and between a nonsynonymous genetic polymorphism in the METTL4 gene and dysesthesia.
Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal ?1-and ?2-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s). We examined the role of ?2-AR in modulating the responsiveness of renal sensory nerves during low- and high-sodium diets. Immunohistochemical analysis suggested the presence of ?2A-AR and ?2C-AR subtypes on renal sensory nerves. During the low-sodium diet, renal pelvic administration of the ?2-AR antagonist rauwolscine or the AT1 receptor antagonist losartan alone failed to alter the ARNA responses to reflex increases in ERSNA. Likewise, renal pelvic release of substance P produced by 250 pM NE (from 8.0 ± 1.3 to 8.5 ± 1.6 pg/min) was not affected by rauwolscine or losartan alone. However, rauwolscine+losartan enhanced the ARNA responses to reflex increases in ERSNA (4,680 ± 1,240%·s), and renal pelvic release of substance P by 250 pM NE, from 8.3 ± 0.6 to 14.2 ± 0.8 pg/min. During a high-sodium diet, rauwolscine had no effect on the ARNA response to reflex increases in ERSNA or renal pelvic release of substance P produced by NE. Losartan was not examined because of low endogenous ANG II levels in renal pelvic tissue during a high-sodium diet. Increased activation of ?2-AR contributes to the reduced interaction between ERSNA and ARNA during low-sodium intake, whereas no/minimal activation of ?2-AR contributes to the enhanced ERSNA-ARNA interaction under conditions of high sodium intake.
Cicha, Michael Z.; Smith, Lori A.; Ruohonen, Saku; Scheinin, Mika; Fritz, Nicolas; Hokfelt, Tomas
Neurosteroids are synthesized either by glial cells, by neurons, or within the context of neuron-glia cross-talk. Various studies suggested neurosteroid involvement in the control of neurodegeneration but there is no evidence showing that the natural protection of nerve cells against apoptosis directly depends on their own capacity to produce neuroprotective neurosteroids. Here, we investigated the interactions between neurosteroidogenesis and apoptosis occurring in sensory structures of rats subjected to neuropathic pain generated by sciatic nerve chronic constriction injury (CCI). Using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), we observed no apoptotic cells in the spinal cord up to 30 days after CCI although pain symptoms such as mechano-allodynia, thermal and mechanical hyperalgesia were evidenced with the Hargreaves's behavioral and von Frey filament tests. In contrast, double-labeling experiments combining TUNEL and immunostaining with antibodies against glutamine synthetase or neuronal nuclei protein revealed apoptosis occurrence in satellite glial cells (SGC) (not in neurons) of CCI rat ipsilateral dorsal root ganglia (DRG) at day 30 after injury. Pulse-chase experiments coupled with high performance liquid chromatography and flow scintillation detection showed that, among numerous biosynthetic pathways converting [(3)H]pregnenolone into various [(3)H]neurosteroids, only [(3)H]estradiol formation was selectively modified and upregulated in DRG of CCI rats. Consistently, immunohistochemical investigations localized aromatase (estradiol-synthesizing enzyme) in DRG neurons but not in SGC. Pharmacological inhibition of aromatase caused apoptosis of CCI rat DRG neurons. Altogether, our results suggest that endogenously produced neurosteroids such as estradiol may be pivotal for the protection of DRG sensory neurons against sciatic nerve CCI-induced apoptosis. PMID:19565659
Schaeffer, Véronique; Meyer, Laurence; Patte-Mensah, Christine; Eckert, Anne; Mensah-Nyagan, Ayikoe G
The extracellular responses of single sensory afferent cell bodies were recorded from the geniculate ganglion of the chicken following chemical, mechanical and thermal stimulation of the oral cavity using glass coated tungsten microelectrodes. Forty eight chemoreceptive units were identified from the anterior and posterior palate, and from the anterior mandibular area of the lower jaw. Their response characteristics to tyrode
Michael J. Gentle
Capsaicin desensitization leads to behavioral changes, some of which are related to schizophrenia, but investigations into these effects have been scarce. The goal of this study was to characterize the consequences of juvenile capsaicin desensitization on different functions: acute and inflammation-induced thermal and mechanical sensitivity, urinary bladder capacity and thermoregulation, and also on the potentially schizophrenia-related impairments in sensory-motor gating, motor activity and cognitive functioning. Male Wistar rats desensitized with increasing doses of subcutaneous capsaicin after weaning were investigated. Heat and mechanical pain sensitivity did not change significantly; however, morphine produced a prolonged decrease in the nociceptive response to inflammation in desensitized animals. Ultrasound examination of the bladder revealed enhanced bladder volume in treated animals. Capsaicin-treated animals had higher body temperature at 22 °C in both dark and light periods, and they also showed prolonged hyperthermia in new environmental circumstances. Warm environment induced a profound impairment of thermoregulation in desensitized animals. The treated animals also showed higher levels of activity during the active phase and at both cool and warm temperatures. The amplitude of the responses to auditory stimuli and prepulse inhibition did not differ between the two groups, but the desensitized animals showed learning impairments in the novel object recognition test. These results suggest that juvenile capsaicin desensitization leads to sustained changes in several functions that may be related to schizophrenia. We propose that capsaicin desensitization, together with other interventions, may lead to an improved chronic animal model of schizophrenia. PMID:24291382
Petrovszki, Zita; Adam, Gábor; Kekesi, Gabriella; Tuboly, Gábor; Morvay, Zita; Nagy, Endre; Benedek, György; Horvath, Gyöngyi
Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
Birrell, Mark A.; Bonvini, Sara J.; Dubuis, Eric; Maher, Sarah A.; Wortley, Michael A.; Grace, Megan S.; Raemdonck, Kristof; Adcock, John J.; Belvisi, Maria G.
The rat trigeminal sensory nuclear complex (TSNC) was examined for Fos protein-like immunoreactive (Fos-LI) neurons induced by electrical stimulation (ES) of the lingual nerve (LN) at 2 weeks after injury to the LN or the inferior alveolar nerve (IAN). Intensity-dependent increase in the number of Fos-LI neurons was observed in the subnucleus oralis (Vo) and caudalis (Vc) of the spinal trigeminal tract nucleus irrespective of nerve injury. The number of Fos-LI neurons induced by ES of the chronically injured LN at A-fiber intensity (0.1 mA) was significantly increased in the Vo but not the Vc. On the other hand, in rats with chronically injured IAN, the number of Fos-LI neurons induced by ES of the LN at C-fiber intensity (10 mA) was significantly increased in the Vc but not the Vo. These results indicated that injury of a nerve innervating intraoral structures increased the c-Fos response of Vo neurons to A-fiber intensity ES of the injured nerve. A similar nerve injury enhanced the c-Fos response of Vc neurons to C-fiber intensity ES of a spared uninjured nerve innervating an intraoral territory neighboring that of the injured nerve. The present result show that nerve injury causes differential effects on c-Fos expression in the Vo and Vc, which may explain complexity of neuropathic pain symptoms in clinical cases. PMID:22456943
Fujisawa, Naoko; Terayama, Ryuji; Yamaguchi, Daisuke; Omura, Shinji; Yamashiro, Takashi; Sugimoto, Tomosada
Akt has been implicated in pro-survival and anti-apoptotic activities in many cell types, including dorsal root ganglion (DRG) and spinal motor neurons. In this immunohistochemical study we have monitored phosphorylated Akt (p-Akt) levels in adult mouse DRGs and spinal cord following unilateral peripheral sciatic nerve transection (axotomy) or carrageenan-induced inflammation. In control animals around half of the lumbar DRG neuron
Tie-Jun Sten Shi; Ping Huang; Jan Mulder; Sandra Ceccatelli; Tomas Hökfelt
1. In the presence of atropine and guanethidine (3 µmol\\/l each), electrical field stimulation (1–20 Hz) produced frequency-dependent relaxations of the histamine-(3 µmol\\/l) induced vascular tone in isolated rings from the guinea-pig pulmonary artery. The electrically-evoked relaxations were abolished by tetrodotoxin (1 µmol\\/l). The amplitude of these nerve-mediated, nonadrenergic non-cholinergic (NANC) relaxations was unaffected by removal of the vascular endothelium
Carlo Alberto Maggi; Riccardo Patacchini; Francesca Perretti; Manuela Tramontana; Stefano Manzini; Pierangelo Geppetti; Paolo Santicioli
The encapsulated sensory endings of mammalian skeletal muscles are all mechanoreceptors. At the most basic functional level they serve as length sensors (muscle spindle primary and secondary endings), tension sensors (tendon organs), and pressure or vibration sensors (lamellated corpuscles). At a higher functional level, the differing roles of individual muscles in, for example, postural adjustment and locomotion might be expected to be reflected in characteristic complements of the various end-organs, their sensory endings and afferent nerve fibres. This has previously been demonstrated with regard to the number of muscle-spindle capsules; however, information on the other types of end-organ, as well as the complements of primary and secondary endings of the spindles themselves, is sporadic and inconclusive regarding their comparative provision in different muscles. Our general conclusion that muscle-specific variability in the provision of encapsulated sensory endings does exist demonstrates the necessity for the acquisition of more data of this type if we are to understand the underlying adaptive relationships between motor control and the structure and function of skeletal muscle. The present quantitative and comparative analysis of encapsulated muscle afferents is based on teased, silver-impregnated preparations. We begin with a statistical analysis of the number and distribution of muscle-spindle afferents in hind-limb muscles of the cat, particularly tenuissimus. We show that: (i) taking account of the necessity for at least one primary ending to be present, muscles differ significantly in the mean number of additional afferents per spindle capsule; (ii) the frequency of occurrence of spindles with different sensory complements is consistent with a stochastic, rather than deterministic, developmental process; and (iii) notwithstanding the previous finding, there is a differential distribution of spindles intramuscularly such that the more complex ones tend to be located closer to the main divisions of the nerve. Next, based on a sample of tendon organs from several hind-foot muscles of the cat, we demonstrate the existence in at least a large proportion of tendon organs of a structural substrate to account for multiple spike-initiation sites and pacemaker switching, namely the distribution of sensory terminals supplied by the different first-order branches of the Ib afferent to separate, parallel, tendinous compartments of individual tendon organs. We then show that the numbers of spindles, tendon organs and paciniform corpuscles vary independently in a sample of (mainly) hind-foot muscles of the cat. Grouping muscles by anatomical region in the cat indicated the existence of a gradual proximo-distal decline in the overall average size of the afferent complement of muscle spindles from axial through hind limb to intrinsic foot muscles, but with considerable muscle-specific variability. Finally, we present some comparative data on muscle-spindle afferent complements of rat, rabbit and guinea pig, one particularly notable feature being the high incidence of multiple primary endings in the rat.
Banks, R W; Hulliger, M; Saed, H H; Stacey, M J
Whilst local anaesthetics when applied directly to laryngeal nerves or topically to the lung can suppress cough, their chronic use is constrained because of dose limiting side effects. However, the effectiveness of local anaesthetics suggests that selectivity targeting nerves in the airway may provide novel approaches for the treatment of cough in the future. There is a considerable wealth of evidence showing that there are different afferent nerve subtypes in the airways. Traditionally C-fibres have been the focus of much research in the cough field since the stimulation of these afferents by capsaicin is able to elicit cough in guinea-pigs and in man, and drugs targeting various proteins expressed in these nerves (e.g. mu-opioid, NOP1, TRPV1, sodium channels) have been shown to be anti-tussive in preclinical models of cough. However, interest in A? fibres has increased recently in light of the discovery of a specific cough receptor in the guinea-pig that is provoked by citric acid and punctate stimulation, but not capsaicin and which has been anatomically linked to A? fibres. There is also some evidence that as a result of inflammation in the airways, A? fibres can begin to express neuropeptides and TRPV1 receptors so that they can become responsive to endogenous activators of this ion channel and to irritants like capsaicin. Consequently, there is considerable interest in targeting either one or both afferent nerve types for the treatment of chronic cough. However, to date the translation of preclinical studies into man has largely been disappointing and certainly there is a need for better preclinical models in this field. There also remain many challenges to overcome at a clinical level, such as what patient group(s) should be used to assess anti-tussive drugs and whether the use of irritants that induce cough in healthy volunteers (such as citric acid or capsaicin) is of any value in the assessment of novel anti-tussive drugs. The development of several continuous monitoring methodologies for measuring cough will hopefully allow better evaluation of treatments in patients with chronic cough. Nonetheless, cough remains a major unmet clinical need in respiratory medicine where new drugs are urgently required. PMID:23524012
Spina, D; Page, C P
24 snake phobic Ss participated in an experimental investigation of systematic desensitization therapy. Ss who experience desensitization showed a greater reduction in phobic behavior (as measured by avoidance behavior in the presence of the phobic object and self-ratings) than did nonparticipating controls. Ss tended to hold or increase therapy gains at a 6-month follow-up evaluation, and gave no evidence of
Peter J. Lang; A. David Lazovik
It is widely thought that, after peripheral injury, some low-threshold mechanoreceptive (LTMR) afferents “sprout” into pain-specific laminae (I–II) of the dorsal horn and are responsible for chronic pain states such as mechanical allodynia. Although recent studies have questioned this hypothesis, they fail to account for a series of compelling results from single-fiber analyses showing extensive projections from large-diameter myelinated afferents into nocireceptive layers after nerve injury. Here we show that, in the thoracic spinal cord of naïve adult mouse, all myelinated nociceptors gave rise to terminal projections throughout the superficial dorsal horn laminae (I–II). Most (70%) of these fibers had large-diameter axons with recurving flame-shaped central arbors that projected throughout the dorsal horn laminae I–V. This morphology was reminiscent of that attributed to sprouted LTMRs described in previous studies. After peripheral nerve axotomy, we found that LTMR afferents with narrow, uninflected somal action potentials did not sprout into superficial laminae of the dorsal horn. Only myelinated noiceptive afferents with broad, inflected somal action potentials were found to give rise to recurving collaterals and project into superficial “pain-specific” laminae after axotomy. We conclude that the previously undocumented central morphology of large, myelinated cutaneous nociceptors may very well account for the morphological findings previously thought to require sprouting of LTMRs.
WOODBURY, C. JEFFERY; KULLMANN, FLORENTA A.; McILWRATH, SABRINA L.; KOERBER, H. RICHARD
Discrimination between axonotmesis and neurotmesis is crucial in traumatic nerve injury. We present the case of a 43-year-old woman which presented hypoesthesia in the fourth and fifth right fingers, started after surgery for Dupuytren syndrome. At ultrasound study, the ulnar digital sensory branch was identified. Before the division into the two terminal branches, a neuroma was observed, while neurotmesis was excluded. This case shows the utility of ultrasonography in peripheral nervous system examination and the possibility of visualization of very small nerves and their terminal branches. PMID:23243650
Renna, Rosaria; Rosaria, Renna; Coraci, Daniele; Daniele, Coraci; De Franco, Paola; Erra, Carmen; Ceruso, Massimo; Padua, Luca
1. Whether the function of the postsynaptic acetylcholine receptor is use-dependently affected by repetitive nerve stimulation in the presence of competitive antagonists was studied in the mouse phrenic nerve-hemidiaphragm preparation. 2. For electrophysiological experiments, the preparation was immobilized by synthetic mu-conotoxin, which preferentially blocks muscular Na-channels causing neither depolarization of the membrane potential, inhibition of quantal transmitter release, nor depression of nicotinic receptor function. 3. High concentrations of cobratoxin depressed indirect twitches and endplate potentials (e.p.ps) without inducing waning of contractilities or run-down of trains of e.p.ps evoked at 10-100 Hz. However, waning and run-down were accelerated after washout of the toxin despite diminished postsynaptic receptor blockade. Once the run-down of e.p.ps was produced by washout or low concentrations of cobratoxin, further depression of e.p.p. amplitude with high concentrations of cobratoxin did not attenuate the e.p.p. run-down. 4. The degrees of waning of tetanus and trains of e.p.ps produced by a very high concentration of tubocurarine (20 microM) were also less than that caused at a 100 fold lower concentration, albeit the amplitudes of twitches and the first e.p.p. were depressed more rapidly and markedly. 5. Tubocurarine, like cobratoxin, depressed the amplitude of miniature endplate potentials (m.e.p.ps) more than e.p.ps. 6. In contrast to the steepened run-down of successive e.p.ps in the presence of low concentrations of either nicotinic antagonists, the amplitude of m.e.p.ps observed during repetitive stimulation was uniform and was not different from that before stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hong, S. J.; Chang, C. C.
We investigated the possible induction of apoptosis of dorsal root ganglion (DRG) neurons and the defect of nerve regeneration after crush injury with reference to the JNK/c-jun and cAMP pathway in streptozocin-induced diabetic rats. In addition, the effects of a PGE1 analogue were tested in diabetic rats. At day 0 (before axonal injury), no TUNEL-positive DRG neurons were observed in any group. From day 1 to 7 after axonal injury, TUNEL-positive DRG neurons were seen in diabetic rats, but not in non-diabetic or PGE1-treated diabetic rats. The regeneration distance at day 7 after crush injury was shorter in diabetic rats than in the other groups of rats. The time course of JNK/c-jun phosphorylation did not parallel apoptosis. At day 7, the cAMP content of DRG was higher than that at day 0 in non-diabetic and PGE1-treated rats, whereas it was not increased after 7 days in diabetic rats. These results indicate that in diabetic rats apoptosis of DRG neurons is induced by axonal injury independently of the JNK/c-jun and cAMP pathway and that PGE1 rescues DRG neurons from apoptosis and improves axonal regeneration in diabetic rats. PMID:10757497
Kogawa, S; Yasuda, H; Terada, M; Maeda, K; Kikkawa, R
IDPN-induced changes in a variety of sensory, motor and autonomic nerves were studied by whole-mount immunocytochemistry. A full range of proximo-distal accumulations of neurofilament-like material was found, from paranuclear round bodies in perikarya to distal and preterminal axonal dilations. Conversely, both terminal areas and nodal-paranodal regions of myelinated axons showed striking, sharply localized loss of neurofilament-immunostaining. The latter change, when transport of neurofilaments is halted by IDPN, may indicate their local processing and/or differential transport at nodal-paranodal regions. PMID:7820635
Ferri, G L; Cichi, A; Bastone, A; Gaudio, R M; Frontali, N; Dahl, D
1. Effects of the alpha 2-adrenoceptor agonists, UK14304 and clonidine, the 5-HT1 receptor agonist, sumatriptan and the kappa-opioid receptor agonist, GR103545, on sensory neurotransmission in histamine-contracted guinea-pig isolated pulmonary artery (GPPA) have been studied. 2. Electrical field stimulation (EFS) induced frequency-dependent relaxations of histamine-contracted GPPA, which were attenuated by tetrodotoxin and capsaicin pretreatment but not by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). 3. Substance P (0.3 microM) induced relaxations which were subject to rapid tachyphylaxis. Neither the NK1 receptor antagonist, (+/-)-CP 96,345, nor desensitization to substance P had any effect of EFS-induced relaxations of histamine-contracted GPPA. 4. Calcitonin gene-related peptide (CGRP; 3 and 30 nM) induced concentration-dependent relaxations of histamine-contracted GPPA. The putative CGRP receptor antagonist, CGRP8-37 (1 microM), markedly attenuated EFS-induced relaxations as well as relaxations induced by a low concentration of CGRP. 5. Sumatriptan (0.1 and 1 microM) and the selective kappa-opioid receptor agonist, GR103545 (10 and 100 nM) had no effect on EFS-induced relaxations of histamine-contracted GPPA. In contrast, the alpha 2-adrenoceptor agonists UK14304 (1-100 nM) and clonidine (300 nM) attenuated responses to EFS, the attenuation of UK14304 (100 nM) being reversed by yohimbine (300 nM). 6. It is concluded that in GPPA, where a presynaptic inhibition of sensory neurotransmission by alpha 2-adrenoceptor activation could be shown, there was no evidence for such modulation by either sumatriptan-sensitive 5-HT1 receptors or kappa-opioid receptors.
Butler, A.; Worton, S. P.; O'Shaughnessy, C. T.; Connor, H. E.
Background and Purpose Hydrogen sulphide (H2S) is a gas that has recently been shown to have biological activity. In the majority of blood vessels studied so far, H2S has been shown to cause vasorelaxation, although contractile responses have been reported. In the present study, we have made a pharmacological assessment of the effects of H2S in mesenteric small arteries isolated from rats. Experimental Approach Rat mesenteric small arteries were studied using pressure myography. In pressurised arteries, responses were obtained to the H2S donor, sodium hydrogen sulphide (NaHS), in the absence and presence of the NOS inhibitor L-NAME, raised extracellular potassium, the KATP channel inhibitor glibenclamide, the Cl– channel blockers DIDS, NPPB and A9C, the TRPV1 receptor desensitizing agent, capsaicin, the CGRP antagonist, olcegepant, the TRPV1 channel blocker capsazepine and the TRPA1 channel blocker HC-030031. Key Results NaHS produced a vasodilator response in rat mesenteric small arteries held at 90 mmHg. Responses to NaHS were not reproducible. Neither, glibenclamide nor, L-NAME inhibited responses to NaHS. DIDS abolished vasodilator responses to NaHS, but these were unaffected by the chloride channel blockers, NPPB and A9C. Responses to NaHS were attenuated after capsaicin pre-treatment, by a CGRP receptor antagonist and an inhibitor of TRPA1 channels. Conclusions and Implications In small arteries isolated from the rat mesentery, NaHS caused a vasodilatation. This response was not reproducible in vitro, since it was mediated by the release of sensory neurotransmitters in a capsaicin-like action. This release was mediated by a H2S-induced activation of TRPA1 channels.
White, Benjamin J O; Smith, Paul A; Dunn, William R
Most small unmyelinated neurons in adult rat dorsal ganglia (DRG) express one or more of the co-receptors targeted by glial cell line-derived neurotrophic factor (GDNF), neurturin and artemin (GFR?1, GFR?2 and GFR?3 respectively). The function of these GDNF family ligands (GFLs) is not fully elucidated but recent evidence suggests GFLs could function in sensory neuron regeneration after nerve injury and peripheral nociceptor sensitisation. In this study, we used immunohistochemistry to determine if the DRG neurons targeted by each GFL change after sciatic nerve injury. We compared complete sciatic nerve transection and the chronic constriction model and found the pattern of changes incurred by each injury was broadly similar. In lumbar spinal cord, there was a widespread increase in neuronal GFR?1 immunoreactivity (IR) in the L1-6 dorsal horn. GFR?3-IR also increased but in a more restricted area. In contrast, GFR?2-IR decreased in patches of superficial dorsal horn and this loss was more extensive after transection injury. No change in calcitonin gene-related peptide-IR was detected after either injury. Analysis of double-immunolabelled L5 DRG sections suggested the main effect of injury on GFR?1- and GFR?3-IR was to increase expression in both myelinated and unmyelinated neurons. In contrast, no change in basal expression of GFR?2-IR was detected in DRG by analysis of fluorescence intensity and there was a small but significant reduction in GFR?2-IR neurons. Our results suggest the DRG neuronal populations targeted by GDNF, neurturin or artemin, and the effect of exogenous GFLs could change significantly after a peripheral nerve injury.
Keast, Janet R.; Forrest, Shelley L.; Osborne, Peregrine B.
The localization of TrkB, a signal transducing receptor for brain-derived neurotrophic factor and neurotrophin-4, was studied in the rat mandibular molar pulp during development and following nerve injury. Sections were incubated with rabbit polyclonal antiserum against the catalytic part of the TrkB receptor, thus only binding to full-length TrkB receptors, and examined by immunofluorescence microscopy and EM immunocytochemistry. At embryonic
E. Foster; M. Risling; K. Fried
ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called "high affinity desensitization." We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called "left flipper") converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain. PMID:24367291
Giniatullin, Rashid; Nistri, Andrea
We performed a morphological, morphometric and toxicological study on the spinal ganglia and peripheral nerves of the rat after chronic administration of cisplatin (cis-dichlorodiammineplatinum II; DDP) with two different schedules. Severe damage of the spinal ganglia neurons was demonstrated with predominant involvement of the nucleus and nucleolus associated with a decrease in the cell size. Morphological and morphometric changes also
G. Cavaletti; G. Tredici; P. Marmiroli; M. G. Petruccioli; I. Barajon; D. Fabbrica
Abstract Consistency in gold chloride staining is essential for anatomical analysis of sensory nerve endings. The gold chloride stain for this purpose has been modified by many investigators, but often yields inconsistent staining, which makes it difficult to differentiate structures and to determine nerve ending distribution in large tissue samples. We introduce additional steps and major changes to the modified Gairns' protocol. We controlled the temperature and mixing rate during tissue staining to achieve consistent staining and complete solution penetration. We subjected samples to sucrose dehydration to improve cutting efficiency. We then exposed samples to a solution containing lemon juice, formic acid and paraformaldehyde to produce optimal tissue transparency with minimal tissue deformity. We extended the time for gold chloride impregnation 1.5 fold. Gold chloride was reduced in the labrum using 25% formic acid in water for 18 h and in the capsule using 25% formic acid in citrate phosphate buffer for 2 h. Citrate binds gold nanoparticles, which minimizes aggregation in the tissue. We stored samples in fresh ultrapure water at 4° C to slow reduction and to maintain color contrast in the tissue. Tissue samples were embedded in Tissue Tek and sectioned at 80 and 100 ?m instead of using glycerin and teasing the tissue apart as in Gairns' modified gold chloride method. We attached sections directly to gelatin subbed slides after sectioning with a cryostat. The slides then were processed and coverslipped with Permount. Staining consistency was demonstrated throughout the tissue sections and neural structures were clearly identifiable. PMID:24476562
Witherspoon, Jw; Smirnova, Iv; McIff, Te
Antigen binding to the B cell receptor (BCR) induces receptor desensitization, a condition characterized by cellular unresponsiveness to subsequent Ag stimulation despite the continued ability to bind Ag. To better understand the molecular mechanism of this unresponsiveness, we have used complementary lymphoma (K46 ?) and Ig transgenic (3-83 ??) mouse models to study regulation of BCR signaling. Our findings in the lymphoma model show that an initial Ag encounter renders receptors unresponsive to subsequent Ag challenge, as measured by their inability to mobilize Ca2+ and to mediate phosphorylation of receptor-proximal kinases, including Lyn, Blk, and Syk. Most importantly, the Ig? and Ig? components of desensitized receptors are not phosphorylated, and receptor-associated kinases are not activated upon Ag challenge. The molecular defect does not appear to result from Lyn inactivation, sequestration, or repression, since Lyn from desensitized cell lysates is activated in vitro by synthetic doubly phosphorylated immunoreceptor tyrosine-based activation motif peptides. A similar deficit in Ag-induced receptor phosphorylation was observed in desensitized B cells from 3-83 ?? transgenic mice. These studies indicate that Ag receptor desensitization reflects an inability to initiate activation of receptor-associated kinases that normally phosphorylate receptor Ig?? subunits, leading to signal propagation.
Vilen, Barbara J.; Famiglietti, Sara J.; Carbone, Amy M.; Kay, Brian K.; Cambier, John C.
Desensitization is a phenomenon that is common to many ligand-gated ion channels but has been demonstrated only rarely with physiological stimulation. Numerous studies describe desensitization of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor by exogenous agonists, but whether synaptic stimulation causes desensitization has been unknown. Synaptic stimulation of NMDA receptors on rat hippocampal neurons resulted in desensitization that was prevented
Gang Tong; Dawn Shepherd; Craig E. Jahr
The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of 20 APs in a train could successfully transit the T-junction (following frequency) was lowest in C-type units, followed by A-type units with inflected descending limbs of the AP, and highest in A-type units without inflections. In C-type units, following frequency was slower than the rate at which AP trains could be produced in either dorsal root axonal segments or in the soma alone, indicating that the T-junction is a site that acts as a low-pass filter for AP propagation. Following frequency was slower for a train of 20 APs than for two, indicating that a cumulative process leads to propagation failure. Propagation failure was accompanied by diminished somatic membrane input resistance, and was enhanced when Ca2+-sensitive K+ currents were augmented or when Ca2+-sensitive Cl? currents were blocked. After peripheral nerve injury, following frequencies were increased in axotomized C-type neurons and decreased in axotomized non-inflected A-type neurons. These findings reveal that the T-junction in sensory neurons is a regulator of afferent impulse traffic. Diminished filtering of AP trains at the T-junction of C-type neurons with axotomized peripheral processes could enhance the transmission of activity that is ectopically triggered in a neuroma or the neuronal soma, possibly contributing to pain generation.
Gemes, Geza; Koopmeiners, Andrew; Rigaud, Marcel; Lirk, Philipp; Sapunar, Damir; Bangaru, Madhavi Latha; Vilceanu, Daniel; Garrison, Sheldon R; Ljubkovic, Marko; Mueller, Samantha J; Stucky, Cheryl L; Hogan, Quinn H
Background Two types of atopic dermatitis (AD) have been proposed, with different pathophysiological mechanisms underlying this seemingly heterogeneous disorder. The extrinsic type shows high IgE levels presumably as a consequence of skin barrier damage and feasible allergen permeation, whereas the intrinsic type exhibits normal IgE levels and is not mediated by allergen-specific IgE. Objectives To investigate the relationship between pruritus perception threshold and skin barrier function of patients with AD in a comparison between the extrinsic and intrinsic types. Methods Enrolled in this study were 32 patients with extrinsic AD, 17 with intrinsic AD and 24 healthy individuals. The barrier function of the stratum corneum was assessed by skin surface hydration and transepidermal water loss (TEWL), and pruritus perception was evaluated by the electric current perception threshold (CPT) of sensory nerves upon neuroselective transcutaneous electric stimulation. Results Skin surface hydration was significantly lower and TEWL was significantly higher in extrinsic AD than intrinsic AD or normal controls. Although there was no statistically significant difference in CPT among extrinsic AD, intrinsic AD and normal controls, CPT was significantly correlated with skin surface hydration and inversely with TEWL in intrinsic AD and normal controls, but not extrinsic AD. Finally, CPT was correlated with the visual analogue scale of itch in the nonlesional skin of patients with extrinsic but not intrinsic AD. Conclusions Patients with extrinsic AD have an impaired barrier, which increases the pre-existing pruritus but rather decreases sensitivity to external stimuli. In contrast, patients with intrinsic AD retain a normal barrier function and sensory reactivity to external pruritic stimuli. PMID:19785593
Mori, T; Ishida, K; Mukumoto, S; Yamada, Y; Imokawa, G; Kabashima, K; Kobayashi, M; Bito, T; Nakamura, M; Ogasawara, K; Tokura, Y
We examined 29 patients with chronic progressive ganglionopathy of different etiology. Neurophysiological abnormalities were dominated by a widespread decrease in sensory nerve action potential amplitudes, which involved both upper and lower limb nerves, even in patients with asymmetrical or patchy clinical presentation. This impairment of sensory nerve conduction, reflecting a nonlength-dependent pattern of peripheral axon degeneration, should be considered the
Giuseppe Lauria; Davide Pareyson; Angelo Sghirlanzoni
This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ?10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ?-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors. PMID:21472496
Ragé, Michael; Van Acker, Nathalie; Knaapen, Michiel W M; Timmers, Maarten; Streffer, Johannes; Hermans, Michel P; Sindic, Christian; Meert, Theo; Plaghki, Léon
This article reviews self-control desensitization research with test anxious college students. The first section presents a discussion of the development of self-control desensitization (SCD) as a modification of systematic desensitization (SD), and procedures which differentiate SCD from SD including treatment rationale, the nature of anxiety…
Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria. PMID:18078936
Jin, Hai Wei; Flatters, Sarah J L; Xiao, Wen Hua; Mulhern, Howard L; Bennett, Gary J
A method to substantially desensitize a metastable intermolecular composite material to electrostatic discharge and friction comprising mixing the composite material with an organic diluent and removing enough organic diluent from the mixture to form a mixture with a substantially putty-like consistency, as well as a concomitant method of recovering the metastable intermolecular composite material.
Busse, James R. (South Fork, CO); Dye, Robert C. (Los Alamos, NM); Foley, Timothy J. (Los Alamos, NM); Higa, Kelvin T. (Ridgecrest, CA); Jorgensen, Betty S. (Jemez Springs, NM); Sanders, Victor E. (White Rock, NM); Son, Steven F. (Los Alamos, NM)
Previous studies have shown that the primary somatosensory cortex of adult mammals undergoes somatotopic reorganization in response to peripheral nerve transection. The present study assesses how cortical organization is affected when a transected nerve subsequently regenerates. The median nerve to one hand of adult owl monkeys was transected and repaired. Following nerve regeneration, the representations of the hand in cortical
John T. Wall; Jon H. Kaas; Mriganka Sur; Randall J. Nelson; Daniel J. Felleman; Michael M. Merzenich
Exposure of animals to an enriched environment triggers widespread modifications in brain circuitry and function. While this paradigm leads to marked plasticity in animals chronically or acutely exposed to the enriched environment, the molecular mechanisms that enable or regulate such modifications require further characterization. To this end, we have investigated the expression profiles of both mRNA and protein products of a candidate-plasticity gene, nerve growth factor induced-A (NGFI-A), in the brains of rats exposed to increased environmental complexity. We found that NGFI-A mRNA is markedly up-regulated throughout the brains of animals exposed to the enriched environment, but not in the brains of either handled-only or undisturbed control groups. The most pronounced effects were observed in the somatosensory and visual cortices, in layers III and V, while more modest increases were observed in all other cortical layers, with the exception of layer I. A striking NGFI-A mRNA up-regulation was also observed in the striatum and hippocampal formation, notably in the CA1 subfield, of animals exposed to the enriched environment paradigm. Immunocytochemistry was also used to investigate the distribution of NGFI-A protein in response to the environmental enrichment protocol. A marked increase in the number of NGFI-A positive nuclei was identified in the enriched environment condition, as compared to undisturbed and handled-only controls, throughout the rat brain. While the greatest number of NGFI-A immunolabeled neurons was found in cortical layers III and V, up-regulation of NGFI-A protein was also detectable in layers II, IV and VI, in both the somatosensory and visual cortices. NGFI-A immunopositive neurons were also more numerous in the CA1 subfield of the hippocampal formation of animals exposed to the enriched environment, but remained at basal levels in both control groups. Our results implicate NGFI-A as one of the possible early genetic signals that ultimately lead to plastic changes in the CNS. PMID:12074899
Pinaud, R; Tremere, L A; Penner, M R; Hess, F F; Robertson, H A; Currie, R W
TRPA1 is an ion channel of the TRP family that is expressed in some sensory neurons. TRPA1 activity provokes sensory symptoms of peripheral neuropathy, such as pain and paraesthesia. We have used a grease gap method to record axonal membrane potential and evoked compound action potentials (ECAPs) in vitro from human sural nerves and studied the effects of mustard oil (MO), a selective activator of TRPA1. Surprisingly, we failed to demonstrate any depolarizing response to MO (50, 250 ?M) in any human sural nerves. There was no effect of MO on the A wave of the ECAP, but the C wave was reduced at 250 ?M. In rat saphenous nerve fibres MO (50, 250 ?M) depolarized axons and reduced the C wave of the ECAP but had no effect on the A wave. By contrast, both human and rat nerves were depolarized by capsaicin (0.5 to 5 ?M) or nicotine (50 to 200 ?M). Capsaicin caused a profound reduction in C fibre conduction in both species but had no effect on the amplitude of the A component. Lidocaine (30 mM) depolarized rat saphenous nerves acutely, and when rat nerves were pretreated with 30 mM lidocaine to mimic the exposure of human nerves to local anaesthetic during surgery, the effects of MO were abolished whilst the effects of capsaicin were unchanged. This study demonstrates that the local anaesthetic lidocaine desensitizes TRPA1 ion channels and indicates that it may have additional mechanisms for treating neuropathic pain that endure beyond simple sodium channel blockade. PMID:23707266
Docherty, Reginald J; Ginsberg, Lionel; Jadoon, Saqiba; Orrell, Richard W; Bhattacharjee, Anupam
These case studies utilized a combination of respondent and operant conditioning in the training of parents as behavior therapists for their own children. Two mothers had to be desensitized to their children's temper tantrums in order to be able to apply contingency management principles in their own homes. Desensitization to the maladaptive behaviors of their children enhanced the effectiveness of
Gary L. Petty
In biological membranes, ionic channels act speeding up ion movements. Each ionic channel is excited by a specific stimulus (i.e. electric, mechanical, chemical, etc.). Chemically activated ionic channels (CAIC), such as the nicotinic acetylcholine receptor (nAChR), suffer desensitization when the receptor site is still occupied by the agonist molecule. The desensitized CAIC is a non functional channel state regarded as a particular case of receptors rundown. CAIC desensitization only involve reduced activity and not their membrane elimination. Desensitization is important to control synaptic transmission and the development of the nervous system. In this review we discuss results related to its production, modulation and some aspects associated to models that consider it. Finally, an approach combining molecular biology and electrophysiology techniques to understand desensitization and its importance in biological systems is presented. PMID:8525756
Quiñonez, M; Rojas, L
The peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine administration on nociceptive responses in a murine model of nerve growth factor (NGF)-induced pain. Cultured DRG neurons treated with arecaidine showed a decreased level of VR1 and SP transcripts. Conversely, we found an increased expression of VR1 and SP transcripts in DRG from M2/M4(-/-) mice compared to WT and M1(-/-) mice, confirming the inhibitory effect in particular of M2 receptors on SP and VR1 expression. Patch-clamp experiments in the whole-cell configuration showed that arecaidine treatment caused a reduction of the fraction of capsaicin-responsive cells, without altering the mean capsaicin-activated current in responsive cells. We also demonstrated that arecaidine prevents PKC? translocation to the plasma membrane after inflammatory agent stimulation, mainly in medium-small sensory neurons. Finally, in mice, we have observed that intraperitoneal injection of arecaidine reduces VR1 expression blocking hyperalgesia and allodynia caused by NGF intraplantar administration. In conclusion, our data demonstrate that in vivo M2 receptor activation induces desensitization to mechanical and heat stimuli by a down-regulation of VR1 expression and by the inhibition of PKC? activity hindering its translocation to the plasma membrane, as suggested by in vitro experiments. PMID:24166293
De Angelis, Federica; Marinelli, Sara; Fioretti, Bernard; Catacuzzeno, Luigi; Franciolini, Fabio; Pavone, Flaminia; Tata, Ada Maria
Objective Hypoxia/reoxygenation (H/R) associated with extracorporeal membrane oxygenation disrupts cerebral autoregulation. However, the underlying mechanisms remain poorly understood. The present study was designed to investigate the role of sensory C-fibers in myogenic responsiveness of cerebral arteries. Methods Arterial diameter and intraluminal pressure were simultaneously measured in vitro on rat posterior cerebral arteries. Results Cerebral arteries constricted in response to graded increase in intraluminal pressure (20–100 mmHg, in 20 mmHg increments). In vitro C-fiber desensitization with capsaicin (1 ?mol/l, 20 minutes) significantly suppressed myogenic constriction by over 50%, but did not affect 5-hydroxytryptamine (0.01–10 ?mol/l) and KCl (120 mmol/l)-induced constriction. Capsazepine (5 ?mol/l, 30 minutes), a selective blocker of neuronal vanilloid receptor TRPV1, had similar inhibitory effect on cerebral myogenic constriction to elevated pressure. Cerebral myogenic constriction was significantly attenuated by H/R; the impairment by H/R was further enhanced after C-fiber desensitization (except at a pressure level of 100 mmHg). Discussion These findings indicate that C-fiber activity contributes to myogenic constriction of cerebral arteries under normal and H/R conditions. H/R-impaired myogenic responsiveness is exaggerated by C-fiber dysfunction. These results raise the possibility that therapeutic strategies directed toward preserving C-fiber nerve endings or supplying its constituent neuropeptides could be developed.
Xie, Hui; Ray, Patricio E.; Short, Billie Lou
Solid explosive can be desensitized by a shock wave too weak to initiate it promptly, and desensitized explosive does not react although its chemical composition is almost unchanged. A strong second shock does not cause reaction until it overtakes the first shock. The first shock, if it is strong enough, accelerates very slowly at first, and then more rapidly as detonation approaches. These facts suggest that there are two competing reactions. One is the usual explosive goes to products with the release of energy, and the other is explosive goes to dead explosive with no chemical change and no energy release. The first reaction rate is very sensitive to the local state, and the second is only weakly so. At low pressure very little energy is released and the change to dead explosive dominates. At high pressure, quite the other way, most of the explosive goes to products. Numerous experiments in both the initiation and the full detonation regimes are discussed and compared in testing these ideas.
Davis, William C [Los Alamos National Laboratory
There is considerable controversy over whether ?-opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G-protein-coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein ?? subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5–8 weeks old) rapid MOPr desensitization induced by the high-efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to ?2-adrenoceptors and somatostatin SST2 receptors. Given that these receptors all couple through G proteins to the same set of G-protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein ?? subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c-Jun N-terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations.
Llorente, Javier; Lowe, Janet D; Sanderson, Helen S; Tsisanova, Elena; Kelly, Eamonn; Henderson, Graeme; Bailey, Chris P
There is considerable controversy over whether ?-opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G-protein-coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein ?? subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5-8 weeks old) rapid MOPr desensitization induced by the high-efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to ?(2)-adrenoceptors and somatostatin SST(2) receptors. Given that these receptors all couple through G proteins to the same set of G-protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein ?? subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c-Jun N-terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations. PMID:23002724
Llorente, Javier; Lowe, Janet D; Sanderson, Helen S; Tsisanova, Elena; Kelly, Eamonn; Henderson, Graeme; Bailey, Chris P
This patent application relates to electroexplosive devices (EEDs) such as detonators, blasting caps and squibs, in particular to a method and device for desensitizing EEDs to electromagnetic radiation and electrostatic charges with the added ability to d...
J. W. Krainiak P. D. Speaks M. S. Cornett
This patent application relates to electroexplosive devices (EEDs) such as detonators, blasting caps and squibs, in particular to a method and device for desensitizing EEDs to electromagnetic radiation and electrostatic charges with the added ability to d...
J. W. Krainiak P. D. Speaks M. S. Cornett
... to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ... cell ; congenital ; gene ; growth factor ; joint ; mutation ; neuropathy ; perception ; protein ; receptor ; recessive ; sensory nerve ; sensory neuropathy ; tissue ; ...
Activation of protein kinases and phosphatases at the plasma membrane often initiates agonist-dependent signalling events. In sensory neurons, AKAP150 (A-kinase-anchoring protein 150) orientates PKA (protein kinase A), PKC (protein kinase C) and the Ca2+/calmodulin-dependent PP2B (protein phosphatase 2B, also known as calcineurin) towards membrane-associated substrates. Recent evidence indicates that AKAP150-anchored PKA and PKC phosphorylate and sensitize the TRPV1 (transient receptor potential subfamily V type 1 channel, also known as the capsaicin receptor). In the present study, we explore the hypothesis that an AKAP150-associated pool of PP2B catalyses the dephosphorylation and desensitization of TRPV1. Biochemical, electrophysiological and cell-based experiments indicate that PP2B associates with AKAP150 and TRPV1 in cultured TG (trigeminal ganglia) neurons. Gene silencing of AKAP150 reduces basal phosphorylation of TRPV1. However, functional studies in neurons isolated from AKAP150?/? mice indicate that the anchoring protein is not required for pharmacological desensitization of TRPV1. Behavioural analysis of AKAP150?/? mice further support this notion, demonstrating that agonist-stimulated desensitization of TRPV1 is sensitive to PP2B inhibition and does not rely on AKAP150. These findings allow us to conclude that pharmacological desensitization of TRPV1 by PP2B may involve additional regulatory components.
Por, Elaine D.; Samelson, Bret K.; Belugin, Sergei; Akopian, Armen N.; Scott, John D.; Jeske, Nathaniel A.
Following proximal peripheral nerve injury, motor recovery is often poor due to prolonged muscle denervation and loss of regenerative potential. The transfer of a sensory nerve to denervated muscle results in improved functional recovery in experimental models. The authors here report the first clinical case of sensory protection. Following a total hip arthroplasty, this patient experienced a complete sciatic nerve palsy with no recovery at 3 months postsurgery and profound denervation confirmed electrodiagnostically. He underwent simultaneous neurolysis of the sciatic nerve and saphenous nerve transfers to the tibialis anterior branch of the peroneal nerve and gastrocnemius branch from the tibial nerve. He noted an early proprioceptive response. Electromyography demonstrated initially selective amelioration of denervation potentials followed by improved motor recovery in sensory protected muscles only. The patient reported clinically significant functional improvements in activities of daily living. The authors hypothesize that the presence of a sensory nerve during muscle denervation can improve functional motor recovery.
Bain, James R.; Hason, Yaniv; Veltri, Karen; Fahnestock, Margaret; Quartly, Caroline
Summary A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait
Luba Kalaydjieva; Amelia Nikolova; Ivo Turnev; Julia Petrova; Anna Hristova; Boryana Ishpekova; Iva Petkova; Alexander Shmarov; Stella Stancheva; L. Middleton; Luciano Merlini; A. Trogu; J. R. Muddle; R. H. M. King; P. K. Thomas
Pharmacological evidence suggests a functional role for spinal nitric oxide (NO) in the modulation of thermal and\\/or inflamma- tory hyperalgesia. To assess the role of NO in nerve injury- induced tactile allodynia, we examined neuronal NO synthase (nNOS) expression in the spinal cord and dorsal root ganglia (DRG) of rats with tactile allodynia because of either tight ligation of the
Z. David Luo; S. R. Chaplan; B. P. Scott; D. Cizkova; N. A. Calcutt; T. L. Yaksh
Clinical and experimental studies have shown that spinal sen- sory neurons become hyperexcitable after axonal injury, and electrophysiological changes have suggested that this may be attributable to changes in sodium current expression. We have demonstrated previously that sodium channel a-III mRNA lev- els are elevated and sodium channel a-SNS mRNA levels are reduced in rat spinal sensory neurons after axotomy.
Theodore R. Cummins; Stephen G. Waxman
Decoupling control of a multivariable system with a desensitizer has been proposed. Interactions between control loops were decoupled by means of a desensitizer and a two-way decoupler. The objective of the desensitizer was to reduce the decoupler sensitivity while the two-way decoupler was for actually decoupling control loops. The proposed control structure was verified on models of a highly interacting system and a distillation column. The control system with desensitizer significantly enhanced the robustness of the decoupling control system.
Wenteng Wu; Jingwei Ko; Hsingwo Lee (National Tsing Hua Univ., Hsinchu (Taiwan, Province of China). Dept. of Chemical Engineering)
Background Aspirin (ASA) is one of the best known and most widely used drugs in the world. Patients with coronary artery disease require prolonged treatments with this drug, which is denied to those patients with histories of adverse reactions to it. Methods In a rapid desensitization protocol a patient with a history of ASA-induced urticaria-angioedema was treated with escalating doses of aspirin administered orally every 25 minutes. Results The patient completed the desensitization protocol in few hours without complications, and currently is able to take 125 mg of ASA per day without adverse reactions. Conclusions This report describes the first desensitization treatment with aspirin carried out in our hospital. No other case was found in the national bibliography.
Alvarez, Mirta; Osoria, Lludenich; Ronquillo, Mercedes; Castro, Raul; Perez, Doguerti; Rodriguez, Jose; Irarragorri, Catalina
The rich diversity of lipids and the specific signalling pathways they recruit provides tremendous scope for modulation of biological functions. Lysophosphatidylinositol (LPI) is emerging as a key modulator of cell proliferation, migration, and function, and holds important pathophysiological implications due to its high levels in diseased tissues, such as in cancer. Here we report a novel role for LPI in sensitization of peripheral sensory neurons, which was evident as exaggerated sensitivity to painful and innocuous pressure. Histopathological analyses indicated lack of involvement of myelin pathology and immune cell recruitment by LPI. Using pharmacological and conditional genetic tools in mice, we delineated receptor-mediated from non-receptor-mediated effects of LPI and we observed that GPR55, which functions as an LPI receptor when heterologously expressed in mammalian cells, only partially mediates LPI-induced actions in the context of pain sensitization in vivo; we demonstrate that, in vivo, LPI functions by activating G?(13) as well as G?(q/11) arms of G-protein signalling in sensory neurons. This study thus reports a novel pathophysiological function for LPI and elucidates underlying molecular mechanisms. PMID:23973358
Gangadharan, Vijayan; Selvaraj, Deepitha; Kurejova, Martina; Njoo, Christian; Gritsch, Simon; Škoricová, Dagmar; Horstmann, Heinz; Offermanns, Stefan; Brown, Andrew J; Kuner, Thomas; Tappe-Theodor, Anke; Kuner, Rohini
The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology. PMID:19233440
Rigoard, P; Buffenoir, K; Wager, M; Bauche, S; Giot, J-P; Robert, R; Lapierre, F
The anatomy of the intratemporal part of the vestibular nerve in man, and the possible age related degenerative changes in the nerve were studied. The form and structure of the vestibular ganglion was studied with the light microscope. A numerical analysis of the vestibular nerve, and caliber spectra of the myelinated fibers in the vestibular nerve branches were studied in individuals of varying ages. It was found that the peripheral endings of the vestibular nerve form a complicated pattern inside the vestibular sensory epithelia. A detailed description of the sensory cells and their surface organelles is included.
This study investigates the influence of allergic inflammation in airway sensory innervation. We conclude that allergic inflammation in the guinea pig leads to both an increase in excitability, as manifested by an increase in the mechanical sensitivity of the airway nerve endings, and an induction of substance P production in airway sensory neurons. The data are consistent with the hypothesis
Bradley J. Undem; Dawn D. Hunter; Mark Liu; Angela Oakragly; Axel Fischer
Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. To address this issue, we studied the expression of T-type Ca2+ currents in small nociceptive dorsal root ganglion (DRG) cells from L4-5 spinal ganglia of adult rats with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve. In control rats, whole cell recordings revealed that T-type currents, measured in 10 mM Ba2+ as a charge carrier, were present in moderate density (20 +/- 2 pA/pF). In rats with CCI, T-type current density (30 +/- 3 pA/pF) was significantly increased, but voltage- and time-dependent activation and inactivation kinetics were not significantly different from those in controls. CCI-induced neuropathy did not significantly change the pharmacological sensitivity of T-type current in these cells to nickel. Collectively, our results indicate that CCI-induced neuropathy significantly increases T-type current expression in small DRG neurons. Our finding that T-type currents are upregulated in a CCI model of peripheral neuropathy and earlier pharmacological and molecular studies suggest that T-type channels may be potentially useful therapeutic targets for the treatment of neuropathic pain associated with partial mechanical injury to the sciatic nerve. PMID:18417624
Jagodic, Miljen M; Pathirathna, Sriyani; Joksovic, Pavle M; Lee, WooYong; Nelson, Michael T; Naik, Ajit K; Su, Peihan; Jevtovic-Todorovic, Vesna; Todorovic, Slobodan M
A method to substantially desensitize a metastable intermolecular composite material to electrostatic discharge and friction comprising mixing the composite material with an organic diluent and removing enough organic diluent from the mixture to form a mixture with a substantially putty-like consistency, as well as a concomitant method of recovering the metastable intermolecular composite material.
Busse, James R. (South Fork, CO); Dye, Robert C. (Los Alamos, NM); Foley, Timothy J. (Los Alamos, NM); Higa, Kelvin T. (Ridgecrest, CA); Jorgensen, Betty S. (Jemez Springs, NM); Sanders, Victor E. (White Rock, NM); Son, Steven F. (Los Alamos, NM)
According to this invention, n-propyl nitrate is rendered insensitive to shock, i.e., is desensitized, by means of a low gamma gas. The low gamma gas is incorporated into the n-propyl nitrate in an amount sufficient to assure that when bubbles are formed ...
B. A. Breslow
Peripheral nerve injuries associated with carotid endarterectomy are fairly common but not emphasized in reported results of carotid endarterectomy. The sensory nerves to the submandibular skin and ear lobe are often damaged. Motor nerves VII, IX, X, XI and XII may be injured at surgery. The commonest motor injuries involve the facial, vagus and hypoglossal nerves. Carotid endarterectomy was studied prospectively over 1 year to document the incidence of nerve injury. Nerve injury occurred in 12% of patients, with facial and vagus nerves being involved in 4% each. Careful surgical technique based on appropriate anatomical knowledge can prevent most of these complications. PMID:3815175
Downs, A R; Jessen, M; Lye, C R
Background Whether the method of local anesthetic administration for continuous femoral nerve blocks —basal infusion versus repeated hourly bolus doses —influences block effects remains unknown. Methods Bilateral femoral perineural catheters were inserted in volunteers (n = 11). Ropivacaine 0.1% was administered through both catheters concurrently: a 6-h continuous 5 ml/h basal infusion on one side and 6 hourly bolus doses on the contralateral side. The primary endpoint was the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle at Hour 6. Secondary end points included quadriceps MVIC at other time points, hip adductor MVIC, and cutaneous sensation 2 cm medial to the distal quadriceps tendon in the 22 h following local anesthetic administration initiation. Results Quadriceps MVIC for limbs receiving 0.1% ropivacaine as a basal infusion declined by a mean (SD) of 84% (19) compared with 83% (24) for limbs receiving 0.1% ropivacaine as repeated bolus doses between baseline and Hour 6 (paired t test P = 0.91). Intrasubject comparisons (left vs. right) reflected a lack of difference as well: the mean basal-bolus difference in quadriceps MVIC at Hour 6 was ?1.1% (95% CI ?22.0 to 19.8%). The similarity did not reach our a priori threshold for concluding equivalence, which was the 95% CI falling within ± 20%. There were similar minimal differences in the secondary endpoints during local anesthetic administration. Conclusions This study did not find evidence to support the hypothesis that varying the method of local anesthetic administration —basal infusion versus repeated bolus doses —influences continuous femoral nerve block effects to a clinically significant degree.
Charous, Matthew T.; Madison, Sarah J.; Suresh, J.; Sandhu, NavParkash S.; Loland, Vanessa J.; Mariano, Edward R.; Donohue, Michael C.; Dutton, Pascual H.; Ferguson, Eliza J.; Ilfeld, Brian M.
Quantitative sensory testing is a reliable way of assessing large and small sensory nerve fiber function. Sensory deficits may be quantified and the data used in parametric statistical analysis in research studies and drug trials. It is an important addition to the neurophysiologic armamentarium, because conventional sensory nerve conduction tests only the large fibers. QST is a psychophysical test and lacks the objectivity of NCS. The results are subject to changes owing to distraction, boredom, mental fatigue, drowsiness, or confusion. When patients are consciously or unconsciously biased toward an abnormal QST result, no psychophysical testing can reliably distinguish these patients from those with organic disease. QST tests the integrity of the entire sensory neuraxis and is of no localizing value. Dysfunction of the peripheral nerves or central nervous system may give rise to abnormalities in QST. As is true for other neurophysiologic tests, QST results should always be interpreted in light of the patient's clinical presentation. Quantitative sensory testing has been shown to be reasonably reproducible over a period of days or weeks in normal subjects. Because longitudinal QST studies of patients in drug trials are usually performed over a period of several months to a few years, reproducibility studies on the placebo-control group should be included. For individual patients, more studies are needed to determine the maximum allowable difference between two QSTs that can be attributed to experimental error. The reproducibility of thermal thresholds may not be as good as that of vibration threshold. Different commercially available QST instruments have different specifications (thermode size, stimulus characteristics), testing protocols, algorithms, and normal values. Only QST instruments and their corresponding methodologies that have been shown to be reproducible should be used for research and patient care. The data in the literature do not allow conclusions regarding the superiority of any QST instruments. The future of QST is promising; however, many factors can affect QST results. As is true for other neurophysiologic tests, QST is susceptible to many extraneous factors and to misuse when not properly interpreted by the clinician. PMID:12795516
Siao, Peter; Cros, Didier P
ObjectiveThe neurophysiological confirmation of carpal tunnel syndrome (CTS) relies on detecting abnormal median nerve transcarpal conduction in the presence of unaffected comparator nerves. We compare the palmar cutaneous median branch (PCBm) with the ulnar sensory nerve conduction to digit 5 (US5) as comparator nerves for diagnosing CTS.
Rahul Rathakrishnan; Aravinda Kannan Therimadasamy; Y. H. Chan; E. P. Wilder-Smith
When it comes to restoring impaired neural function by means of surgical reconstruction, sensory nerves have always been in the role of the neglected child when compared with motor nerves. Especially in the head and neck area, with its either sensory, motor or mixed cranial nerves, an impaired sensory function can cause severe medical conditions. When performing surgery in the head and neck area, sustaining neural function must not only be highest priority for motor but also for sensory nerves. In cases with obvious neural damage to sensory nerves, an immediate neural repair, if necessary with neural interposition grafts, is desirable. Also in cases with traumatic trigeminal damage, an immediate neural repair ought to be considered, especially since reconstructive measures at a later time mostly require for interposition grafts. In terms of the trigeminal neuralgia, commonly thought to arise from neurovascular brainstem compression, a pharmaceutical treatment is considered as the state of the art in terms of conservative therapy. A neurovascular decompression of the trigeminal root can be an alternative in some cases when surgical treatment is sought after. Besides the above mentioned therapeutic options, alternative treatments are available.
Iro, Heinrich; Bumm, Klaus; Waldfahrer, Frank
The ?2-adrenergic receptor (?2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the ?2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective ?2AR desensitization at the whole cell level.
Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye
Prostaglandins (PG's) increase short-circuit current (I/sub sc/), inhibit NaCl absorption, and stimulate Cl secretion in rabbit ileum. These changes occur with the following PGs; E/sub 3/, E/sub 1/, nitrilo-I/sub 2/ and, to a lesser extent, with A/sub 2/, D/sub 2/, and F/sub 2..cap alpha../. Arachidonic acid (AA) also stimulates secretion. The PG- or AA-stimulated I/sub sc/ does not persist, however, and on prolonged exposure tachyphylaxis develops. Resensitization of the I/sub sc/ response to PGE/sub 2/ is rapid, being essentially complete in 15 min after the PG is removed. Desensitization to AA is not reflected by diminished PG generation. PGE/sub 2/ release from the mucosa after AA addition is constant, although the AA-stimulated I/sub sc/ decreases. I/sub sc/ measurements indicate that PGE/sub 2/ at slightly below its EC/sub 50/ partially desensitizes and a near-maximal concentration completely desensitizes to PGE/sub 2/ but does not, however, inhibit the subsequent change in I/sub sc/ caused by theophylline or vasoactive intestinal peptide (VIP). Adenosine 3',5'-cyclic monophosphate (cAMP) measurements suggest that desensitization applies to cAMP production. PGE/sub 2/ (10/sup -5/ M) increases mucosal cAMP three- to sevenfold, but this elevation is transient; a second challenge dose, which fails to elicit a I/sub sc/ change, also fails to increase mucosal cAMP. Adenylate cyclase measurements from untreated and PGE/sub 2/-treated enterocytes demonstrate a decrease in stimulation by PGE/sub 2/ but not in stimulation by VIP, fluoride, or 5-guanylylimidodiphosphate.
Musch, M.W.; Field, M.; Miller, R.J.; Stoff, J.S.
Human recombinant erythropoietins (EPO) and darbepoetins are widely used for anemias associated with chronic kidney disease. Allergic reactions to erythropoetins and darbepoetins have only occasionally been reported. These skin reactions include pruritus, wheals at the injection site, orofacial anaphylaxis and anjioedema. In this article, we report an 11 year-old female who experienced generalized erithematous skin eruption and desquamation after both erythropoietin and darbepoetin treatments. We successfully used darbepoetin with the support of premedication and desensitization. PMID:24129045
Tahan, F; Akar, H H; Dursun, I; Yilmaz, K
Ca2+/calmodulin-mediated negative feedback is a prototypical regulatory mechanism for Ca2+-permeable ion channels. In olfactory sensory neurons (OSNs), such regulation on the cyclic nucleotide-gated (CNG) channel is considered a major mechanism of OSN adaptation. To determine the role of Ca2+/calmodulin desensitization of the olfactory CNG channel, we introduced a mutation in the channel subunit CNGB1b in mice that rendered the channel resistant to fast desensitization by Ca2+/calmodulin. Contrary to expectations, mutant OSNs showed normal receptor current adaptation to repeated stimulation. Rather, they displayed slower response termination and, consequently, reduced ability to transmit olfactory information to the olfactory bulb. They also displayed reduced response decline during sustained odorant exposure. These results suggest that Ca2+/calmodulin-mediated CNG channel fast desensitization is less important in regulating the sensitivity to recurring stimulation than previously thought and instead functions primarily to terminate OSN responses. PMID:18466748
Song, Yijun; Cygnar, Katherine D; Sagdullaev, Botir; Valley, Matthew; Hirsh, Sarah; Stephan, Aaron; Reisert, Johannes; Zhao, Haiqing
We report a 25-year-old man with a history of uncontrolled migrainous headaches who developed third nerve palsy and sensory loss over V1 distribution of trigeminal nerve, during an attack of severe migraine. Gadolinium-enhanced MRI of the brain and cavernous sinus was normal and did not disclose nerve enhancement. CT angiogram was also normal. The patient recovered uneventfully in 2 weeks on oral steroids. The commonest cranial nerve implicated in ophthalmoplegic migraine is the occulomotor nerve. Involvement of the fifth nerve has never been reported. PMID:23715838
Sharma, Bhawna; Sannegowda, Raghavendra Bakki; Kumar, Sunil; Dubey, Parul
Phototropism is induced by blue light, which also induces desensitization, a partial or total loss of phototropic responsiveness. The fluence and fluence-rate dependence of desensitization and recovery from desensitization have been measured for etiolated and red light (669-nm) preirradiated Arabidopsis thaliana seedlings. The extent of desensitization increased as the fluence of the desensitizing 450-nm light was increased from 0.3 to 60 micromoles m-2 s-1. At equal fluences, blue light caused more desensitization when given at a fluence rate of 1.0 micromole m-2 s-1 than at 0.3 micromole m-2 s-1. In addition, seedlings irradiated with blue light at the higher fluence rate required a longer recovery time than seedlings irradiated at the lower fluence rate. A red light preirradiation, probably mediated via phytochrome, decreased the time required for recovery from desensitization. The minimum time for detectable recovery was about 65 s, and the maximum time observed was about 10 min. It is proposed that the descending arm of the fluence-response relationship for first positive phototropism is a consequence of desensitization, and that the time threshold for second positive phototropism establishes a period during which recovery from desensitization occurs. PMID:11537496
Janoudi, A K; Poff, K L
Objective Clinical experience suggests that the majority of schwannomas arise within sensory ganglia, suggesting that intraganglionic glial cells represent a potential cell of origin for schwannomas. To support this clinical impression, we reviewed magnetic resonance imaging (MRI) studies performed over a 5 year period at our institution to determine the relationship of cranial and spinal nerve schwannomas with the ganglia of the associated nerves. Study design Retrospective cohort study Setting Tertiary referral center Patients Patients undergoing imaging study at our institution over a 5 year period. Intervention(s) Radiographical images at our institution were reviewed as well as published studies to determine the anatomic location of schwannomas. Main outcome measure(s) Anatomical location of schwannomas Results A total of 372 patients were found over the 5-year study period, 31 of those were diagnosed with neurofibromatosis type 2 (NF2). Vestibular schwannomas comprised the greatest number of schwannomas, followed by spinal schwannomas. In NF2 patients, spinal schwannomas were the most common tumor, followed by vestibular schwannomas. In NF2 patients and those with sporadic schwannomas, the overwhelming majority of tumors arose in nerves with a sensory component and were associated with sensory ganglia of the nerves (562/607, 92.6%). Very few tumors arose from pure motor nerves. This is supported by review of published articles on anatomic location of schwannomas. Conclusions Schwannomas are strongly associated anatomically with ganglia of sensory nerves. These findings raise the possibility that intraganglionic glial cells give rise to the majority of schwannomas.
Tryggvason, Geir; Barnett, Andrew; Kim, John; Soken, Hakan; Maley, Joan; Hansen, Marlan R.
Vascular tone is controlled by endothelium and nerves innervating blood vessels. Endothelium releases various substances such as PGI2 (Prostacyclin), NO (nitric oxide), TXA2 (thromboxane A2) and ET-1 (endothelin-1). It is well documented that ethanol affects vascular responses mediated by these substances. On the other hand, peripheral vascular tone is also regulated not only by sympathetic adrenergic nerves but also by nonadrenergic noncholinergic (NANC) nerves. NANC nerves include NO nerves and sensory nerves which release calcitonin gene-related peptide (CGRP) and nerve-mediated hyperpolarizing factor (NDHF). However, effect of ethanol on nerve-mediated vascular responses remains poorly understood. Therefore, this review summarizes the effect of ethanol on the sympathetic adrenergic nerve-mediated vasoconstriction and the sensory nerve-mediated vasorelaxation. PMID:21706814
Kudo, Risa; Hatake, Katsuhiko
The purpose of the present study was to investigate the GSR during systematic desensitization. Three groups of females each were preselected for high snake fear. Outcome measures indicated that the desensitization group reduced phobic behavior most, followed by the relaxation group, and then the exposure groups. (Author)
Hyman, Edward T.; Gale, Elliot N.
Biofeedback training to reduce test anxiety among university students was investigated. Biofeedback training with systematic desensitization was compared to an automated systematic desensitization program not using EMG feedback. Biofeedback training is a useful technique for reducing test anxiety, but not necessarily more effective than systematic…
Romano, John L.; Cabianca, William A.
Desensitization is a clinical procedure whereby incremental doses of a drug are administered over several hours to a sensitive patient until a therapeutic dose and clinical tolerance are achieved. Clinical tolerance may occur in part by attenuating the mast cell response. In the present study, primary human skin mast cells were used to establish and characterize an in vitro model of desensitization. Mast cells in culture were armed with allergen-specific (4-hydroxy-3-nitro-phenylacety and Der p2) and non-specific IgE antibodies, and then desensitized by incremental exposures to 4-hydroxy-3-nitrophenylacety-BSA. This desensitization procedure abrogated the subsequent degranulation response to the desensitizing allergen, to an unrelated allergen, and to IgG anti-Fc?RI, but not to C5a, substance P, compound 48/80, and calcium ionophore. Desensitized cells regained their Fc?RI-dependent degranulation capability by 24–48 h after free allergen had been removed. Therefore, sensitized human skin mast cells are reversibly desensitized in vitro by exposure to incremental doses of that allergen, which also cross-desensitizes them to an unrelated allergen.
Zhao, Wei; Gomez, Gregorio; Macey, Matthew; Kepley, Christopher L.
Degree of transfer and fear change associated with four levels of desensitization, pseudodesensitization, and no treatment were assessed in snakephobic students. Desensitization subjects reported significantly less anxiety than no-treatment controls when repeating their highest pretreatment responses, but were no different from either control…
Kennedy, Thomas D.; Kimura, Harry K.
Until now, more than 800 distinct G protein-coupled receptors (GPCRs) have been identified in the human genome. The four subtypes of the adenosine receptor (A1, A2A, A2B and A3 receptor) belong to this large family of GPCRs that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body and involved in a variety of physiological processes and diseases, there is great interest in understanding how the different subtypes are regulated, as a basis for designing therapeutic drugs that either avoid or make use of this regulation. The major GPCR regulatory pathway involves phosphorylation of activated receptors by G protein-coupled receptor kinases (GRKs), a process that is followed by binding of arrestin proteins. This prevents receptors from activating downstream heterotrimeric G protein pathways, but at the same time allows activation of arrestin-dependent signalling pathways. Upon agonist treatment, adenosine receptor subtypes are differently regulated. For instance, the A1Rs are not (readily) phosphorylated and internalize slowly, showing a typical half-life of several hours, whereas the A2AR and A2BR undergo much faster downregulation, usually shorter than 1 h. The A3R is subject to even faster downregulation, often a matter of minutes. The fast desensitization of the A3R after agonist exposure may be therapeutically equivalent to antagonist occupancy of the receptor. This review describes the process of desensitization and internalization of the different adenosine subtypes in cell systems, tissues and in vivo studies. In addition, molecular mechanisms involved in adenosine receptor desensitization are discussed.
Klaasse, Elisabeth C.; de Grip, Willem J.; Beukers, Margot W.
Hypertension is accompanied by increased arterial endothelin-1 (ET-1) and decreased arterial contraction to ET-1. By contrast, veins remain responsive to ET-1 in hypertension. Isometric contraction was used to test the hypothesis that veins do not desensitize to ET-1 to the extent of arteries, possibly because of the presence of functional ETA and ETB receptors on veins and only functional ETA receptors on arteries. Contraction to ET-1 after exposure to ET-1 (100 nmol/L) was abolished in aortae, while in veins 36.3 +/- 0.2% of maximal contraction to ET-1 remained. Aortae were unresponsive to the ETA receptor agonist ET-1(1-31) (100 nmol/L) after ET-1 exposure, while 21.9 +/- 0.6% of maximum venous contraction to ET-1 (1-31) remained. In a similar manner, the venous ETB receptor did not lose responsiveness to the ETB receptor agonist sarafotoxin 6c (S6c, 100 nmol/L); aortae did not contract to S6c. In ET-1-desensitized veins, the ETB receptor antagonist BQ-788 (100 nmol/L) decreased maximum contraction to ET-1, but did not alter potency (-log EC50 control = 8.14 +/- 0.01 mol/L; BQ-788 = 8.13 +/- 0.04 mol/L). The ETA receptor antagonist atrasentan (100 nmol/L) blocked remaining venous contraction to ET-1 (control = 8.05 +/- 0.05 mol/L; atrasentan = unmeasurable). Maintained responsiveness to ET-1 in veins occurs primarily via the ETA receptor, while in arteries the ETA receptor is responsible for desensitization to ET-1. PMID:15076222
Thakali, Keshari; Fink, Gregory D; Watts, Stephanie W
Background: Many patients with chronic tendinosis have experienced early pain relief after application of bipolar radiofrequency treatment. It is hypothesized that the mechanism of action may be the acute degeneration and\\/or ablation of sensory nerve fibers.Hypothesis: After ablation or degeneration by bipolar radiofrequency, nerve fibers will have the ability to regenerate with time.Study Design: Controlled laboratory study.Methods: Eighteen Sprague-Dawley rats
Nobuyasu Ochiai; James P. Tasto; Seiji Ohtori; Norimasa Takahashi; Hideshige Moriya; David Amiel
The aim of this study is to verify whether degeneration of skin receptors or intradermal nerve endings by topical application of capsaicin modifies the double peak response obtained by submaximal anodal stimulation. Five healthy volunteers topically applied capsaicin to the finger-tip of digit III (on the distal phalanx) four times daily for 4-5 weeks. Before and after local capsaicin applications, we studied the following electrophysiological findings: compound sensory action potential (CSAP), double peak response, sensory threshold and double peak stimulus intensity. Local capsaicin application causes disappearance or decrease of the second component of the double peak, which gradually increases after the suspension of capsaicin. Conversely, no significant differences were observed for CSAP, sensory threshold and double peak stimulus intensity. This study suggests that the second component of the double peak may be a diagnostic tool suitable to show an impairment of the extreme segments of sensory nerve fibres in distal sensory axonopathy in the early stages of damage, when receptors or skin nerve endings are impaired but undetectable by standard nerve conduction studies. PMID:17972041
Aprile, I; Tonali, P; Stalberg, E; Di Stasio, E; Caliandro, P; Foschini, M; Vergili, G; Padua, L
Sural nerve presents great topographic variability and it is responsible for sensory innervation of the posterolateral side of the distal third of the leg and lateral aspect of the foot. Entrapment of the nerve could be caused by compression due to fascial thickening, while the symptomatology includes sensory alterations and deficits at the nerve distribution area. We report a cadaveric case of a variant sural nerve that presented a distinct entrapment site. A supernumerary sensory branch was encountered originating from the common peroneal nerve, while the peroneal component of the sural nerve was observed to take a course within a fibrous fascial tunnel 3.1 cm in length that caused nerve fixation and flattening. The tension applied to the aforementioned branch was shown to worsen during passive forcible foot plantaflexion and inversion. The etiology, diagnosis and the treatment options are discussed comprehensively.
Natsis, Konstantinos; Tzika, Maria; Ioannidis, Orestis
We report on magnetic resonance neurography (MRN) as a supplementary diagnostic tool in sciatic nerve injection injury. The\\u000a object of the study was to test if T2-weighted (w) contrast within the sciatic nerve serves as an objective criterion for\\u000a sciatic injection injury. Three patients presented with acute sensory and\\/or motor complaints in the distribution of the sciatic\\u000a nerve after dorsogluteal
Mirko Pham; Carsten Wessig; Jörg Brinkhoff; Karlheinz Reiners; Guido Stoll; Martin Bendszus
\\u000a The relationship between nerve injury and pain is pervasive in medicine, being both a simple, common experience and an important\\u000a diagnostic tool. Acute trauma to a nerve is almost always painful and has been experienced by many people in association with\\u000a sports and workplace activities. In these cases, injuries occur usually because of nerve stretching or compression, damaging\\u000a sensory axons
Robert R. Myers; Rochelle Wagner; Linda S. Sorkin
End-to-side (ETS) nerve repair, in which the distal stump of a transected nerve is coapted to the side of an uninjured donor nerve, has been suggested as a technique for repair of peripheral nerve injuries where the proximal nerve stump is unavailable or a significant nerve gap exists. Full review of the ETS literature suggests that sensory recovery after ETS repair results in some, but not robust, regeneration. Sensory axons will sprout without deliberate injury. However, motor axons only regenerate after deliberate nerve injury. Experimental and clinical experience with ETS neurorrhaphy has rendered mixed results. Continued research into ETS nerve repair is warranted. ETS techniques should not yet replace safer and more reliable techniques of nerve repair except when some, but not good, sensory recovery is appropriate and a deliberate injury to the donor motor nerve is made. PMID:18928893
Dvali, Linda T; Myckatyn, Terence M
OBJECTIVES—Poisoning by organophosphate insecticides causes cholinergic toxicity. Organophosphate induced delayed polyneuropathy (OPIDP) is a sensory-motor distal axonopathy which usually occurs after ingestion of large doses of certain organophosphate insecticides and has so far only been reported in patients with preceding cholinergic toxicity. Surprisingly, it was recently reported by other authors that an exclusively sensory neuropathy developed in eight patients after repeated unquantified exposures to chlorpyrifos, which did not cause clear-cut cholinergic toxicity. The objective was to assess whether an exclusively sensory neuropathy develops in patients severely poisoned by various OPs.?METHODS—Toxicological studies and electrophysiological measurements were performed in peripheral motor and sensory nerves in 11 patients after acute organophosphate poisoning among which two subjects were poisoned with chlorpyrifos.?RESULTS—Three patients developed OPIDP, including one poisoned by chlorpyrifos. Exclusively sensory neuropathy was never seen after either single or repeated acute organophosphate poisoning. A mild sensory component was associated with a severe motor component in two of the three cases of OPIDP, the other was an exclusively motor polyneuropathy.?CONCLUSION—A sensory-motor polyneuropathy caused by organophosphate insecticides might occur after a severe poisoning and the sensory component, if present, is milder than the motor one. Bearing in mind the toxicological characteristics of these organophosphate insecticides, other causes should be sought for sensory peripheral neuropathies in patients who did not display severe cholinergic toxicity a few weeks before the onset of symptoms and signs.??
Moretto, A.; Lotti, M.
G protein-coupled receptors (GPCRs) are involved in a multitude of signaling processes and respond to a wide range of ligands. The activity of GPCRs is subject to three principal modes of regulation: desensitization, trafficking, and down-regulation. Desensitization is defined as a loss in the responsiveness of a signaling system. The generally established paradigm for GPCR desensitization involves receptor phosphorylation by GPCR kinases (GRKs), initiated by agonist-induced conformational changes in the receptor or by kinases activated by specific signaling pathways. GRKs have several interaction domains and may be able to contribute to receptor desensitization through mechanisms that do not involve the kinase activity of GRK. Pao and Benovic discuss some of these interactions and their relevance for the regulation of GPCR signaling.
Christina S. Pao (Thomas Jefferson University;The Kimmel Cancer Center, Department of Microbiology and Immunology REV); Jeffrey L. Benovic (Thomas Jefferson University;The Kimmel Cancer Center, Department of Microbiology and Immunology REV)
1. In developing chick skeletal muscle, extracellular adenosine 5'-triphosphate (ATP) elicits an early excitatory conductance increase followed by a late potassium conductance increase. Both of these responses desensitize profoundly. Intracellular recordings and whole-cell voltage-clamp recordings were made in order to examine the time course and mechanism of desensitization and the recovery from desensitization. 2. Most of the loss of responsiveness to ATP occurred during the first minute of exposure to ATP. For the excitatory conductance, the loss of responsiveness to ATP resulted in part from long-lasting activation of the ATP-sensitive channels and in part from entrance into an inactive (non-conducting) state. In contrast, desensitization of the potassium conductance was entirely the result of a relatively fast transition to an inactive state. 3. Recovery from desensitization took many hours for both responses and was quite sensitive to temperature. 4. Recovery from desensitization for both responses was prevented by preincubation with the glycosylation inhibitor, tunicamycin. Several lines of evidence suggest that tunicamycin treatment blocked the delivery of new ATP receptors to the cell surface. 5. The recovery of the early response to ATP following exposure to two non-competitive inhibitors of the ATP response was also examined. These two compounds are thought to covalently modify the receptor. After exposure to either of these inhibitors, responsiveness to ATP returned over a time course that was similar to the time course of recovery from desensitization. 6. These results indicate that, following activation, ATP receptors do not become available for reactivation, and that recovery from desensitization is due to the insertion of newly synthesized receptors into the plasma membrane.
Thomas, S A; Hume, R I
Objective: To study the clinical profile and outcome of surgery for injection nerve palsies. Materials and Methods: This is a retrospective study of patients with INP who were treated at our institute during May 2000 to May 2009. Clinical, electroneuromyography (ENMG), and operative findings were noted. Intraoperative nerve action potential monitoring was not used in any case. Outcome of patients who were followed was reviewed. Results: INP comprised 92 (11%) of 837 nerve injury patients. Seventy one patients were children less than 16 years. The nerves involved were sciatic in 80 patients, radial in 8, and others in four. Fifty seven patients had power, grade 0/5. ENMG studies revealed absent compound muscle action potential in 64 and absent sensory nerve action potential in 67 patients. Thirty nine (42.3%) of 92 patients underwent surgery. The mean duration since injury in these patients was 5.2 months (3 months to 11 months). All underwent neurolysis. Only 18 patients who underwent surgery had a follow up of more than 3 months. Ten (55.5%) patients had good or fair outcome after surgery. Except for grade of motor deficit prior to surgery, none of the variables were found to significantly affect the outcome. Conclusion: The outcome of INP is generally good and many patients recover spontaneously. The outcome of surgery is dependent on preoperative motor power.
Kakati, Arindhom; Bhat, Dhananjaya; Devi, Bhagavathula Indira; Shukla, Dhaval
Sjögren’s syndrome (SS) is an important but poorly recognized cause of peripheral neuropathy. Several forms of peripheral nerve dysfunction occur, including trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy and pure sensory neuronopathy. The pathological findings vary and the definite treatment is not known. Here we present 4 cases of acute ataxic sensory polyneuropathy with SS, and the experience of
Wei-Hung Chen; Jiann-Horng Yeh; Hou-Chang Chiu
The intact sciatic nerve contains levels of nerve growth factor (NGF) that are comparable to those of densely innervated peripheral target tissues of NGF-responsive (sympathetic and sensory) neurons. There, the high NGF levels are reflected by cor- respondingly high mRNA N~F levels. In the intact sciatic nerve, mRNA N~F levels were very low, thus in- dicating that the contribution of
R. Heumann; Christine Bandtlow; Hans Thoenen
Previous studies demonstrated that Schwann cells (SCs) express distinct motor and sensory phenotypes, which impact the ability of these pathways to selectively support regenerating neurons. In the present study, unbiased microarray analysis was used to examine differential gene expression in denervated motor and sensory pathways in rats. Several genes that were significantly upregulated in either denervated sensory or motor pathways were identified and two secreted factors were selected for further analysis: osteopontin (OPN) and clusterin (CLU) which were upregulated in denervated motor and sensory pathways, respectively. Sciatic nerve transection induced upregulation of OPN and CLU and expression of both returned to baseline levels with ensuing regeneration. In vitro analysis using exogenously applied OPN induced outgrowth of motor but not sensory neurons. CLU, however, induced outgrowth of sensory neurons, but not motor neurons. To assess the functional importance of OPN and CLU, peripheral nerve regeneration was examined in OPN and CLU(-/-) mice. When compared with OPN(+/+) mice, motor neuron regeneration was reduced in OPN(-/-) mice. Impaired regeneration through OPN(-/-) peripheral nerves grafted into OPN(+/+) mice indicated that loss of OPN in SCs was responsible for reduced motor regeneration. Sensory neuron regeneration was impaired in CLU(-/-) mice following sciatic nerve crush and impaired regeneration nerve fibers through CLU(-/-) nerve grafts transplanted into CLU(+/+) mice indicated that reduced sensory regeneration is likely due to SC-derived CLU. Together, these studies suggest unique roles for SC-derived OPN and CLU in regeneration of peripheral motor and sensory axons. PMID:24478351
Wright, Megan C; Mi, Ruifa; Connor, Emmalynn; Reed, Nicole; Vyas, Alka; Alspalter, Manula; Coppola, Giovanni; Geschwind, Daniel H; Brushart, Thomas M; Höke, Ahmet
Opioid tolerance and dependence are important phenomena. The contribution of acute ?-opioid receptor regulatory mechanisms to the development of analgesic tolerance or physical dependence are unknown, and even the mechanisms underlying relatively rapid receptor desensitization in single cells are unresolved. To a large degree, the uncertainty surrounding the mechanisms and consequences of short-term regulation of ?-opioid receptors in single cells arises from the limitations in the experimental design in many of the studies that have investigated these events. Receptor overexpression and use of assays in which regulatory mechanisms are likely to blunt control determinations have led to measurements of opioid receptor activity that are likely to be insensitive to receptor uncoupling. Together with uncertainties concerning molecular details of ?-opioid receptor interactions with potential regulatory molecules such as G protein-coupled receptor kinases and arrestins, we are left with an incomplete picture crudely copied from the well-worked-out regulatory schema for ?2-adrenoceptors. As a consequence, suggestions that clinically relevant ?-opioid receptor agonists may have different propensities to produce tolerance and dependence that arise from their differential recruitment of regulatory mechanisms are premature, and have not yet been appropriately assessed, nor explained in the context of a thoroughly established regulatory scheme. In this commentary, we outline the experimental limitations that have given rise to conflicting ideas about how ?-opioid receptors are regulated, and identify the issues we feel still need to be addressed before we can understand why morphine promotes receptor trafficking differently to other opioids.
Connor, Mark; Osborne, Peregrine B; Christie, MacDonald J
Since 1976, experimental and clinical studies have suggested the superiority of vascularized nerve grafts. In this study, a 27-year experience of the senior author is presented regarding vascularized nerve grafts and fascia for complex upper extremity nerve reconstruction. The factors influencing outcomes as well as a comparison with conventional nerve grafts is presented. Since 1981, 21 vascularized nerve grafts, other than vascularized ulnar nerve, were used for reconstruction of nerve injuries in the upper extremity. Indications were prolonged denervation time, failure of the previously used conventional nerve grafts, and excessive scar in the recipient site. Injury was in the hand/wrist area (n?=?5), in the forearm (n?=?4), in the elbow (n?=?2), in the arm (n?=?4), or in the plexus (n?=?6). Vascularized sural (n?=?9), saphenous (n?=?8), superficial radial (n?=?3), and peroneal (superficial and deep) nerves were used. The mean follow-up was 31.4 months. Vascularized nerve grafts for upper extremity injuries provided good to excellent sensory return in severely scarred upper extremities in patients in whom conventional nerve grafts had failed. They have also provided relief of causalgia after painful neuroma resection and motor function recovery in selective cases even for above the elbow injuries. Small diameter vascularized nerve grafts should be considered for bridging long nerve gaps in regions of excessive scar or for reconstructions where conventional nerve grafts have failed.
Kostopoulos, Vasileios K.
Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins. PMID:24792390
Danigo, Aurore; Magy, Laurent; Richard, Laurence; Sturtz, Franck; Funalot, Benoît; Demiot, Claire
\\u000a Together, the relationship between the mechanical response of neural tissues and the related mechanisms of injury provide\\u000a a foundation for defining relevant thresholds for injury. The nerves and nerve roots are biologic structures with specific\\u000a and important functions, and whose response to mechanical loading can have immediate, long-lasting and widespread consequences.\\u000a In particular, when nerves or nerve roots are mechanically
Kristen J. Nicholson; Beth A. Winkelstein
Mechanism of action of a desensitizing fluoride toothpaste delivering calcium and phosphate ingredients in the treatment of dental hypersensitivity. Part II: comparison with a professional treatment for tooth hypersensitivity.
Tooth hypersensitivity can occur when gum recession causes exposure of dentin. Tiny tubules, which permeate dentin, provide open passageways from the mouth to the intradental nerve in the pulpal cavity. Under such circumstances, stimuli in the mouth can cause pressure on the intradental nerve, leading to pain. Sealing the outside of the tubules with an impermeable substance can effectively treat hypersensitivity. One such clinically proven composition is a professionally applied tooth desensitizer, which has been shown to initially produce a layer of amorphous calcium phosphate (ACP) on the surface of dentin. Under the influence of fluoride, ACP reforms as hydroxyapatite (HAP), which has essentially the same composition as tooth mineral. Three fluoride toothpastes that deliver calcium and phosphate salts to the teeth also have been demonstrated in clinical trials to relieve hypersensitivity. This study compared the mechanism of action of these toothpastes to that of the professional desensitizer. A single application of the professional desensitizer or multiple applications of any of the three toothpastes was shown to reduce dentin permeability. A conventional fluoride toothpaste also was found to inhibit fluid flow through the dentin but to a lesser degree than the other toothpastes. The desensitizer and the three toothpastes were found to occlude the dentinal tubules with a layer of calcium phosphate that had a calcium-to-phosphate ratio consistent with the formation of ACP or HAP. The morphology of the coherent mineral layer formed by Arm & Hammer Enamel Care Sensitive was similar, especially to that produced by the desensitizer. In contrast, the conventional toothpaste left localized areas of surface residue composed of silica particles. The mechanism of action of the three toothpastes that deliver calcium and phosphate salts is the same as that of the professional desensitizer. PMID:19998729
Charig, Andrew J; Thong, Stephen; Flores, Florita; Gupta, Shivank; Major, Elizabeth; Winston, Anthony E
Clopidogrel is an antiplatelet drug widely used for treatment and prevention of a variety of cardiovascular diseases. We report a successful desensitization to clopidogrel in a 70-year-old Caucasian man with delayed hypersensitivity (HS) reaction. He developed lip, hand and foot swelling, erythematous papular non-pruritic lesions and arthralgias 2 weeks after starting treatment with clopidogrel 75 mg/d. A 3-hour desensitization protocol was started, achieving a cumulative dose of 154 mg without any reaction, and a daily dose of 75 mg was recommended. On the 4th day, the patient developed skin lesions similar to the previously described. He was treated with topical steroids and oral antihistamines, and the daily dose of clopidogrel was reduced to 20 mg. A new desensitization protocol was established, with a slow dose increment, according to the patient's response. It was only possible to achieve the dose of 75 mg/d after 2 months. Although well tolerated by most patients, HS reactions with clopidogrel may occur and desensitization is rising as a safe alternative in those patients. In delayed reactions with cutaneous lesions, a slower desensitization protocol may be necessary, as in this case. PMID:24702878
Barreira, P; Cadinha, S; Malheiro, D; Moreira da Silva, J P
The suprascapular nerve branches provide efferent innervation to the supraspinatus and infraspinatus muscles as well as sensory innervation to the shoulder joint. This study was carried out to verify the spinal root origins and innervations of the suprascapular nerve. Fifty samples of the suprascapular nerve taken from 37 adult Korean cadavers were used in this study. The suprascapular nerve was found to comprise the ventral rami of the C5 and C6 in 76.0% of the fifty samples; C4, C5, and C6 nerves in 18.0%; and C5 nerve in only 6.0%. The C5 nerve was consistently shown to be the largest in mean diameter and was found to be a major contributor of nerve fibers leading to the suprascapular nerve. This study shows that the main spinal component of the suprascapular nerve is C5 nerve. In most cases, the rate of the involvement of the C4 and C6 nerves (18.0 and 94.0%, respectively) with the suprascapular nerve was less than that of C5 nerve. C4 and C5 nerves were shown to contribute nerve fibers to the supraspinatus and infraspinatus muscles and to both shoulder joints, whereas C6 nerve displayed variable patterns of innervation. PMID:19937327
Shin, Chuog; Lee, Seo-Eun; Yu, Kee-Hyun; Chae, Han-Kyo; Lee, Kyu-Seok
Mechanism of action of a desensitizing fluoride toothpaste delivering calcium and phosphate ingredients in the treatment of dental hypersensitivity. Part III: Prevention of dye penetration through dentin vs a calcium- and phosphate-free control.
It is generally accepted that the pain of dental hypersensitivity resulting from gum recession is from the movement of fluid within the exposed tubules of dentin, causing changes in pressure on the nerve within the pulpal cavity. One method of treating hypersensitivity is to occlude the tubules, preventing fluid movement. This article discusses the use of a dye penetration technique, which establishes this mechanism of action for a desensitizing fluoride toothpaste containing calcium and phosphate. Two groups of intact teeth were perfectly sealed with enamel paint. Windows 100-micro to 200-micro deep were opened on opposite sides of each tooth at the dentin-enamel junction and briefly etched using 20% polyacrylic acid. One batch of teeth was treated eight times for 30 mins each with a 1:3 slurry of the desensitizing toothpaste and another set with a similar slurry prepared from a calcium- and phosphate-free control. A 0.85% aqueous solution of acid red fuchsin dye was applied to each window and allowed to dry. After a brief rinse, the teeth were sectioned across the windows. Almost no dye penetration was seen in teeth treated with the desensitizing toothpaste; however, extensive penetration through the dentin was visible in the control-treated teeth. The differences in dye penetration for the two sets of teeth were significant by both subjective (P < .001) and objective (P < .01) measures. Tubule occlusion because of calcium and phosphate ions from the desensitizing toothpaste accounts for its tooth desensitizing efficacy. PMID:20158016
Winston, Anthony E; Charig, Andrew J; Thong, Stephen
Ganglions of the upper extremity are common. Radial nerve dysfunction, particularly radial sensory dysfunction, is a rare finding in association with a ganglion. We present our experience with two such ganglia and a review of the literature.
Lifchez, Scott D.; Dzwierzynski, William W.
Autologous nerve grafting is the current standard for bridging large gaps in major sensory and motor nerves. It allows both function and pain improvement with predictable results. Clinical observations of nerve elongation caused by tumours have prompted experimental animal studies of induced gradual elongation of the nerve stump proximal to the gap. This technique allows direct suturing of the two nerve ends to bridge the gap. Here, we describe a case of neuroma-in-continuity of the median nerve managed by resection and direct suture after nerve elongation with a tissue expander. We are not aware of similar reported cases. Secondary repair 3 years after the initial injury improved the pain and hypersensitivity and restored a modest degree of protective sensory function (grade S1). PMID:24704261
Jeudy, J; Raimbeau, G; Rabarin, F; Fouque, P A; Saint-Cast, Y; Césari, B; Bigorre, N
Desensitization to violence is cited frequently as being an outcome of exposure to media violence and a condition that contributes to increased aggression. This article initiates the development of a conceptual model for describing possible relationships among violent video games, brain function, and desensitization by using empathy and attitudes toward violence as proxy measures of desensitization. More work is needed to understand how specific game content may affect brain activity, how brain development may be affected by heavy play at young ages, and how personality and lifestyle variables may moderate game influence. Given the current state of knowledge, recommendations are made for clinicians to help parents monitor and limit exposure to violent video games and encourage critical thinking about media violence. PMID:15936665
Funk, Jeanne B
Acute infusion reactions to both chemotherapeutic agents and humanized monoclonal antibodies can occur, which may limit therapeutic options for treatment of malignancies and chronic inflammatory diseases. Many of these acute infusion reactions are consistent with a type I hypersensitivity reaction, including anaphylaxis. If a patient experiences a significant acute infusion reaction, often the recommendation is to discontinue the medication and find an alternative agent. However, the "second-line" agent may be more toxic or inferior. If the reaction is likely a type I or type IV hypersensitivity reaction, one option is to undergo desensitization to the offending drug. Drug desensitization is the process of readministering a needed drug in incremental doses over hours or days until a full therapeutic dose is tolerated. This article will review the current literature on indications and outcomes for drug desensitization in the management of allergy to either chemotherapeutic agents or monoclonal antibodies. PMID:24994467
Hsu Blatman, Karen S; Castells, Mariana C
Hereditary sensory radicular neuropathy exhibits autosomal dominant inheritance with complete penetrance in males and incomplete penetrance in females. Newer tests of small sensory nerve function were used in screening 8 family members aged between 14 and 66 years. All exhibited some frequent features of the disorder with an onset in the 2nd or 3rd decade, foot ulceration, foot callus, loss of pin prick, thermal and light touch sensation, and some reduction in vibration acuity and proprioception in the lower limbs. The hands were involved in 3 of 8, muscle involvement was present in 5 of 8, but deafness was not detected by audiometry. Nerve conduction velocity, sensory action potentials, latency and amplitude, thermal acuity, vibration acuity and axon reflex flares were measured in all patients. One sural nerve biopsy confirmed the presence of peripheral fibre loss in this predominantly sensory neuropathy. Chemically evoked axon reflex tests were used to evaluate the extent of primary sensory nerve fibre involvement. All patients were tested using a Moor MBF 3-D dual channel laser Doppler velocimeter. Acetylcholine or phenylephrine iontophoretically applied as 16 mC doses evoked absent or tiny axon reflexes in areas of impaired pin prick sensation. By contrast, direct microvascular dilator responses to nitroprusside (smooth muscle dependent) and acetylcholine (endothelium-dependent) were present but somewhat reduced in areas with defective neurogenic inflammation. These results differ significantly from the responses obtained in age-matched healthy controls (P < 0.05). Foot pressure analysis was performed for orthoses in 2 affected members with foot ulceration using the Musgrave Footprint system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1343862
Westerman, R A; Block, A; Nunn, A; Delaney, C A; Hahn, A; Dennett, X; Carr, R W
The surgical removal of lower third molars endangers both the lingual and inferior alveolar nerves. Patients sustaining an injury to either of these nerves must be managed correctly, and this requires a diagnosis of the injury type and regular monitoring of the recovery of sensation. Surgical intervention for a damaged inferior alveolar nerve is not usually indicated but may be undertaken: if the nerve is completely divided and the severed ends are misaligned; if a bony fragment has compressed the mandibular canal; or if the patient suffers from persistent neuropathic pain. In contrast, after injury to the lingual nerve, if sensory testing demonstrates no neural recovery within 3-4 months, exploration of the injury site and microsurgical repair of the damaged nerve is indicated. PMID:14558203
Loescher, A R; Smith, K G; Robinson, P P
Aspirin or acetylsalicylic acid is an important therapy for many cardiology patients but hypersensitivity to this drug affects around 1% of the population and intolerance may affect up to 20%. While alternative medications to aspirin are available, in many cases there is a compelling need for aspirin therapy. In these patients, aspirin desensitization may be considered. However, this is a complex issue with a lack of international standardization. This article reviews the available evidence for aspirin desensitization and provides practical advice for the management of these patients.
Lambrakis, Phil; Rushworth, Gordon F.; Adamson, Jane
This is a summary of the current knowledge of sensory receptors in skin of the bill of the platypus, Ornithorhynchus anatinus, and the snout of the echidna, Tachyglossus aculeatus. Brief mention is also made of the third living member of the monotremes, the long-nosed echidna, Zaglossus bruijnii. The monotremes are the only group of mammals known to have evolved electroreception. The structures in the skin responsible for the electric sense have been identified as sensory mucous glands with an expanded epidermal portion that is innervated by large-diameter nerve fibres. Afferent recordings have shown that in both platypuses and echidnas the receptors excited by cathodal (negative) pulses and inhibited by anodal (positive) pulses. Estimates give a total of 40,000 mucous sensory glands in the upper and lower bill of the platypus, whereas there are only about 100 in the tip of the echidna snout. Recording of electroreceptor-evoked activity from the brain of the platypus have shown that the largest area dedicated to somatosensory input from the bill, S1, shows alternating rows of mechanosensory and bimodal neurons. The bimodal neurons respond to both electrosensory and mechanical inputs. In skin of the platypus bill and echidna snout, apart from the electroreceptors, there are structures called push rods, which consist of a column of compacted cells that is able to move relatively independently of adjacent regions of skin. At the base of the column are Merkel cell complexes, known to be type I slowly adapting mechanoreceptors, and lamellated corpuscles, probably vibration receptors. It has been speculated that the platypus uses its electric sense to detect the electromyographic activity from moving prey in the water and for obstacle avoidance. Mechanoreceptors signal contact with the prey. For the echidna, a role for the electrosensory system has not yet been established during normal foraging behaviour, although it has been shown that it is able to detect the presence of weak electric fields in water. Perhaps the electric sense is used to detect moving prey in moist soil.
Proske, U; Gregory, J E; Iggo, A
Ulnar, median, and radial proximal nerve action potentials (PNAPs) were recorded from the axilla and supraclavicularly, with stimulation of the nerves at the elbow or the radial groove, in 30 control subjects for each nerve. In addition to routine nerve conduction studies, wrist to elbow median nerve action potentials were recorded proximal to the lesion in 76 patients with carpal tunnel syndrome of varying degrees of severity to determine the effect that the distal lesion might have on more proximal nerve conduction. Utilizing this information, PNAPs, standard nerve conduction studies, and needle electrode examinations were carried out in patients with focal elbow area nerve or brachial plexus lesions producing axonotmesis. PNAPs confirmed the site of the lesions producing axonotmesis when localization was possible with standard nerve conduction and/or needle electrode studies and were the sole means by which localization of the lesions producing only sensory axonotmesis was accomplished. PMID:9313994
White, J C
Brown adipose tissue (BAT) thermogenic activity and growth are controlled by its sympathetic nervous system (SNS) innervation, but nerve fibers containing sensory-associated neuropeptides [substance P, calcitonin gene-related peptide (CGRP)] also suggest sensory innervation. The central nervous system (CNS) projections of BAT afferents are unknown. Therefore, we used the H129 strain of the herpes simplex virus-1 (HSV-1), an anterograde transneuronal viral tract tracer used to delineate sensory nerve circuits, to define these projections. HSV-1 was injected into interscapular BAT (IBAT) of Siberian hamsters and HSV-1 immunoreactivity (ir) was assessed 24, 48, 72, 96, and 114 h postinjection. The 96- and 114-h groups had the most HSV-1-ir neurons with marked infections in the hypothalamic paraventricular nucleus, periaqueductal gray, olivary areas, parabrachial nuclei, raphe nuclei, and reticular areas. These sites also are involved in sympathetic outflow to BAT suggesting possible BAT sensory-SNS thermogenesis feedback circuits. We tested the functional contribution of IBAT sensory innervation on thermogenic responses to an acute (24 h) cold exposure test by injecting the specific sensory nerve toxin capsaicin directly into IBAT pads and then measuring core (Tc) and IBAT (TIBAT) temperature responses. CGRP content was significantly decreased in capsaicin-treated IBAT demonstrating successful sensory nerve destruction. TIBAT and Tc were significantly decreased in capsaicin-treated hamsters compared with the saline controls at 2 h of cold exposure. Thus the central sensory circuits from IBAT have been delineated for the first time, and impairment of sensory feedback from BAT appears necessary for the appropriate, initial thermogenic response to acute cold exposure.
Vaughan, Cheryl H.
A Sex of Subject x Sex of Counselor interaction in the desensitization of test anxiety among 44 college students suggested consideration of the sex variable. Results showed significant treatment effects by both male and female counselors and a significant interaction effect by the male counselor with female subjects. (Author)
Geer, Carol A.; Hurst, James C.
This study investigated the impact of group systematic desensitization (SD) on varied aspects of sexual functioning in primary and secondary nonorgasmic women. After serving as their own controls, 22 women (eight primary, 14 secondary) received 15 sessions of group SD using four common hierarchies of sexual scenes. The measures were administered to each subject and her regular sex partner at
Wayne M. Sotile; Peter R. Kilmann
Mori F, Pucci N, Rossi ME, de Martino M, Azzari C, Novembre E. Oral desensitization to milk: how to choose the starting dose! Pediatr Allergy Immunol 2010: 21: e450–e453. © 2009 John Wiley & Sons A/S A renewed interest in oral desensitization as treatment for food allergy has been observed in the last few years. We studied a novel method based on the end point skin prick test procedure to establish the starting dose for oral desensitization in a group of 30 children higly allergic to milk. The results (in terms of reactions to the first dose administered) were compared with a group of 20 children allergic to milk as well. Such control group started to swallow the same dose of 0.015 mg/ml of milk. None reacted to the first dose when administered according to the end point skin prick test. On the other side, ten out of 20 children (50%) from the control group showed mild allergic reactions to the first dose of milk. In conclusion the end point skin prick test procedure results safe and easy to be performed in each single child in order to find out the starting dose for oral desensitization to milk, also by taking into account the individual variability.
Mori, Francesca; Pucci, Neri; Rossi, Maria Elisabetta; de Martino, Maurizio; Azzari, Chiara; Novembre, Elio
In determining whether the technique of desensitization would reduce the initial anxiety experienced by the beginning counselor trainee, analyses of the data revealed significantly less self-reported anxiety in the experimental group. No differences were found in heart rate, skin resistance, and tape-evaluation measures. (Author/CG(
Monke, Robert H.
We have examined glutamate receptor desensitization in voltage-clamped embryonic chicken spinal cord neurons and postnatal rat hippocampal neurons maintained in culture. Rapid currents that rose in 0.8-3.6 msec were evoked when glutamate was ionophoresed with 0.5- to 1.0-msec pulses. With prolonged pulses or brief, repetitive pulses, glutamate-evoked currents decayed rapidly in a manner that was independent of holding potential. A similar desensitization occurred following close-range pressure ejection of glutamate. The rapid, desensitizing glutamate current exhibited a linear current-voltage relation and it was not blocked by 2-amino-5-phosphonovalerate, suggesting that it was mediated by N-methyl-D-aspartate-insensitive (G2) receptors. Desensitization of G2 receptors may be agonist-dependent: currents evoked by kainate, a selective G2 agonist, did not decay, whereas prior application of glutamate did reduce the size of kainate responses. The appearance of the rapid current depended critically on the position of the ionophoretic pipette. Such glutamate-receptor "hot spots" often corresponded to points of contact with neighboring neurites, which raises the possibility that they are located at synapses. Images
Trussell, L O; Thio, L L; Zorumski, C F; Fischbach, G D
Since Shapiro's introduction of Eye Movement Desensitization and Reprocessing (EMDR) in 1989, it has been a highly controversial therapeutic technique. Critical reviews of Shapiro's initial study have highlighted many methodological shortcomings in her work. And early empirical research that followed Shapiro's original study has been criticized…
Erwin, Terry McVannel
A balance is described with Langmuir binding of weights to each side. This simple physical system, when coupled with a previously derived equation for the equivalent displacement of weight that perturbs the equilibrium of a balance, models two-state, receptor systems in pharmacology for receptor activation. Surprisingly, this system also shows desensitization similar to many drug-receptor systems. Although understanding the biophysics
Advances in the field of peripheral nerve surgery have increased our understanding of the complex cellular and molecular events involved in nerve injury and repair. Application of these important discoveries has led to important developments in the techniques of nerve repair, nerve grafting, nerve allografts, end-to-side repairs, and nerve-to-nerve transfers. As our understanding of this dynamic field increases, further improvement in functional outcomes after nerve injury and repair can be expected. PMID:12737353
Dvali, Linda; Mackinnon, Susan
Purpose: This study tested the hypothesis that some sensory innervation to the lower incisor teeth comes from reentry of the terminal branches of the mental nerve through the labial plate of the anterior mandible.Patients and Methods: Ten cadaveric heads (20 sides) were dissected and studied to determine whether the mental nerve crossed the midline or reentered the labial plate. Using
M. A Pogrel; R Smith; R Ahani
A 59-year-old woman with a long-standing diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) developed facial numbness and exophthalmos. Sural nerve biopsy revealed onion bulb formation consistent with CIDP. Neurologic examinations revealed distal dominant muscle atrophy with areflexia and impairment of all sensory modalities; cranial nerve involvement, including bilateral exophthalmos, left-side facial palsy, and left-side periorbital hypoesthesia; and swelling of the sural and subclavian nerves. MRI demonstrated marked thickening of bilateral ophthalmic nerves (figure). Such a finding has been reported rarely in the literature.(1) Neurologists should be aware that patients with CIDP might show exophthalmos due to ophthalmic nerve hypertrophy. PMID:24778284
Okuzumi, Ayami; Hatano, Taku; Nakahara, Toshiki; Yokoyama, Kazumasa; Hattori, Nobutaka
The posterior femoral cutaneous nerve is a sensory nerve comprised of fibers originating from the anterior and posterior divisions of the first three sacral segments. It exists the pelvis distal to the piriformis muscle and proceeds distally, superficial to and between the medial and lateral hamstring musculature. The nerve's major cutaneous distribution is the posterior aspect of the thigh and a variable area of the posterior calf. An electrophysiologic technique to assess the peripheral axons of the posterior femoral cutaneous nerve is described. A recording electrode is placed 6cm proximal to the midpopliteal fossa and the nerve is stimulated supramaximally 12cm proximally on a line between the active electrode and the ischial tuberosity. A ground electrode is placed just proximal to the active recording electrode. The lower extremities of 40 individuals with a mean age of 34 years (20 to 78 years) were examined. The mean peak latency of the response is 2.8 (2.3 to 3.4) msec +/- 0.2msec with a mean amplitude of 6.5 (4.1 to 12.0) microV +/- 1.5 microV. This technique may facilitate the proximal evaluation of lower extremity peripheral neuropathies, lesions of the posterior femoral cutaneous nerve, or the assessment of the peripheral nervous system in persons with lower extremity amputations. PMID:2241545
Dumitru, D; Nelson, M R
The sural nerve is a sensory nerve, usually formed in the distal part of the leg by the union of the lateral sural cutaneous nerve or the communicating fibular branch with the medial sural cutaneous nerve. The aim of this paper is to present a case of a variant formation of the sural nerve and a review of the literature related to this case. During the dissection of an adult male cadaver, the medial sural cutaneous nerve and communicating fibular branch, after respectively deriving from the tibial and common fibular nerve, were noticed to continue their course without any formation of a unique nerve trunk on the posterior side of both lower limbs. A transverse communicating branch, connecting these two nerves, was present in both legs. As the sural nerve is of significant diagnostic and therapeutic importance, detailed knowledge of the sural nerve's anatomy and its contributing nerves is also of great importance. PMID:23917949
Vuksanovic-Bozaric, Aleksandra; Radunovic, Miroslav; Radojevic, Nemanja; Abramovic, Marija
The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained “smoldering activation” occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human ?4?2, ?3?4 and ?7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of ?4?2 AChRs was centered at 0.13 µM, a level found in smokers. However, nicotine produced smoldering activation of ?3?4 and ?7 AChRs at concentrations well above levels found in smokers. The ?4?2 expressing cell line contains a mixture of two stoichiometries, namely (?4?2)2?2 and (?4?2)2?4. The (?4?2)2?2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of ?4?2 AChRs, but full agonists on ?3?4 and ?7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (?4?2)2?4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.
Campling, Barbara G.; Kuryatov, Alexander; Lindstrom, Jon
Six techniques of nerve repair were compared with respect to their morphologic findings and ultimate motor and sensory function. Only when the nerve repair was encased in a thin and elastic tube of Silastic approximately 1 cm in length and with an interna...
T. B. Ducker G. J. Hayes
The objective of this appraisal is to shed light on the various approaches to screen sensory information in the human gut. Understanding and characterization of sensory symptoms in gastrointestinal disorders is poor. Experimental methods allowing the investigator to control stimulus intensity and modality, as well as using validated methods for assessing sensory response have contributed to the understanding of pain mechanisms. Mechanical stimulation based on impedance planimetry allows direct recordings of luminal cross-sectional areas, and combined with ultrasound and magnetic resonance imaging, the contribution of different gut layers can be estimated. Electrical stimulation depolarizes free nerve endings non-selectively. Consequently, the stimulation paradigm (single, train, tetanic) influences the involved sensory nerves. Visual controlled electrical stimulation combines the probes with an endoscopic approach, which allows the investigator to inspect and obtain small biopsies from the stimulation site. Thermal stimulation (cold or warm) activates selectively mucosal receptors, and chemical substances such as acid and capsaicin (either alone or in combination) are used to evoke pain and sensitization. The possibility of multimodal (e.g. mechanical, electrical, thermal and chemical) stimulation in different gut segments has developed visceral pain research. The major advantage is involvement of distinctive receptors, various sensory nerves and different pain pathways mimicking clinical pain that favors investigation of central pain mechanisms involved in allodynia, hyperalgesia and referred pain. As impairment of descending control mechanisms partly underlies the pathogenesis in chronic pain, a cold pressor test that indirectly stimulates such control mechanisms can be added. Hence, the methods undoubtedly represent a major step forward in the future characterization and treatment of patients with various diseases of the gut, which provides knowledge to clinicians about the underlying symptoms and treatment of these patients.
Brock, Christina; Arendt-Nielsen, Lars; Wilder-Smith, Oliver; Drewes, Asbj?rn Mohr
Purpose In this study, the effect of calcium sodium phosphosilicate (NovaMin) desensitizing agent, which is a powder-based system, and hydroxyethyl methacrylate and glutaraldehyde (Gluma desensitizer), which is liquid-based system, on dentinal tubule occlusion was analyzed by scanning electron microscope. The effects of the above two along with one control group were compared to determine the more effective method of sealing the dentinal tubules after initial application. Methods Twenty specimens were allocated to each of 3 groups: Control, Gluma desensitizer, and NovaMin. Two additional samples were also prepared and treated with Gluma and NovaMin; these samples were longitudinally fractured. The specimens were prepared from extracted sound human premolars and were stored in 10% formalin at room temperature. The teeth were cleaned of gross debris and then sectioned to provide one to two dentin specimens. The dentin specimens were etched with 6% citric acid for 2 minutes and rinsed in distilled water. Control discs were dried, and the test discs were treated with the desensitizing agents as per the manufacturer's instructions. The discs as well as longitudinal sections were later analyzed under the scanning electron microscope. The proportions of completely occluded, partially occluded, and open tubules within each group were calculated. The ratios of completely and partially occluded tubules to the total tubules for all the groups was determined, and the data was statistically analyzed using nonparametric tests and statistical significance was calculated. Results NovaMin showed more completely occluded tubules (0.545±0.051) while Gluma desensitizer showed more partially occluded tubules (0.532±0.075). The differences among all the groups were statistically significant (P? 0.05). Conclusion Both materials were effective in occluding dentinal tubules but NovaMin appeared more promising in occluding tubules completely after initial application.
Joshi, Surabhi; Gowda, Ashwini Shivananje
Glutamate (GLU) plays a key role in the transmission and modulation of sensory input to the trigeminal caudal nuclei (TCN). In the present study, we investigated the regulation of previously taken-up [3H]D-aspartate ([3H]D-ASP) release from nerve terminals isolated from rat caudal brainstem, in particular from the zone containing the TCN. TCN neurons can be considered integrative relay neurons linking peripheral and central pain mechanisms. Understanding the mechanisms that control the release of GLU in this area could lead to more effective treatment of migraines and other types of pain associated with the trigeminal nerve. In isolated rat caudal brainstem synaptosomes, exposure to AMPA dose-dependently potentiated [K+](e)-stimulated release of [3H]D-ASP (maximum increase: 218±13.08%; EC(50): 1.60±0.08 ?M). This effect was inhibited by selective AMPA-receptor antagonists (competitive [NBQX] and non-competitive [GYKI52466]) but not by the kainate receptor subunit antagonists NS102 and ACET. AMPA-evoked responses were significantly enhanced by preventing AMPA receptor desensitization with cyclothiazide (10 ?M). Basal release of [3H]D-ASP was stimulated by millimolar concentrations of ATP (maximum increase: 197.80±11.85%; EC(50): 545±3.15 ?M) and by the selective P2X7-receptor agonist benzoylbenzoyl-ATP. ATP also potentiated the release of [3H]D-ASP induced by depolarization. Its effect on basal [3H]D-ASP release was inhibited by the selective P2X7-receptor antagonist A-438079 and by the non-selective antagonist PPADS, but it was only partially suppressed by the ionotropic purinergic receptor antagonist TNP-ATP. Our findings demonstrate that glutamatergic nerve terminals in rat caudal brainstem express AMPA receptors that can facilitate [3H]D-ASP during terminal depolarization and P2X7 receptors that can also enhance this release under basal conditions. PMID:20673841
D'Amico, M; Samengo, I; Navarra, P; Taglialatela, M; Martire, M
Peripheral nerve injury leads to deficient recovery of sensation and a causative factor may be that only 50–60% of primary sensory neurons succeed in regenerating axons after primary nerve repair. In this study, an in vivo rat sciatic nerve injury and regeneration model was combined with laser microdissection and quantitative real-time polymerase chain reaction with the aim of examining the
Adam J. Reid; Dag Welin; Mikael Wiberg; Giorgio Terenghi; Lev N. Novikov
Our aim was to objectively evaluate the efficacy of ob- turator nerve anesthesia after a parasacral block. Pa- tientsscheduledforkneesurgeryhadabaselineadduc- tor strength evaluation. After a parasacral block with 30 mL 0.75% ropivacaine, sensory deficit in the sciatic distribution (temperature discrimination) and adduc- tor strength were assessed at 5-min intervals. Patients with an incomplete sensory block (defined as a temper- ature discrimination
Denis Jochum; Gabriella Iohom; Olivier Choquet; Dioukamady Macalou; Samba Ouologuem; Pascal Meuret; Freddy Kayembe; Michel Heck; Paul-Michel Mertes
Nerve injury occurs in 1% to 2% of patients who undergo total hip arthroplasty and is more frequent in patients who need acetabular reconstruction for dysplasia and those undergoing revision arthroplasty. Injury to the peroneal division of the sciatic nerve is most common, but the superior gluteal, obturator, and femoral nerves can also be injured. Nerve injury can be classified as neurapraxia, axonotmesis, or neurotmesis. The worst prognosis is seen in patients with complete motor and sensory deficits and in patients with causalgic pain. Prevention is of overriding importance, but use of ankle-foot orthoses and prompt management of pain syndromes can be useful in the treatment of patients with nerve injury. Electrodiagnostic studies hold promise in complex cases; however, their intraoperative role requires objective, prospective, controlled scientific study before routine use can be recommended. PMID:10217818
DeHart, M M; Riley, L H
Assessed the comparative effectiveness of cognitive, arousal reduction, and combined cognitive and arousal reduction treatments for test anxiety. 48 test-anxious volunteers who had scored above 32 on the Debilitating Anxiety scale of the Alpert-Haber Achievement Anxiety Test were assigned randomly to 1 of 2 graduate-student therapists, who provided (a) cognitive therapy, (b) systematic desensitization, (c) a combination of cognitive therapy
Kenneth A. Holroyd
\\u000a Drug-induced anaphylaxis prevents the utilization of antibiotic drugs to patients in need of first-line therapy, including\\u000a those with cystic fibrosis. Avoidance of antibiotic therapy may be limited by the severity of the infection and the microbial\\u000a sensitivity. Rapid desensitization for antibiotic-induced drug allergies is the induction of temporary clinical unresponsiveness\\u000a to antibiotics by gradual reintroduction of small doses of antibiotic
Tito Rodriguez Bouza; Ross I. Palis; Henry J. Legere; Mariana C. Castells
The two amino acids ?-amino butyric acid (GABA) and glycine mediate fast inhibitory neurotransmission in different CNS areas and serve pivotal roles in the spinal sensory processing. Under healthy conditions, they limit the excitability of spinal terminals of primary sensory nerve fibers and of intrinsic dorsal horn neurons through pre- and postsynaptic mechanisms, and thereby facilitate the spatial and temporal discrimination of sensory stimuli. Removal of fast inhibition not only reduces the fidelity of normal sensory processing but also provokes symptoms very much reminiscent of pathological and chronic pain syndromes. This review summarizes our knowledge of the molecular bases of spinal inhibitory neurotransmission and its organization in dorsal horn sensory circuits. Particular emphasis is placed on the role and mechanisms of spinal inhibitory malfunction in inflammatory and neuropathic chronic pain syndromes.
Zeilhofer, Hanns Ulrich; Wildner, Hendrik; Yevenes, Gonzalo E.
PBX-9404 and Composition B-3 were desensitized by subjecting them to shocks in the pressure range 10 to 24 kbar. Results show that the collapse of voids, and thus the activation of hot spots by shock waves, takes time and may require more than 5 ..mu..s. This time is, in a way, a counterpart of the induction time for shock initiation of a homogeneous explosive. Gittings' data are adduced to extend the results to 100 kbar and to show that at high pressures desensitization occurs in a very brief time window. When the voids have been collapsed, the relatively homogeneous explosive is resistant to detonation through an Arrhenius type of reaction because of the lower shock temperature resulting from double shocking. This conclusion is supported by experiments on single crystals of HMX and by shock temperature calculations. The time required for desensitization of PBX-9404 is related to pressure by the expression p/sup 2.2/tau = 1150. 21 references, 5 figures, 5 tables.
Campbell, A.W.; Travis, J.R.
As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA???80%), our center adopted a pretransplant multi-modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed-model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub-analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000-10,000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant-sensitized recipients who did not receive therapy. In summary, an aggressive multi-modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort. PMID:24666831
Snyder, L D; Gray, A L; Reynolds, J M; Arepally, G M; Bedoya, A; Hartwig, M G; Davis, R D; Lopes, K E; Wegner, W E; Chen, D F; Palmer, S M
More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg. PMID:24621089
Abu Jawdeh, Bassam G; Cuffy, Madison C; Alloway, Rita R; Shields, Adele Rike; Woodle, E Steve
We report a case in which motor cortex stimulation (MCS) improved neuropathic facial pain due to peripheral nerve injury and restored tactile and thermal sensory loss. A 66-year-old man developed intractable trigeminal neuropathic pain after trauma of the supraorbital branch of the Vth nerve, associated with tactile and thermal sensory loss in the painful area. MCS was performed using neuronavigation and transdural electric stimulation to localize the upper facial area on the motor cortex. One month after surgery, pain was decreased from 80/100 to 20/100 on visual analogic scale, and sensory discrimination improved in the painful area. Two months after surgery, quantitative sensory testing confirmed the normalization of thermal detection thresholds. This case showed that MCS could restore tactile and thermal sensory loss, resulting from peripheral nerve injury. Although the mechanisms leading to this effect remain unclear, this observation enhanced the hypothesis that MCS acts through modulation of the sensory processing. PMID:19350361
Fontaine, Denys; Bruneto, Jean Louis; El Fakir, Hasna; Paquis, Philippe; Lanteri-Minet, Michel
The phosphorylation of ?-opioid receptors (MOPRs) by G protein-coupled receptor kinases (GRKs), followed by arrestin binding, is thought to be a key pathway leading to desensitization and internalization. The present study used the combination of intracellular and whole-cell recordings from rats and mice, as well as live cell imaging of Flag-tagged MOPRs from mouse locus ceruleus neurons, to examine the role of protein kinases in acute desensitization and receptor trafficking. Inhibition of GRKs by using heparin or GRK2-mutant mice did not block desensitization or alter the rate of recovery from desensitization. The nonselective kinase inhibitor staurosporine did not reduce the extent of [Met(5)]enkephalin (ME)-induced desensitization but increased the rate of recovery from desensitization. In the presence of staurosporine, ME-activated FlagMOPRs were internalized but did not traffic away from the plasma membrane. The increased rate of recovery from desensitization correlated with the enhancement in the recycling of receptors to the plasma membrane. ME-induced MOPR desensitization persisted and the trafficking of receptors was modified after inhibition of protein kinases. The results suggest that desensitization of MOPRs may be an early step after agonist binding that is modulated by but is not dependent on kinase activity. PMID:22113080
Arttamangkul, Seksiri; Lau, Elaine K; Lu, Hsin-Wei; Williams, John T
To investigate the mechanisms of alpha 1-adrenergic vascular desensitization, osmotic minipumps containing either saline (n = 9) or amidephrine mesylate (AMD) (n = 9), a selective alpha 1-adrenergic receptor agonist, were implanted subcutaneously in dogs with chronically implanted arterial and right atrial pressure catheters and aortic flow probes. After chronic alpha 1-adrenergic receptor stimulation, significant physiological desensitization to acute AMD challenges was observed, i.e., pressor and vasoconstrictor responses to the alpha 1-adrenergic agonist were significantly depressed (p < 0.01) compared with responses in the same dogs studied in the conscious state before pump implantation. However, physiological desensitization to acute challenges of the neurotransmitter norepinephrine (NE) (0.1 micrograms/kg per minute) in the presence of beta-adrenergic receptor blockade was not observed for either mean arterial pressure (MAP) (30 +/- 7 versus 28 +/- 5 mm Hg) or total peripheral resistance (TPR) (29.8 +/- 4.9 versus 28.9 +/- 7.3 mm Hg/l per minute). In the presence of beta-adrenergic receptor plus ganglionic blockade after AMD pump implantation, physiological desensitization to NE was unmasked since the control responses to NE (0.1 micrograms/kg per minute) before the AMD pumps were now greater (p < 0.01) than after chronic AMD administration for both MAP (66 +/- 5 versus 32 +/- 2 mm Hg) and TPR (42.6 +/- 10.3 versus 23.9 +/- 4.4 mm Hg/l per minute). In the presence of beta-adrenergic receptor, ganglionic, plus NE-uptake blockade after AMD pump implantation, desensitization was even more apparent, since NE (0.1 micrograms/kg per minute) induced even greater differences in MAP (33 +/- 5 versus 109 +/- 6 mm Hg) and TPR (28.1 +/- 1.8 versus 111.8 +/- 14.7 mm Hg/l per minute). The maximal force of contraction induced by NE in the presence or absence of endothelium was significantly decreased (p < 0.05) in vitro in mesenteric artery rings from AMD pump dogs compared with saline control dogs. Furthermore, alpha 1-adrenergic receptor density, as determined by [3H]prazosin binding in membrane preparations from vessels in the mesentery, was decreased (8.2 +/- 1.0 versus 18.4 +/- 1.4 fmol/mg protein, p < 0.001) without any change in Kd in the AMD pump dogs compared with the saline pump dogs.(ABSTRACT TRUNCATED AT 400 WORDS).
Kiuchi, K.; Vatner, D. E.; Uemura, N.; Bigaud, M.; Hasebe, N.; Hempel, D. M.; Graham, R. M.; Vatner, S. F.
The sural nerve is a small sensory nerve innervating the lateral aspect of the ankle and foot. Clinical symptoms of pathology may present as atypical sensory changes in this region. We present the normal anatomy and ultrasound technique for examination of the sural nerve based on an anatomical dissection, as well as imaging in a normal volunteer. We also present a case series (n=10) of different conditions of the sural nerve that we encountered based on a review of interesting cases from 4 institutions. The pathological conditions included neuropathy related to stripping or venous laser surgery, compression by abscess, Lyme disease, nerve tumors, traumatic transsection, and encasement by fibrous plaque and edema. Ultrasound with its exquisite resolution is the preferred imaging method for examining the sural nerve in patients with unexplained sensory changes at the lateral aspect of the ankle and foot. PMID:23809918
Belsack, Dries; Jager, Tjeerd; Scafoglieri, Aldo; Vanderdood, Kurt; Van Hedent, Eddy; Vanhoenacker, Filip; Marcelis, Stefaan; De Maeseneer, Michel
A trio of papers has resolved an outstanding controversy regarding the function of Merkel cells and their afferent nerve fiber partners. Merkel cells sense mechanical stimuli (through Piezo2), fire action potentials, and are sufficient to activate downstream sensory neurons. PMID:24937283
Vásquez, Valeria; Scherrer, Gregory; Goodman, Miriam B
Impaired NGF production and release has been documented in aged animals, suggesting that decreased NGF receptor stimulation may be one factor contributing to neuronal dysfunction with aging. Other studies have suggested that aging may be associated with impaired intracellular responses to NGF. Because aging-associated neuronal dysfunction contributes to morbidity and mortality in the geriatric population, it is important to determine whether the effects of aging on sensory neuron function and survival are reversible. In the present study, we observed significantly decreased neurite outgrowth and neuronal survival in short-term cultures (0-96 h) of dorsal root ganglion (DRG) neurons from aged (>22 months) Fisher 344 x Brown Norway F1 hybrid rats, compared to young (4-6 month) and middle-aged (14 month) animals. From 24 to 96 h in culture, diminished survival of aged neurons appeared to be due to an increased rate of apoptotic cell death. DRG neurons from aged animals also exhibited significantly decreased whole cell, high-threshold voltage-dependent calcium currents, with a larger proportion of L-type current, compared to youthful and middle-aged animals. Treatment of aged DRG neurons with NGF restored neurite outgrowth, neuronal survival and calcium current amplitude and subtype distribution to those observed in youthful DRG neurons. PMID:11146059
Hall, K E; Sheng, H C; Srinivasan, S; Spitsbergen, J M; Tuttle, J B; Steers, W D; Wiley, J W
Clunealgia is caused by neuropathy of inferior cluneal branches of the posterior femoral cutaneous nerve resulting in pain in the inferior gluteal region. Image-guided anesthetic nerve injections are a viable and safe therapeutic option in sensory peripheral neuropathies that provides significant pain relief when conservative therapy fails and surgery is not desired or contemplated. The authors describe two cases of clunealgia, where computed-tomography-guided technique for nerve blocks of the posterior femoral cutaneous nerve and its branches was used as a cheaper, more convenient, and faster alternative with similar face validity as the previously described magnetic-resonance-guided injection. PMID:24667042
Kasper, Jared M; Wadhwa, Vibhor; Scott, Kelly M; Chhabra, Avneesh
We report the first case of direct surgical injury to a pudendal nerve branch during radical perineal prostatectomy. A 65-year-old patient presented with typical symptoms of a pudendal nerve lesion after radical perineal prostatectomy. As the patient did not respond to conservative treatment, surgical exploration and exeresis of the injured sensory branch of the pudendal nerve was necessary, resulting in pain improvement. Urologic surgeons should be aware of the typical symptoms after iatrogenic injury to the pudendal nerve or its branches. Early diagnosis and neurosurgical intervention are important to obtain a more favorable outcome. PMID:16461104
Gillitzer, R; Hampel, C; Wiesner, C; Pahernik, S; Melchior, S W; Thüroff, J W
Background Altered sensory information arising from damaged knee joint structures has been hypothesized as a contributing factor to persistent muscle dysfunction following injury. Methods Composite femoral nerve sensory signal was measured in 24 rabbits randomly allocated (8 per group) to receive surgical anterior cruciate ligament (ACL) transection with or without autograft reconstruction or nothing (control). Two-weeks after the intervention composite afferent signals were recorded from the femoral nerve. Side-to-side ratios (surgical side vs contralateral healthy side) for peak femoral nerve afferent composite signal were used for comparison. Results Femoral nerve afferent signal ratios were significantly higher in the ACL-R (2.21?±?0.74) group when compared to the ACL-T (1.28?±?0.61, P?=?0.02) group and Control group (1.31?±?0.78, P?=?0.03). Conclusion The magnitude of sensory information recorded on the femoral nerve is increased following ACL injury and reconstruction surgery, but not after an isolated ACL injury in rabbits.
Aspirin exacerbated respiratory disease (AERD) is induced by acetylsalicylic acid (ASA) and/or nonsteroidal antiinflammatory drugs (NSAIDs). Effects of desensitization on many mediators have been examined previously, but few studies addressed the influence of desensitization on T lymphocytes and T lymphocyte-derived cytokines. This study was performed to examine peripheral blood lymphocyte (PBL) cytokine expression in aspirin-sensitive patients who have asthma before and after aspirin desensitization. In this study, the release of interleukin-2 (IL-2), interleukin-4 (IL-4), and interferon-gamma (IFN-?) by CD4+ T lymphocytes prior to aspirin desensitization were also measured at intracellular levels, and expression of these cytokines after 1 month aspirin desensitization was evaluated. Twelve patients with AERD were included in the study. Two different control groups were formed, one consisted of 15 healthy people and second 12 aspirin tolerant asthmatic (ATA) patients using aspirin. A blood sample was collected prior to desensitization, and the tests were repeated by taking a second blood sample 1 month after the 4-day desensitization treatment. The proportion of lymphocytes secreting IFN-? in the study group was 15.61 ± 4.40 % before desensitization and 15.08 ± 5.89 % after desensitization. The rate of IFN-? secreting CD4+ T lymphocytes was 20.51 ± 4.41 % in the normal control group and 16.07 ± 5.7 % in the ATA group (p = 0.021). The ratio of CD4+ T lymphocyte secreting IFN-? was reduced in patients with AERD before desensitization compared to normal control group (p = 0.040). The levels of IL-2, IL-4, and the subsets of lymphocyte were not different before and after desensitization compared to control groups. PMID:23912646
Aktas, Ayse; Kurt, Emel; Gulbas, Zafer
Objective The detailed outcome of surgical repair of high isolated clean sharp (HICS) ulnar nerve lesions has become relevant in view of the recent development of distal nerve transfer. Our goal was to determine the outcome of HICS ulnar nerve repair in order to create a basis for the optimal management of these lesions. Methods High ulnar nerve lesions are defined as localized in the area ranging from the proximal forearm to the axilla just distal to the branching of the medial cord of the brachial plexus. A meta-analysis of the literature concerning high ulnar nerve injuries was performed. Additionally, a retrospective study of the outcome of nerve repair of HICS ulnar nerve injuries at our institution was performed. The Rotterdam Intrinsic Hand Myometer and the Rosén-Lundborg protocol were used. Results The literature review identified 46 papers. Many articles presented outcomes of mixed lesion groups consisting of combined ulnar and median nerves, or the outcome of high and low level injuries was pooled. In addition, outcome was expressed using different scoring systems. 40 patients with HICS ulnar nerve lesions were found with sufficient data for further analysis. In our institution, 15 patients had nerve repair with a median interval between trauma and reconstruction of 17 days (range 0–516). The mean score of the motor and sensory domain of the Rosen's Scale instrument was 58% and 38% of the unaffected arm, respectively. Two-point discrimination never reached less then 12 mm. Conclusion From the literature, it was not possible to draw a definitive conclusion on outcome of surgical repair of HICS ulnar nerve lesions. Detailed neurological function assessment of our own patients showed that some ulnar nerve function returned. Intrinsic muscle strength recovery was generally poor. Based on this study, one might cautiously argue that repair strategies of HICS ulnar nerve lesions need to be improved.
Post, Rene; de Boer, Kornelis S.; Malessy, Martijn J. A.
The human body has five basic sensory functions: touch, vision, hearing, taste, and smell. The effectiveness of one or more of these human sensory functions can be impaired as a result of trauma, congenital defects, or the normal ageing process. Converting one type of function into another, or translating a function to a different part of the body, could result in a better quality of life for a person with diminished sensorial capabilities.
Recovery from peripheral nerve damage, especially for a transected nerve, is rarely complete, resulting in impaired motor function, sensory loss, and chronic pain with inappropriate autonomic responses that seriously impair quality of life. In consequence, strategies for enhancing peripheral nerve repair are of high clinical importance. Tension is a key determinant of neuronal growth and function. In vitro and in vivo experiments have shown that moderate levels of imposed tension (strain) can encourage axonal outgrowth; however, few strategies of peripheral nerve repair emphasize the mechanical environment of the injured nerve. Toward the development of more effective nerve regeneration strategies, we demonstrate the design, fabrication, and implementation of a novel, modular nerve-lengthening device, which allows the imposition of moderate tensile loads in parallel with existing scaffold-based tissue engineering strategies for nerve repair. This concept would enable nerve regeneration in two superposed regimes of nerve extension—traditional extension through axonal outgrowth into a scaffold and extension in intact regions of the proximal nerve, such as that occurring during growth or limb-lengthening. Self-sizing silicone nerve cuffs were fabricated to grip nerve stumps without slippage, and nerves were deformed by actuating a telescoping internal fixator. Poly(lactic co-glycolic) acid (PLGA) constructs mounted on the telescoping rods were apposed to the nerve stumps to guide axonal outgrowth. Neuronal cells were exposed to PLGA using direct contact and extract methods, and they exhibited no signs of cytotoxic effects in terms of cell morphology and viability. We confirmed the feasibility of implanting and actuating our device within a sciatic nerve gap and observed axonal outgrowth following device implantation. The successful fabrication and implementation of our device provides a novel method for examining mechanical influences on nerve regeneration.
Chuang, Ting-Hsien; Wilson, Robin E.; Love, James M.; Fisher, John P.
In 46 patients 63 nerves of upper extremities were sutured and clinico-electroneuromyographic investigations performed. The restitution of motor and sensory functions ran slowly over 7 to 36 months depending on the level injured. Full restoration of motor functions surpassed the restoration of sensory functions in the autonomic zone of the nerve lesioned. Electroneuromyographic investigation showed that clinical healing provides no real indices of the final nerve regeneration as the nervous condition velocity remained altered. This allows recommending nonsurgical treatment for several months after surgery under electroneuromyographic control. PMID:2665400
Kankava, D M; Baratashvili, N N; Kvirkveliia, N B
Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCR-based signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illustrate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous examples in which gene duplication and sequence divergence have created novel sensory specificities. This is the evolutionary basis for the observed diversity in temperature- and ligand-dependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli.
Julius, David; Nathans, Jeremy
Evidence has shown that factors other than the central pharmacological effects of nicotine are important in promoting smoking behavior. One such non-nicotine effect includes sensory stimulation, which may promote smoking by developing learned associations with nicotine's rewarding effects, or by constituting a rewarding experience independent of nicotine. The present study used internal tobacco industry documents to examine industry efforts to understand and manipulate stimulation of the sensory nerves by tobacco smoke, and the influence of sensory stimulation on smoker behavior. Research focused on sensory nerves of the head and neck, including the olfactory nerve, which carries flavor and odor, and the trigeminal nerve, which carries irritant information. The tobacco industry maintained a systematic research program designed to elucidate an understanding of responses of sensory nerves to nicotine and other components of tobacco smoke, and attempted to develop nicotine-like compounds that would enhance sensory responses in smokers. Industry research appeared intended to aid in the development of new products with greater consumer appeal. The potential influence of sensory response in enhancing nicotine dependence through an associative mechanism was acknowledged by the tobacco industry, but evidence for research in this area was limited. These findings add to evidence of industry manipulation of sensory factors to enhance smoking behavior and may have implications for development of more effective treatment strategies, including more "acceptable" nicotine replacement therapies. PMID:17978985
Megerdichian, Christine L; Rees, Vaughan W; Wayne, Geoffrey Ferris; Connolly, Gregory N
Autologous nerve transplantation (ANT) is the clinical gold standard for the reconstruction of peripheral nerve defects. A large number of bioengineered nerve guides have been tested under laboratory conditions as an alternative to the ANT. The step from experimental studies to the implementation of the device in the clinical setting is often substantial and the outcome is unpredictable. This is mainly linked to the heterogeneity of clinical peripheral nerve injuries, which is very different from standardized animal studies. In search of a reproducible human model for the implantation of bioengineered nerve guides, we propose the reconstruction of sural nerve defects after routine nerve biopsy as a first or baseline study. Our concept uses the medial sural nerve of patients undergoing diagnostic nerve biopsy (?2?cm). The biopsy-induced nerve gap was immediately reconstructed by implantation of the novel microstructured nerve guide, Neuromaix, as part of an ongoing first-in-human study. Here we present (i) a detailed list of inclusion and exclusion criteria, (ii) a detailed description of the surgical procedure, and (iii) a follow-up concept with multimodal sensory evaluation techniques. The proximal medial sural nerve biopsy model can serve as a preliminarynature of the injuries or baseline nerve lesion model. In a subsequent step, newly developed nerve guides could be tested in more unpredictable and challenging clinical peripheral nerve lesions (e.g., following trauma) which have reduced comparability due to the different nature of the injuries (e.g., site of injury and length of nerve gap).
van Neerven, Sabien G. A.; Claeys, Kristl G.; O'Dey, Dan mon; Brook, Gary A.; Sellhaus, Bernd; Schulz, Jorg B.; Weis, Joachim; Pallua, Norbert
The sensory system plays a key role in the generation of behavior by providing the nervous system with information about the environment and feedback about body movements such that motor output can continuously be adapted to changing circumstances. Although the effects of sensory organs on nervous system function have been demonstrated in many systems, the impact of sensory activity has rarely been studied in conditions in which motor output and sensory activity can interact as they do in behaving animals. In such situations, emergent properties may surface and govern the characteristics of the motor system. We studied the dynamics of sensorimotor interaction with a combination of electrophysiological experiments and computational modeling in the locust flight pattern generator, including its sensory components. The locust flight motor output is produced by a central pattern generator that interacts with phasic sensory feedback from the tegula, a proprioceptor that signals downstroke movement of the wing. We modeled the flight control system, and we tested the model predictions by replacing tegula feedback in the animal with artificial feedback through computer-controlled electric stimulation of the appropriate sensory nerves. With reference to the cycle frequency in the locust flight rhythm, our results show that motor patterns can be regulated via the variation of sensory feedback loops. In closed-loop conditions, tegula feedback strength determines cycle frequency in the model and the biological preparation such that stronger feedback results in lower frequencies. This regulatory mechanism appears to be a general emergent property of negative feedback systems. PMID:17728446
Ausborn, Jessica; Stein, Wolfgang; Wolf, Harald
Evaluates effect of the counselor's level of anxiety on students taking part in test anxiety desensitization workshops. Results indicate the number of sessions attended by students is inversely related to the counselor's level of anxiety. Implications for counselor screening in desensitization work are mentioned. (Author)
Hudesman, John; Wiesner, Ezra
The responses of crayfish muscle fibres to bath application or long ionophoresis of L-glutamate were studied in normal and low Ca2+ solutions. The smaller responses recorded in low Ca2+ solutions have characteristics suggesting a faster desensitization. Desensitization and recovery have complex kinetics. Desensitization is faster and recovery slower when external Ca2+ concentration is reduced. Both components of the recovery phase, which can be fitted by the sum of two exponentials, are affected by the external Ca2+ concentration. Recovery can be accelerated by external Ca2+ ionophoresis onto desensitized glutamate receptors. Responses to brief glutamate pulses of low intensity are not affected by Ca2+ reduction. For higher intensities, signs of desensitization are detectable early in the rising phase of the response. Concanavalin A (Con A) blocks both desensitization and Ca2+ dependence with similar time courses. Whether or not the preparation has been treated with Con A, the slowly rising responses recorded in isotonic Ca2+ do not show signs of desensitization. Con A causes a partial blockade of the glutamate response. The Ca2+ dependence of the glutamate response can be explained by the Ca2+ dependence of the desensitization process, the cation acting at ectocellular sites of the muscle membrane.
Flooding and systematic desensitization procedures were investigated for possible interactions with subject arousal level on reduction in phobic reactions. No such interaction was found. Behaviorally and on GSR response, both flooding and systematic desensitization were effective, but only the latter was effective on subjective reports. (NG)
Suarez, Yolanda; And Others
Grafts of optic nerve were placed end-toend with the proximal stumps of severed common peroneal nerves in inbred mice. It was found that fraying the proximal end of adult optic nerve grafts to disrupt the glia limitans increased their chances of being penetrated by regenerating peripheral nerve fibres. Suturing grafts to the proximal stump also enhanced their penetration by axons.
P. N. Anderson; P. Woodham; M. Turmaine
Monoclonal antibodies (mAb) have become the standard of care for numerous diseases. However, side effects including infusion and hypersensitivity reactions experienced by patients continue to be a limiting factor in their use. In the therapy of cancer, treatment choices are frequently limited and minimizing side effects of a life-saving or life-prolonging therapy becomes of the utmost importance. We report the successful use of a rapid desensitization protocol in a patient with NHL, treated with a novel antibody-drug conjugate, chimeric monoclonal antibody linked to the antimitotic agent monomethyl auristatin E (MMAE) Brentuximab vedotin, who had previously developed a hypersensitivity reaction. PMID:24918568
Story, Sara K; Petrov, Andrej A; Geskin, Larisa J
This paper develops a robust divided difference filtering approach based on the concept of Desensitized Kalman Filtering. The filters are formulated using a minimum variance cost function, augmented with a penalty function consisting of a weighted norm of the state sensitivities. Solutions are provided for first and second-order Divided Difference Filters. The resulting filters are non-minimum variance but exhibit reduced sensitivity to deviations in the assumed plant model parameters. The proposed algorithms are demonstrated using Monte Carlo simulation techniques for an induction motor state estimation problem with parameter uncertainties. PMID:23721743
Karlgaard, Christopher D; Shen, Haijun
In rat dorsal root ganglia, histochemical staining of carbonic anhydrase (CA) and cholinesterase (CE) yields a reciprocal pattern of activity: Sensory processes are CA positive and CE negative, whereas motor processes are CA negative and CE positive. In rat infraorbital nerve (a sensory peripheral nerve), we saw extensive CA staining of nearly 100% of the myelinated axons. Although CE reactivity in myelinated axons was extremely rare, we did observe CE staining of unmyelinated autonomic fibers. Four weeks after transection of infraorbital nerves, CA-stained longitudinal sections of the proximal stump demonstrated 3 distinct morphological zones. A fraction of the viable axons retained CA activity to within 2 mm of the distal extent of the stump, and the stain is capable of resolving growth sprouts being regenerated from these fibers. Staining of unmyelinated autonomic fibers in serial sections shows that CE activity was not retained as far distally as is the CA sensory staining.
Wilke, R. A.; Riley, D. A.; Sanger, J. R.
The standard technique in the management of chronic low ulnar nerve injuries includes excision of the neuroma and reconstruction using sural nerve grafts in the fully anaesthetised patient. It has been shown that using this standard technique, disappointing results may be observed and that significant improvement in results could be obtained if intra-operative matching of sensory and motor fascicles is performed. This study reports on eight patients with chronic ulnar nerve injuries managed using the technique of electrical fascicular orientation and sural nerve grafting. In all patients, intra-operative electrical stimulation of the fascicles in the proximal stump was done in the awake state. Several refinements in technique are described including detailing pre-operative patient education, anaesthetic considerations and in the technique of nerve dissection. Assessment was done using a sensory grading system mainly based on static two-point discrimination and a motor grading system based on intrinsic muscle function and key pinch power. At final follow up satisfactory sensory (S3+ or S4) and motor (M3 or M4) recovery was obtained in almost all cases. It was concluded that intra-operative electrical fascicular orientation was reliable and that our refinements in the technique ensured better communication with the patient during surgery, resulted in a smoother awakening without apprehension, and provided an easier nerve dissection with preservation of the blood supply of the distal nerve segment. PMID:15488501
Al-Qattan, M M
Desensitization of the ?-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Monitoring the release of intracellular Ca2+ ([Ca2+]i), we reported that [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO)-induced receptor desensitization requires receptor phosphorylation and recruitment of ?-arrestins (?Arrs), while morphine-induced receptor desensitization does not. In current studies, we established that morphine-induced MOR desensitization is protein kinase C (PKC)-dependent. By using RNA interference techniques and subtype specific inhibitors, PKC? was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. In contrast, DAMGO did not increase PKC? activity and DAMGO-induced MOR desensitization was not affected by modulating PKC? activity. Among the various proteins within the receptor signaling complex, G?i2 was phosphorylated by morphine-activated PKC?. Moreover, mutating three putative PKC phosphorylation sites, Ser44, Ser144 and Ser302 on G?i2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca2+]i release, and this desensitization could be reversed by pretreating the cells with PKC? inhibitor or overexpressing G?i2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other G?i-coupled receptors, such as the CB1.
Chu, Ji; Zheng, Hui; Zhang, Yuhan; Loh, Horace H.; Law, Ping-Yee
Desensitization of the micro-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Monitoring the release of intracellular Ca(2+) ([Ca(2+)](i)), we reported that [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO)-induced receptor desensitization requires receptor phosphorylation and recruitment of beta-arrestins (betaArrs), while morphine-induced receptor desensitization does not. In current studies, we established that morphine-induced MOR desensitization is protein kinase C (PKC)-dependent. By using RNA interference techniques and subtype specific inhibitors, PKCepsilon was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. In contrast, DAMGO did not increase PKCepsilon activity and DAMGO-induced MOR desensitization was not affected by modulating PKCepsilon activity. Among the various proteins within the receptor signaling complex, Galphai2 was phosphorylated by morphine-activated PKCepsilon. Moreover, mutating three putative PKC phosphorylation sites, Ser(44), Ser(144) and Ser(302) on Galphai2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca(2+)](i) release, and this desensitization could be reversed by pretreating the cells with PKCepsilon inhibitor or overexpressing Galphai2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other Galphai-coupled receptors, such as the CB1. PMID:20043990
Chu, Ji; Zheng, Hui; Zhang, Yuhan; Loh, Horace H; Law, Ping-Yee
Our objective was to investigate the pathway of the lingual nerve and find out whether it can be identified using ultrasonography (US) intraorally. It is a dominant sensory nerve that branches from the posterior division of the mandibular aspect of the trigeminal nerve, and is one of the two most injured nerves during oral surgery. Its anatomy in the region of the third molar has been associated with lingual nerves of variable morphology. If surgeons can identify its precise location using US, morbidity should decrease. We searched published anatomical and specialty texts, journals, and websites for reference to its site and US. Cadavers (28 nerves) were dissected to analyse its orientation at the superior lingual alveolar crest (or lingual shelf). Volunteers (140 nerves) had US scans to identify the nerve intraorally. Our search of published books and journals found that descriptions of the nerve along the superior lingual alveolar crest were inadequate. We found no US studies of the nerve in humans. Dissections showed that the nerve was above (n=6, 21%) and below (n=22, 79%) the crest of the lingual plate. US scans showed 140 lingual nerves intraorally in 70 volunteers. The nerve lay either above or below the superior lingual alveolar crest, which led us to develop a high/low classification system. US can identify the lingual nerve and help to classify it preoperatively to avoid injury. Our results suggest that clinical anatomy of the lingual nerve includes the superior lingual alveolar crest at the third and second molars because of its surgical importance. US scans can successfully identify the nerve intraorally preoperatively. PMID:23182453
Benninger, Brion; Kloenne, Jessica; Horn, Jean Lois
Exposure to many neurotoxic compounds has been shown to produce a sensory system dysfunction. Neurophysiological assessment of sensory function in humans and animal models often uses techniques known as sensory evoked potentials. Because both humans and animals show analogous res...
Catecholamines have been extensively reported to be present in most animal groups, including members of Echinodermata. In this study, we investigated the presence and distribution of catecholaminergic nerves in two members of the Holothuroidea, Holothuria glaberrima (Selenka, 1867) (Aspidochirotida, Holothuroidea) and Holothuria mexicana (Ludwig, 1875) (Aspidochirotida, Holothuroidea), by using induced fluorescence for catecholamines on tissue sections and immunohistochemistry with an antibody that recognizes tyrosine hydroxylase. The presence of a catecholaminergic nerve plexus similar in distribution and extension to those previously reported in other members of Echinodermata was observed. This plexus, composed of cells and fibers, is found in the ectoneural component of the echinoderm nervous system and is continuous with the circumoral nerve ring and the radial nerves, tentacular nerves, and esophageal plexus. In addition, fluorescent nerves in the tube feet are continuous with the catecholaminergic components of the radial nerve cords. This is the first comprehensive report on the presence and distribution of catecholamines in the nervous system of Holothuroidea. The continuity and distribution of the catecholaminergic plexus strengthen the notion that the catecholaminergic cells are interneurons, since these do not form part of the known sensory or motor circuits and the fluorescence is confined to organized nervous tissue.
Diaz-Balzac, Carlos A.; Mejias, Wigberto; Jimenez, Luis B.
Crocodilians hunt at night, waiting half-submerged for land-bound prey to disturb the water surface. Here I show that crocodilians have specialized sensory organs on their faces that can detect small disruptions in the surface of the surrounding water, and which are linked to a dedicated, hypertrophied nerve system. Such 'dome' pressure receptors are also evident in fossils from the Jurassic period, indicating that these semi-aquatic predators solved the problem of combining armour with tactile sensitivity many millions of years ago. PMID:12015589
The neurotransmitter glutamate mediates excitatory synaptic transmission by activating ionotropic glutamate receptors (iGluRs). In Caenorhabditis elegans, the GLR-1 receptor subunit is required for glutamate-gated current in a subset of interneurons that control avoidance behaviors. Current mediated by GLR-1-containing iGluRs depends on SOL-1, a transmembrane CUB-domain protein that immunoprecipitates with GLR-1. We have found that reconstitution of glutamate-gated current in heterologous cells depends on three proteins, STG-1 (a C. elegans stargazin-like protein), SOL-1, and GLR-1. Here, we use genetic and pharmacological perturbations along with rapid perfusion electrophysiological techniques to demonstrate that SOL-1 functions to slow the rate and limit the extent of receptor desensitization as well as to enhance the recovery from desensitization. We have also identified a SOL-1 homologue from Drosophila and show that Dro SOL1 has a conserved function in promoting C. elegans glutamate-gated currents. SOL-1 homologues may play critical roles in regulating glutamatergic neurotransmission in more complex nervous systems. PMID:16818875
Walker, Craig S; Francis, Michael M; Brockie, Penelope J; Madsen, David M; Zheng, Yi; Maricq, Andres V
ABSTRACT Objectives The purpose of present article was to review aetiological factors, mechanism, clinical symptoms, and diagnostic methods as well as to create treatment guidelines for the management of inferior alveolar nerve injury during dental implant placement. Material and Methods Literature was selected through a search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were inferior alveolar nerve injury, inferior alveolar nerve injuries, inferior alveolar nerve injury implant, inferior alveolar nerve damage, inferior alveolar nerve paresthesia and inferior alveolar nerve repair. The search was restricted to English language articles, published from 1972 to November 2010. Additionally, a manual search in the major anatomy, dental implant, periodontal and oral surgery journals and books were performed. The publications there selected by including clinical, human anatomy and physiology studies. Results In total 136 literature sources were obtained and reviewed. Aetiological factors of inferior alveolar nerve injury, risk factors, mechanism, clinical sensory nerve examination methods, clinical symptoms and treatment were discussed. Guidelines were created to illustrate the methods used to prevent and manage inferior alveolar nerve injury before or after dental implant placement. Conclusions The damage of inferior alveolar nerve during the dental implant placement can be a serious complication. Clinician should recognise and exclude aetiological factors leading to nerve injury. Proper presurgery planning, timely diagnosis and treatment are the key to avoid nerve sensory disturbances management.
Wang, Hom-Lay; Sabalys, Gintautas
We report a case in which motor cortex stimulation (MCS) improved neuropathic facial pain due to peripheral nerve injury and\\u000a restored tactile and thermal sensory loss. A 66-year-old man developed intractable trigeminal neuropathic pain after trauma\\u000a of the supraorbital branch of the Vth nerve, associated with tactile and thermal sensory loss in the painful area. MCS was\\u000a performed using neuronavigation
Denys Fontaine; Jean Louis Bruneto; Hasna El Fakir; Philippe Paquis; Michel Lanteri-Minet
Direct interfacing of transected peripheral nerves with advanced robotic prosthetic devices has been proposed as a strategy for achieving natural motor control and sensory perception of such bionic substitutes, thus fully functionally replacing missing limbs in amputees. Multi-electrode arrays placed in the brain and peripheral nerves have been used successfully to convey neural control of prosthetic devices to the user. However, reactive gliosis, micro hemorrhages, axonopathy and excessive inflammation currently limit their long-term use. Here we demonstrate that enticement of peripheral nerve regeneration through a non-obstructive multi-electrode array, after either acute or chronic nerve amputation, offers a viable alternative to obtain early neural recordings and to enhance long-term interfacing of nerve activity. Non-restrictive electrode arrays placed in the path of regenerating nerve fibers allowed the recording of action potentials as early as 8?days post-implantation with high signal-to-noise ratio, as long as 3?months in some animals, and with minimal inflammation at the nerve tissue-metal electrode interface. Our findings suggest that regenerative multi-electrode arrays of open design allow early and stable interfacing of neural activity from amputated peripheral nerves and might contribute towards conveying full neural control and sensory feedback to users of robotic prosthetic devices.
Garde, Kshitija; Keefer, Edward; Botterman, Barry; Galvan, Pedro; Romero, Mario I.
The aim of this study was to clarify the distribution pattern and innervation territory of the mental nerve (MN) in the skin and mucosa by topographic examination by Sihler's staining, thereby providing reference anatomical information for surgical procedures and to enable prediction of regions of sensory disturbance following nerve damage. Ten human specimens were subjected to Sihler's staining, which is a highly accurate method for visualizing the distribution of nerve fibers without altering their topography. Each branch of the MN overlapped adjacent branches (five cases), or else they were distributed individually at the lower lip (five cases). The MN anastomosed with some branches of the facial nerve near the mental foramen. Moreover, some branches of the MN anastomosed with the buccal nerve of the trigeminal nerve, which supplies sensation to the skin and mucosa over the lateral region of the lower lip (six cases). The details of the distribution pattern and innervations territory of the MN presented herein may enable the prediction of a region of sensory disturbance following MN damage. Moreover, knowledge of the pattern of synapses with adjacent branches of other nerves, such as the facial (marginal mandibular and cervical branches) and the buccal nerves, might help to improve our understanding around incomplete anesthesia during the surgical procedures in oral & maxillofacial region. PMID:24222330
Won, Sung-Yoon; Yang, Hun-Mu; Woo, Hee-Soon; Chang, Ki-Yeon; Youn, Kwan-Hyun; Kim, Hee-Jin; Hu, Kyung-Seok
OBJECTIVE--Adrenomyeloneuropathy (AMN) is an X linked metabolic disorder presenting with progressive spastic paraparesis in the third to fifth decade of life. Although peripheral neuropathy is also present in most patients, prominent pyramidal signs may make its clinical recognition difficult. The objective was to characterise the peripheral neuropathy in patients with AMN by nerve conduction studies. METHODS--Nerve conduction studies were performed in 99 men known to have AMN and in 38 heterozygous women, all of whom had neurological disabilities. RESULTS--Of the 13 variables obtained, at least one was abnormal in 82% of patients. The abnormalities were more common in men than in women (87% v 67%); in legs than in arms (77% v 38%); in motor than in sensory conduction (80% v 39%); and in latency (distal and F wave) and velocity compared with amplitude (80% v 29%). Twenty six patients had at least one nerve variable value in the demyelinating range. Four variables (sural velocity, peroneal amplitude, peroneal velocity, and peroneal F wave) were correlated with the expanded disability status scale; five variables (peroneal velocity, tibial H reflex, median distal latency, median conduction velocity, and median F wave latency) were correlated with serum very long chain fatty acids (VLCFAs); and two variables (sural amplitude and peroneal distal latency) were more likely to be abnormal in patients with normal adrenal function than in patients with Addison's disease. CONCLUSIONS--Nerve conduction studies in patients with AMN are often abnormal and suggest a mixture of axonal loss and multifocal demyelination. Their correlation with disability status and serum VLCFAs suggests that measures from nerve conduction studies may be useful in evaluating future treatments. Images
Chaudhry, V; Moser, H W; Cornblath, D R
Four transmembrane tyrosine kinases constitute the ErbB protein family: epidermal growth factor receptor (EGFR) or ErbB1, ErbB2, ErbB3, and ErbB4. In general, the structure and mechanism of the activation of these members are similar. However, significant differences in homologous desensitization are known between EGFR and ErbB4. Desensitization of ligand-occupied EGFR occurs by endocytosis, while that of ErbB4 occurs by selective cleavage at the cell surface. Because ErbB4 is abundantly expressed in neurons from fetal to adult brains, elucidation of the desensitization mechanism is important to understand neuronal development and synaptic functions. Recently, it has become clear that heterologous desensitization of EGFR and ErbB4 are induced by endocytosis and cleavage, respectively, similar to homologous desensitization. It has been reported that heterologous desensitization of EGFR is induced by serine phosphorylation of EGFR via the p38 mitogen-activated protein kinase (p38 MAP kinase) pathway in various cell lines, including alveolar epithelial cells. In contrast, the protein kinase C pathway is involved in ErbB4 cleavage. In this review, we will describe recent advances in the desensitization mechanisms of EGFR and ErbB4, mainly in alveolar epithelial cells and hypothalamic neurons, respectively. PMID:24553453
Yamamoto, Hideyuki; Higa-Nakamine, Sayomi; Noguchi, Nobuhiro; Maeda, Noriko; Kondo, Yutaka; Toku, Seikichi; Kukita, Ichiro; Sugahara, Kazuhiro
Rat hepatocytes contain several types of Ca2+-linked receptors, all of which stimulate glycogen breakdown by increasing cytosolic free Ca2+ concentration [( Ca2+]c). In vivo desensitization of this Ca2+ messenger system was studied in hepatocytes isolated from either pheochromocytoma (PHEO)-harboring and chronically norepinephrine (NE)-infused rats. Homologous desensitization for alpha 1-adrenergic receptor-mediated phosphorylase activation developed in the early stage of PHEO rats (3-4 wk after implantation), whereas, in the later stage of tumor development or in the NE-infused rats, phosphorylase responses to all Ca2+-mobilizing stimulations were subsensitive (heterologous desensitization). In the homologous desensitization, the [Ca2+]c response to alpha 1-adrenergic stimulation was selectively reduced. We found, using the phenoxybenzamine inactivation method, that there was a linear relationship between alpha 1 receptor density and the [Ca2+]c response; consequently, the blunted [Ca2+]c response to alpha 1-adrenergic stimulation could not be explained by the 34% downregulation of alpha 1 receptors seen in these rats. These results indicated that uncoupling at a step proximal to alpha 1 receptor-stimulated [Ca2+]c increase is also of primary importance in homologous desensitization of phosphorylase activation. On the other hand, heterologous desensitization also involved alteration(s) at steps distal to the rise in [Ca2+]c. Our data demonstrate that prolonged exposure to catecholamines results in desensitization of the [Ca2+]c mobilization pathway and may involve multiple mechanisms.
Tsujimoto, G; Tsujimoto, A; Kato, K; Hashimoto, K
The frequency of hypersensitivity reactions (HSR) to drugs has risen in the last 10 years owing to increased exposure to better and more allergenic medications including monoclonal antibodies. HSRs prevent patients from using their first-line therapy, leading to decreased quality of life and life expectancy. Although premedication with antihistamines, leukotriene blockers, and corticosteroids can protect against mild-to-moderate HSR, none of these medications has provided protection against anaphylaxis. Rapid drug desensitization is a treatment option for patients with HSR to their first-line medication that protects against anaphylaxis.Although the mechanisms of drug desensitization are not completely understood, in vitro mast cell models of IgE antigen desensitization have led to the design of safe and effective in vivo protocols aimed at protecting highly sensitized patients from hypersensitivity reactions and anaphylaxis. This review provides an insight into the mechanisms of IgE/mast cell desensitization, the principles and practice of drug desensitization, and an overview of the different desensitization protocols and their safety and efficacy profiles. Drug desensitization should only be performed by allergists, trained nurses, and experienced pharmacists, since this high-risk procedure involves reintroducing allergenic medication to highly sensitized patients, with the consequent potential for severe or fatal HSRs. PMID:24834769
Castells Guitart, M C
Human A431 and rat glioma C6 cells exposed to isoproterenol (ISO) underwent a time and dose dependent loss of ISO-stimulated adenylate cyclase (AC) activity (desensitization). In addition, ..beta..-adrenergic receptors (..beta..AR) became less accessible to the hydrophilic antagonist (/sup 3/H)CGP-12177 and redistributed from the heavier density plasma membrane fraction to a lighter density membrane fraction (sequestration). Pretreatment of the cells with Concanavalin A (Con A) or phenylarsine oxide blocked sequestration but not desensitization. ..beta..AR of membranes prepared from Con A-pretreated cells exhibited a reduced affinity for ISO after desensitization as measured by the half-maximal concentration of ISO required to stimulate AC (Kact) and to compete for antagonist binding (IC50). Membranes were exposed to alkali to inactivate AC and ..beta..AR was transferred to a foreign AC by membrane fusion with polyethylene glycol. ..beta..AR from desensitized cells exhibited a reduced affinity for ISO (both Kact and IC50) and a reduced ability to stimulate the foreign AC. In addition, ..beta..AR from desensitized cells remained accessible to (/sup 3/H)CGP-12177 in the fused membranes. The authors conclude that the primary, essential step in desensitization is a reduction in ..beta..AR function. In contrast, ..beta..AR sequestration is not a prerequisite but a secondary event in the desensitization process.
Kassis, S.; Olasmaa, M.; Fishman, P.H.
The beta-adrenoceptor agonist, isoprenaline, inhibited the immunoglobulin E-mediated release of histamine from human lung mast cells (HLMC). Long-term (24 h) exposure of HLMC to isoprenaline reduced the subsequent effectiveness of isoprenaline to inhibit histamine release. The extent of this functional desensitization was variable with some HLMC preparations resistant and others highly susceptible. We sought to determine whether the variability in the degree of functional desensitization was influenced by genetic polymorphisms in the beta2-adrenoceptor. HLMC preparations were genotyped at two polymorphic loci, positions 16 (arg to gly) and 27 (gln to glu), and the effect of desensitizing conditions (24 h with 10(-6) M isoprenaline) on the subsequent ability of isoprenaline (10(-7) M) to inhibit histamine release from HLMC was determined (n = 72). In HLMC preparations expressing beta2-adrenoceptors with arg (wild-type) or gly (mutant) at position 16, desensitization was 71 +/- 5% (n = 18) or 43 +/- 5%, (n = 26), respectively, whereas the desensitization was 59 +/- 6% (n = 28) for heterozygotes at this position. In HLMC preparations expressing beta2-adrenoceptors with gln (wild-type) or glu (mutant) at position 27, desensitization was 65 +/- 5% (n = 25) or 28 +/- 7% (n = 17), respectively, whereas the desensitization was 61 +/- 5% (n = 30) for heterozygotes at this position. These data suggest that mutant (gly16 and glu27) forms of the receptor are resistant to desensitization compared to wild-type (arg16 and gln27) forms. However, analyses to determine the relative contributions of positions 16 and 27 suggest that position 27 is more important in influencing the degree of functional desensitization. PMID:10762003
Chong, L K; Chowdry, J; Ghahramani, P; Peachell, P T
This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.
Kung, Ling-Hsuan; Gong, Kerui; Adedoyin, Mary; Ng, Johnson; Bhargava, Aditi; Ohara, Peter T.; Jasmin, Luc
This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold. PMID:23844184
Kung, Ling-Hsuan; Gong, Kerui; Adedoyin, Mary; Ng, Johnson; Bhargava, Aditi; Ohara, Peter T; Jasmin, Luc
Tachyphylaxis may have contributed to the failure of the motilide ABT-229 [N-ethyl, N-methyl 4'' deoxy erythromycin (EM)-B enolether] in clinical trials. We compared the desensitizing potency of structurally related motilides [EM-A, EM-A enolether (ME4), N-ethyl, N-methyl EM-A (ME36), EM-B enolether (ME67), N-ethyl, N-methyl EM-A enolether (EM523), ABT-229 and 4'' deoxy EM-A enolether (KOS1326)] in a Chinese hamster ovary (CHO)-K1 cell line expressing the human motilin receptor (MTLR) and in rabbit duodenal segments. CHO-MTLR cells were preincubated with motilides prior to stimulation with motilin. The negative logarithm of the preincubation concentration reducing the maximal motilin-induced Ca(2+) flux to 50% was calculated (pDC(50)). Internalization was visualized in CHO-K1 cells containing an enhanced green fluorescent protein (EGFP)-tagged MTLR and quantified in binding experiments. The contractile response of repeated stimulations was measured in duodenal segments. In CHO-MTLR cells, the pDC(50) was ABT-229 (8.78) > motilin (7.77) > EM-A (4.78), different from their order of potency to induce Ca(2+) release (pEC(50)): motilin (9.39) > ABT-229 (8.46) > EM-A (7.11). In cells with the EGFP-tagged MTLR, ABT-229 decreased membrane fluorescence by 25 +/- 2% compared with 16 +/- 2% for motilin and 8 +/- 2% for EM-A. Binding studies confirmed that EM-A did not induce MTLR internalization (residual binding 96 +/- 4% compared with motilin, 31 +/- 3% and ABT-229, 21 +/- 1%). Comparison of the pDC(50) and pEC(50) values of the other motilides ME4 (5.90; 8.08), ME67 (6.03; 8.12), ME36 (3.32; 6.62), EM-523 (6.02; 8.22), and KOS1326 (7.32; 8.14) suggested that the strong desensitizing properties of ABT-229 are mostly related to the removal of the 4''-OH of the cladinose sugar. The decline of the contractile response in duodenal segments correlated with the pDC(50). The ability to desensitize and internalize the MTLR is not only determined by potency. This may be an important criterion for the development of a clinically useful compound. PMID:15764739
Thielemans, Leen; Depoortere, Inge; Perret, Jason; Robberecht, Patrick; Liu, Yaoquan; Thijs, Theo; Carreras, Chris; Burgeon, Emmanuel; Peeters, Theo L
BACKGROUND: Although many nerve prostheses have been proposed in recent years, in the case of consistent loss of nervous tissue peripheral nerve injury is still a traumatic pathology that may impair patient's movements by interrupting his motor-sensory pathways. In the last few decades tissue engineering has opened the door to new approaches;: however most of them make use of rigid
Silvia Panseri; Carla Cunha; Joseph Lowery; Ubaldo Del Carro; Francesca Taraballi; Stefano Amadio; Angelo Vescovi; Fabrizio Gelain
Background It is well-known that chronic administration of ?2AR agonists can induce ?2AR desensitization. Our previous study showed that Rho guanine nucleotide dissociation inhibitor 2 (RhoGDI2) overexpression induced beta-2 adrenergic receptor (?2AR) desensitization in airway smooth muscle cells. The purpose of this study was to further study the function of RhoGDI2 in ?2AR desensitization by ?2AR desensitization mouse model. Methods Studies were performed using a ?2AR desensitization mice model induced by salbutamol. The mice were randomly divided into five groups (n=45): RhoGDI2 overexpression group (n=10); RhoGDI2 siRNA group (n=10); empty viral vector group (n=10); experimental control group (n=10); blank control group—without any drug treatment (n=5). The first four groups were used the same methods and the same dose to establish ?2AR desensitization mice model by salbutamol. The first three groups that salbutamol-treated were used for intratracheal delivery of lentiviral vectors. Airway hyperreactivity was measured through a whole-body plethysmograph system. RhoGDI2, ?2AR, GRK2 mRNA and protein expression levels were then detected by RT-PCR and western blot analyses in fresh lung tissues. As well as the activity of GRK was assessed by light-dependent phosphorylation of rhodopsin. Results We successfully constructed ?2AR desensitization mouse model. As expected, airway responsiveness after inhaling acetylcholine chloride (Ach) was markedly increased in the RhoGDI2 overexpression group compared to experimental control group and blank control group when concentrations of Ach was 45 mg/mL (all P<0.05), while, it was markedly decreased in the RhoGDI2 siRNA group compared to experimental control group (P<0.05). RhoGDI2, GRK2 expressions and GRK enzymatic activity were significantly increased in RhoGDI2 overexpression group compared to experimental control group and blank control group (all P<0.05). RhoGDI2, GRK2 expressions and GRK enzymatic activity were significantly decreased in RhoGDI2 siRNA group compared to experimental control group and blank control group (all P<0.05). Conversely, ?2AR expression were significantly lower in RhoGDI2 overexpression group compared to experimental control group and blank control group (all P<0.05), exhibiting an inverse correlation with RhoGDI2 expression. Conclusions To sum up, our present studies found that RhoGDI2 might induce ?2AR desensitization and GRK2 might take part in RhoGDI2-mediated ?2AR desensitization.
Ni, Songshi; Zhao, Jing; Fu, Zhenxue
We have recently shown that manual stimulation of target muscles promotes functional recovery after transection and surgical\\u000a repair to pure motor nerves (facial: whisking and blink reflex; hypoglossal: tongue position). However, following facial nerve\\u000a repair, manual stimulation is detrimental if sensory afferent input is eliminated by, e.g., infraorbital nerve extirpation.\\u000a To further understand the interplay between sensory input and motor
H. Bendella; S. P. Pavlov; M. Grosheva; A. Irintchev; S. K. Angelova; D. Merkel; N. Sinis; K. Kaidoglou; E. Skouras; S. A. Dunlop; Doychin N. Angelov
Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor-that is, intraepidermal nerve fibres-of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions. PMID:24840972
Bennett, Gary J; Doyle, Timothy; Salvemini, Daniela
We present surgicoanatomical topographic relations of nerves and plexuses in the retroperitoneal space: 1) six named parietal nerves, branches of the lumbar plexus: iliohypogastric, ilioinguinal, genitofemoral, lateral femoral cutaneous, obturator, femoral. 2) The sacral plexus is formed by the lumbosacral trunk, ventral rami of S1-S3, and part of S4; the remainder of S4 joining the coccygeal plexus. From this plexus originate the superior gluteal nerve, which passes backward through the greater sciatic foramen above the piriformis muscle; the inferior gluteal nerve also courses through the greater sciatic foramen, but below the piriformis; 3) sympathetic trunks: right and left lumbar sympathetic trunks, which comprise four interconnected ganglia, and the pelvic chains; 4) greater, lesser, and least thoracic splanchnic nerves (sympathetic), which pass the diaphragm and join celiac ganglia; 5) four lumbar splanchnic nerves (sympathetic), which arise from lumbar sympathetic ganglia; 6) pelvic splanchnic nerves (nervi erigentes), providing parasympathetic innervation to the descending colon and pelvic splanchna; and 7) autonomic (prevertebral) plexuses, formed by the vagus nerves, splanchnic nerves, and ganglia (celiac, superior mesenteric, aorticorenal). They include sympathetic, parasympathetic, and sensory (mainly pain) fibers. The autonomic plexuses comprise named parts: aortic, superior mesenteric, inferior mesenteric, superior hypogastric, and inferior hypogastric (hypogastric nerves). PMID:20349652
Mirilas, Petros; Skandalakis, John E
Lipofibromatous hamartomas (LFHs) are rare benign tumors that typically present as slow-growing firm masses in the subcutaneous soft tissue of the extremities. These often develop in young adults on the volar aspects of the hands, wrists, and forearms along major nerves and their branches. Only a single case of LFH growth along a cranial nerve has been reported.A 41-year-old man presented with a subcutaneous soft mass of the cheek. Histologically, the mass consisted of a proliferating fibrofatty tissue that surrounded and infiltrated the nerve structure and it was confirmed to be an LFH. After surgical excision, the patient experienced mild facial numbness and motor disturbance on the side ipsilateral to the resection. Because complete excision of the mass can cause sensory or motor disturbances, an accurate diagnosis and proper subsequent treatment, such as partial decompression, are necessary. PMID:24926723
Chong, Yosep; Byeon, Jun Hee; Lee, Ahn Hee; Lee, Eun Jung
We report three patients with a typical clinical picture of unilateral meralgia paresthetica in whom routine nerve conduction studies were normal. However, cortical somatosensory evoked potentials were absent after lateral femoral cutaneous nerve (LFCN) stimulation on the affected side. After stimulation of the LFCN in the anterosuperior iliac spine (ASIS) region and recording the responses distal to conventional sites (20 cm from the ASIS), sensory nerve action potentials (SNAPs) were absent in the symptomatic leg, but present in the normal leg. We suggest that thigh paresthesias may be caused by a distal LFCN lesion. Eliciting this requires recording SNAPs distal to conventional sites. PMID:17685466
Kushnir, Mark; Klein, Colin; Kimiagar, Yitzhak; Pollak, Lea; Rabey, Jose M
Isolated posterior femoral cutaneous nerve (PFCN) lesions are rare, with only six cases reported in the modern literature and one case documented with a nerve conduction study. A 25-year-old woman had sensory loss in the posterolateral thigh after two right gluteal intramuscular injections. Nerve conduction studies using Dumitru's technique showed a 9microV response on the asymptomatic side, but no response on the symptomatic side, and no abnormalities on needle examination of the back and lower extremities. Although a single case does not prove the validity of a technique, this case provides the rare opportunity to demonstrate the utility of Dumitru's technique. PMID:10943764
Tong, H C; Haig, A
The aim of the method for quantifying hierarchy stimuli by Galvanic Skin Resistance recordings is to improve the results of systematic desensitization by attenuating the subjective influences in hierarchy construction which are common in traditional procedures. (Author/CS)
Barabasz, Arreed F.
In hypersensitive reactions to native L-asparaginase, either premedication and desensitization or substitution with polyethylene glycol conjugated asparaginase (PEG-ASP) is preferred. Anaphylaxis with PEG-ASP is rare. An 8-year-old girl and a 2.5-year-old boy, both diagnosed as having acute lymphoblastic leukemia, presented with native L-asparaginase hypersensitivity and substitution with PEG-ASP was preferred. They received a premedication (methylprednisolone, hydroxyzine and ranitidine) followed by desensitization with PEG-ASP infusion. Both patients developed anaphylaxis with peg-asparaginase. These are the first reported cases of anaphylactic reaction to PEG-ASP, despite the application of both premedication and desensitization. Anaphylaxis with PEG-ASP is very rare and premedication and desensitization protocols may not prevent these hypersensitive reactions. PMID:23910807
Sahiner, Umit M; Yavuz, S Tolga; Gökce, Muge; Buyuktiryaki, Betul; Altan, Ilhan; Aytac, Selin; Tuncer, Murat; Tuncer, Ayfer; Sackesen, Cansin
We examined the initial expression of synaptic function in the embryonic chick trigeminal nucleus using voltage-sensitive dye recording. Brainstem preparations with three trigeminal nerve afferents, the ophthalmic nerve (N.V1), maxillary nerve (N.V2) and mandibular nerve (N.V3), were dissected from 5.5- to 6.5-day-old chick embryos. In our previous study [Sato et al., 1999], we detected slow signals corresponding to glutamatergic excitatory postsynaptic potentials and identified the principal sensory nucleus of the trigeminal nerve (Pr5), spinal sensory nucleus of the trigeminal nerve (Sp5) and trigeminal motor nucleus. In this study, we examined the effects of removing Mg(2+) from the physiological solution, which enhanced N-methyl-d-aspartate receptor function in the sensory nuclei. In 6.5-day-old (St 29) embryos, the slow signal was observed in Pr5 and Sp5 only when N.V1 was stimulated, whereas it appeared in Mg(2+)-free solution with every nerve stimulation. In 6-day-old (St 28) embryos, the slow signal was observed in Sp5 with N.V1 stimulation, and the appearance of synaptic function in Mg(2+)-free solution varied, depending on the nerves and preparations used. In 5.5-day-old (St 27) embryos, synaptic function was not detected even when external Mg(2+) was removed. These results indicate that the initial expression of synaptic function in the trigeminal system occurs earlier than previously considered, and that the developmental organization of synaptic function differs among the three trigeminal nerves and between the two sensory nuclei. PMID:24769319
Momose-Sato, Yoko; Sato, Katsushige
Peripheral nerve injury primarily occurs due to trauma as well as factors such as tumors, inflammatory diseases, congenital deformities, infections, and surgical interventions. The surgical procedure to be performed as treatment depends on the etiology, type of injury, and the anatomic region. The goal of treatment is to minimize loss of function due to motor and sensory nerve loss at the distal part of the injury. Regardless of the cause of the injury, the abnormal nerve regeneration due to incomplete nerve regeneration, optimal treatment of peripheral nerve injuries should provide adequate coaptation of proximal and distal sides without tension, preserving the neurotrophic factors within the repair line. The gold standard for the treatment of nerve defects is the autograft; however, due to denervation of the donor site, scarring, and neuroma formation, many studies have aimed to develop simpler methods, better functional results, and less morbidity. In this study, a defect 1 cm in length was created on the sciatic nerve of rats. The rats were treated with the following procedures: group 1, autograft; group 2, allogeneic aorta graft; group 3, diced cartilage graft in allogeneic aorta graft; and group 4, tubularized cartilage graft in allogeneic aorta graft. Group 5 was the control group. The effects of cartilage tissue in nerve regeneration were evaluated by functional and histomorphological methods.Group 1, for which the repair was performed with an autograft, was evaluated to be the most similar to the control group. There was not a statistically significant difference in myelination and Schwann cell rates between group 2, in which an allogeneic aorta graft was used, and group 3, in which diced cartilage in an allogeneic aorta graft was used. In group 4, myelination and Schwann cell formation were observed; however, they were scattered and irregular, likely due to increased fibrosis.In all of the groups, nerve regeneration at various rates was observed both functionally and histomorphologically. This study demonstrates that cartilage tissue has promoting effects in nerve regeneration. PMID:23917545
Frat, Cemal; Geyik, Ylmaz; Aytekin, Ahmet Hamdi; Gül, Mehmet; Kam?l, Suat; Yi?itcan, Birgül; Ozcan, Cemal
Willardiine [(S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione] is a naturally occurring heterocyclic excitatory amino acid present in the seeds of Acacia and Mimosa. A series of 5-substituted willardiines were synthesized in single enantiomeric forms and tested for activity at AMPA/kainate receptors, using whole-cell recording from mouse embryonic hippocampal neurons. The (S)- but not (R)-isomers of willardiine and 5-bromowillardiine were potent agonists, producing rapidly but incompletely desensitizing responses. At equilibrium, (S)-5-fluorowillardiine (EC50, 1.5 microM) was seven times more potent than (R,S)-AMPA (EC50, 11 microM) and 30 times more potent than willardiine (EC50, 45 microM); the potency sequence was fluoro greater than nitro greater than chloro approximately bromo greater than iodo greater than willardiine. Willardiines produce strikingly different degrees of desensitization: at saturating doses the equilibrium response to the weakly desensitizing agonist (S)-5-iodowillardiine was similar in amplitude to the response to kainate and 10 times larger than the response to the strongly desensitizing agonist (S)-willardiine. The desensitization sequence was fluoro greater than willardiine greater than nitro approximately chloro greater than bromo greater than iodo greater than kainate. Cross-desensitization experiments confirm that willardiines bind to the same receptors activated by kainate and AMPA, and show that both the rapidly desensitizing and equilibrium responses to willardiines are mediated by the same receptor: (S)-5-iodowillardiine blocked activation of the rapidly desensitizing response evoked by (S)-willardiine and (S)-5-fluorowillardiine, while the latter agonists blocked the equilibrium response to (S)-5-iodowillardiine. A slowly decaying inward tail current was recorded after a brief application of (S)-5-fluorowillardiine but not (S)-willardiine, consistent with a model in which willardiines bind with different affinity to desensitized receptors, such that following removal of agonist, receptors trapped in the desensitized state can return to the open state before dissociation of agonist terminates receptor activation. Willardiines are the first compounds characterized in which simple changes in molecular structure are associated with marked differences in the ability of agonists to produce desensitization of AMPA/kainate receptors. PMID:1371315
Patneau, D K; Mayer, M L; Jane, D E; Watkins, J C
Neural fibrolipomatous hamartoma is a rare benign tumour commonly involving the median nerve. Other less frequently involved nerves include the ulnar, radial, brachial plexus, superficial peroneal nerve, inferior calcaneal nerve and median plantar nerve. Involvement of sural nerve has not been reported in the available literature so far. A three-year-old female child presented with a painless swelling over the posterolateral aspect of left leg with no associated motor or sensory deficits. Radiological investigations revealed a fat density lesion with interspersed neural element in the subcutaneous plane of the left leg. Histopathological examination of the excised specimen showed features of a fibrolipomatous hamartoma of the nerve. This report describes the occurrence of fibrolipomatous hamartoma in the sural nerve for the first time in the literature. This rare tumour should be considered in the differential diagnosis of such lesions. PMID:24763237
Parihar, A; Verma, S; Senger, M; Agarwal, A; Bansal K, K; Gupta, R
Investigated basic change processes accompanying several social-learning procedures from the perspective of a dual-process theory of avoidance behavior. 48 snake-phobic Ss were administered either symbolic desensitization, symbolic modeling, live modeling combined with guided participation (contact desensitization), or no treatment. All 3 approaches produced generalized and enduring reductions in fear arousal and avoidance behavior and positive changes in attitudes. Modeling with
Albert Bandura; Edward B. Blanchard; Brunhilde Ritter
The nicotinic acetylcholine receptor (nAChR) is a member of the important Cys-loop ligand-gated ion channel superfamily that modulates neuronal excitability. After responding to their agonists, their actions are terminated either by removal of ligand or by fast and slow desensitization, processes that play an important role in modulating the duration of conducting states and hence of integrated neuronal behavior. We monitored structural changes occurring during fast and slow desensitization in the transmembrane domain of the Torpedo nAChR using time–resolved photolabeling with the hydrophobic probe 3-(trifluoromethyl)-3-(m-iodophenyl) diazirine (TID). After channel opening, TID photolabels a residue on the ?-subunit’s M2–M3 loop and a cluster of four residues on ?M1 and ?M2, defining an open state pocket [Arevalo, E. et al. (2005) J. Biol. Chem. 280, 13631–13640]. We now find that photolabeling of this pocket persists during the transition to the fast desensitized state, decreasing only with the transition to the slow desensitized state. In contrast, photoincorporation in the channel lumen at the conserved 9? leucines on the second transmembrane helix (M2–9?) decreased successively during the resting to open and open to fast desensitized state transitions, implying that the local conformation is different in each state, a conclusion consistent with the hypothesis that there are separate gates for channel opening and desensitization. Thus, although during fast desensitization there is a conformation change in the channel lumen at the level of M2–9?, there is none in the regions of the ?-subunit’s M2–M3 loop and the interior of its M1–M4 helix bundle until slow desensitization occurs.
Yamodo, Innocent H.; Chiara, David C.; Cohen, Jonathan B.; Miller, Keith W.
Nitrates such as nitroglycerin (GTN) and NO-donors such as S-nitrosothiols are clinically vasoactive via stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major-draw back to a widely used cardiovascular therapy. We recently showed that exposure to NO and to S-nitrosothiols causes S-nitrosylation of sGC, which directly desensitizes sGC to stimulation by NO. Here we test the hypothesis that desensitization of sGC by S-nitrosylation is a mechanism of nitrate tolerance. Our results established that vascular tolerance to nitrates can be recapitulated in vivo by S-nitrosylation via exposure to cell membrane permeable S-nitrosothiols and that sGC is S-nitrosylated and desensitized in the tolerant, treated-tissues. We next determined that a) GTN treatment of primary aortic smooth muscle cells induces S-nitrosylation of sGC and its desensitization as a function of GTN concentration; b) S-nitrosylation and desensitization are prevented by treatment with N-acetyl-cysteine, a precursor of glutathione, used clinically to prevent development of nitrate tolerance; c) S-nitrosylation and desensitization are reversed by cessation of GTN treatment. Finally, we demonstrated that in vivo development of nitrate tolerance and cross-tolerance by 3-day chronic GTN treatment correlates with S-nitrosylation and desensitization of sGC in tolerant tissues. These results suggest that in vivo nitrate tolerance is mediated, in part, by desensitization of sGC via GTN-dependent S-nitrosylation.
Sayed, Nazish; Kim, David D.; Fioramonti, Xavier; Iwahashi, Toru; Duran, Walter N.; Beuve, Annie
A VARIETY of ligand-gated ion channels undergo a fast activation process after the rapid application of agonist and also a slower transition towards desensitized or inactivated closed channel states when exposure to agonist is prolonged1-5. Desensitization involves at least two distinct closed states in the acetylcholine receptor, each with an affinity for agonists higher than those of the resting or
F. Revah; D. Bertrand; J.-L. Galzi; A. Devillers-Thiéry; C. Mulle; N. Hussy; S. Bertrand; M. Ballivet; J.-P. Changeux
GABA(B) receptors assemble from principle and auxiliary subunits. The principle subunits GABA(B1) and GABA(B2) form functional heteromeric GABA(B(1,2)) receptors that associate with homotetramers of auxiliary KCTD8, -12, -12b, or -16 (named after their K(+) channel tetramerization domain) subunits. These auxiliary subunits constitute receptor subtypes with distinct functional properties. KCTD12 and -12b generate desensitizing receptor responses while KCTD8 and -16 generate largely non-desensitizing receptor responses. The structural elements of the KCTDs underlying these differences in desensitization are unknown. KCTDs are modular proteins comprising a T1 tetramerization domain, which binds to GABA(B2), and a H1 homology domain. KCTD8 and -16 contain an additional C-terminal H2 homology domain that is not sequence-related to the H1 domains. No functions are known for the H1 and H2 domains. Here we addressed which domains and sequence motifs in KCTD proteins regulate desensitization of the receptor response. We found that the H1 domains in KCTD12 and -12b mediate desensitization through a particular sequence motif, T/NFLEQ, which is not present in the H1 domains of KCTD8 and -16. In addition, the H2 domains in KCTD8 and -16 inhibit desensitization when expressed C-terminal to the H1 domains but not when expressed as a separate protein in trans. Intriguingly, the inhibitory effect of the H2 domain is sequence-independent, suggesting that the H2 domain sterically hinders desensitization by the H1 domain. Evolutionary analysis supports that KCTD12 and -12b evolved desensitizing properties by liberating their H1 domains from antagonistic H2 domains and acquisition of the T/NFLEQ motif. PMID:23035119
Seddik, Riad; Jungblut, Stefan P; Silander, Olin K; Rajalu, Mathieu; Fritzius, Thorsten; Besseyrias, Valérie; Jacquier, Valérie; Fakler, Bernd; Gassmann, Martin; Bettler, Bernhard
?-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance. PMID:22914548
Levitt, Erica S; Williams, John T
While acutely administered corticotropin-releasing factor (CRF) and acute stress each activate neurons of the locus coeruleus (LC, desensitization to both develops with repeated treatment. The present experiments were designed to investigate whether cross-desensitization develops between CRF and stress. Because acute hemodynamic stress caused by intravenous infusion of sodium nitroprusside increases LC electrophysiological discharge rate via a CRF-dependent mechanism, it was
Lisa H. Conti; Stephen L. Foote
Background: Cervical Radiculopathy (CR) is a neurologic condition characterised by dysfunction of a cervical spinal nerve, the roots of the nerve, or both. Diagnostic criteria for CR are not well defined, and no universally accepted criteria for its diagnosis have been established. Clinical examination, radiological imaging and electrophysiologic evaluation are the different modalities to diagnose CR. The incidence of Cervical Spondylosis and related conditions is increasing in the present scenario and the use of radiologic examination is time consuming and uneconomical for the common Indian setup. Thus, there is a definite need to establish a cost effective, reliable, and accurate means for establishing the diagnosis of cervical radiculopathy. Electrodiagnostic tests are the closest to fulfill these criteria. Aim: To evaluate diagnostic utility of various motor and sensory nerve conduction study parameters in cervical radiculopathy. Setting and Design: It was a cross-sectional study conducted on 100 subjects of age > 40 years. Material and Methods: The consecutive patients clinically diagnosed to have cervical radiculopathy, referred from department of Orthopaedics were prospectively recruited for the motor and sensory nerve conduction study using RMS EMG EP Mark-II. Parameters studied were Compound Muscle Action Potential (CMAP), Distal Motor Latency (DML) and Conduction Velocity (CV) for motor nerves and Sensory Nerve Action Potential (SNAP) and CV for sensory nerves. Statistical Analysis: Study observations and results were analysed to find the Specificity, Sensitivity, Positive Predictive Value and Negative Predictive Value using SPSS 16.0. Results: Among various motor nerve conduction parameters CMAP was found to be more sensitive with high positive predicative value. CV was found to have greater specificity and DML had least negative predictive value. Sensory nerve conduction parameters were found to have less sensitivity but higher specificity as compared to motor parameters. Conclusion: Nerve conduction studies are useful supportive diagnostic tool for suspected cervical radiculopathy as they are found to have reliable sensitivity and specificity.
Pawar, Sachin; Kashikar, Aditi; Shende, Vinod; Waghmare, Satish
Epithelial Na(+) channel (ENaC)/degenerin family members are involved in mechanosensation, blood pressure control, pain sensation, and the expression of fear. Several of these channel types display a form of desensitization that allows the channel to limit Na(+) influx during prolonged stimulation. We used site-directed mutagenesis and chemical modification, functional analysis, and molecular dynamics simulations to investigate the role of the lower palm domain of the acid-sensing ion channel 1, a member of the ENaC/degenerin family. The lower palm domains of this trimeric channel are arranged around a central vestibule, at ?20 Å above the plasma membrane and are covalently linked to the transmembrane channel parts. We show that the lower palm domains approach one another during desensitization. Residues in the palm co-determine the pH dependence of desensitization, its kinetics, and the stability of the desensitized state. Mutations of palm residues impair desensitization by preventing the closing movement of the palm. Overexpression of desensitization-impaired channel mutants in central neurons allowed--in contrast to overexpression of wild type--a sustained signaling response to rapid pH fluctuations. We identify and describe here the function of an important regulatory domain that most likely has a conserved role in ENaC/degenerin channels. PMID:24018065
Roy, Sophie; Boiteux, Céline; Alijevic, Omar; Liang, Chungwen; Bernèche, Simon; Kellenberger, Stephan
Szechuan peppers contain hydroxy-?-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-?-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal.
Klein, Amanda H.; Sawyer, Carolyn M.; Zanotto, Karen L.; Ivanov, Margaret A.; Cheung, Susan; Carstens, Mirela Iodi; Furrer, Stephan; Simons, Christopher T.; Slack, Jay P.
This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves. PMID:24502845
Watson, C Peter N; Mackinnon, Susan E; Dostrovsky, Jonathan O; Bennett, Gary J; Farran, R Peter; Carlson, Torie
A 20-year-old man with mild myopathy, external ophthalmoparesis, epilepsy, and diffuse white matter hyperintensity in the brain on magnetic resonance imaging had partial merosin deficiency in muscle and absent merosin in the endoneurium. Motor and sensory nerve conduction velocities were slow. Nerve biopsy showed reduction of large myelinated fibers, short internodes, enlarged nodes, excessive variability of myelin thickness, tomacula, and uncompacted myelin, but no evidence of segmental demyelination, naked axons, or onion bulbs. Thus, in congenital muscular dystrophy, merosin expression may be dissociated in different tissues, and the neuropathy is sensory-motor and due to abnormal myelinogenesis. PMID:12661054
Di Muzio, A; De Angelis, M V; Di Fulvio, P; Ratti, A; Pizzuti, A; Stuppia, L; Gambi, D; Uncini, A
We have investigated the acute desensitization of acetylcholine-activated GIRK current (IK(ACh)) in cultured adult rat atrial myocytes. Acute desensitization of IK(ACh) is observed as a partial relaxation of current with a half-time of < 5 s when muscarinic M2 receptors are stimulated by a high concentration (> 2 ?mol l?1) of ACh. Under this condition experimental manoeuvres that cause a decrease in the amplitude of IK(ACh), such as partial block of M2 receptors by atropine, intracellular loading with GDP-?-S, or exposure to Ba2+, caused a reduction in desensitization. Acute desensitization was also identified as a decrease in current amplitude and a blunting of the response to saturating [ACh] (20 ?mol l?1) when the current had been partially activated by a low concentration of ACh or by stimulation of adenosine A1 receptors. A reduction in current analogous to acute desensitization was observed when ATP-dependent K+ current (IK(ATP)) was activated either by mitochondrial uncoupling using 2,4-dinitrophenole (DNP) or by the channel opener rilmakalim. Adenovirus-driven overexpression of Kir2.1, a subunit of constitutively active inwardly rectifying K+ channels, resulted in a large Ba2+-sensitive background K+ current and a dramatic reduction of ACh-activated current. Adenovirus-driven overexpression of GIRK4 (Kir3.4) subunits resulted in an increased agonist-independent GIRK current paralleled by a reduction in IK(ACh) and removal of the desensitizing component. These data indicate that acute desensitization depends on K+ current flow, independent of the K+ channel species, suggesting that it reflects a reduction in electrochemical driving force rather than a bona fide signalling mechanism. This is supported by the observation that desensitization is paralleled by a significant negative shift in reversal potential of IK(ACh). Since the ACh-induced hyperpolarization shows comparable desensitization properties as IK(ACh), this novel current-dependent desensitization is a physiologically relevant process, shaping the time course of parasympathetic bradycardia.
Bender, Kirsten; Wellner-Kienitz, Marie-Cecile; Bosche, Leif I; Rinne, Andreas; Beckmann, Christian; Pott, Lutz
Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2?cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84?days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals. In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy.
Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2?cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84?days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals.In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy. PMID:22546145
van Neerven, Sabien Ga; Bozkurt, Ahmet; O'Dey, Dan Mon; Scheffel, Juliane; Boecker, Arne H; Stromps, Jan-Philipp; Dunda, Sebastian; Brook, Gary A; Pallua, Norbert
Peripheral nerve injury is often followed by incomplete and unsatisfactory functional recovery and may be associated with sensory and motor impairment of the affected limb. Therefore, a novel method is needed to improve the speed of recovery and the final functional outcome after peripheral nerve injuries. This report investigates the effect of lentiviral-mediated transfer of conserved dopamine neurotrophic factor (CDNF) on regeneration of the rat peripheral nerve in a transection model in vivo. We observed notable overexpression of CDNF protein in the distal sciatic nerve after recombinant CDNF lentiviral vector application. We evaluated sciatic nerve regeneration after surgery using light and electron microscopy and the functional recovery using the sciatic functional index and target muscle weight. HE staining revealed better ordered structured in the CDNF-treated group at 8 weeks post-surgery. Quantitative analysis of immunohistochemistry of NF200 and S-100 in the CDNF group revealed significant improvement of axonal and Schwann cell regeneration compared with the control groups at 4 weeks and 8 weeks after injury. The thickness of the myelination around the axons in the CDNF group was significantly higher than in the control groups at 8 weeks post-surgery. The CDNF group displayed higher muscle weights and significantly increased sciatic nerve index values. Our findings suggest that CDNF gene therapy could provide durable and stable CDNF protein concentration and has the potential to enhance peripheral nerve regeneration, morphological and functional recovery following nerve injury, which suggests a promising strategy for peripheral nerve repair. PMID:24076387
Cheng, Lei; Liu, Yi; Zhao, Hua; Zhang, Wen; Guo, Ying-Jun; Nie, Lin
Traumatic brachial plexus injuries can be devastating, causing partial to total denervation of the muscles of the upper extremities. Surgical reconstruction can restore motor and/or sensory function following nerve injuries. Direct nerve-to-nerve transfers can provide a closer nerve source to the target muscle, thereby enhancing the quality and rate of recovery. Restoration of elbow flexion is the primary goal for patients with brachial plexus injuries. A 4-year-old right-hand-dominant male sustained a fracture of the left scapula in a car accident. He was treated conservatively. After the accident, he presented with motor weakness of the left upper extremity. Shoulder abduction was grade 3 and elbow flexor was grade 0. Hand function was intact. Nerve conduction studies and an electromyogram were performed, which revealed left lateral and posterior cord brachial plexopathy with axonotmesis. He was admitted to Rehabilitation Medicine and treated. However, marked neurological dysfunction in the left upper extremity was still observed. Six months after trauma, under general anesthesia with the patient in the supine position, the brachial plexus was explored through infraclavicular and supraclavicular incisions. Each terminal branch was confirmed by electrophysiology. Avulsion of the C5 roots and absence of usable stump proximally were confirmed intraoperatively. Under a microscope, neurotization from the musculocutaneous nerve to two medial pectoral nerves was performed with nylon 8-0. Physical treatment and electrostimulation started 2 weeks postoperatively. At a 3-month postoperative visit, evidence of reinnervation of the elbow flexors was observed. At his last follow-up, 2 years following trauma, the patient had recovered Medical Research Council (MRC) grade 4+ elbow flexors. We propose that neurotization from medial pectoral nerves to musculocutaneous nerve can be used successfully to restore elbow flexion in patients with brachial plexus injuries. PMID:23115676
Yu, Dong-Woo; Kim, Min-Su; Jung, Young-Jin; Kim, Seong-Ho
Traumatic brachial plexus injuries can be devastating, causing partial to total denervation of the muscles of the upper extremities. Surgical reconstruction can restore motor and/or sensory function following nerve injuries. Direct nerve-to-nerve transfers can provide a closer nerve source to the target muscle, thereby enhancing the quality and rate of recovery. Restoration of elbow flexion is the primary goal for patients with brachial plexus injuries. A 4-year-old right-hand-dominant male sustained a fracture of the left scapula in a car accident. He was treated conservatively. After the accident, he presented with motor weakness of the left upper extremity. Shoulder abduction was grade 3 and elbow flexor was grade 0. Hand function was intact. Nerve conduction studies and an electromyogram were performed, which revealed left lateral and posterior cord brachial plexopathy with axonotmesis. He was admitted to Rehabilitation Medicine and treated. However, marked neurological dysfunction in the left upper extremity was still observed. Six months after trauma, under general anesthesia with the patient in the supine position, the brachial plexus was explored through infraclavicular and supraclavicular incisions. Each terminal branch was confirmed by electrophysiology. Avulsion of the C5 roots and absence of usable stump proximally were confirmed intraoperatively. Under a microscope, neurotization from the musculocutaneous nerve to two medial pectoral nerves was performed with nylon 8-0. Physical treatment and electrostimulation started 2 weeks postoperatively. At a 3-month postoperative visit, evidence of reinnervation of the elbow flexors was observed. At his last follow-up, 2 years following trauma, the patient had recovered Medical Research Council (MRC) grade 4+ elbow flexors. We propose that neurotization from medial pectoral nerves to musculocutaneous nerve can be used successfully to restore elbow flexion in patients with brachial plexus injuries.
Yu, Dong-Woo; Kim, Min-Su; Jung, Young-Jin
Objective To evaluate the incidence of postsurgical sensory complications in patients with scalp masses and classify the locations of them from a surgical standpoint according to anatomical considerations. Methods A total of 121 patients who underwent surgery for scalp mass were included in this study. The authors reviewed medical records and preoperative radiologic images. We investigated the complications related to sensory changes after procedure. Enrolled patients have been divided into three groups. Group A included patients with tumors above the superior nuchal line (SNL), Group B with tumors within the trapezius muscle area and patients who had tumors on the lateral trapezius muscle area were assigned to Group C. We compared the incidence related to postoperative sensory complications and summarized their additional treatments for these with clinical outcome. Results There were 12 patients (10%) with sensory complications related on the mass excision site (Group A: 1 patient, Group B: 2 patients, Group C: 9 patients). Six patients were affected with lesser occipital nerve (LON), 2 patients on greater occipital nerve (GON) and 4 patients on GON and LON. Over 6 months after surgery, two of the twelve patients with sensory complications did not have complete recovered pain in spite of proper medications and local chemical neurolysis with 1.0% lidocaine and dexamethasone. Conclusion Occipital neuropathy should be considered as a complication related excision of scalp mass. The sensory complications are more frequent in Group C because of the anatomical characteristics of the occipital nerves and there were no statistical difference for other variables.
Yang, Jin Seo; Cho, Yong Jun; Kang, Suk Hyung
Ultrastructure studies of the anterior sensory organs of the house fly larva (Musca domestica) are reported. Ultrastructure studies of the sensory setae and Haller's organ are reported for a hard tick Amblyomma americanum and a soft tick Argas arboreus. C...
R. C. Axtell
Systemic artemin promotes regeneration of dorsal roots to the spinal cord after crush injury. However, it is unclear whether systemic artemin can also promote peripheral nerve regeneration, and functional recovery after partial lesions distal to the dorsal root ganglion (DRG) remains unknown. In the present investigation, male Sprague Dawley rats received axotomy, ligation, or crush of the L5 spinal nerve or sham surgery. Starting the day of injury, animals received intermittent subcutaneous artemin or vehicle across 2weeks. Sensory thresholds to tactile or thermal stimuli were monitored for 6weeks after injury. Immunohistochemical analyses of the DRG and nerve regeneration were performed at the 6-week time point. Artemin transiently reversed tactile and thermal hypersensitivity after axotomy, ligation, or crush injury. Thermal and tactile hypersensitivity reemerged within 1week of treatment termination. However, artemin-treated rats with nerve crush, but not axotomy or ligation, subsequently showed gradual return of sensory thresholds to preinjury baseline levels by 6weeks after injury. Artemin normalized labeling for NF200, IB4, and CGRP in nerve fibers distal to the crush injury, suggesting persistent normalization of nerve crush-induced neurochemical changes. Sciatic and intradermal administration of dextran or cholera toxin B distal to the crush injury site resulted in labeling of neuronal profiles in the L5 DRG, suggesting regeneration functional restoration of nonmyelinated and myelinated fibers across the injury site into cutaneous tissue. Artemin also diminished ATF3 and caspase 3 expression in the L5 DRG, suggesting persistent neuroprotective actions. A limited period of artemin treatment elicits disease modification by promoting sensory reinnervation of distal territories and restoring preinjury sensory thresholds. PMID:24269493
Wang, Ruizhong; Rossomando, Anthony; Sah, Dinah W Y; Ossipov, Michael H; King, Tamara; Porreca, Frank
Sensory systems, in particular those of vision and hearing, are known to mimic some of the characteristics of a linear, temporal energy integrator. Experiments conducted on the project have demonstrated that the sense of touch is endowed with the same pro...
J. J. Zwislocki
This article features the National Institute of Trauma and Loss in Children (TLC), a program that has demonstrated via field testing, exploratory research, time series studies, and evidence-based research studies that its Structured Sensory Intervention for Traumatized Children, Adolescents, and Parents (SITCAP[R]) produces statistically…
Steele, William; Kuban, Caelan
Capitalizing on the resources available within a city block, this resource guide for the emotionally handicapped (K-6) describes methods and procedures for developing sensory awareness in the urban out-of-doors. Conceptual focus is on interdependency ("living things are interdependent"). Involvement in the environment (observing, thinking, doing)…
Capsaicin, the pungent ingredient of red pepper has become not only a "hot" topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8% capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author's 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor "Transient Receptor Potential Vanilloid 1" (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of "capsaicin-sensitive" tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special "multisteric" gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states. PMID:24941663
Regulation of N-methyl-d-aspartate receptor (NMDAR) activity by desensitization is important in physiological and pathological states; NMDAR desensitization contributes in shaping synaptic responses and may be protective by limiting calcium influx during sustained glutamate insults. We previously reported that glycine-independent desensitization decreases during hippocampal neuronal development, correlating with NMDAR synaptic localization and association with postsynaptic density 95 (PSD-95). PSD-95/Discs large/zona occludens (PDZ)-1,2 domains of PSD-95 bind to the C-terminus of NMDAR NR2 subunits. The role of PSD-95 in anchoring signaling proteins near NMDARs is well documented. To determine if PSD-95-induced changes in NMDAR desensitization occur because of direct binding to NR2 or due to recruitment of regulatory proteins, we tested the effects of various PSD-95 constructs on NMDAR currents in human embryonic kidney 293 (HEK293) cells and neurons. In HEK cells, wild-type PSD-95 significantly reduced wild-type NMDAR desensitization without altering currents of NMDARs containing NR2A-S1462A, a mutation that abolishes PSD-95 binding. The PSD-95 N-terminus truncated after the PDZ1-2 domains was sufficient for this effect in neurons with low endogenous PSD-95 levels; in NMDAR-expressing HEK cells, the effect persisted when PSD-95 multimerization was eliminated. Moreover other PSD-95 family members with highly homologous PDZ1-2 domains significantly reduced NMDAR desensitization. In mature neurons, disruption of PSD-95/NMDAR interaction through protein kinase C (PKC) activation increased desensitization to levels found in immature neurons, and this effect was not due to PKC direct regulation of NMDAR activity. We conclude that direct binding of PSD-95 increases stability of NMDAR responses to agonist exposure in neuronal and nonneuronal cells. PMID:18400955
Sornarajah, Lavan; Vasuta, Oana Cristina; Zhang, Lily; Sutton, Christine; Li, Bo; El-Husseini, Alaa; Raymond, Lynn A
Desensitization of platelets to 5-hydroxytryptamine (5HT) (1 microM), during active removal of the agonist by the platelet 5HT-uptake system, was studied at the level of signal transduction. Desensitization to 5HT was dose-dependent and homologous. Without occupation of the 5HT2 receptor, neither an increase in cytosolic [Ca2+] (30 nM ionomycin), nor a separate or simultaneous activation of protein kinase C (by 10 microM 1-oleoyl-2-acetylglycerol), could induce desensitization to 5HT (1 microM). During the early phase of desensitization, the 5HT2 receptor was coupled to phospholipase C, whereas during the late phase of desensitization this coupling was disconnected. However, after disappearance of the agonist, the coupling in the resting platelet recovered quickly, and was nearly complete (82%) after 30 min. During this resensitization, the 5HT-inducibility of activation of phospholipase C, of the increase in cytosolic [Ca2+] and of stimulation of protein kinase C were restored in parallel. The time course for resensitization of the 5HT-induced increase in cytosolic [Ca2+] was independent of the presence of extracellular Ca2+. It is concluded that, after dissociation of 5HT from the platelet 5HT2-receptor, 5HT-induced responses rapidly resensitize. Because of its short duration and the parallelism in recovery between the different 'down-stream phospholipase C' intracellular transduction signals, it is considered that desensitization arises from a reversible change in the transduction mechanism at a step up to or including the activation of phospholipase C. Neither desensitization nor resensitization to 5HT is dependent on the presence of extracellular Ca2+. Images Figure 7
Roevens, P; de Chaffoy de Courcelles, D
Cell signaling is often mediated by the binding of multiple ligands to multisubunit receptors. The probabilistic nature and sometimes slow rate of binding encountered with diffusible ligands can impede attempts to determine how the ligand occupancy controls signaling in such protein complexes. We describe a solution to this problem that uses a photoswitched tethered ligand as a 'ligand clamp' to induce rapid and stable binding and unbinding at defined subsets of subunits. We applied the approach to study gating in ionotropic glutamate receptors (iGluRs), ligand-gated ion channels that mediate excitatory neurotransmission and plasticity at glutamatergic synapses in the brain. We probed gating in two kainate-type iGluRs, GluK2 homotetramers and GluK2-GluK5 heterotetramers. Ultrafast (submillisecond) photoswitching of an azobenzene-based ligand on specific subunits provided a real-time measure of gating and revealed that partially occupied receptors can activate without desensitizing. The findings have implications for signaling by locally released and spillover glutamate. PMID:24561661
Reiner, Andreas; Isacoff, Ehud Y
Objectives. The aim of the present study was to review the published literature in order to identify relevant studies for inclusion and to determine whether there was any evidence on the clinical effectiveness of selected desensitizing toothpastes, calcium sodium phosphosilicate (CSPS), amorphous calcium phosphate (ACP), nanohydroxyapatite, and casein phosphopeptide-amorphous calcium phosphate (tooth mousse) on reducing dentine hypersensitivity (DH). Materials and Methods. Following a review of 593 papers identified from searching both electronic databases (PUBMED) and hand searching of relevant written journals, only 5 papers were accepted for inclusion. Results. Analysis of the included studies (3 CSPS and 2 ACP) would suggest that there may be some benefit for patients using these products for reducing DH. No direct comparative studies were available to assess all these products under the same conditions neither were there any comparative randomised controlled studies that compared at least two of these products in determining their effectiveness in treating DH. Conclusions. Due to the small number of included studies, there are limited clinical data to support any claims of clinical efficacy of these OTC products. Further studies are therefore required to determine the efficacy of these products in well-controlled RCT studies with a larger sample size.
Talioti, E.; Hill, R.; Gillam, D. G.
Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.
Quigley, A. F.; Bulluss, K. J.; Kyratzis, I. L. B.; Gilmore, K.; Mysore, T.; Schirmer, K. S. U.; Kennedy, E. L.; O'Shea, M.; Truong, Y. B.; Edwards, S. L.; Peeters, G.; Herwig, P.; Razal, J. M.; Campbell, T. E.; Lowes, K. N.; Higgins, M. J.; Moulton, S. E.; Murphy, M. A.; Cook, M. J.; Clark, G. M.; Wallace, G. G.; Kapsa, R. M. I.
This brief paper summarizes what is known about sensory integration and sensory integration dysfunction (DSI). It outlines evaluation of DSI, treatment approaches, and implications for parents and teachers, including compensatory strategies for minimizing the impact of DSI on a child's life. Review of origins of sensory integration theory in the…
DiMatties, Marie E.; Sammons, Jennifer H.
Lorna Jean King is interviewed concerning the present status of sensory integration as a treatment modality in the area of mental health. Topics covered are: use of sensory integration techniques with adults and adolescents in both chronic and acute mental health settings; goals and expected outcomes of using sensory integration techniques; cost-effectiveness of these techniques; differences between occupational therapy and
Barbara W. Posthuma
A significant fraction of military soldiers sustain nerve injury and use tobacco or nicotine containing products. Healing of nerve injuries is influenced by many factors, such as degree of original injury, healing potential of the nerve, and general health of patient. However, recently, it has been demonstrated that the presence of retained insoluble metal fragments decreases healing. The effects of systemic nicotine administration, with or without metal fragments at the site of nerve injury, were evaluated. Both the nicotine-administered groups (nicotine, nicotine + shrapnel) showed significant increase in the peroneal function compared with untreated controls, as assessed by paw area (p < 0.05). Furthermore, to test possible role of altered sensory function, we used the hot plate assay. Latency to withdraw paw from a hot plate was significantly shorter in nicotine groups (p < 0.05). These data indicate that nicotine improves sensory and motor aspects of nerve function, in the presence or absence of shrapnel. PMID:22165666
Rittenhouse, Bradley; Hill-Pryor, Crystal D; McConathy, Adam; Parker, Peter; Franco, Nelson; Toussaint, Esra; Barker, Darrell; Prasad, Balakrishna; Pizarro, Jose M
Objective This study was conducted to ascertain the correlation between preserved pelvic nerve networks and bladder function after laparoscopic nerve-sparing radical hysterectomy. Methods Between 2009 and 2011, 53 patients underwent total laparoscopic radical hysterectomies. They were categorized into groups A, B, and C based on the status of preserved pelvic nerve networks: complete preservation of the pelvic nerve plexus (group A, 27 cases); partial preservation (group B, 13 cases); and complete sacrifice (group C, 13 cases). To evaluate bladder function, urodynamic studies were conducted preoperatively and postoperatively at 1, 3, 6, and 12 months after surgery. Results No significant difference in sensory function was found between groups A and B. However, the sensory function of group C was significantly lower than that of the other groups. Group A had significantly better motor function than groups B and C. No significant difference in motor function was found between groups B and C. Results showed that the sensory nerve is distributed predominantly at the dorsal half of the pelvic nerve networks, but the motor nerve is predominantly distributed at the ventral half. Conclusion Various types of total laparoscopic nerve-sparing radical hysterectomies can be tailored to patients with cervical carcinomas.
Fujiwara, Kazuko; Ebisawa, Keiko; Hada, Tomonori; Ota, Yoshiaki; Andou, Masaaki
The topography of the middle-latency N110 after radial nerve stimulation suggested a generator in SII. To support this hypothesis, we have tried to identify a homologous component in the tibial nerve SEP (somatosensory evoked potential). Evoked potentials following tibial nerve stimulation (motor+sensory threshold) were recorded with 29 electrodes (bandpass 0.5–500 Hz, sampling rate 1000 Hz). For comparison, the median nerve
C Kany; R.-D Treede
Highlights: •CDNF was successfully transfected by a lentiviral vector into the distal sciatic nerve. •CDNF improved S-100, NF200 expression and nerve regeneration after sciatic injury. •CDNF improved the remyelination and thickness of the regenerated sciatic nerve. •CDNF improved gastrocnemius muscle weight and sciatic functional recovery. -- Abstract: Peripheral nerve injury is often followed by incomplete and unsatisfactory functional recovery and may be associated with sensory and motor impairment of the affected limb. Therefore, a novel method is needed to improve the speed of recovery and the final functional outcome after peripheral nerve injuries. This report investigates the effect of lentiviral-mediated transfer of conserved dopamine neurotrophic factor (CDNF) on regeneration of the rat peripheral nerve in a transection model in vivo. We observed notable overexpression of CDNF protein in the distal sciatic nerve after recombinant CDNF lentiviral vector application. We evaluated sciatic nerve regeneration after surgery using light and electron microscopy and the functional recovery using the sciatic functional index and target muscle weight. HE staining revealed better ordered structured in the CDNF-treated group at 8 weeks post-surgery. Quantitative analysis of immunohistochemistry of NF200 and S-100 in the CDNF group revealed significant improvement of axonal and Schwann cell regeneration compared with the control groups at 4 weeks and 8 weeks after injury. The thickness of the myelination around the axons in the CDNF group was significantly higher than in the control groups at 8 weeks post-surgery. The CDNF group displayed higher muscle weights and significantly increased sciatic nerve index values. Our findings suggest that CDNF gene therapy could provide durable and stable CDNF protein concentration and has the potential to enhance peripheral nerve regeneration, morphological and functional recovery following nerve injury, which suggests a promising strategy for peripheral nerve repair.
Cheng, Lei; Liu, Yi; Zhao, Hua; Zhang, Wen; Guo, Ying-Jun; Nie, Lin, E-mail: email@example.com
Segmental demyelination and axonal degeneration of motor nerves induced by lead exposure is well known in man, and animals. The effect of lead acetate exposure to man may involve the cranial nerves, since vertigo and sensory neuronal deafness have been reported among lead workers. However, there are few reports concerning the dose-effects of lead acetate both to the peripheral nerve and the cranial VII nerve with measurement of blood lead concentration. The authors investigated the effects of lead acetate to the cochlea and the VIII nerve using CM (cochlear microphonics) and AP (action potential) of the guinea pigs. The effects of lead acetate to the sciatic nerve were measured by MCV of the sciatic nerve with measurement of blood lead concentration.
Yamamura, K.; Maehara, N.; Terayama, K.; Ueno, N.; Kohyama, A.; Sawada, Y.; Kishi, R.
Over a two-year period this study evaluated the condition of 65 athletes with nerve injuries. These injuries represent the spectrum of nerve injuries likely to be encountered in sports medicine clinics. (Author/MT)
Collins, Kathryn; And Others
Nerve stimulator applies and/or measures precisely controlled force and/or displacement to nerve so response of nerve measured. Consists of three major components connected in tandem: miniature probe with spherical tip; transducer; and actuator. Probe applies force to nerve, transducer measures force and sends feedback signal to control circuitry, and actuator positions force transducer and probe. Separate box houses control circuits and panel. Operator uses panel to select operating mode and parameters. Stimulator used in research to characterize behavior of nerve under various conditions of temperature, anesthesia, ventilation, and prior damage to nerve. Also used clinically to assess damage to nerve from disease or accident and to monitor response of nerve during surgery.
Tcheng, Ping; Supplee, Frank H., Jr.; Prass, Richard L.
A personal field chemical warfare nerve agent detector has therein a transducer having two microchemical cantilever oscillators. One of the cantilever oscillators has deposited, as an end-mass, a chemically selective substance on the cantilever. The nerve...
E. S. Kolesar
The aim of the present study was to develop a chronic in vivo model of pulmonary ?2-adrenoceptor desensitization and to elucidate the nature and molecular basis of this state. Subcutaneous infusion of rats with albuterol for 7 days compromised the ability of albuterol, given acutely, to protect against acetylcholine-induced bronchoconstriction. The bronchoprotective effect of prostaglandin E2, but not forskolin, was also impaired, indicating that the desensitization was heterologous and that the primary defect in signaling was upstream of adenylyl cyclase. ?2-Adrenoceptor density was reduced in lung membranes harvested from albuterol-treated animals, and this was associated with impaired albuterol-induced cyclic adenosine monophosphate (cAMP) accumulation and activation of cAMP-dependent protein kinase ex vivo. Gs? expression was reduced in the lung and tracheae of albuterol-treated rats, and cholera toxin–induced cAMP accumulation was blunted. Chronic treatment of rats with albuterol also increased cAMP phosphodiesterase activity and G protein–coupled receptor kinase-2, but the extent to which these events contributed to ?2-adrenoceptor desensitization was unclear given that forskolin was active in both groups of animals and that desensitization was heterologous. Collectively, these results indicate that albuterol effects heterologous desensitization of pulmonary Gs-coupled receptors in this model, with downregulation of Gs? representing a primary molecular etiology.
Finney, Paul A.; Belvisi, Maria G.; Donnelly, Louise E.; Chuang, Tsu-Tshen; Mak, Judith C.W.; Scorer, Carol; Barnes, Peter J.; Adcock, Ian M.; Giembycz, Mark A.
Aim: The aim of this in vitro study was to compare the shear bond strengths of two different dentin bonding agents with two different desensitizers. Materials and Methods: Eighty molars were taken which were ground to expose the dentin. The teeth were divided into two major groups. Each major group was subdivided into four subgroups of 10 samples each. Groups Ia and IIa were treated as dry bonding groups, groups Ib and IIb were treated as a moist bonding groups, groups Ic and IIc were rewetted with Gluma desensitizer, and groups Id and IId were rewetted with vivasens desensitizer. Major group I was treated with Gluma comfort bond and Charisma. Major group II was treated Prime and Bond NT and TPH. The samples were thermo cycled and shear bond test was performed using an Instron machine. The data were analyzed using one-way analysis of variance and Tukey's Honestly significant different test. Results: The results revealed that the specimens rewetted with Gluma desensitizer showed the highest shear bond strength compared to all other groups, irrespective of the bonding agent or composite resin used. Conclusions: It can be concluded that rewetting with desensitizer provided better bond strength than the other groups.
Ravikumar, N; Shankar, P; Indira, R
Brief exposure of platelets to thrombin makes them less sensitive to subsequent activation by thrombin, a phenomenon demonstrated by Shuman, Botney, and Fenton [J. Clin. Invest., 63, 1211-1218, 1979] by incubating prostacyclin-inhibited platelets with thrombin; after removal of thrombin and prostacyclin, the platelets were selectively desensitized to subsequent activation by thrombin. The conditions for this desensitization have been further defined. Inhibition of thrombin-induced platelet activation by prostacyclin was not absolute, it was only temporary, it could be overcome with higher thrombin concentrations, and it varied with platelet concentration and temperature. With low enough thrombin concentrations, high enough prostacyclin concentrations and short enough times of exposure, platelets could be pretreated with thrombin with no evidence of activation. After addition of hirudin to inhibit thrombin, the platelets were washed and tested for thrombin-induced secretion of ATP. Desensitization to thrombin depended on the concentration of thrombin during pretreatment and on the length of pretreatment, consistent with a catalytic modification of a receptor. A less extensive desensitization was observed when platelets without inhibitor were incubated with a sub-threshold level of thrombin before addition of an activating concentration of thrombin. This desensitization also varied with the time of pretreatment and the concentration of sub-threshold thrombin. PMID:6356458
McGowan, E B; Detwiler, T C
Background The neurotrophin Nerve Growth factor (NGF) is known to influence the phenotype of mature nociceptors, for example by altering synthesis of neuropeptides, and changes in NGF levels have been implicated in the pathophysiology of chronic pain conditions such as neuropathic pain. We have tested the hypothesis that after partial nerve injury, NGF accumulates within the skin and causes ‘pro-nociceptive’ phenotypic changes in the remaining population of sensory nerve fibres, which could underpin the development of neuropathic pain. Results Eleven days after chronic constriction injury of the rat mental nerve the intra-epidermal nerve fibre density of the chin skin from had reduced from 11.6?±?4.9 fibres/mm to 1.0?±?0.4 fibres/mm; this slowly recovered to 2.4?±?2.0 fibres/mm on day 14 and 4.0?±?0.8 fibres/mm on day 21. Cold hyperalgesia in the ipsilateral lower lip was detectable 11 days after chronic constriction injury, although at this time skin [NGF] did not differ between sides. At 14 days post-injury, there was a significantly greater [NGF] ipsilaterally compared to contralaterally (ipsilateral?=?111?±?23 pg/mg, contralateral?=?69?±?13 pg/mg), but there was no behavioural evidence of neuropathic pain at this time-point. By 21 days post-injury, skin [NGF] was elevated bilaterally and there was a significant increase in the proportion of TrkA-positive (the high-affinity NGF receptor) intra-epidermal nerve fibres that were immunolabelled for the neuropeptide Calcitonin Gene-related peptide. Conclusions The temporal mismatch in behaviour, skin [NGF] and phenotypic changes in sensory nerve fibres indicate that increased [NGF] does not cause hyperalgesia after partial mental nerve injury, although it may contribute to the altered neurochemistry of cutaneous nerve fibres.
The axonal projection pattern of sensory neurons typically is regulated by environmental signals, but how different sensory afferents can establish distinct projections in the same environment remains largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons project subtype-specific axonal branches in the ventral nerve cord, and we show that the Tripartite motif protein, Anomalies in sensory axon patterning (Asap) is a critical determinant of the axonal projection patterns of different C4da neurons. Asap is highly expressed in C4da neurons with both ipsilateral and contralateral axonal projections, but the Asap level is low in neurons that have only ipsilateral projections. Mutations in asap cause a specific loss of contralateral projections, whereas overexpression of Asap induces ectopic contralateral projections in C4da neurons. We also show by biochemical and genetic analysis that Asap regulates Netrin signaling, at least in part by linking the Netrin receptor Frazzled to the downstream effector Pico. In the absence of Asap, the sensory afferent connectivity within the ventral nerve cord is disrupted, resulting in specific larval behavioral deficits. These results indicate that different levels of Asap determine distinct patterns of axonal projections of C4da neurons by modulating Netrin signaling and that the Asap-mediated axonal projection is critical for assembly of a functional sensory circuit.
Morikawa, Rei K.; Kanamori, Takahiro; Yasunaga, Kei-ichiro; Emoto, Kazuo
The axonal projection pattern of sensory neurons typically is regulated by environmental signals, but how different sensory afferents can establish distinct projections in the same environment remains largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons project subtype-specific axonal branches in the ventral nerve cord, and we show that the Tripartite motif protein, Anomalies in sensory axon patterning (Asap) is a critical determinant of the axonal projection patterns of different C4da neurons. Asap is highly expressed in C4da neurons with both ipsilateral and contralateral axonal projections, but the Asap level is low in neurons that have only ipsilateral projections. Mutations in asap cause a specific loss of contralateral projections, whereas overexpression of Asap induces ectopic contralateral projections in C4da neurons. We also show by biochemical and genetic analysis that Asap regulates Netrin signaling, at least in part by linking the Netrin receptor Frazzled to the downstream effector Pico. In the absence of Asap, the sensory afferent connectivity within the ventral nerve cord is disrupted, resulting in specific larval behavioral deficits. These results indicate that different levels of Asap determine distinct patterns of axonal projections of C4da neurons by modulating Netrin signaling and that the Asap-mediated axonal projection is critical for assembly of a functional sensory circuit. PMID:22084112
Morikawa, Rei K; Kanamori, Takahiro; Yasunaga, Kei-ichiro; Emoto, Kazuo
The normal ratio between the amplitude of the sensory evoked potential (SEP) at the wrist on stimulating digits 1, 2, 3, and 5 was determined in 44 healthy adult subjects. The first digit had the larger amplitude, and the fifth digit the smallest SEP. The amplitude expresses the density of sensory innervation in each finger. The ratio between the amplitude of different fingers varied according to the age of the subject. The amplitude of the SEP from a digit innervated by the median nerve decreased in the elderly more than the SEP amplitude of the digit innervated by the ulnar nerve, probably because of a chronic compression in the carpal tunnel. The changes in the normal amplitude ratio can be applied to the topographic diagnosis of radicular and brachial plexus lesions if a fixed segmental sensory innervation of the hand is accepted. In 44 right handed subjects the amplitude of the sensory evoked potentials at the wrist was significantly larger in the left hand. This asymmetry of sensory innervation between hands could be physiological, and suggests a greater density of sensory innervation in the left hand of right handed subjects.
Cruz Martinez, A; Barrio, M; Perez Conde, M C; Ferrer, M T
Current approaches for treating peripheral nerve injury have resulted in promising, yet insufficient functional recovery compared to the clinical standard of care, autologous nerve grafts. In order to design a construct that can match the regenerative potential of the autograft, all facets of nerve tissue must be incorporated in a combinatorial therapy. Engineered biomaterial scaffolds in the future will have to promote enhanced regeneration and appropriate reinnervation by targeting the highly sensitive response of regenerating nerves to their surrounding microenvironment. PMID:23790730
Marquardt, Laura M; Sakiyama-Elbert, Shelly E
Neurotmesis must be surgically treated by direct end-to-end suture of the two nerve stumps or by a nerve graft harvested from elsewhere in the body in case of tissue loss. To avoid secondary damage due to harvesting of the nerve graft, a tube-guide can be used to bridge the nerve gap. Previously, our group developed and tested hybrid chitosan membranes for peripheral nerve tubulization and showed that freeze-dried chitosan type III membranes were particularly effective for improving peripheral nerve functional recovery after axonotmesis. Chitosan type III membranes have about 110 microm pores and about 90% of porosity, due to the employment of freeze-drying technique. The present study aimed to verify if chitosan type III membranes can be successfully used also for improving peripheral nerve functional recovery after neurotmesis of the rat sciatic nerve. Sasco Sprague-Dawley adult rats were divided into 6 groups: Group 1: end-to-end neurorrhaphy enwrapped by chitosan membrane type III (End-to-EndChitll); Group 2: 10mm-nerve gap bridged by an autologous nerve graft enwrapped by chitosan membrane type III (Graf180degreeChitIII); Group 3: 10 mm-nerve gap bridged by chitosan type III tube-guides (GapChitIII); These 3 experimental groups were compared with 3 control groups, respectively: Group 4: 10 mm-nerve gap bridged by an autologous nerve graft (Graft180degree); Group 5: 10 mm-nerve gap bridged by PLGA 90:10 tube-guides (PLGA); Group 6: end-to-end neurorrhaphy alone (End-to-End). Motor and sensory functional recovery were evaluated throughout a healing period of 20 weeks using extensor postural thrust (EPT), withdrawal reflex latency (WRL) and ankle kinematics. Regenerated nerves withdrawn at the end of the experiment were analysed histologically. Results showed that nerve regeneration was successful in all experimental and control groups and that chitosan type III tubulization induced a significantly better nerve regeneration and functional recovery in comparison to PLGA tubulization control. Further investigation is needed to explore the mechanisms at the basis of the positive effects of chitosan type III on axonal regeneration. PMID:21287974
Simões, Maria J; Amado, Sandra; Gärtner, Andrea; Armada-Da-Silva, Paulo A S; Raimondo, Stefania; Vieira, Marcia; Luís, Ana L; Shirosaki, Yuki; Veloso, António P; Santos, José D; Varejão, Artur S P; Geuna, Stefano; Maurício, Ana C
Synesthesia, the conscious, idiosyncratic, repeatable, and involuntary sensation of one sensory modality in response to another, is a condition that has puzzled both researchers and philosophers for centuries. Much time has been spent proving the condition’s existence as well as investigating its etiology, but what can be learned from synesthesia remains a poorly discussed topic. Here, synaesthesia is presented as a possible answer rather than a question to the current gaps in our understanding of sensory perception. By first appreciating the similarities between normal sensory perception and synesthesia, one can use what is known about synaesthesia, from behavioral and imaging studies, to inform our understanding of “normal” sensory perception. In particular, in considering synesthesia, one can better understand how and where the different sensory modalities interact in the brain, how different sensory modalities can interact without confusion ? the binding problem ? as well as how sensory perception develops.
Harvey, Joshua Paul
Diabetic peripheral neuropathy (DPN) is one of the most common complications of chronic diabetes mellitus. Pathological characteristics of DPN include axonal atrophy, nerve demyelination, and delayed regeneration of peripheral sensory nerve fibers. The goal of treatment in DPN is not only to ameliorate neurological symptoms but also to slow or reverse the underlying neurodegenerative process. Schwann cells and neurotrophic factors play important roles in the repair and regeneration of peripheral nerves. The present paper reviews current studies and evidence regarding the neurological effects of traditional Chinese medicine, with an emphasis on recent developments in the area of nerve repair and regeneration in DPN.
Piao, Yuanlin; Liang, Xiaochun
Lesson is designed to introduce students to cranial nerves through the use of an introductory lecture. Students will then create a three-dimensional model of the cranial nerves. An information sheet will accompany the model in order to help students learn crucial aspects of the cranial nerves.
Juliann Garza (University of Texas-Pan American Physician Assistant Studies)
Lymphatic fluid is a plasma filtrate that can be viewed as having biological activity through the passive accumulation of molecules from the interstitial fluid. The possibility that lymphatic fluid is part of an active self-contained signaling process that parallels the endocrine system, through the activation of G-protein coupled receptors (GPCR), has remained unexplored. We show that the GPCR lysophosphatidic acid 5 (LPA5) is found in sensory nerve fibers expressing calcitonin gene-related peptide (CGRP) that innervate the lumen of lymphatic lacteals and enteric nerves. Using LPA5 as a model for nutrient-responsive GPCRs present on sensory nerves, we demonstrate that dietary protein hydrolysate (peptone) can induce c-Fos expression in enterocytes and nerves that express LPA5. Mesenteric lymphatic fluid (MLF) mobilizes intracellular calcium in cell models expressing LPA5 upon feeding in a time- and dose-dependent manner. Primary cultured neurons of the dorsal root ganglia expressing CGRP are activated by MLF, which is enhanced upon LPA5 overexpression. Activation is independent of the known LPA5 agonists, lysophosphatidic acid and farnesyl pyrophosphate. These data bring forth a pathway for the direct stimulation of sensory nerves by luminal contents and interstitial fluid. Thus, by activating LPA5 on sensory nerves, MLF provides a means for known and yet to be identified constituents of the interstitial fluid to act as signals to comprise a "neurolymphocrine" system. PMID:24578341
Poole, Daniel P; Lee, Mike; Tso, Patrick; Bunnett, Nigel W; Yo, Sek Jin; Lieu, TinaMarie; Shiu, Amy; Wang, Jen-Chywan; Nomura, Daniel K; Aponte, Gregory W
Sleepwalking is a frequently reported side effect of zolpidem which is a short-acting hypnotic drug potentiating activity of GABA(A) receptors. Paradoxically, the most commonly used medications for somnambulism are benzodiazepines, especially clonazepam, which also potentiate activity of GABA(A) receptors. It is proposed that zolpidem-induced sleepwalking can be explained by the desensitization of GABAergic receptors located on serotonergic neurons. According to the proposed model, the delay between desensitization of GABA receptors and a compensatory decrease in serotonin release constitutes the time window for parasomnias. The occurrence of sleepwalking depends on individual differences in receptor desensitization, autoregulation of serotonin release and drug pharmacokinetics. The proposed mechanism of interaction between GABAergic and serotonergic systems can be also relevant for zolpidem abuse and zolpidem-induced hallucinations. It is therefore suggested that special care should be taken when zolpidem is used in patients taking at the same time selective serotonin reuptake inhibitors. PMID:21565448
Juszczak, Grzegorz R
Nociceptive sensory neurons (SNs) in Aplysia provide useful models to study both memory and adaptive responses to nerve injury. Induction of long-term memory in many species, includ- ing Aplysia, is thought to depend on activation of cAMP- dependent protein kinase (PKA). Because Aplysia SNs display similar alterations in models of memory and after nerve injury, a plausible hypothesis is that
Xiaogang Liao; John D. Gunstream; Matthew R. Lewin; Richard T. Ambron; Edgar T. Walters
Target-derived influences of nerve growth factor on neuronal survival and differentiation are well documented, though effects of other neurotrophins are less clear. To examine the influence of NT-3 neurotrophin overexpression in a target tissue of sensory and sympathetic neurons, transgenic mice were isolated that overexpress NT- 3 in the epidermis. Overexpression of NT-3 led to a 42% increase in the number of dorsal root ganglia sensory neurons, a 70% increase in the number of trigeminal sensory neurons, and a 32% increase in sympathetic neurons. Elevated NT-3 also caused enlargement of touch dome mechanoreceptor units, sensory end organs innervated by slowly adapting type 1 (SA1) neurons. The enlarged touch dome units of the transgenics had an increased number of associated Merkel cells, cells at which SA1s terminate. An additional alteration of skin innervation in NT-3 transgenics was an increased density of myelinated circular endings associated with the piloneural complex. The enhancement of innervation to the skin was accompanied by a doubling in the number of sensory neurons expressing trkC. In addition, measures of nerve fibers in cross- sectional profiles of cutaneous saphenous nerves of transgenics showed a 60% increase in myelinated fibers. These results indicate that in vivo overexpression of NT-3 by the epidermis enhances the number of sensory and sympathetic neurons and the development of selected sensory endings of the skin.
Sensations of the dorsal surface of the hand are supplied by the radial and ulnar nerves with the boundary between these two\\u000a nerves classically being the midline of the fourth digit. Overlap and variations of this division exist and a communicating\\u000a branch (RUCB) between the radial and ulnar nerves could potentially explain variations in the sensory examination of the dorsal
Marios Loukas; Robert G. Louis Jr; Christopher T. Wartmann; R. Shane Tubbs; Senem Turan-Ozdemir; Jessica Kramer
Recent studies have suggested that cyclic AMP (cAMP) may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels and morphological changes suggestive of cell maturation along the granulocyte pathway. However, cells cultured with 10(-5) M dimaprit showed more than an 80% decrease in their cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent, dose-dependent and completely prevented by 10(-3) M cimetidine. Desensitization of HL-60 cells for 4 hr with 10(-5) M dimaprit followed by the addition of 10(-3) M cimetidine resulted in total recovery of the cAMP response in less than 24 hr. The pharmacologically inactive analog N-methyldimaprit (SKandF 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of (/sup 3/H)tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Based on these results, the authors suggest that H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase.
Sawutz, D.G.; Kalinyak, K.; Whitsett, J.A.; Johnson, C.L.
Desensitization of µ-opioid receptors (MORs) develops over 5-15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, ?-chlornaltrexamine (?-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein-coupled K(+) channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu(5)]-enkephalin. After acute desensitization or partial irreversible block of MORs with ?-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity. PMID:24748657
Williams, John T
Four cases of redundant nerve roots of the cauda equina are reported, and the pertinent literature is reviewed. This disorder mainly affects males. The clinical history ranges from months to decades. The illness often starts with low back pain or sciatica, or both. Motor and sensory impairment of the legs dominate the further course of the disease. Serpentine filling defects in the column of contrast are a characteristic (but inconstant) feature on myelograms. Abatement of signs and symptoms occurs following adequate decompression of the redundant roots. PMID:6272439
Pau, A; Viale, E S; Turtas, S; Viale, G L
Summary Sensory ganglia from 9-day chick embryos were grown on collagen coated coverslips for 36 h in the presence of nerve growth factor, producing a profuse neuritic outgrowth. The cultures were then incubated for varying periods in a colloidal suspension of thorium dioxide, and the pinocytotic uptake of this marker was followed by electron microscopy. Following brief exposures (3 min),
Peter R. Weldon
Insects are the most successful group of living things in terms of the number of species, the biomass and their extreme survival and reproduction capabilities. Entomological research has revealed that insect sensory systems are crucial for their extremely successful conquering and exploitation of every habitat niche on earth planet. Compared with human beings, insect central nerve system (mainly brain) is
Axel W. Krings
Cultured dorsal root ganglion (DRG) neurons from chick embryos were extremely susceptible to the antineoplastic drugs, cisplatin, vincristine and taxol even in the presence of saturating levels of the neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We previously reported that a low concentration of radicicol enhanced the survival and neurite outgrowth of the embryonic sensory
Contemporary sensory gating definitions are generally tied to the perceptual and attentional phenomenology described by McGhie and Chapman, including abnormalities in the quality of sensory input, heightened awareness of background noises, and poor selective attention reported by individuals with schizophrenia. Despite these explicit phenomenological origins, little is known about the experiential phenomena underlying contemporary operationalizations of the sensory gating construct, such as whether the construct is restricted to experiences associated with the modulation of sensory percepts includes selective attention and distractibility or even whether the construct is accessible via self-report. Because clarification of these issues has important implications for the development and testing of psychological theories and the study of psychopathology, a series of studies was conducted to (a) empirically identify the major dimensions of sensory gating-like perceptual and attentional phenomenology in healthy young adults and (b) develop a psychometrically sound self-report rating scale to capture these dimensions, the Sensory Gating Inventory (SGI). Factor analyses of Likert items measuring a broad range of sensory gating-like subjective experiences revealed 1 primary factor that encompassed anomalies of perceptual modulation (eg, perceptions of heightened stimulus sensitivity and sensory inundation) and 3 other factors measuring disturbances in the processes of focal and radial attention as well as exacerbation of sensory gating-like anomalies by fatigue and stress. Psychometrically, the SGI demonstrated strong reliability and validity. An empirically based conceptual demarcation of the sensory gating construct is offered, and directions for future research are described. PMID:20525773
Hetrick, William P; Erickson, Molly A; Smith, David A
Contemporary sensory gating definitions are generally tied to the perceptual and attentional phenomenology described by McGhie and Chapman, including abnormalities in the quality of sensory input, heightened awareness of background noises, and poor selective attention reported by individuals with schizophrenia. Despite these explicit phenomenological origins, little is known about the experiential phenomena underlying contemporary operationalizations of the sensory gating construct, such as whether the construct is restricted to experiences associated with the modulation of sensory percepts includes selective attention and distractibility or even whether the construct is accessible via self-report. Because clarification of these issues has important implications for the development and testing of psychological theories and the study of psychopathology, a series of studies was conducted to (a) empirically identify the major dimensions of sensory gating–like perceptual and attentional phenomenology in healthy young adults and (b) develop a psychometrically sound self-report rating scale to capture these dimensions, the Sensory Gating Inventory (SGI). Factor analyses of Likert items measuring a broad range of sensory gating–like subjective experiences revealed 1 primary factor that encompassed anomalies of perceptual modulation (eg, perceptions of heightened stimulus sensitivity and sensory inundation) and 3 other factors measuring disturbances in the processes of focal and radial attention as well as exacerbation of sensory gating–like anomalies by fatigue and stress. Psychometrically, the SGI demonstrated strong reliability and validity. An empirically based conceptual demarcation of the sensory gating construct is offered, and directions for future research are described.
Hetrick, William P.; Smith, David A.
Background Following acute organophosphorus (OP) poisoning patients complain of numbness without objective sensory abnormalities or other features of OP induced delayed polyneuropathy. The aim of this study was to measure peripheral nerve function after acute exposure to OP. Methods A cohort study was conducted with age, gender and occupation matched controls. Motor nerve conduction velocity (MNCV), amplitude and area of compound muscle action potential (CMAP), sensory nerve conduction velocity (SNCV), F- waves and electromyography (EMG) on the deltoid and the first dorsal interosseous muscles on the dominant side were performed, following acute OP poisoning. All neurophysiological assessments except EMG were performed on the controls. Assessments were performed on the day of discharge from the hospital (the first assessment) and six weeks (the second assessment) after the exposure. The controls were assessed only once. Results There were 70 patients (50 males) and 70 controls. Fifty-three patients attended for the second assessment. In the first assessment MNCV of all the motor nerves examined, CMAP amplitude and SNCV of ulnar nerve, median and ulnar F-wave occurrence in the patients were significantly reduced compared to the controls. In the second assessment significant reduction was found in SNCV of both sensory nerves examined, MNCV of ulnar nerve, CMAP amplitude of common peroneal nerve, F-wave occurrence of median and ulnar nerves. No abnormalities were detected in the patients when compared to the standard cut-off values of nerve conduction studies except F-wave occurrence. EMG studies did not show any abnormality. Conclusion There was no strong evidence of irreversible peripheral nerve damage following acute OP poisoning, however further studies are required.
Jayasinghe, Sudheera S.; Pathirana, Kithsiri D.; Buckley, Nick A.
Peripheral nerve injuries are often associated with loss of nerve tissue and require autologous nerve grafts to provide a physical substrate for axonal growth. Biosynthetic neural conduits could be an alternative treatment strategy in such injuries. The present study investigates the long-term effects of a tubular fibrin conduit on neuronal regeneration, axonal sprouting and recovery of muscle weight following peripheral nerve injury and repair in adult rats. Sciatic axotomy was performed proximally in the thigh to create a 10-mm gap between the nerve stumps. The injury gap was bridged by using a 14-mm-long fibrin glue conduit, entubulating 2 mm of the nerve stump at each end. A reversed autologous nerve graft was used as a control. The regenerative response from sensory and motor neurones was evaluated following retrograde labelling with Fast Blue fluorescent tracer. In control experiments, at 16 weeks following peripheral nerve grafting, 5184 (±574 standard error of mean (SEM)) sensory dorsal root ganglion neurones and 1001 (±37 SEM) spinal motor neurones regenerated across the distal nerve-graft interface. The fibrin conduit promoted regeneration of 60% of sensory neurones and 52% of motor neurones when compared to the control group. The total number of myelinated axons in the distal nerve stump in the fibrin-conduit group reached 86% of the control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89% of the controls, respectively. The present results suggest that a tubular fibrin conduit can be used to promote neuronal regeneration following peripheral nerve injury. PMID:20005193
Pettersson, Jonas; Kalbermatten, Daniel; McGrath, Aleksandra; Novikova, Liudmila N
We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation. PMID:24760915
Hebert, Jacqueline S; Olson, Jaret L; Morhart, Michael J; Dawson, Michael R; Marasco, Paul D; Kuiken, Todd A; Chan, K Ming
Loss of sensitivity to thrombin following an initial response is characteristic of a number of cell types, including platelets. It has recently been proposed that thrombin receptors resemble other G protein-coupled receptors, but that activation involves a novel mechanism in which thrombin cleaves the receptor, exposing a new N terminus that serves as the ligand for the receptor. Based upon this model, we have examined the mechanism of thrombin receptor desensitization by comparing the effects of thrombin with those of a peptide corresponding to the N-terminal sequence of the receptor following proteolysis by thrombin: SFLLRNPNDKYEPF or TRP42/55. Like thrombin, TRP42/55 stimulated pertussis toxin-sensitive inositol 1,4,5-trisphosphate formation, raised cytosolic Ca2+, and inhibited cAMP formation in the megakaryoblastic HEL cell line. Exposure to either thrombin or TRP42/55 desensitized the cells to both, but not to a third agonist, neuropeptide Y. The rate of recovery after desensitization depended upon the order of agonist addition. Resensitization of the cell to thrombin following a brief exposure to thrombin required up to 24 h and could be inhibited with cycloheximide. Resensitization to TRP42/55 after exposure to thrombin, or to thrombin after exposure to TRP42/55, on the other hand, was detectable within 30 min and could be inhibited by serine/threonine phosphatase inhibitors, but not by cycloheximide. Loss of responsiveness to thrombin and TRP42/55 was also observed following addition of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). However, while the protein kinase inhibitor staurosporine completely prevented the desensitization caused by TPA, it had only a limited effect on the desensitization caused by TRP42/55. These results demonstrate that the G protein-mediated effects of thrombin can be reproduced by a receptor-derived peptide and suggest that desensitization occurs by at least two mechanisms. The first, which is seen with thrombin, but not TRP42/55, involves proteolysis and requires protein synthesis for recovery. The second, which occurs with TRP42/55 and TPA, as well as with thrombin, involves phosphorylation, possibly of the receptor itself. Although protien kinase C is activated by thrombin and is presumably responsible for the desensitization caused by TPA, it does not appear to play a major role in receptor desensitization caused by thrombin and TRP42/55. This suggests that other kinases, such as those which inactivate adrenergic receptors and rhodopsin, are involved in the down-regulation of thrombin receptor function. PMID:1313426
Brass, L F
Desensitization is the process of rendering an individual who is allergic to a food or chemical substance like a drug able to tolerate the agent. This is usually accomplished by exposing the patient to incrementally increasing doses, injecting the offending agent over periods of time as is done in situations of grass or tree pollen allergy. In the current case report we demonstrate the first method to desensitize a patient to the anti-TNF medicament etanercept using immune suppressants rather than the older technique of incrementally increasing injection doses. PMID:24085054
Fellner, Michael J; Yohe, Nicholas
We report a case of a skydiver with isolated musculocutaneous nerve injury, which occurred after prolonged positioning of the arm during simulated freefall in a vertical wind-tunnel. Musculocutaneous nerve injury is rare, and the mechanism of isolated injury to this nerve is not entirely understood. Isolated peripheral nerve injuries such as this easily mimic other injuries and can be difficult to diagnose. The skydiver complained of right arm weakness and numbness that began after training in a vertical wind-tunnel. Exam revealed weakness in right elbow flexion and forearm supination, and diminished sensation in the right lateral forearm. Electrodiagnostic testing revealed a decreased amplitude in the right lateral antebrachial cutaneous nerve sensory nerve action potential, and fibrillations and positive sharp waves in the biceps and brachialis muscles. By 5 months, the subject reported complete sensory and motor recovery. Physical and electrodiagnostic findings corresponded to the distribution of the musculocutaneous nerve. The mechanism of injury was likely the prolonged abducted, extended, and externally rotated position of the shoulder during simulated freefall. Although isolated nerve injuries are uncommon, unusual activities and physiologic demands of athletes can result in such injuries. It is important to be aware of peripheral nerve injuries to facilitate proper diagnosis and management. PMID:17321836
Mautner, Kenneth; Keel, John C
Prolonged agonist stimulation of the ?-opioid receptor (MOR) initiates receptor regulatory events that rapidly attenuate receptor-mediated signaling (homologous desensitization). Emerging evidence suggests that persistent MOR stimulation can also reduce responsiveness of effectors to other G-protein-coupled receptors, termed heterologous desensitization. However, the mechanisms by which heterologous desensitization is triggered by MOR stimulation are unclear. This study used whole-cell patch-clamp recordings of ligand activated G-protein-activated inwardly rectifying potassium channel currents in mouse brain slices containing locus ceruleus (LC) neurons to determine the effects of prolonged stimulation of MOR on ?(2)-adrenoceptor (?(2)-AR) function. The results show distinct and sequential development of homologous and heterologous desensitization during persistent stimulation of MOR in LC neurons with Met(5)-enkephalin (ME). ME stimulation of MOR promoted rapid homologous desensitization that reached a steady state after 5 min and partially recovered over 30 min. Longer stimulation of MOR (10 min) induced heterologous desensitization of ?(2)-AR function that exhibited slower recovery than homologous desensitization. Heterologous (but not homologous) desensitization required ?-arrestin-2 (?arr-2) because it was nearly abolished in ?arr-2-knockout (ko) mice. Heterologous (but not homologous) desensitization was also prevented by inhibition of ERK1/2 and c-Src signaling in wild-type (wt) mouse LC neurons. Heterologous desensitization may be physiologically relevant during exposure to high doses of opioids because ?(2)-AR-mediated slow inhibitory postsynaptic currents were depressed in wt but not ?arr-2 ko LC neurons after prolonged exposure to opioids. Together, these findings demonstrate a novel mechanism by which ?arr-2 can regulate postsynaptic responsiveness to neurotransmitter release. PMID:22689562
Dang, Vu C; Chieng, Billy C; Christie, MacDonald J
The evidence describing the autonomic innervation of body fat is reviewed with a particular focus on the role of the sympathetic neurotransmitters. In compiling the evidence, a strong case emerges for the interaction between autonomic nerves and perivascular adipose tissue (PVAT). Adipocytes have been shown to express receptors for neurotransmitters released from nearby sympathetic varicosities such as adrenoceptors (ARs), purinoceptors and receptors for neuropeptide Y (NPY). Noradrenaline can modulate both lipolysis (via ?2- and ?3-ARs) and lipogenesis (via ?1- and ?3-ARs). ATP can inhibit lipolysis (via P1 purinoceptors) or stimulate lipolysis (via P2y purinoceptors). NPY, which can be produced by adipocytes and sympathetic nerves, inhibits lipolysis. Thus the sympathetic triad of transmitters can influence adipocyte free fatty acid (FFA) content. Substance P (SP) released from sensory nerves has also been shown to promote lipolysis. Therefore, we propose a mechanism whereby sympathetic neurotransmission can simultaneously activate smooth muscle cells in the tunica media to cause vasoconstriction and alter FFA content and release from adjacent adipocytes in PVAT. The released FFA can influence endothelial function. Adipocytes also release a range of vasoactive substances, both relaxing and contractile factors, including adiponectin and reactive oxygen species. The action of adipokines (such as adiponectin) and reactive oxygen species (ROS) on cells of the vascular adventitia and nerves has yet to be fully elucidated. We hypothesise a strong link between PVAT and autonomic fibres and suggest that this poorly understood relationship is extremely important for normal vascular function and warrants a detailed study. PMID:24560685
Bulloch, Janette M; Daly, Craig J
Respiratory tract reflex responses are an important defense mechanism against noxious airborne materials. This study was aimed at defining the effects of adenosine on sensory irritation responsiveness and its role in odorant-irritant interactions. These experiments were aimed at testing the hypothesis that adenosine, through the A2 receptor, enhances trigeminal nerve responses to multiple irritants and that odorants enhance responsiveness to irritants through A2 pathways in the female C57Bl/6 mouse. The adenosine precursor, AMP, immediately and markedly increased the sensory irritation response to capsaicin, cyclohexanone, and styrene, irritants that activate chemosensory nerves through differing receptor pathways. The neuromodulatory effect was blocked by the general adenosine receptor antagonist theophylline and by the A2 receptor-specific antagonist DMPX. Multiple odorants were examined, including R-carvone (spearmint), linalool (lavender), trimethylamine (rotting fish), mercaptoethanol, and ethyl sulfide (stench and rotten eggs). Of these, only mercaptoethanol and ethyl sulfide exhibited neuromodulatory effects, enhancing the sensory irritation response to styrene or cyclohexanone. This effect was blocked by theophylline and DMPX indicating the importance of adenosine A2 receptor pathways in this effect. These results highlight that trigeminal chemosensory responsiveness is not static, but can be quickly modulated by adenosine and select odors resulting in hyperresponsive states. PMID:23162088
Willis, Daniel N; Morris, John B
To investigate the susceptibility of the group II metabotropic glutamate receptor mGlu2 to agonist-induced desensitization, the receptor was stably expressed in Chinese hamster ovary (CHO-mGlu2) or C6 glioma cells (C6-mGlu2). Exposure of CHO-mGlu2 cells to the group II mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-1; 10 ?M) for up to 15 h did not affect the subsequent ability of LCCG-1 to inhibit forskolin-stimulated cAMP accumulation. Similarly, in C6-mGlu2 cells, prolonged exposure to LCCG-1 also did not affect the subsequent ability of LCCG-1 to inhibit cAMP formation. In contrast, exposure of CHO-mGlu2 cells to the protein kinase C activator phorbol myristate acetate (PMA) suppressed the ability of LCCG-1 to inhibit cAMP formation. Using an in vitro model of group II mGlu receptor activity, the hemisected neonatal rat spinal cord preparation, the ability of the selective group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC) to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) did not desensitize when applied for up to 2 h. Together these results indicate that in contrast to most G protein-coupled receptors, the mGlu2 receptor is resistant to agonist-induced homologous desensitization, and that in vitro data suggests that resistance to desensitization is a physiologically relevant property of this mGlu receptor subtype. PMID:20826132
Lennon, Siân M; Rivero, Guadalupe; Matharu, Annelise; Howson, Patrick A; Jane, David E; Roberts, Peter J; Kelly, Eamonn
Although the pelvic autonomic plexus may be considered a mixture of sympathetic and parasympathetic nerves, little information on its composite fibers is available. Using 10 donated elderly cadavers, we investigated in detail the topohistology of nerve fibers in the posterior part of the periprostatic region in males and the infero-anterior part of the paracolpium in females. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were used as parasympathetic nerve markers, and tyrosine hydroxylase (TH) was used as a marker of sympathetic nerves. In the region examined, nNOS-positive nerves (containing nNOS-positive fibers) were consistently predominant numerically. All fibers positive for these markers appeared to be thin, unmyelinated fibers. Accordingly, the pelvic plexus branches were classified into 5 types: triple-positive mixed nerves (nNOS+, VIP+, TH+, thick myelinated fibers + or -); double-positive mixed nerves (nNOS+, VIP-, TH+, thick myelinated fibers + or -); nerves in arterial walls (nNOS-, VIP+, TH+, thick myelinated fibers-); non-parasympathetic nerves (nNOS-, VIP-, TH+, thick myelinated fibers + or -); (although rare) pure sensory nerve candidates (nNOS-, VIP-, TH-, thick myelinated fibers+). Triple-positive nerves were 5-6 times more numerous in the paracolpium than in the periprostatic region. Usually, the parasympathetic nerve fibers did not occupy a specific site in a nerve, and were intermingled with sympathetic fibers. This morphology might be the result of an "incidentally" adopted nerve fiber route, rather than a target-specific pathway.
Hieda, Keisuke; Sasaki, Hiromasa; Murakami, Gen; Abe, Shinichi; Matsubara, Akio; Miyake, Hideaki; Fujisawa, Masato