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Sample records for repeated opioid administration

  1. Effects of repeated psychostimulant administration on the prodynorphin system activity and kappa opioid receptor density in the rat brain.

    PubMed

    Turchan, J; Przewłocka, B; Lasoń, W; Przewłocki, R

    1998-08-01

    The prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. To elucidate the activity of the endogenous prodynorphin system upon treatment with psychostimulants, we investigated the effect of single and repeated cocaine and amphetamine on the prodynorphin messenger RNA level, the prodynorphin-derived peptide alpha-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of kappa opioid receptors in those brain regions was also assessed. Rats were injected with cocaine following a "binge" administration pattern, 20 mg/kg i.p. every hour for 3 h, one (single treatment) or five days (chronic treatment). Amphetamine, 2.5 mg/kg i.p. was administered once (single treatment) or twice a day for five days (chronic treatment). As shown by an in situ hybridization study, the prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chronic (at 3 and 24 h) cocaine administration. The prodynorphin messenger RNA level in the nucleus accumbens was markedly elevated after single or repeated amphetamine administration. A similar tendency was observed in the striatum. Acute cocaine and amphetamine administration had no effect on the alpha-neoendorphin tissue level, whereas chronic administration of those drugs elevated the alpha-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on alpha-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h after drug injection. In contrast, single and chronic (at 24 and 48 h) amphetamine administration profoundly elevated the release of alpha-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10(-5)-10(-6) M) decreased the basal release of alpha-neoendorphin in the nucleus accumbens slices of naive rats, but it did not change the stimulated

  2. Opioid Prescribing After Nonfatal Overdose and Association With Repeated Overdose: A Cohort Study.

    PubMed

    Larochelle, Marc R; Liebschutz, Jane M; Zhang, Fang; Ross-Degnan, Dennis; Wharam, J Frank

    2016-01-05

    Nonfatal opioid overdose is an opportunity to identify and treat substance use disorders, but treatment patterns after the overdose are unknown. To determine prescribed opioid dosage after an opioid overdose and its association with repeated overdose. Retrospective cohort study. A large U.S. health insurer. 2848 commercially insured patients aged 18 to 64 years who had a nonfatal opioid overdose during long-term opioid therapy for noncancer pain between May 2000 and December 2012. Nonfatal opioid overdose was identified using International Classification of Diseases, Ninth Revision, Clinical Modification, codes from emergency department or inpatient claims. The primary outcome was daily morphine-equivalent dosage (MED) of opioids dispensed from 60 days before to up to 730 days after the index overdose. We categorized dosages as large (≥100 mg MED), moderate (50 to <100 mg MED), low (<50 mg MED), or none (0 mg MED). Secondary outcomes included time to repeated overdose stratified by daily dosage as a time-varying covariate. Over a median follow-up of 299 days, opioids were dispensed to 91% of patients after an overdose. Seven percent of patients (n = 212) had a repeated opioid overdose. At 2 years, the cumulative incidence of repeated overdose was 17% (95% CI, 14% to 20%) for patients receiving high dosages of opioids after the index overdose, 15% (CI, 10% to 21%) for those receiving moderate dosages, 9% (CI, 6% to 14%) for those receiving low dosages, and 8% (CI, 6% to 11%) for those receiving no opioids. The cohort was limited to commercially insured adults. Almost all patients continue to receive prescription opioids after an overdose. Opioid discontinuation after overdose is associated with lower risk for repeated overdose. Health Resources and Services Administration.

  3. Population Pharmacokinetic Modeling After Repeated Administrations of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Use Disorder.

    PubMed

    Laffont, Celine M; Gomeni, Roberto; Heidbreder, Christian; Jones, J P; Nasser, Azmi F

    2016-07-01

    RBP-6000 is a novel sustained-release formulation of buprenorphine for the treatment of opioid use disorder, which has been designed for once-monthly (28 days) subcutaneous (SC) injections. A population pharmacokinetic (PK) model was developed to describe the time course of buprenorphine plasma concentrations after repeated SC injections of RBP-6000 at 50 mg, 100 mg, 200 mg, or 300 mg in treatment-seeking opioid-dependent subjects previously on sublingual buprenorphine (Subutex(®) ) treatment. The μ-opioid receptor occupancy was predicted using a previously developed PK/PD Emax model. The results of the population PK analysis jointly with the predicted level of μ-opioid receptor occupancy provided quantitative criteria for clinical dose selection for RBP-6000: the dose of 300 mg every 28 days seems appropriate for immediately achieving an effective exposure after the first SC injection and to maintain effective levels of exposure during chronic treatment. Furthermore, simulations conducted to evaluate the potential impact of a holiday in drug intake indicated that in the unexpected event of a 2-week holiday, levels of μ-opioid receptor occupancy remained consistently above 70% with no significant loss of drug efficacy. This analysis indicated that RBP-6000 has the potential for becoming an effective treatment for opioid-dependent subjects by addressing compliance issues associated with the current once-a-day treatments.

  4. A review of opioid prescribing practices and associations with repeat opioid prescriptions in a contemporary outpatient HIV clinic.

    PubMed

    Önen, Nur F; Barrette, Ernie-Paul; Shacham, Enbal; Taniguchi, Toshibumi; Donovan, Michael; Overton, Edgar T

    2012-07-01

    Among persons in current HIV outpatient care, data on opioid prescribing are lacking. This study aims to evaluate predictors of repeat opioid prescribing and to characterize outpatient opioid prescribing practices. Retrospective cross-sectional study of persons ≥18 years in HIV outpatient care who completed an annual behavioral assessment between June 2008 and June 2009. Persons were grouped by ≤1 and ≥2 opioid prescriptions (no-repeat-opioid and repeat-opioids, respectively). Independent predictors for repeat-opioids were evaluated. Opioid prescribing practices were characterized in a sub-study of persons prescribed any opioid. Overall, 659 persons were included, median age 43 years, 70% men, and 68% African American. Independent predictors of repeat-opioids (88 [13%] persons) included opportunistic illnesses (both current and previous), depression, peripheral neuropathy, and hepatitis C coinfection (P<0.05). In the subgroup, 140 persons received any opioid prescription (96% short-acting, 33% tramadol). Indications for opioid prescribing were obtained in 101 (72%) persons, with 97% for noncancer-related pain symptoms. Therapeutic response was documented on follow-up in 67 (48%) persons, with no subjective relief of symptoms in 63%. Urine drug screens were requested in 6 (4%) persons, and all performed were positive for illicit drugs. Advanced HIV disease and greater medical and neuropsychiatric comorbidity predict repeat opioid prescribing, and these findings reflect the underlying complexities in managing pain symptoms in this population. We also highlight multiple deficiencies in opioid prescribing practices and nonadherence to guidelines, which are of concern as effective and safe pain management for our HIV-infected population is an optimal goal. © 2011 The Authors. Pain Practice © 2011 World Institute of Pain.

  5. A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids.

    PubMed

    Uekuzu, Yoshihiro; Higashiguchi, Takashi; Futamura, Akihiko; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Awa, Hiroko; Chihara, Takeshi

    2017-03-01

    There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events.

  6. Co-administration of delta- and mu-opioid receptor agonists promotes peripheral opioid receptor function

    PubMed Central

    Schramm, Cicely L.; Honda, Christopher N.

    2010-01-01

    Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of μ- and δ-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the μ- and δ-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naïve rats and on potassium-evoked release of CGRP from sciatic nerves of naïve rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally-restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another μ-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, δ-opioid receptor agonists enhance the effect of μ-opioid receptor agonists in the periphery, and local co-administration of δ- and μ-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain. PMID:20970925

  7. Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms.

    PubMed

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2017-07-01

    We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone-induced hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in MOR signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and mitogen-activated protein kinase inhibitors were coadministered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund's adjuvant was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming, and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.

  8. Retrospective Analysis of Opioid Medication Incidents Requiring Administration of Naloxone

    PubMed Central

    Neil, Katherine; Marcil, Allison; Kosar, Lynette; Dumont, Zack; Ruda, Lisa; McMillan, Kaitlyn

    2013-01-01

    Background: Opioid analgesics are high-alert medications known to cause adverse drug events. Objectives: The purpose of this study was to determine the cause of opioid incidents requiring administration of naloxone, an opioid reversal agent. The specific objectives were to determine the number of opioid incidents and the proportion of incidents documented through occurrence reporting and to characterize the incidents by phase in the medication-use process, by type of incident, and by drug responsible for toxic effects. Methods: A retrospective chart analysis was conducted using records from 2 acute care centres in the Regina Qu’Appelle Health Region. The study included inpatients who received naloxone for reversal of opioid toxicity resulting from licit, in-hospital opioid use. Cases were classified as preventable or nonpreventable. Preventable cases were analyzed to determine the phase of the medication-use process during which the incident occurred. These cases were also grouped thematically by the type of incident. The drug most likely responsible for opioid toxicity was determined for each case. The proportion of cases documented by occurrence reporting was also noted. Results: Thirty-six cases involving administration of naloxone were identified, of which 29 (81%) were deemed preventable. Of these 29 preventable cases, the primary medication incident occurred most frequently in the prescribing phase (23 [79%]), but multiple phases were often involved. The cases were grouped into 6 themes according to the type of incident. Morphine was the drug that most frequently resulted in toxic effects (18 cases [50%]). Only two of the cases (5.6%) were documented by occurrence reports. Conclusion: Preventable opioid incidents occurred in the acute care centres under study. A combination of medication safety initiatives involving multiple disciplines may be required to decrease the incidence of these events and to better document their occurrence. PMID:24159230

  9. A history of neuraxial administration of local analgesics and opioids.

    PubMed

    Brill, S; Gurman, G M; Fisher, A

    2003-09-01

    The history of intrathecal and epidural anaesthesia is in parallel with the development of general anaesthesia. As ether anaesthesia (1846) is considered the first modern anaesthetic since its use by Morton 157 yr ago, so Bier made history by using cocaine for intrathecal anaesthesia in 1898. The first published report on opioids for intrathecal anaesthesia belongs to a Romanian surgeon, Racoviceanu-Pitesti, who presented his experience at Paris in 1901. It was almost a century before the opioids were used for epidural analgesia. Behar and his colleagues published the first report on the epidural use of morphine for the treatment of pain in The Lancet in 1979. Epidural and intrathecal opioids are today part of a routine regimen for intra- and postoperative analgesia. Over the last 30 yr, the use of epidural opioids has became a standard for analgesia in labour and delivery, and for the management of chronic pain. Finally, epidural opioids have been shown to have a pre-emptive effect, when used before major surgery. We present the evolution of neuraxial anaesthesia and the history of intrathecal and epidural administration of opioids.

  10. Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

    PubMed Central

    Araldi, Dioneia; Ferrari, Luiz F.

    2015-01-01

    The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. SIGNIFICANCE STATEMENT The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids. PMID:26354917

  11. Opioid analgesic administration in patients with suspected drug use.

    PubMed

    Kreling, Maria Clara Giorio Dutra; Mattos-Pimenta, Cibele Andrucioli de

    2017-01-01

    To identify the prevalence of patients suspected of drug use according to the nursing professionals' judgement, and compare the behavior of these professionals in opioid administration when there is or there is no suspicion that patient is a drug user. A cross-sectional study with 507 patients and 199 nursing professionals responsible for administering drugs to these patients. The Chi-Square test, Fisher's Exact and a significance level of 5% were used for the analyzes. The prevalence of suspected patients was 6.7%. The prevalence ratio of administration of opioid analgesics 'if necessary' is twice higher among patients suspected of drug use compared to patients not suspected of drug use (p = 0.037). The prevalence of patients suspected of drug use was similar to that of studies performed in emergency departments. Patients suspected of drug use receive more opioids than patients not suspected of drug use. Identificar a prevalência de pacientes com suspeita de uso de drogas conforme opinião de profissionais de enfermagem e comparar a conduta desses profissionais na administração de opioides quando há ou não suspeita de que o paciente seja usuário de drogas. Estudo transversal com 507 pacientes e 199 profissionais de enfermagem responsáveis pela administração de medicamentos a esses pacientes. Para as análises foram utilizados os testes de Qui-Quadrado, Exato de Fisher e um nível de significância de 5%. A prevalência de pacientes suspeitos foi 6,7%. A razão de prevalência de administração de analgésicos opioides "se necessário" é duas vezes maior entre os pacientes suspeitos em relação aos não suspeitos (p=0,037). A prevalência de suspeitos foi semelhante à de estudos realizados em departamentos de emergência. Os suspeitos de serem usuários de drogas recebem mais opioides do que os não suspeitos.

  12. Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-α up-regulation in the sciatic nerve of rats with neuropathic pain

    PubMed Central

    Vicario, Nunzio; Parenti, Rosalba; Aricò, Giuseppina; Turnaturi, Rita; Scoto, Giovanna Maria; Chiechio, Santina

    2016-01-01

    Despite mu opioid receptor agonists are the cornerstones of moderate-to-severe acute pain treatment, their effectiveness in chronic pain conditions is controversial. In contrast to mu opioid receptor agonists, a number of studies have reported the effectiveness of delta opioid receptor agonists on neuropathic pain strengthening the idea that delta opioid receptors gain importance when chronic pain develops. Among other effects, it has been shown that delta opioid receptor activation in optic nerve astrocytes inhibits tumor necrosis factor-α-mediated inflammation in response to severe hypoxia. Considering the involvement of tumor necrosis factor-α in the development and maintenance of neuropathic pain, with this study we sought to correlate the effect of delta opioid receptor agonist on the development of mechanical allodynia to tumor necrosis factor-α expression at the site of nerve injury in rats subjected to chronic constriction injury of the sciatic nerve. To this aim, we measured the levels of tumor necrosis factor-α in the sciatic nerve of rats with neuropathic pain after repeated injections with a delta opioid receptor agonist. Results obtained demonstrated that repeated administrations of the delta opioid receptor agonist SNC80 (10 mg/kg, i.p. for seven consecutive days) significantly inhibited the development of mechanical allodynia in rats with neuropathic pain and that the improvement of neuropathic symptom was timely related to the reduced expression of tumor necrosis factor-α in the rat sciatic nerve. We demonstrated also that when treatment with the delta opioid receptor agonist was suspended both allodynia and tumor necrosis factor-α up-regulation in the sciatic nerve of rats with neuropathic pain were restored. These results show that persistent delta opioid receptor activation significantly attenuates neuropathic pain and negatively regulates sciatic nerve tumor necrosis factor-α expression in chronic constriction injury rats. PMID:27590071

  13. Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors.

    PubMed

    Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D; Carlton, Susan M; Walker, Brendan M; Bruchas, Michael R; Morón, Jose A

    2015-09-02

    Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid

  14. Effects exerted by otilonium bromide administration on precipitated opioid withdrawal syndrome in rats.

    PubMed

    Pinelli, A; Trivulzio, S; Vignati, S

    1997-09-26

    An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to prevent the altered physiological profiles by utilising otilonium bromide. Morphine was administered in three daily i.p. injections for 4 days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day). Naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Otilonium bromide was administered orally at 0, 2, 4 and 8 mg/kg, 120 min before the naloxone administration. Signs like faecal and urine excretion, rectal temperature and pain threshold levels, salivation, jumping and wet dog shakes were affected in different ways. Notably the administration of otilonium bromide in rats receiving morphine together with naloxone decreased the intensity of certain withdrawal symptoms, such as excretion of faeces, wet dog shake behaviour, and elevated the nociceptive threshold values. The effects exhibited by otilonium bromide administration may be explained through its calcium antagonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of some acute opioid withdrawal signs in heroin addicts.

  15. Assessment of the appropriateness of naloxone administration to patients receiving long-term opioid therapy.

    PubMed

    Facey, Caroline; Brooks, David; Boland, Jason W

    2016-01-01

    The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain. To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy. This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included. A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group. No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

  16. Opioid disposition in human sweat after controlled oral codeine administration.

    PubMed

    Schwilke, Eugene W; Barnes, Allan J; Kacinko, Sherri L; Cone, Edward J; Moolchan, Eric T; Huestis, Marilyn A

    2006-08-01

    Characterization of opioid excretion in sweat is important for accurate interpretation of sweat tests in drug treatment, criminal justice, and workplace drug testing programs. Participants (n=20) received placebo, 3 low (60 mg/70 kg) or 3 high (120 mg/70 kg) codeine sulfate doses (used as a model for opioid excretion) within 1 week. Codeine and metabolites in sweat were collected with PharmChek Sweat Patches; hourly patches were applied for 1 to 15 h (n=775) and weekly patches for 7 days (n=118). Patches were analyzed by solid-phase extraction and gas chromatography-mass spectrometry for codeine, norcodeine, morphine, normorphine, and 6-acetylmorphine. Limits of quantification were 2.5 ng/patch (codeine and morphine) and 5 ng/patch (other analytes). Codeine was the only analyte identified in 12.6% of hourly patches and 83.3% of weekly sweat patches worn during dosing. Weekly patch concentrations (SD) were 38.6 (59.9) ng/patch [median (range), 15.9 (0-225.1) ng/patch] for low and 34.1 (32.7) ng/patch [24.0 (0-96.2) ng/patch] for high codeine doses. Codeine detected 1 week after dosing was 4.6 (5.3) ng/patch [median (range), 4.0 (0-17.1) ng/patch; n=11] after low and 7.7 (7.1) ng/patch [6.9 (0-20.5) ng/patch; n=10] after high doses. In total, 2.6% of hourly, 38.5% of low-dose, and 45.5% of high-dose weekly patches contained codeine at the proposed Substance Abuse and Mental Health Services Administration cutoff. Codeine was the only analyte detected, at highly variable concentrations, up to 2 weeks after dosing. These results are consistent, considering the complex processes of codeine deposition in sweat. Sweat testing is a useful alternative technique for qualitative monitoring of opioid use.

  17. Morphine Analgesia Modification in Normotensive and Hypertensive Female Rats after Repeated Fluoxetine Administration.

    PubMed

    Kosiorek-Witek, Anna; Makulska-Nowak, Helena Elżbieta

    2016-01-01

    The purpose of this investigation was to determine through the use of fluoxetine the effect of administering a serotonin reuptake inhibitor over several days on the antinociceptive action of μ-morphine type opioid receptor agonist. Investigations were performed on rats of both sexes, both the WKY normotensive strains as well as on the SHR genetically conditioned hypertensive strains. Results showed that the efficacy of morphine analgesia is higher in the SHR strain compared to normotensive rats (WKY). Surprisingly, repeated administration of fluoxetine reduced morphine analgesia, with the weakening of opioid antinociceptive action comparable to the duration of serotonin reuptake inhibitor administration. It was also concluded that the antinociceptive action of morphine in female rats and the alteration of its efficacy as a result of fluoxetine premedication for several days depend on oestrus cycle phase. The highest sensitivity of female rats to morphine was reported in the dioestrus and oestrus phases; much lower values were reported for the metoestrus phase.

  18. Opioid Abuse after TBI

    DTIC Science & Technology

    2014-07-01

    experiments to evaluate the hypothesis that TBI causes changes in the analgesic response to opioids following acute and repeated drug administration...behaviors and may induce alteration in the brain reward, particularly expression of the dopamine receptor subtype 2. All studies are on-going...TBI causes changes in the analgesic response to opioids following acute and repeated drug administration. Aim 2: Investigate the hypothesis that

  19. Characterization of prescription opioid abuse in the United States: focus on route of administration.

    PubMed

    Kirsh, Kenneth; Peppin, John; Coleman, John

    2012-12-01

    Prescription opioids are prescribed increasingly for the management of chronic pain, and this has been accompanied by a dramatic rise in opioid-related abuse, addiction, and overdose deaths. Reports of abuse involving nonoral administration (e.g., snorting, injecting) of prescription opioids are increasing, although the epidemiology of oral versus nonoral abuse is not well understood. Available data indicate that oral abuse is far more common,with 72% to 97% of opioid abusers perferring oral administration. Factors associated with nonoral administration include longer duration of opioid abuse, male gender, and rural setting. Extended-release opioids, because of their relatively high drug load, may be attractive to experienced abusers seeking to manipulate the formulation to facilitate a rapid onset of effect. Putative abuse-deterrent formulations have been developed to decrease the likelihood or consequences of nonoral abuse. In addition, Risk Evaluation and Mitigation Strategies (REMS) are now required for prescribed extended-release/long-acting opioids by the US Food and Drug Administration, although their effectiveness in reducing the risk of abuse, addiction, and overdose has not been evaluated. Physicians should remain vigilant when prescribing opioids and should exercise appropriate patient selection, perform risk analysis and stratification, and maintain continuous patient monitoring to ensure the benefits outweigh these important risks.

  20. Perioperative opioid administration in children with and without developmental delay undergoing outpatient dental surgery.

    PubMed

    Conner, Erin R; Musser, Erica D; Colpitts, Kelsey M; Laochamroonvorapongse, Dean L; Koh, Jeffrey L

    2017-02-01

    Prior research has indicated that children with developmental delay (DD) experience qualitative and quantitative differences in health care (Boulet et al., 2009). In the perioperative setting, there is concern that children with DD may be more likely to experience postoperative complications including agitation and nausea/vomiting than typically developing patients (TDP). Differences in the administration and dosage of perioperative opioids may contribute to this, however, empirical investigations are lacking. The purpose of this research was to compare the experience of postoperative nausea/vomiting and agitation, as well as to examine perioperative opioid administration, among children with DD as compared to TDP. Retrospective original research. Operating room, postanesthesia care unit. 1145 patients (1-20.9years, ASA I-III, 23.9% with a history of DD) who had undergone outpatient dental surgery involving extraction/restorations under general anesthesia. Data was obtained and analyzed from the medical records of both DD and TDP across a five-year period. Data included the experience of agitation, nausea/vomiting, as well as perioperative medication administration. Postoperative agitation and nausea/vomiting did not differ significantly between the DD and TDP groups. Children with DD were significantly less likely to receive opioids during both the intra and postoperative period (χ(2)=10.02, p=0.001 and χ(2)=8.08, p=0.003, respectively). Further, higher dosage of intraoperative opioids was predictive of reduced administration of postoperative opioids among TDP; however, no significant association was observed between the dosage of intraoperative opioids and administration of postoperative opioids in the DD group. Children with DD experience similar rates of postoperative complications including nausea/vomiting and agitation as TDP. DD children were less likely to receive both intra and postoperative opioids than TDP. Importantly, while the dosage of

  1. T394A Mutation at the μ Opioid Receptor Blocks Opioid Tolerance and Increases Vulnerability to Heroin Self-Administration in Mice.

    PubMed

    Wang, Xiao-Fei; Barbier, Elisabeth; Chiu, Yi-Ting; He, Yi; Zhan, Jia; Bi, Guo-Hua; Zhang, Hai-Ying; Feng, Bo; Liu-Chen, Lee-Yuan; Wang, Jia Bei; Xi, Zheng-Xiong

    2016-10-05

    The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine. In addition, this mutation also caused an increase in intravenous heroin self-administration and in nucleus accumbens dopamine response to heroin. These findings suggest that T394 phosphorylation following MOR activation causes MOR internalization and desensitization, which subsequently contributes to the development of tolerance in both opioid analgesia and opioid reward. Accordingly, T394A mutation blocks opioid tolerance and leads to an increase in brain dopamine response to opioids and in opioid-taking behavior. Thus, the T394 may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction.

  2. Chronic very low dose naltrexone administration attenuates opioid withdrawal expression.

    PubMed

    Mannelli, Paolo; Gottheil, Edward; Peoples, James F; Oropeza, Veronica C; Van Bockstaele, Elisabeth J

    2004-08-15

    Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression. Forty-one male Sprague-Dawley rats were implanted with morphine or placebo pellets for eight days. Starting on day 3, some rats received naltrexone in their drinking water (5 mg/L), or unadulterated water. On day 8, rats were injected with saline or naltrexone (100 mg/kg) and evaluated for behavioral signs of withdrawal. Next, sections through the locus coeruleus (LC) and nucleus of the solitary tract (NTS), brainstem areas exhibiting cellular activation following opiate withdrawal, were processed for c-Fos to detect early gene expression. Finally, the same nuclei were examined for protein kinase A regulatory subunit II (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), using Western blot analysis. Withdrawal was attenuated and c-Fos, PKA, and pCREB expression was decreased in the NTS and LC of rats receiving chronic very low doses of naltrexone. Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.

  3. Alternate Routes of Administration and Risk for HIV among Prescription Opioid Abusers

    PubMed Central

    Surratt, Hilary; Kurtz, Steven P.; Cicero, Theodore J

    2012-01-01

    Route of administration is an important contributor to the adverse health consequences of prescription medication abuse. The present study examines characteristics associated with non-oral routes of administration among a large sample of prescription opioid abusers, and explores needle related HIV risk behaviors as well. 791 opioid abusers completed a one-time, structured interview including complete histories of illicit and prescription drug abuse, and route of drug administration. The most common method of pill use was oral (91%), followed by intranasal (53.1%), injection (23.8%), and smoking (14.5%). The youngest prescription opioid abusers, ages 18–24, displayed significantly higher odds of employing alternate route of administration, and also of re-using nonsterile needles for injection. HIV prevention programming should be developed for young prescription opioid injectors. PMID:22026525

  4. Patterns of opioid use for chronic noncancer pain in the Veterans Health Administration from 2009 to 2011.

    PubMed

    Edlund, Mark J; Austen, Mark A; Sullivan, Mark D; Martin, Bradley C; Williams, James S; Fortney, John C; Hudson, Teresa J

    2014-11-01

    Although opioids are frequently prescribed for chronic noncancer pain (CNCP) among Veterans Health Administration (VHA) patients, little has been reported on national opioid prescribing patterns in the VHA. Our objective was to better characterize the dosing and duration of opioid therapy for CNCP in the VHA. We analyzed national VHA administrative and pharmacy data for fiscal years 2009 to 2011. For individuals with CNCP diagnoses and any opioid use in the fiscal year, we calculated the distribution of individual mean daily opioid dose, individual total days covered with opioids in a year, and individual total opioid dose in a year. We also investigated the factors associated with being in the top 5% of individuals for total opioid dose in a year, which we term receipt of high-volume opioids. About half of the patients with CNCP received opioids in a given fiscal year. The median daily dose was 21 mg morphine equivalents. Approximately 4.5% had a mean daily dose higher than 120 mg morphine equivalents. The median days covered in a year was 115 to 120 days in these years for those receiving opioids. Fifty-seven percent had at least 90 days covered with opioids per year. Major depression and posttraumatic stress disorder were positively associated with receiving high-volume opioids, but nonopioid substance use disorders were not. Among VHA patients with CNCP, chronic opioid therapy occurs frequently, but for most patients, the average daily dose is modest. Doses and duration of therapy were unchanged from 2009 to 2011.

  5. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.

    PubMed

    Zedler, Barbara; Xie, Lin; Wang, Li; Joyce, Andrew; Vick, Catherine; Kariburyo, Furaha; Rajan, Pradeep; Baser, Onur; Murrelle, Lenn

    2014-11-01

    Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids. Wiley Periodicals, Inc.

  6. Opioid administration following spinal cord injury: Implications for pain and locomotor recovery

    PubMed Central

    Woller, Sarah A.; Hook, Michelle A.

    2013-01-01

    Approximately one-third of people with a spinal cord injury (SCI) will experience persistent neuropathic pain following injury. This pain negatively affects quality of life and is difficult to treat. Opioids are among the most effective drug treatments, and are commonly prescribed, but experimental evidence suggests that opioid treatment in the acute phase of injury can attenuate recovery of locomotor function. In fact, spinal cord injury and opioid administration share several common features (e.g. central sensitization, excitotoxicity, aberrant glial activation) that have been linked to impaired recovery of function, as well as the development of pain. Despite these effects, the interactions between opioid use and spinal cord injury have not been fully explored. A review of the literature, described here, suggests that caution is warranted when administering opioids after SCI. Opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain, decrease locomotor recovery, and leave individuals at risk for infection. Considering these negative implications, it is important that guidelines are established for the use of opioids following spinal cord and other central nervous system injuries. PMID:23501709

  7. U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.

    PubMed

    Schenk, S; Partridge, B; Shippenberg, T S

    1999-06-01

    Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.

  8. Antinociceptive effects of tramadol in co-administration with metamizol after single and repeated administrations in rats.

    PubMed

    Moreno-Rocha, Luis Alfonso; Domínguez-Ramírez, Adriana Miriam; Cortés-Arroyo, Alma Rosa; Bravo, Guadalupe; López-Muñoz, Francisco Javier

    2012-11-01

    Combinations of two analgesic drugs of the same or different class are widely used in clinical therapy to enhance its antinociceptive effects and reduce the side effects. In order to evaluate a possible antinociceptive synergistic interaction of metamizol s.c., a nonsteroidal antiinflammatory drug (NSAID), and tramadol s.c., an atypical opioid (opioid receptor agonist), were administered alone or in combination. In the present study, the antinociceptive efficacy and the possible development of pharmacological tolerance produced by the combination tramadol plus metamizol during a 4-day treatment in rats using the plantar test was evaluated. Male Wistar rats were s.c. injected with tramadol (17.8 mg/kg), metamizol (177.8 mg/kg) or the combination tramadol plus metamizol three times a day for 4 days. Both metamizol and tramadol produced antinociceptive effects with a low rate trend towards tolerance development at the end of the treatment. The antinociceptive efficacy of tramadol and metamizol co-administration gradually decreased after the second injection. These data suggest that when the combination is given in a unique administration it results in an important potentiation of their individual antinociceptive effects. But, the repeated coadministration of tramadol plus metamizol results in a development of tolerance.

  9. Receipt of Prescription Opioids in a National Sample of Pregnant Veterans Receiving Veterans Health Administration Care.

    PubMed

    Kroll-Desrosiers, Aimee R; Skanderson, Melissa; Bastian, Lori A; Brandt, Cynthia A; Haskell, Sally; Kerns, Robert D; Mattocks, Kristin M

    2016-01-01

    A growing number of reproductive-age women veterans are returning from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). In 2010, 42% of women veterans receiving Veterans Health Administration (VHA) services were aged 18 to 45. Prescription opioid use has increased among all veterans over the past decade; however, exposure among pregnant veterans has not been examined. We identified 2,331 women who delivered babies within the VHA system between 2001 and 2010. Delivery, opioid prescribing history, and demographic and health-related variables were obtained from a national database of veterans receiving VHA services. Receipt of an opioid prescription was defined as any filled VHA prescription for opioids in the 280-day pregnancy window before delivery. We developed a multivariable logistic regression model adjusted for sociodemographic, service-related, psychiatric diagnosis, and physical health variables to examine the odds of filling an opioid prescription during the pregnancy window. Ten percent of pregnant veterans received VHA prescription opioids during their pregnancy window. Significant factors associated with opioid prescriptions included presence of any psychiatric diagnosis (adjusted odds ratio [aOR], 1.67; 95% CI, 1.24-2.26), diagnosis of back problems (aOR, 2.94; 95% CI, 1.92-4.49), or other nontraumatic joint disorders (aOR, 2.20; 95% CI, 1.36-3.58). This study suggests that a substantial proportion of women veterans received VHA prescriptions for opioids during pregnancy. Providers should be aware of the potential risks of prescription opioid use during pregnancy, assess for potential undertreatment of psychiatric diagnoses, and consider alternate pain management strategies when possible. Published by Elsevier Inc.

  10. Repeated administration of adenosine increases its cardiovascular effects in rats.

    PubMed

    Vidrio, H; García-Márquez, F; Magos, G A

    1987-01-20

    Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

  11. Effect of opioid administration on cardiorespiratory and muscle oxygenation during lifting in chronic back pain patients.

    PubMed

    Bhambhani, Yagesh; Gross, Douglas P; Haykowsky, Mark; Rashiq, Saifudin

    2010-05-01

    The objectives of this study were to examine the effects of opioid administration on the acute cardiorespiratory and muscle oxygenation responses during a repetitive lifting and lowering test (RLL) to voluntary fatigue in participants with chronic low back pain (LBP). Written informed consent was obtained from 27 LBP participants (mean age 50.9 +/- 16.4 years) who completed one testing session during which they were administered a saline placebo and opioid (1 microg/kg of fentanyl intravenously) in random order. The participants performed the RLL at a rate that they felt that they could sustain for an 8-h working day. Acute opioid administration increased the total lifting time and total work done during RLL by 35 and 48%, respectively (p < 0.05). However, the increased work capacity was accompanied by a significant (p < 0.05) increase in oxygen cost of 22% per unit amount of work done and significant (p < 0.05) increases in heart rate (7%) and ventilation rate (10%). Near infrared spectroscopic analysis of erector spinae oxygenation and blood volume responses during RLL indicated no significant (p > 0.05) differences between the opioid and placebo phases. These findings suggest that the increased energy cost of lifting as a result of opioid administration was due to enhanced central oxygen transport and not peripheral muscle oxygen extraction.

  12. Trends and regional variation in opioid overdose mortality among Veterans Health Administration patients, fiscal year 2001 to 2009.

    PubMed

    Bohnert, Amy S B; Ilgen, Mark A; Trafton, Jodie A; Kerns, Robert D; Eisenberg, Anna; Ganoczy, Dara; Blow, Frederic C

    2014-07-01

    Opioid-related mortality has increased in the United States in the past decade. The purpose of this study was to examine trends and regional variation in opioid prescribing and overdose rates in a national health system, the Veterans Health Administration. Annual cohorts of Veterans Health Administration patients were identified on the basis of medical records, and overdose mortality was determined from National Death Index records. State-level prescribing and overdose rates were mapped to provide information on regional variability. There were significant increases between 2001 and 2009 in the rate of overdoses associated with nonsynthetic opioids (β=0.53, 95% confidence interval, 0.35, 0.70) and methadone (β=0.63, 95% confidence interval, 0.37, 0.90) but not synthetic/semisynthetic opioids. State-level overdose rates had a moderate correlation with the average proportion of patients in that state receiving opioids (r=0.29). The present study demonstrates that the increases in prescription opioid overdoses observed in the general population are also found in the patient population of a national health system and provides further evidence of the population-level association between trends in opioid prescribing and opioid overdose deaths. There is substantial regional variation in both opioid prescribing and opioid-related overdose rates, and these data can inform region-specific overdose prevention strategies and opioid policy.

  13. Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats.

    PubMed

    Moreno-Rocha, Luis Alfonso; López-Muñoz, Francisco Javier; Medina-López, José Raúl; Domínguez-Ramírez, Adriana Miriam

    2016-11-01

    Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P < 0.05). Nevertheless, this effect decreased about 53% after the chronic treatment (3 doses per day, for 4 days). No pharmacokinetic interaction between metamizol and tramadol was found under acute treatment (P > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites' pharmacokinetics (P < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

  14. Effects of fentanyl administration on locomotor response in horses with the G57C μ-opioid receptor polymorphism.

    PubMed

    Wetmore, Lois A; Pascoe, Peter J; Shilo-Benjamini, Yael; Lindsey, Jane C

    2016-08-01

    OBJECTIVE To determine the locomotor response to the administration of fentanyl in horses with and without the G57C polymorphism of the μ-opioid receptor. ANIMALS 20 horses of various breeds and ages (10 horses heterozygous for the G57C polymorphism and 10 age-, breed-, and sex-matched horses that did not have the G57C polymorphism). PROCEDURES The number of steps each horse took was counted over consecutive 2-minute periods for 20 minutes to determine a baseline value. The horse then received a bolus of fentanyl (20 μg/kg, IV), and the number of steps was again counted during consecutive 2-minute periods for 60 minutes. The mean baseline value was subtracted from each 2-minute period after fentanyl administration; step counts with negative values were assigned a value of 0. Data were analyzed by use of a repeated-measures ANOVA. RESULTS Data for 19 of 20 horses (10 horses with the G57C polymorphism and 9 control horses without the G57C polymorphism) were included in the analysis. Horses with the G57C polymorphism had a significant increase in locomotor activity, compared with results for horses without the polymorphism. There was a significant group-by-time interaction. CONCLUSIONS AND CLINICAL RELEVANCE Horses heterozygous for the G57C polymorphism of the μ-opioid receptor had an increased locomotor response to fentanyl administration, compared with the response for horses without this polymorphism. The clinical impact of this finding should be investigated.

  15. Intranasal oxycodone self-administration in non-dependent opioid abusers

    PubMed Central

    Middleton, L.S.; Lofwall, M.R.; Nuzzo, P.A.; Siegel, A.; Walsh, S.L.

    2013-01-01

    Oxycodone, an opioid with known abuse liability, is misused by the intranasal route. Our objective was to develop a model of intranasal oxycodone self-administration useful for assessing the relative reinforcing effects of opioids and potential pharmacotherapies for opioid use disorders. Healthy, sporadic intranasal opioid abusers (n=8; 7 M, 1 F) completed this inpatient 2.5-week, randomized, double blind, placebo-controlled, crossover study. Each intranasal oxycodone dose (0, 14 & 28 mg) was tested in a separate 3-day block of sessions. The first day of each block was a sample session in which the test dose was given. Two randomized progressive ratio sessions were conducted on the next 2 days: 1) subjects could work for the test dose over 7 trials (1/7th of total dose/trial), and 2) subjects could work for either a portion of the dose (1/7th) or money ($3) over 7 trials. Physiological and subjective measures were collected before and after drug administration for all sessions. Subjects never worked to self-administer placebo regardless of whether money was available. In both self-administration sessions, oxycodone self-administration was dose-dependent. Subjects worked less for drug (28 mg oxycodone) when money was available, but only modestly so. Oxycodone dose-dependently increased VAS ratings of positive drug effects (e.g., ‘like’) during sample sessions (p<0.05). These reports were positively correlated with self-administration behavior (e.g., ‘like’, r=0.65). These data suggest that both procedures are sensitive for detecting the reinforcing properties of intranasal oxycodone and may be employed to further explore the characteristics of opioid compounds and potential pharmacotherapies for treatment. PMID:22686495

  16. Intranasal oxycodone self-administration in non-dependent opioid abusers.

    PubMed

    Middleton, Lisa S; Lofwall, Michelle R; Nuzzo, Paul A; Siegel, Anthony J; Walsh, Sharon L

    2012-08-01

    Oxycodone, an opioid with known abuse liability, is misused by the intranasal route. Our objective was to develop a model of intranasal oxycodone self-administration useful for assessing the relative reinforcing effects of opioids and potential pharmacotherapies for opioid use disorders. Healthy, sporadic intranasal opioid abusers (n = 8; 7 M, 1 F) completed this inpatient 2.5-week, randomized, double-blind, placebo-controlled, crossover study. Each intranasal oxycodone dose (0, 14 & 28 mg) was tested in a separate 3-day block of sessions. The first day of each block was a sample session in which the test dose was given. Two randomized progressive ratio sessions were conducted on the next 2 days: (1) subjects could work for the test dose over 7 trials (1/7th of total dose/trial), and (2) subjects could work for either a portion of the dose (1/7th) or money ($3) over 7 trials. Physiological and subjective measures were collected before and after drug administration for all sessions. Subjects never worked to self-administer placebo regardless of whether money was available. In both self-administration sessions, oxycodone self-administration was dose-dependent. Subjects worked less for drug (28 mg oxycodone) when money was available but only modestly so. Oxycodone dose-dependently increased VAS ratings of positive drug effects (e.g., "like") during sample sessions (p < .05). These reports were positively correlated with self-administration behavior (e.g., "like," r = .65). These data suggest that both procedures are sensitive for detecting the reinforcing properties of intranasal oxycodone and may be used to further explore the characteristics of opioid compounds and potential pharmacotherapies for treatment.

  17. Opioid overdose education and naloxone distribution: Development of the Veterans Health Administration's national program.

    PubMed

    Oliva, Elizabeth M; Christopher, Melissa L D; Wells, Daina; Bounthavong, Mark; Harvey, Michael; Himstreet, Julianne; Emmendorfer, Thomas; Valentino, Michael; Franchi, Mariano; Goodman, Francine; Trafton, Jodie A

    To prevent opioid-related mortality, the Veterans Health Administration (VHA) developed a national Opioid Overdose Education and Naloxone Distribution (OEND) program. VHA's OEND program sought national implementation of OEND across all medical facilities (n = 142). This paper describes VHA's efforts to facilitate nationwide health care system-based OEND implementation, including the critical roles of VHA's national pharmacy services and academic detailing services. VHA is the first large health care system in the United States to implement OEND nationwide. Launching the national program required VHA to translate a primarily community-based public health approach to OEND into a health care system-based approach that distributed naloxone to patients with opioid use disorders as well as to patients prescribed opioid analgesics. Key innovations included developing steps to implement OEND, pharmacy developing standard naloxone rescue kits, adding those kits to the VHA National Formulary, centralizing kit distribution, developing clinical guidance for issuing naloxone kits, and supporting OEND as a focal campaign of academic detailing. Other innovations included the development of patient and provider education resources (e.g., brochures, videos, accredited training) and implementation and evaluation resources (e.g., technical assistance, clinical decision support tools). Clinical decision support tools that leverage VHA national data are available to clinical staff with appropriate permissions. These tools allow staff and leaders to evaluate OEND implementation and provide actionable next steps to help them identify patients who could benefit from OEND. Through fiscal year 2016, VHA dispensed 45,178 naloxone prescriptions written by 5693 prescribers to 39,328 patients who were primarily prescribed opioids or had opioid use disorder. As of February 2, 2016, there were 172 spontaneously reported opioid overdose reversals with the use of VHA naloxone prescriptions. VHA

  18. Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths.

    PubMed

    Rando, Jessica; Broering, Derek; Olson, James E; Marco, Catherine; Evans, Stephen B

    2015-09-01

    This study sought to answer the question, "Can police officers administer intranasal naloxone to drug overdose victims to decrease the opioid overdose death rate?" This prospective interventional study was conducted in Lorain County, OH, from January 2011 to October 2014. Starting October 2013, trained police officers administered naloxone to suspected opioid overdose victims through a police officer naloxone prescription program (NPP). Those found by the county coroner to be positive for opioids at the time of death and those who received naloxone from police officers were included in this study. The rate of change in the total number of opioid-related deaths in Lorain County per quarter year, before and after initiation of the NPP, and the trend in the survival rate of overdose victims who were given naloxone were analyzed by linear regression. Significance was established a priori at P < .05. Data from 247 individuals were eligible for study inclusion. Opioid overdose deaths increased significantly before initiation of the police officer NPP with average deaths per quarter of 5.5 for 2011, 15.3 for 2012, and 16.3 for the first 9 months of 2013. After initiation of the police officer NPP, the number of opioid overdose deaths decreased each quarter with an overall average of 13.4. Of the 67 participants who received naloxone by police officers, 52 (77.6%) survived, and 8 (11.9%) were lost to follow-up. Intranasal naloxone administration by police first responders is associated with decreased deaths in opioid overdose victims. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Central administration of metastin increases food intake through opioid neurons in chicks.

    PubMed

    Khan, Md Sakirul Islam; Ohkubo, Takeshi; Masuda, Naoto; Tachibana, Tetsuya; Ueda, Hiroshi

    2009-06-01

    Metastin, an RFamide peptide, has been isolated from human placenta and possesses several physiological actions in mammals. However, little is known about this bioactive peptide in avian species. This study was conducted to assess the effect of metastin on feeding behavior of chicks (Gallus gallus). The food intake of chicks is significantly increased by the intracerebroventricular injection of metastin. Beta-funaltrexamine, a mu-opioid receptor antagonist, significantly attenuates metastin-induced food intake in chicks. In contrast, delta- and kappa-opioid receptor antagonists did not show any influence on metastin-induced food intake in chicks. In addition, administration of N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence metastin-induced food intake. Taken together, this study shows the orexigenic effect of metastin in chicks and suggests that this effect is mediated by mu-opioid receptor.

  20. Long-term effect of morphine administration in young rats on the analgesic opioid response in adult life.

    PubMed

    Rozisky, Joanna Ripoll; Dantas, Giovana; Adachi, Lauren Spezia; Alves, Viviane Soares; Ferreira, Maria Beatriz Cardoso; Sarkis, João José Freitas; Torres, Iraci Lucena Da Silva

    2008-10-01

    Neonates, infants and children are often exposed to pain from invasive procedures during intensive care and during the post-operative period. Opioid anesthesia and post-operative opioid analgesia have been used in infants and result in clinical benefits. The objectives of this study were to verify the effect of repeated 5 microg morphine administration (subcutaneous), once a day for 7 days in 8-day-old rats, at P8 until P14. To verify the long-term effect of morphine, the animals were submitted to a second exposure of 5mg/kg (intraperitoneal) of morphine at P80 until P86. Animals that received morphine for 7 days, at P14 did not develop tolerance, however at P80, rats demonstrated greater morphine analgesia. At P86, after 7 days of morphine administration, animals showed classical tolerance. These findings may have important implications for the human neonate, suggesting a possible explanation for the differences in the requirements of morphine observed in the youngest patients.

  1. Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration.

    PubMed

    Green, Jody L; Bucher Bartelson, Becki; Le Lait, M Claire; Roland, Carl L; Masters, Elizabeth T; Mardekian, Jack; Bailey, J Elise; Dart, Richard C

    2017-06-01

    Prescription opioid abuse and misuse is a serious and growing public health issue. While the most common form of abuse is swallowing intact tablets/capsules, some abusers manipulate, or tamper with, these medications by altering the dosage form to allow for non-oral routes of administration (e.g., injection, inhalation) in order to achieve more rapid or enhanced psychoactive effects. Because administration of opioids via non-oral routes results in greater systemic availability and more rapid central nervous system penetration, we hypothesized that death and major medical outcomes occur more frequently with non-oral routes compared to oral route alone. This retrospective cohort study analyzed data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center Program to investigate relative risk of prescription opioid abuse via oral and non-oral routes. While the oral route was the most commonly reported route of abuse (64.0%), non-oral routes were reported in 14.6% exposures and unknown routes in 21.4% exposures. The relative risk of an exposure resulting in death or major effect was 2.43 (95% CI 1.97, 2.99) if non-oral routes were reported compared to exposures involving oral route only. Analysis of acute health events recorded by poison centers indicates that death or major effects are twice as likely to occur with intentional abuse of prescription opioids via non-oral routes of administration than ingestion alone. Effective interventions to prevent abuse via non-oral routes of solid dosage forms of prescription opioids, such as abuse-deterrent formulations could have a significant public health impact. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Systemic and spinal administration of the mu opioid, remifentanil, produces antinociception in amphibians.

    PubMed

    Mohan, Shekher; Stevens, Craig W

    2006-03-18

    Remifentanil is a relatively new opioid analgesic related to the fentanyl family of mu opioid receptor agonists and is used clinically for its unique property of having an ultra-short duration of action. However, there is little preclinical data on the analgesic (antinociceptive) effects of remifentanil and none obtained in non-mammalian animal models. The antinociceptive effects of remifentanil were assessed by using the acetic acid test in amphibians. Systemic and spinal administration of remifentanil was made by subcutaneous and intraspinal injections in the Northern grass frog, Rana pipiens. After administration, remifentanil produced dose-dependent and long-lasting antinociceptive effects which persisted for five hours after systemic administration but gave a shorter duration of action after spinal delivery. The antinociceptive effects of remifentanil were significantly blocked by pretreatment with systemic naltrexone. Systemic and spinal administration of remifentanil produced log dose-response curves which yielded ED50 values of 7.1 nmol/g and 3.2 nmol/animal respectively. The relative antinociceptive potency of remifentanil compared to other opioids administered to amphibians is similar to that found in mammalian models.

  3. Dental Opioid Prescribing and Multiple Opioid Prescriptions Among Dental Patients: Administrative data from the South Carolina Prescription Drug Monitoring Program

    PubMed Central

    McCauley, Jenna L.; Hyer, J. Madison; Ramakrishnan, V. Ramesh; Leite, Renata; Melvin, Cathy L.; Fillingim, Roger B.; Frick, Christie; Brady, Kathleen T.

    2016-01-01

    Background Despite increased attention to dentists’ role in curbing opioid misuse, abuse, and diversion, information regarding prescribing practices and the frequency of multiple concurrent opioid prescriptions among dental patients is limited. Methods Prescription drug monitoring program (PDMP) data for South Carolina representing dispensed medication for patients prescribed at least one opioid by a dentist over the most recently available two-year frame (2012–2013) was reviewed. Descriptive analyses examined: (1) types, frequency of dental opioid prescriptions; and, (2) frequency of existing multiple concurrent opioid prescriptions among dental patients. Results Nearly all dispensed dental opioid prescriptions (99.9%; n = 653,650) were for immediate release opioids and were initial fills (96.2%). Hydrocodone (76.1%) and oxycodone (12.2%) combination products were the most frequently dispensed opioids prescribed by dentists. Individuals under 21 years of age received 11.2% of dentist prescribed opioids dispensed. Patients with multiple concurrent opioid prescriptions were identified within 30-day (n=113,818), 90-day (n=166,124), and 180-day (n=205,576) timeframes. Conclusions Dentists prescribed a high volume of immediate release opioids dispensed in South Carolina. A notable minority of dental patients had incident(s) of multiple pre-existing opioid prescriptions, a factor implicated in patient misuse, abuse, overdose, and diversion Practical Implications Use of a PDMP prior to prescribing provides a record of controlled substances dispensed to a patient, and may inform prescribing, coordination of care, and addiction screening or referral. Patients should be provided information regarding misuse behaviors and their risks, as well as the importance of secure storage and disposal of leftover opioid medications. PMID:27055600

  4. Endogenous opioid release in the human brain reward system induced by acute amphetamine administration.

    PubMed

    Colasanti, Alessandro; Searle, Graham E; Long, Christopher J; Hill, Samuel P; Reiley, Richard R; Quelch, Darren; Erritzoe, David; Tziortzi, Andri C; Reed, Laurence J; Lingford-Hughes, Anne R; Waldman, Adam D; Schruers, Koen R J; Matthews, Paul M; Gunn, Roger N; Nutt, David J; Rabiner, Eugenii A

    2012-09-01

    We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [(11)C]carfentanil binding with positron emission tomography (PET). Twelve healthy male volunteers underwent [(11)C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [(11)C]carfentanil binding from baseline to post-amphetamine scans (ΔBP(ND)) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest. [(11)C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [(11)C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure.

    PubMed

    Vassoler, Fair M; Oliver, David J; Wyse, Cristina; Blau, Ashley; Shtutman, Michael; Turner, Jill R; Byrnes, Elizabeth M

    2017-02-01

    The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5-25 mg/kg, s.c.) or saline for 10 days (P30-39). During adulthood, animals were bred with drug-naïve colony males. Male and female adult offspring (F1 animals) were tested for morphine self-administration acquisition, progressive ratio, extinction, and reinstatement at three doses of morphine (0.25, 0.75, 1.25 mg/kg/infusion). Grandoffspring (F2 animals, from the maternal line) were also examined. Additionally, gene expression changes within the nucleus accumbens were examined with RNA deep sequencing (PacBio) and qPCR. There were dose- and sex-dependent effects on all phases of the self-administration paradigm that indicate decreased morphine reinforcement and attenuated relapse-like behavior. Additionally, genes related to synaptic plasticity, as well as myelin basic protein (MBP), were dysregulated. Some, but not all, effects persisted into the subsequent (F2) generation. The results demonstrate that even limited opioid exposure during adolescence can have lasting effects across multiple generations, which has implications for mechanisms of the transmission of drug abuse liability in humans. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Opioid and adjuvant analgesics: compared and contrasted.

    PubMed

    Khan, Mohammed Ilyas Ahmed; Walsh, Declan; Brito-Dellan, Norman

    2011-08-01

    AAs (1-2 days). Rotation among opioids is a useful therapeutic strategy to improve analgesic response or minimize toxicity. Most AAs are unsuitable for rescue dosing because of their pharmacological characteristics. The mu agonist side effect profile is similar among the different opioid agents, regardless of the route of administration. The appropriate use of AAs will reduce opioid-related side effects. No apparent tolerance to analgesia develops with AAs. Abrupt discontinuation of an opioid after chronic repeated use for more than a few days will cause a withdrawal syndrome of variable severity. Adjuvant analgesics are an essential tool in cancer pain.

  7. Abuse risks and routes of administration of different prescription opioid compounds and formulations

    PubMed Central

    2011-01-01

    Background Evaluation of tamper resistant formulations (TRFs) and classwide Risk Evaluation and Mitigation Strategies (REMS) for prescription opioid analgesics will require baseline descriptions of abuse patterns of existing opioid analgesics, including the relative risk of abuse of existing prescription opioids and characteristic patterns of abuse by alternate routes of administration (ROAs). This article presents, for one population at high risk for abuse of prescription opioids, the unadjusted relative risk of abuse of hydrocodone, immediate release (IR) and extended release (ER) oxycodone, methadone, IR and ER morphine, hydromorphone, IR and ER fentanyl, IR and ER oxymorphone. How relative risks change when adjusted for prescription volume of the products was examined along with patterns of abuse via ROAs for the products. Methods Using data on prescription opioid abuse and ROAs used from 2009 Addiction Severity Index-Multimedia Version (ASI-MV®) Connect assessments of 59,792 patients entering treatment for substance use disorders at 464 treatment facilities in 34 states and prescription volume data from SDI Health LLC, unadjusted and adjusted risk for abuse were estimated using log-binomial regression models. A random effects binary logistic regression model estimated the predicted probabilities of abusing a product by one of five ROAs, intended ROA (i.e., swallowing whole), snorting, injection, chewing, and other. Results Unadjusted relative risk of abuse for the 11 compound/formulations determined hydrocodone and IR oxycodone to be most highly abused while IR oxymorphone and IR fentanyl were least often abused. Adjusting for prescription volume suggested hydrocodone and IR oxycodone were least often abused on a prescription-by-prescription basis. Methadone and morphine, especially IR morphine, showed increases in relative risk of abuse. Examination of the data without methadone revealed ER oxycodone as the drug with greatest risk after adjusting for

  8. Neonatal administration of thimerosal causes persistent changes in mu opioid receptors in the rat brain.

    PubMed

    Olczak, Mieszko; Duszczyk, Michalina; Mierzejewski, Pawel; Bobrowicz, Teresa; Majewska, Maria Dorota

    2010-11-01

    Thimerosal added to some pediatric vaccines is suspected in pathogenesis of several neurodevelopmental disorders. Our previous study showed that thimerosal administered to suckling rats causes persistent, endogenous opioid-mediated hypoalgesia. Here we examined, using immunohistochemical staining technique, the density of μ-opioid receptors (MORs) in the brains of rats, which in the second postnatal week received four i.m. injections of thimerosal at doses 12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray, caudate putamen and hippocampus were examined. Thimerosal administration caused dose-dependent statistically significant increase in MOR densities in the periaqueductal gray and caudate putamen, but decrease in the dentate gyrus, where it was accompanied by the presence of degenerating neurons and loss of synaptic vesicle marker (synaptophysin). These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development.

  9. Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum

    PubMed Central

    Chefer, Vladimir I.; Shippenberg, Toni S.

    2013-01-01

    Rationale Acute systemic administration of salvinorin A, a naturally occurring κ-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow. Objectives Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed. Materials and methods Salvinorin A was administered via the dialysis probe (0; 20–200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day×5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment. Results Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced. Conclusions These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ. PMID:18246329

  10. Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration.

    PubMed

    Olsén, Lena; Bondesson, Ulf; Broström, Hans; Tjälve, Hans; Ingvast-Larsson, Carina

    2008-08-01

    The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.

  11. Development of an opioid self-administration assay to study drug seeking in zebrafish.

    PubMed

    Bossé, Gabriel D; Peterson, Randall T

    2017-09-29

    The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Take-home naloxone treatment for opioid emergencies: a comparison of routes of administration and associated delivery systems.

    PubMed

    Elzey, Mark J; Fudin, Jeffrey; Edwards, Eric S

    2017-09-01

    Naloxone reversal of opioid-induced respiratory depression outside of medical facilities has become more prevalent because of the escalating opioid epidemic in the USA. Take-home naloxone for treatment of opioid emergencies is now being recommended by numerous federal, state, and professional organizations. Areas covered: The scope of the opioid overdose epidemic is reviewed along with practical, clinical, regulatory, and usability considerations for take-home naloxone routes of administration currently available and associated delivery systems. Specific opioid-related factors are discussed in detail with emphasis placed on life-threatening respiratory depression and naloxone antagonism. A clinical overview, including pharmacokinetic and FDA approval information for each take-home naloxone product is discussed in detail as well as the impact of take-home naloxone in the community. Finally, given these products are to be used in a panic-stricken, life-threatening opioid emergency, an analysis of available usability data is provided with proposed directions for further study. Expert opinion: Based on the available clinical evidence, auto-injectable naloxone should be the preferred administration route for take-home naloxone treatment until additional safety, efficacy, and comparative outcomes data are available for unconventional routes of administration that unequivocally provide equal or superior results.

  13. Opioid Self-Administration is Attenuated by Early-Life Experience and Gene Therapy for Anti-Inflammatory IL-10 in the Nucleus Accumbens of Male Rats

    PubMed Central

    Lacagnina, Michael J; Kopec, Ashley M; Cox, Stewart S; Hanamsagar, Richa; Wells, Corinne; Slade, Susan; Grace, Peter M; Watkins, Linda R; Levin, Edward D; Bilbo, Staci D

    2017-01-01

    Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement. PMID:28436446

  14. Trends in prevalent and incident opioid receipt: an observational study in Veterans Health Administration 2004-2012.

    PubMed

    Mosher, H J; Krebs, E E; Carrel, M; Kaboli, P J; Weg, M W Vander; Lund, B C

    2015-05-01

    Improved understanding of temporal and regional trends may support safe and effective prescribing of opioids. We describe national, regional, and facility-level trends and variations in opioid receipt between fiscal years (FY) 2004 and 2012. Observational cohort study using Veterans Health Administration (VHA) administrative databases. All patients receiving primary care within 137 VHA healthcare systems during a given study year and receiving medications from VHA one year before and during a given study year. Prevalent and incident opioid receipt during each year of the study period. The overall prevalence of opioid receipt increased from 18.9% of all veteran outpatients in FY2004 to 33.4% in FY2012, a 76.7% relative increase. In FY2012, women had higher rates of prevalent opioid receipt than men (42.4% vs. 32.9%), and the youngest veterans (18-34 years) had higher prevalent opioid receipt compared to the oldest veterans (≥ 80 years) (47.6% vs. 17.9%). All regions in the United States saw increased rates of prevalent opioid receipt during this time period. Prevalence rates varied widely by facility: in FY2012, the lowest-prescribing facility had a rate of 13.5%, and the highest of 50.8%. Annual incident opioid receipt increased from 8.8% in FY2004 to 10.2% in FY2011, with a decline to 9.8% in FY2012. Incident prescribing increased at some facilities and decreased at others. Facilities with high prevalent prescribing tended to have flat or decreasing incident prescribing rates during the study time frame. Rates of opioid receipt increased throughout the study time frame, with wide variation in prevalent and incident rates across geographical region, sex, and age groups. Prevalence and incidence rates reflect distinct prescribing practices. Areas with the highest prevalence tended to have lower increases in incident opioid receipt over the study period. This likely reflects facility-level variations in prescribing practices as well as baseline rates of prevalent

  15. The risk of action by the Drug Enforcement Administration against physicians prescribing opioids for pain.

    PubMed

    Jung, Beth; Reidenberg, Marcus M

    2006-01-01

    Fear of government actions against physicians for prescribing opioids for their chronic pain patients is a cause for undertreatment of pain. This study was conducted to assess the risk of action by the federal Drug Enforcement Administration (DEA). The DEA responded to a written request with a list of all DEA arrests in fiscal 2003. The Federal Register was reviewed for all revocations of DEA registrations for 2003 and 2004. There were 47 arrests in 2003 from among 963,385 doctors registered with the DEA and 56 revocations of registration seen in the 2003 and 2004 period. The reasons for these actions included loss of medical license, fraud, substance abuse by prescriber, sex in exchange for prescriptions, and prescribing without seeing patient. For the majority of cases, there was information to believe that a documented doctor-patient relationship with a chronic pain patient did not exist. When adequate documentation exists in the medical record, the risk of civil, criminal, or administrative action being taken by the DEA against a physician for prescribing opioids for a chronic pain patient is small.

  16. Nurses and opioids: results of a bi-national survey on mental models regarding opioid administration in hospitals

    PubMed Central

    Guest, Charlotte; Sobotka, Fabian; Karavasopoulou, Athina; Ward, Stephen; Bantel, Carsten

    2017-01-01

    Objective Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses’ mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. Material and methods A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses’ mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580) and one German (n=799) hospital between September 2014 and February 2015. Results A total of 511 (37.1%) questionnaires were returned. Mean (standard deviation) age of participants were 37 (11) years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87% did not regard opioids as drugs to help patients die, and 72% did not view them as drugs of abuse. More English (41%) than German (28%) nurses were afraid of criminal investigations and were constantly aware of side effects (UK, 94%; Germany, 38%) when using opioids. Four latent variables were identified which likely influence nurses’ mental models: “conscious decision-making”; “medication-related fears”; “practice-based observations”; and “risk assessment”. They were predicted by strength of religious beliefs and indicators of informal learning such as experience but not by indicators of formal learning such as conference attendance. Conclusion Nurses in both countries employ analytical and affective mental

  17. Route of administration for illicit prescription opioids: a comparison of rural and urban drug users

    PubMed Central

    2010-01-01

    Background Nonmedical prescription opioid use has emerged as a major public health concern in recent years, particularly in rural Appalachia. Little is known about the routes of administration (ROA) involved in nonmedical prescription opioid use among rural and urban drug users. The purpose of this study was to describe rural-urban differences in ROA for nonmedical prescription opioid use. Methods A purposive sample of 212 prescription drug users was recruited from a rural Appalachian county (n = 101) and a major metropolitan area (n = 111) in Kentucky. Consenting participants were given an interviewer-administered questionnaire examining sociodemographics, psychiatric disorders, and self-reported nonmedical use and ROA (swallowing, snorting, injecting) for the following prescription drugs: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, OxyContin® and other oxycodone. Results Among urban participants, swallowing was the most common ROA, contrasting sharply with substance-specific variation in ROA among rural participants. Among rural participants, snorting was the most frequent ROA for hydrocodone, methadone, OxyContin®, and oxycodone, while injection was most common for hydromorphone and morphine. In age-, gender-, and race-adjusted analyses, rural participants had significantly higher odds of snorting hydrocodone, OxyContin®, and oxycodone than urban participants. Urban participants had significantly higher odds of swallowing hydrocodone and oxycodone than did rural participants. Notably, among rural participants, 67% of hydromorphone users and 63% of morphine users had injected the drugs. Conclusions Alternative ROA are common among rural drug users. This finding has implications for rural substance abuse treatment and harm reduction, in which interventions should incorporate methods to prevent and reduce route-specific health complications of drug use. PMID:20950455

  18. Effects of repeated oxycodone administration on its analgesic and subjective effects in normal, healthy volunteers

    PubMed Central

    Cooper, Ziva D; Sullivan, Maria A; Vosburg, Suzanne K; Manubay, Jeanne M; Haney, Margaret; Foltin, Richard W; Evans, Suzette M; Kowalczyk, William J; Saccone, Phillip A; Comer, Sandra D

    2012-01-01

    Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration, yet this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine if tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone’s (0, 5, and 20 mg/70 kg, p.o.) were compared, using a within-session cumulative dosing procedure, on the 1st and 5th days of the ‘daily’ dosing phase to assess for tolerance; active oxycodone was administered on the 2nd-4th days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the 1st and 5th day of a 5-day ‘intermittent’ dosing phase; placebo medication was administered on the 2nd–4th days of the intermittent dosing phase. A 9-day ‘washout’ period occurred between phases when no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the Cold-Pressor Test (CPT), pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the 1st and 5th days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the 5th day compared to the 1st day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the 1st and 5th days of either dosing phase were detected. Though obtained under limited experimental conditions, these

  19. Chronic heroin self-administration desensitizes mu opioid receptor-activated G-proteins in specific regions of rat brain.

    PubMed

    Sim-Selley, L J; Selley, D E; Vogt, L J; Childers, S R; Martin, T J

    2000-06-15

    In previous studies from our laboratory, chronic noncontingent morphine administration decreased mu opioid receptor-activated G-proteins in specific brainstem nuclei. In the present study, mu opioid receptor binding and receptor-activated G-proteins were examined after chronic heroin self-administration. Rats were trained to self-administer intravenous heroin for up to 39 d, achieving heroin intake up to 366 mg. kg(-1). d(-1). mu opioid-stimulated [(35)S]GTPgammaS and [(3)H]naloxone autoradiography were performed in adjacent brain sections. Agonist-stimulated [(35)S]GTPgammaS autoradiography also examined other G-protein-coupled receptors, including delta opioid, ORL-1, GABA(B), adenosine A(1), cannabinoid, and 5-HT(1A). In brains from heroin self-administering rats, decreased mu opioid-stimulated [(35)S]GTPgammaS binding was observed in periaqueductal gray, locus coeruleus, lateral parabrachial nucleus, and commissural nucleus tractus solitarius, as previously observed in chronic morphine-treated animals. In addition, decreased mu opioid-stimulated [(35)S]GTPgammaS binding was found in thalamus and amygdala after heroin self-administration. Despite this decrease in mu-activated G-proteins, [(3)H]naloxone binding demonstrated increased mu opioid receptor binding in several brain regions after heroin self-administration, and there was a significant decrease in mu receptor G-protein efficiency as expressed as a ratio between agonist-activated G-proteins and mu receptor binding. No effects on agonist-stimulated [(35)S]GTPgammaS binding were found for any other receptor examined. The effect of chronic heroin self-administration to decrease mu-stimulated [(35)S]GTPgammaS binding varied between regions and was highest in brainstem and lowest in the cortex and striatum. These results not only provide potential neuronal mechanisms that may contribute to opioid tolerance and dependence, but also may explain why various chronic effects of opioids develop to different degrees.

  20. Development and applications of the Veterans Health Administration's Stratification Tool for Opioid Risk Mitigation (STORM) to improve opioid safety and prevent overdose and suicide.

    PubMed

    Oliva, Elizabeth M; Bowe, Thomas; Tavakoli, Sara; Martins, Susana; Lewis, Eleanor T; Paik, Meenah; Wiechers, Ilse; Henderson, Patricia; Harvey, Michael; Avoundjian, Tigran; Medhanie, Amanuel; Trafton, Jodie A

    2017-02-01

    Concerns about opioid-related adverse events, including overdose, prompted the Veterans Health Administration (VHA) to launch an Opioid Safety Initiative and Overdose Education and Naloxone Distribution program. To mitigate risks associated with opioid prescribing, a holistic approach that takes into consideration both risk factors (e.g., dose, substance use disorders) and risk mitigation interventions (e.g., urine drug screening, psychosocial treatment) is needed. This article describes the Stratification Tool for Opioid Risk Mitigation (STORM), a tool developed in VHA that reflects this holistic approach and facilitates patient identification and monitoring. STORM prioritizes patients for review and intervention according to their modeled risk for overdose/suicide-related events and displays risk factors and risk mitigation interventions obtained from VHA electronic medical record (EMR)-data extracts. Patients' estimated risk is based on a predictive risk model developed using fiscal year 2010 (FY2010: 10/1/2009-9/30/2010) EMR-data extracts and mortality data among 1,135,601 VHA patients prescribed opioid analgesics to predict risk for an overdose/suicide-related event in FY2011 (2.1% experienced an event). Cross-validation was used to validate the model, with receiver operating characteristic curves for the training and test data sets performing well (>.80 area under the curve). The predictive risk model distinguished patients based on risk for overdose/suicide-related adverse events, allowing for identification of high-risk patients and enrichment of target populations of patients with greater safety concerns for proactive monitoring and application of risk mitigation interventions. Results suggest that clinical informatics can leverage EMR-extracted data to identify patients at-risk for overdose/suicide-related events and provide clinicians with actionable information to mitigate risk. (PsycINFO Database Record

  1. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    PubMed Central

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today. PMID:27882209

  2. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    PubMed

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  3. Combined Use of Opioids and Antidepressants in the Treatment of Pain: A Review of Veterans Health Administration Data for Patients with Pain Both With and Without Co-morbid Depression.

    PubMed

    Sellinger, John J; Sofuoglu, Mehmet; Kerns, Robert D; Rosenheck, Robert A

    2016-12-01

    Musculoskeletal pain is prevalent among Veterans treated within the Veterans Health Administration (VHA). Depression is highly co-prevalent, and antidepressants are increasingly being used for psychiatric and analgesic benefit. The current study examined prescribing patterns of antidepressants and opioids in the context of musculoskeletal pain using a national VHA database. All Veterans diagnosed with musculoskeletal pain who attended at least one appointment through the VHA during Fiscal Year 2012 were dichotomized based on the presence or absence of a depression diagnosis. We compared the proportion in each group that were prescribed antidepressants to the entire sample and repeated this comparison along a continuum of the number of annual opioid prescriptions received (ranging in five categories from no opioids up to >20 scripts). Of the 5.1 million Veterans seen, 19.1 % were diagnosed with musculoskeletal pain, of whom, 27.2 % were diagnosed with major depressive disorder. Antidepressants were prescribed to 78.41 % of patients with musculoskeletal pain and depression, compared to 20.23 % of those without depression. For both groups, antidepressant use increased linearly as annual opioid fills increased. Across the categories of opioid use, patients with depression showed a 13.98 % increase in antidepressant use, compared to a 33.97 % increase in the non-depressed group. Results suggest that antidepressants are frequently prescribed to patients with musculoskeletal pain who are using opioids, consistent with multi-modal pharmacotherapy. Increasing use of antidepressants in conjunction with escalating opioid prescribing, particularly in the absence of diagnosed depression, suggests that antidepressants are being used in both groups to complement opioid therapy.

  4. Sex differences in chronic pain management practices for patients receiving opioids from the Veterans Health Administration.

    PubMed

    Oliva, Elizabeth M; Midboe, Amanda M; Lewis, Eleanor T; Henderson, Patricia T; Dalton, Aaron L; Im, Jinwoo J; Seal, Karen; Paik, Meenah C; Trafton, Jodie A

    2015-01-01

    Women experience chronic pain and use pain-related health care at higher rates than men. It is not known whether the pain-related health care female veterans receive is consistent with clinical practice guideline recommendations or whether receipt of this care differs between men and women. The aim of this study was to identify whether sex differences in chronic pain management care exist for patients served by the Veterans Health Administration (VHA). Data on patient demographics, diagnostic criteria, and health care utilization were extracted from VHA administrative databases for fiscal year 2010 (FY10). Patients in this study included all VHA patients (excluding metastatic cancer patients) who received more than 90 days of a short-acting opioid medication or a long-acting opioid medication prescription in FY10 study. Multilevel logistic regressions were conducted to identify sex differences in receipt of guideline-recommended chronic pain management. A total of 480,809 patients met inclusion criteria. Female patients were more likely to receive most measures of guideline-recommended care for chronic pain including mental health assessments, psychotherapy, rehabilitation therapy, and pharmacy reconciliation. However, women were more likely to receive concurrent sedative prescriptions, which is inconsistent with guideline recommendations. Most of the observed sex differences persisted after controlling for key demographic and diagnostic differences. Findings suggest that female VHA patients are more likely to receive an array of pain management practices than male patients, including both contraindicated and recommended polypharmacy. Quality improvement efforts to address underutilization of mental health and rehabilitative services for pain by male patients and polypharmacy in female patients should be considered. Wiley Periodicals, Inc.

  5. Opioid Abuse after Traumatic Brain Injury: Evaluation Using Rodent Models

    DTIC Science & Technology

    2012-07-01

    susceptible to the rewarding effects of opioids . We are currently conducting experiments to evaluate the hypothesis that TBI causes changes in the...analgesic response to opioids following acute and repeated drug administration. We are secondly in the midst of testing the hypothesis that moderate...TBI increases the susceptibility for opioid abuse as measured by an alteration in the rewarding properties of oxycodone. We have completed the first

  6. Effects of environmental enrichment on self-administration of the short-acting opioid remifentanil in male rats.

    PubMed

    Hofford, Rebecca S; Chow, Jonathan J; Beckmann, Joshua S; Bardo, Michael T

    2017-09-15

    Opioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting μ-opioid remifentanil. Rats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21 days of age and were trained to lever press for 1 or 3 μg/kg/infusion remifentanil in young adulthood. Acquisition of self-administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated. In all phases, Enr rats lever pressed significantly less than Std and Iso rats, with Enr rats pressing between 9 and 40% the amount of Iso rats. Enr rats did not acquire remifentanil self-administration when trained with 1 μg/kg/infusion, did not increase responding over increasing FR when trained at either dose, and their dose-response curves were flattened compared to Std and Iso rats. When expressed as economic demand curves, Enr rats displayed a decrease in both essential value (higher α) and reinforcer intensity (Q 0) compared to Std and Iso rats at the 1 μg/kg/infusion training dose. Environmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse.

  7. Receipt of Pharmacotherapy for Opioid Use Disorder by Justice-Involved U.S. Veterans Health Administration Patients

    PubMed Central

    Finlay, Andrea K.; Harris, Alex H.S.; Rosenthal, Joel; Blue-Howells, Jessica; Clark, Sean; McGuire, Jim; Timko, Christine; Frayne, Susan M.; Smelson, David; Oliva, Elizabeth; Binswanger, Ingrid

    2016-01-01

    Background Pharmacotherapy – methadone, buprenorphine, or naltrexone – is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement. Methods Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics. Results The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65–0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds. Conclusions Targeted efforts to increase receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications. PMID:26832998

  8. Receipt of pharmacotherapy for opioid use disorder by justice-involved U.S. Veterans Health Administration patients.

    PubMed

    Finlay, Andrea K; Harris, Alex H S; Rosenthal, Joel; Blue-Howells, Jessica; Clark, Sean; McGuire, Jim; Timko, Christine; Frayne, Susan M; Smelson, David; Oliva, Elizabeth; Binswanger, Ingrid

    2016-03-01

    Pharmacotherapy - methadone, buprenorphine, or naltrexone - is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement. Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics. The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65-0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds. Targeted efforts to improve receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications. Published by Elsevier Ireland Ltd.

  9. [Long-term administration of opioids for non-tumor pain - LONTS guideline provides an orientation].

    PubMed

    Petzke, Frank

    2015-10-01

    The long-term usage of opioid analgesics (> 3 months) for chronic, non-cancer related pain is critically discussed nationally and internationally. There are indications of under- and oversupply as well as misuse of opioids in Germany, but an "opioid epidemic" such as is evident in the USA cannot be detected at present.The S3-guideline LONTS (long-term usage of opioid analgesics for non-cancer related pain)serves as an orientation to improve provision of opioids and contains statements about the available evidence, indications and contraindications of use, as well as practical recommendations for managing a long-term opioid therapy. © Georg Thieme Verlag Stuttgart · New York.

  10. Use of infusion devices for epidural or intrathecal administration of spinal opioids.

    PubMed

    Kwan, J W

    1990-08-01

    The use of infusion devices for epidural or intrathecal administration of spinal opioids is described. The risks of infection and mechanical catheter complications, the need for escalating doses, reservoir volume, drug stability, and cost are practical considerations associated with use of both external and internal infusion systems. Use of patient criteria to identify suitable candidates for intraspinal administration of pain medication helps ensure successful management. The criteria for intraspinal delivery pumps are safety, accuracy, reliability, ease of management by the patient and the health-care professional, and compatibility of the drug with the pump components. The primary factors to consider when comparing pumps to be used for intraspinal delivery of pain medication are the volume and flow rate requirements of the devices. External portable infusion devices are classified according to the mechanism of operation into three primary groups: syringe pumps, peristaltic mechanisms, and elastomeric reservoir pumps. Portable patient-controlled analgesia pumps that have syringes, flexible reservoir bags, and elastomeric reservoirs have been developed. Implanted systems with flow rates that are preset at the factory make pain management more difficult when the patient requires changes or escalations in doses over time. A programmable implanted pump is available. Two advantages of continuous epidural or intrathecal infusion are (1) the peaks and valleys of pain relief with bolus injections are eliminated and (2) the need for multiple injections is reduced. Patient-controlled analgesia (PCA) pumps enhance the efficacy of continuous infusions by allowing the patient to administer bolus doses to control acute pain.

  11. Peripheral administration of a μ-opioid receptor agonist DAMGO suppresses the anxiolytic and stimulatory effects of caffeine.

    PubMed

    Sudakov, S K; Nazarova, G A; Alekseeva, E V; Kolpakov, A A

    2015-01-01

    We studied the possibility of modulation of the stimulatory and anxiolytic effects of caffeine by activation of μ-opioid receptors in the gastrointestinal tract. Caffeine in a dose of 10 mg/kg (but not in a dose of 100 mg/kg) had a strong anxiolytic and psychostimulant effect. This effect was manifested in a significant increase in the time spent in the open arms of the elevated plus-maze, elevation of locomotor activity, and stimulation of metabolism. Administration of DAMGO to animals receiving caffeine in a dose of 10 mg/kg abolished the anxiolytic and psychostimulant effects of caffeine. By contrast, administration of DAMGO to rats receiving caffeine in a dose of 100 mg/kg had the anxiolytic effect. Activation of peripheral μ-opioid receptors is followed by the inhibition of the central μ-opioid system. We observed a decrease in the number of μ-opioid receptors in the midbrain and cerebral cortex and inhibition of β-endorphin release from nerve ending of the cingulate cortex in rats. These changes are probably followed by activation of the adenosine system in the brain. Caffeine dose should be increased to achieve the effect. Therefore, the anxiolytic and stimulatory effects of caffeine in a dose of 10 mg/kg are abolished under these conditions. By contrast, the anxiolytic effect of caffeine in a dose of 100 mg/kg (not observed under normal conditions) develops after this treatment.

  12. Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients.

    PubMed

    Zedler, Barbara; Xie, Lin; Wang, Li; Joyce, Andrew; Vick, Catherine; Brigham, Janet; Kariburyo, Furaha; Baser, Onur; Murrelle, Lenn

    2015-08-01

    Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05). RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated. © 2015 The Authors Pain Medicine published by Wiley Periodicals, Inc. on behalf of American Academy of Pain Medicine.

  13. An improved technique for repeated gavage administration to rat neonates.

    PubMed

    Watanabe, Chiaki; Kuwagata, Makiko; Yoshimura, Shinsuke; Azegami, Jiro; Kojima, Kouichi; Ono, Hiroshi; Nagao, Tetsuji

    2003-09-01

    The technique for gavage administration to rat nurslings was improved to allow determination of the direct effects of chemical substances in the nurslings. Rat neonates were treated with distilled water from postnatal day 1 through 20 using this technique. The viability of neonates during the administration period was comparable to that of untreated neonates. No adverse effects of this technique on the development of neonates were found, and no histological alterations of the esophagus or pharynx. Therefore, we conclude that use of our improved gavage administration method will contribute to ensuring successful neonatal development and thus allowing accurate assessment of the toxicological effects of test compounds on rat nurslings.

  14. EFFECT OF SINGLE AND REPEATED TETRACYCLINE ADMINISTRATION ON THE PHAGOCYTIC FUNCTION OF RETICULENDOTHELIAL SYSTEMS

    DTIC Science & Technology

    upon repeated administration. The effect of single and repeated administration of chlortetracycline, tetracycline , and oxytetracycline on the absorptive function of mouse RES were studied....It was previously established that single administration of chlortetracycline and oxytetracycline to white mice stimulates the absorptive function of...the reticulo-endothelial system (RES) in several cases, depending on the dose of the preparation. Clinical use of tetracyclines is practically never

  15. Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys.

    PubMed

    Nakao, Kaoru; Hirakata, Mikito; Miyamoto, Yohei; Kainoh, Mie; Wakasa, Yoshio; Yanagita, Tomoji

    2016-01-01

    Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

  16. Microsomal enzyme induction following repeated oral administration of LAAM.

    PubMed

    Masten, L W; Price, S R; Burnett, C J

    1978-04-01

    The oral administration of 1-alpha-acetylmethadol (LAAM) in the mouse was shown to cause a significant elevation in the hepatic LAAM N-demethylase activity. Compared to the self-induction phenomena found with methadone and propoxyphene, LAAM was three and two times more potent, respectively, on a molar basis than these two structurally similar narcotic analogs. Moreover, microsomal induction by LAAM resulted in significant elevations of aminopyrine N-demethylase and aniline hydroxylase activities. These effects were also correlated with a dose related decrement of pentobarbital sleeping time. Thus LAAM appears to be a relatively potent inducer of microsomal metabolism.

  17. Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats

    PubMed Central

    Wiebelhaus, Jason M.; Walentiny, D. Matthew

    2016-01-01

    Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone’s abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose- and time-dependent effects of acute and repeated oxycodone administration in a frequency-rate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and rate-decreasing effects maintained by ICSS similar to μ-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose- and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects. PMID:26491062

  18. Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats.

    PubMed

    Wiebelhaus, Jason M; Walentiny, D Matthew; Beardsley, Patrick M

    2016-01-01

    Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone's abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose- and time-dependent effects of acute and repeated oxycodone administration in a frequency-rate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and rate-decreasing effects maintained by ICSS similar to μ-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose- and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects.

  19. Early Repeated Administration of CXCR4 Antagonist AMD3100 Dose-Dependently Improves Neuropathic Pain in Rats After L5 Spinal Nerve Ligation.

    PubMed

    Xie, Fang; Wang, Yun; Li, Xueyang; Chao, Yu-Chieh; Yue, Yun

    2016-09-01

    AMD3100 is a specific C-X-C chemokine receptor type 4 (CXCR4) antagonist which blocks the interaction between CXCR4 and CXCL12. Multiple lines of evidence suggest that AMD3100 has analgesic effects on many pathological pain states, including peripheral neuropathic pain. However, little is known about the underlying mechanisms. In the current study, we investigated the effect of different doses of AMD3100 on neuropathic pain in rats after L5 spinal nerve ligation. We used naloxone methiodide (NLXM) to further determine whether AMD3100-mediated analgesic effect was opioid-dependent. Behavioral study showed that early repeated administration of AMD3100 (2 and 5 mg/kg, i.p.) dose-dependently alleviates peripheral neuropathic pain. Flow cytometry, immunofluorescence and NLXM experiments showed that AMD3100 alleviates neuropathic pain partially by augmenting leukocyte-derived endogenous opioid secretion. Furthermore, we found that pro-inflammatory cytokines were down-regulated by AMD3100 using Enzyme-linked Immunosorbent Assay. Our data indicate that AMD3100 dose-dependently alleviates neuropathic pain partially by augmenting leukocyte-derived endogenous opioid secretion. This finding suggests that AMD3100 may be a viable pharmacotherapeutic strategy for the treatment of neuropathic pain.

  20. Cannabinoid-opioid interactions in drug discrimination and self-administration: effect of maternal, postnatal, adolescent and adult exposure to the drugs.

    PubMed

    Spano, M S; Fadda, P; Fratta, W; Fattore, L

    2010-04-01

    Cannabinoids and opioids are known to strictly interact in many physiological and pathological functions, including addiction. The endogenous opioid system is significantly influenced by maternal or perinatal cannabinoid exposure, major changes concerning operant behaviour in adult animals. Copious data suggests that adolescence is also a particularly sensitive period of life not only for the initiation of abusing illicit drugs, but also for the effects that these drugs exert on the neural circuitries leading to drug dependence. This paper examines the role played by the age of drug exposure in the susceptibility to discriminative and reinforcing effects of both cannabinoids and opioids. We first revisited evidence of alterations in the density and functionality of mu-opioid and CB1 cannabinoid receptors in reward-related brain regions caused by either maternal, postnatal, adolescent or adult exposure to opioids and cannabinoids. Then, we reviewed behavioural evidence of the long-term consequences of exposure to opioids and cannabinoids during gestation, postnatal period, adolescence or adulthood, focusing mostly on drug discrimination and self-administration studies. Overall, evidence confirms a neurobiological convergence of the cannabinoid and opioid systems that is manifest at both receptor and behavioural levels. Although discrepant results have been reported, some data support the gateway hypothesis that adolescent cannabis exposure contributes to greater opioid intake in adulthood. However, it should be kept into consideration that in humans genetic, environmental, and social factors could influence the direct neurobiological effects of early cannabis exposure to the progression to adult drug abuse.

  1. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.

  2. Systematic review of the predisposing, enabling, and reinforcing factors which influence nursing administration of opioids in the postoperative period.

    PubMed

    Yin, Hai-Hui; Tse, Mimi M Y; Wong, Frances K Y

    2015-10-01

    To provide an overview of the administration of opioid analgesics by nurses when prescription is on an "as-needed" basis for postoperative pain, and to identify the important factors that determine the decisions of nurses, by using the framework of predisposing, reinforcing, and enabling causes in educational diagnosis and evaluation. Multiple databases were searched for the period from 2000-2012. Out of a total of 1755 citations and 148 abstracts retrieved, 39 studies met the criteria for inclusion. Studies were considered eligible for review if they focused on situations or factors influencing a nurse's performance in pain assessment and the administration of opioid analgesics in postoperative pain management. The topics of the descriptive and qualitative studies presented four themes: (i) nurses' knowledge and attitudes about pain management; (ii) the situation of nurses' work practices in administrating range orders for opioid analgesics; (iii) factors that influenced nurses' work practices; and (iv) perceived barriers to effective pain management from the nurse's perspective. The experimental studies investigated the effects of different approaches in nurses' pain management practices in postoperative settings and their outcomes for patients. A knowledge deficit was observed to be the reason in most cases for a nurse's failure to administrate adequate analgesics for postoperative pain relief. Pain-related education for nurses is the cornerstone to improve pain management. The integration of enabling and reinforcing factors will help nurses to develop the ability to make the decision to engage in a comprehensive intervention to improve pain management and patient outcomes. © 2015 The Authors. Japan Journal of Nursing Science © 2015 Japan Academy of Nursing Science.

  3. Evaluation of knowledge and confidence following opioid overdose prevention training: A comparison of types of training participants and naloxone administration methods.

    PubMed

    Ashrafioun, Lisham; Gamble, Stephanie; Herrmann, Michele; Baciewicz, Gloria

    2016-01-01

    The purpose of the current study was to assess the effect of opioid overdose prevention training on participants' knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations as a function of naloxone administration (i.e., injection vs. intranasal spray) and participant type (friend/family, provider, "other"). Opioid overdose prevention trainings were offered throughout a mid-sized metropolitan area in the northeast. Participants (n = 428) were trained to administer naloxone via intramuscular injection (n = 154) or intranasal spray (n = 274). All training participants were given pre-post assessments of knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations. Participants' overall knowledge and confidence increased significantly from pre- to post-training (ps < .001). There was no significant association between knowledge and route of administration or participant type. Knowledge significantly increased from pre- to post-training in all participant types (ps < .001). Confidence improved significantly from pre- to post-training across both routes of administration (ps < .001). However, confidence was higher among those who were trained using the intranasal naloxone compared to those who were trained using the intramuscular injection naloxone at pre- (p = .011) and post-training (p < .001). Confidence increased from pre- to post-training in each of the participant types (ps < .001). Post-hoc tests revealed that confidence was higher among providers and friends/family members compared to "other" participants, such as first responders, only at post-training (p < .05). Opioid overdose trainings are effective in increasing knowledge and confidence related to opioid overdose situations. Findings suggest that trainees are more confident administering naloxone via intranasal spray compared to injection. Future research should attempt to identify other factors that may increase the

  4. Tachykinin NK1 receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation

    PubMed Central

    Tumati, Suneeta; Largent-Milnes, Tally M.; Keresztes, Attila I.; Yamamoto, Takashi; Vanderah, Todd W.; Roeske, William R.; Hruby, Victor J.; Varga, Eva V.

    2012-01-01

    Prolonged morphine treatment increases pain sensitivity in many patients. Enhanced spinal Substance P release is one of the adaptive changes associated with sustained opioid exposure. In addition to pain transmitting second order neurons, spinal microglia and astrocytes also express functionally active Tachykinin NK1 (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK1 receptors in morphine withdrawal-mediated spinal microglia and astrocyte activation. Our data indicate that intrathecal co-administration (6 days, twice daily) of a selective Tachykinin NK1 receptor antagonist (N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 μg/injection) attenuates spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in morphine-withdrawn rats. Furthermore, covalent linkage of the opioid agonist with a Tachykinin NK1 antagonist pharmacophor yielded a bivalent compound that did not augment spinal microglia or astrocyte marker or pro-inflammatory mediator immunoreactivity and did not cause paradoxical pain sensitization upon drug withdrawal. Thus, bivalent opioid/Tachykinin NK1 receptor antagonists may provide a novel paradigm for long-term pain management. PMID:22724132

  5. Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation.

    PubMed

    Tumati, Suneeta; Largent-Milnes, Tally M; Keresztes, Attila I; Yamamoto, Takashi; Vanderah, Todd W; Roeske, William R; Hruby, Victor J; Varga, Eva V

    2012-06-05

    Prolonged morphine treatment increases pain sensitivity in many patients. Enhanced spinal Substance P release is one of the adaptive changes associated with sustained opioid exposure. In addition to pain transmitting second order neurons, spinal microglia and astrocytes also express functionally active Tachykinin NK₁ (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK₁ receptors in morphine withdrawal-mediated spinal microglia and astrocyte activation. Our data indicate that intrathecal co-administration (6 days, twice daily) of a selective Tachykinin NK₁ receptor antagonist (N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 μg/injection)) attenuates spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats. Furthermore, covalent linkage of the opioid agonist with a Tachykinin NK₁ antagonist pharmacophore yielded a bivalent compound that did not augment spinal microglia or astrocyte marker or pro-inflammatory mediator immunoreactivity and did not cause paradoxical pain sensitization upon drug withdrawal. Thus, bivalent opioid/Tachykinin NK₁ receptor antagonists may provide a novel paradigm for long-term pain management.

  6. Opioid system in L-DOPA-induced dyskinesia.

    PubMed

    Pan, Jing; Cai, Huaibin

    2017-01-01

    L-3, 4-Dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is a major clinical complication in the treatment of Parkinson's disease (PD). This debilitating side effect likely reflects aberrant compensatory responses for a combination of dopaminergic neuron denervation and repeated L-DOPA administration. Abnormal endogenous opioid signal transduction pathways in basal ganglia have been well documented in LID. Opioid receptors have been targeted to alleviate the dyskinesia. However, the exact role of this altered opioid activity is remains under active investigation. In the present review, we discuss the current understanding of opioid signal transduction in the basal ganglia and how the malfunction of opioid signaling contributes to the pathophysiology of LID. Further study of the opioid system in LID may lead to new therapeutic targets and improved treatment of PD patients.

  7. Opioid dependence

    PubMed Central

    2009-01-01

    Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three approaches to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final aim is relapse prevention. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimes. PMID:21696648

  8. Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons.

    PubMed

    James, Alex S; Chen, Jane Y; Cepeda, Carlos; Mittal, Nitish; Jentsch, James David; Levine, Michael S; Evans, Christopher J; Walwyn, Wendy

    2013-11-01

    Medium-sized spiny neurons (MSNs), the predominant neuronal population of the striatum, are an integral component of the many cortical and limbic pathways associated with reward-related behaviors. A differential role of the D1 receptor-enriched (D1) MSNs of the striatonigral direct pathway, as compared with the D2 receptor-enriched (D2) MSNs of the striatopallidal indirect pathway, in mediating the addictive behaviors associated with cocaine is beginning to emerge. However, whether opioids, well-known analgesics with euphoric properties, similarly induce dissociable signaling adaptations in these neurons remains unclear. Transgenic mice expressing green fluorescent protein (GFP)-labeled D1 or D2 neurons were implanted with intravenous jugular catheters. Mice learned to self-administer 0.1mg/kg/infusion of the opioid remifentanil during 2h sessions over 13 contiguous days. Thereafter, the electrophysiological properties of D1- and D2-MSNs in the shell region of the nucleus accumbens (NAc) were assessed. We found that prior opioid exposure did not alter the basic membrane properties nor the kinetics or amplitude of miniature excitatory postsynaptic currents (mEPSCs). However, when challenged with the mu opioid receptor (μOR) agonist DAMGO, the characteristic inhibitory profile of this receptor was altered. DAMGO inhibited the frequency of mEPSCs in D1-MSNs from control mice receiving saline and in D2-MSNs from mice exposed to remifentanil or saline, but this inhibitory profile was reduced in D1-MSNs from mice receiving remifentanil. Remifentanil exposure also altered the probability of glutamate release onto D1-, but not D2-MSNs. Together these results suggest a D1-pathway specific effect associated with the acquisition of opioid-seeking behaviors.

  9. Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons

    PubMed Central

    James, Alex S.; Chen, Jane Y.; Cepeda, Carlos; Mittal, Nitish; Jentsch, James David; Levine, Michael S.; Evans, Christopher J.; Walwyn, Wendy

    2013-01-01

    Medium-sized spiny neurons (MSNs), the predominant neuronal population of the striatum, are an integral component of the many cortical and limbic pathways associated with reward-related behaviors. A differential role of the D1 receptor-enriched (D1) MSNs of the striatonigral direct pathway, as compared with the D2 receptor-enriched (D2) MSNs of the striatopallidal indirect pathway, in mediating the addictive behaviors associated with cocaine is beginning to emerge. However, whether opioids, well-known analgesics with euphoric properties, similarly induce dissociable signaling adaptations in these neurons remains unclear. Transgenic mice expressing Green Fluorescent Protein (GFP)-labeled D1 or D2 neurons were implanted with intravenous jugular catheters and trained to self-administer the opioid remifentanil. D1- and D2-GFP mice learned to self-administer 0.1 mg/kg/infusion remifentanil during 2hr sessions over 13 contiguous days. Thereafter, the electrophysiological properties of D1 and D2 MSNs in the shell region of the nucleus accumbens (NAc) were assessed. We found that prior opioid exposure did not alter the basic membrane properties nor the kinetics or amplitude of miniature excitatory postsynaptic currents (mEPSCs). However, when challenged with the mu opioid receptor (µOR) agonist DAMGO, the characteristic inhibitory profile of this receptor was altered. DAMGO inhibited the frequency of mEPSCs in D1-MSNs from control mice receiving saline and in D2-MSNs from mice exposed to remifentanil or saline, but this inhibitory profile was reduced in D1-MSNs from mice receiving remifentanil. Remifentanil exposure also altered the probability of glutamate release onto D1-, but not D2-MSNs. Together these results suggest a D1-pathway specific effect associated with the acquisition of opioid-seeking behaviors. PMID:23968589

  10. A prospective study of liver enzyme and other changes following repeat administration of halothane and enflurane.

    PubMed

    Fee, J P; Black, G W; Dundee, J W; McIlroy, P D; Johnston, H M; Johnston, S B; Black, I H; McNeill, H G; Neill, D W; Doggart, J R; Merrett, J D; McDonald, J R; Bradley, D S; Haire, M; McMillan, S A

    1979-12-01

    A prospective study of liver enzymes and other measurements following repeat administrations of halothane or enflurane was carried out in patients undergoing minor urological operations. The patient populations were similar with respect to frequency of factors which might influence liver function, social habits, drug therapy and time intervals between administrations. Sixty-three received two or more administrations of halothane and 66 received two or more administrations of enflurane, both drugs given with nitrous oxide in oxygen. There was a greater frequency of increased enzymatic activity following repeat administrations of halothane than following enflurane and the average alanine aminotransferase and gamma glutamyl transpeptidase concentrations were increased to a greater degree following halothane than enflurane. There was no change in the eosinophil count and no significant postoperative morbidity. Change in alanine aminotransferase, lactate dehydrogenase and gamma glutamyl transpeptidase occured more frequently in obese patients receiving halothane.

  11. Impact of age, sex and route of administration on adverse events after opioid treatment in the emergency department: A retrospective study

    PubMed Central

    Daoust, Raoul; Paquet, Jean; Lavigne, Gilles; Piette, Éric; Chauny, Jean-Marc

    2015-01-01

    BACKGROUND: The efficacy of opioids for acute pain relief in the emergency department (ED) is well recognized, but treatment with opioids is associated with adverse events ranging from minor discomforts to life-threatening events. OBJECTIVE: To assess the impact of age, sex and route of administration on the incidence of adverse events due to opioid administration in the ED. METHODS: Real-time archived data were analyzed retrospectively in a tertiary care urban hospital. All consecutive patients (≥16 years of age) who were assigned to an ED bed and received an opioid between March 2008 and December 2012 were included. Adverse events were defined as: nausea/vomiting (minor); systolic blood pressure (SBP) <90 mmHg, oxygen saturation (Sat) <92% and respiration rate <10 breaths/min (major) within 2 h of the first opioid doses. RESULTS: In the study period, 31,742 patients were treated with opioids. The mean (± SD) age was 55.8±20.5 years, and 53% were female. The overall incidence of adverse events was 12.0% (95% CI 11.6% to 12.4%): 5.9% (95% CI 5.6% to 6.2%) experienced nausea/vomiting, 2.4% (95% CI 2.2% to 2.6%) SBP <90 mmHg, 4.7% (95% CI 4.5% to 4.9%) Sat that dropped to <92% and 0.09% respiration rate <10 breaths/min. After controlling for confounding factors, these adverse events were associated with: female sex (more nausea/vomiting, more SBP <90 mmHg, less Sat <92%); age ≥65 years (less nausea/vomiting, more SBP <90 mmHg, more Sat <92%); and route of administration (intravenous > subcutaneous > oral). CONCLUSIONS: The incidence of adverse events associated with opioid administration in the ED is generally low and is associated with age, sex and route of administration. PMID:25664538

  12. Patient-reported opioid analgesic requirements after elective inguinal hernia repair: A call for procedure-specific opioid-administration strategies.

    PubMed

    Mylonas, Konstantinos S; Reinhorn, Michael; Ott, Lauren R; Westfal, Maggie L; Masiakos, Peter T

    2017-08-01

    A better understanding of the analgesia needs of patients who undergo common operative procedures is necessary as we address the growing opioid public health crisis in the United States. The aim of this study was to evaluate patient experience with our opioid prescribing practice after elective inguinal hernia repairs. A prospective, observational study was conducted between October 1, 2015, and September 30, 2016, in a single-surgeon, high-volume, practice of inguinal hernia operation. Adult patients undergoing elective inguinal herniorrhaphy under local anesthesia with intravenous sedation were invited to participate. All patients were prescribed 10 opioid analgesic tablets postoperatively and were counseled to reserve opioids for pain not controlled by nonopioid analgesics. Their experience was captured by completing a questionnaire 2 to 3 weeks postoperatively during their postoperative visit. A total of 185 patients were surveyed. The majority of the participants were males (177, 95.7%) and ≥60 years old (96, 51.9%). Of the 185 patients, 159 (85.9%) reported using ≤4 opioid tablets; 110 patients (59.5%) reported that they used no opioid analgesics postoperatively. None of the patients was taking opioids within 7 days of their postoperative appointment. Of the 147 patients who were employed, 111 (75.5%) reported missing ≤3 work days, 57 of whom (51.4%) missed no work at all. Patients who were employed were more likely to take opioid analgesics postoperatively (P = .049). Patients who took no opioid analgesics experienced less maximum (P < .001) and persistent groin pain (P = .037). Pain interfered less with daily activities (P = .012) and leisure activities (P = .018) for patients who did not use opioids. The majority of our patients reported that they did not require any opioid analgesics, and nearly all of those who thought that they did need opioids used <5 tablets. Our data suggest that for elective inguinal hernia repair under a local

  13. Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior.

    PubMed

    Schenk, S; Partridge, B

    2001-04-01

    Previous research has indicated that pretreatment with the kappa-opioid receptor agonist, U69593, decreased the ability of experimenter-administered cocaine to reinstate extinguished cocaine self-administration behavior. This effect was specific to cocaine-produced drug seeking since U69593 failed to attenuate the ability of experimenter-administered amphetamine to reinstate extinguished cocaine self-administration behavior. One possibility is that U69593 selectively attenuates the behavioral effects of the drug that was originally self-administered. In order to test this hypothesis, the present study examined the effect of U69593 (0.0 or 0.32 mg/kg) on the reinstatement of extinguished amphetamine self-administration behavior produced by experimenter-administered injections of cocaine and amphetamine. Following extinction of amphetamine self-administration (0.04 mg/kg/infusion) the ability of cocaine (0.0, 5.0, 10.0 or 20.0 mg/kg) or amphetamine (0.0, 0.3, 1.0 or 3.0 mg/kg) to reinstate extinguished self-administration behavior was measured. Both drugs reinstated extinguished responding and the reinstatement was attenuated by pretreatment with U69593. The data indicate that the ability of U69593 to decrease drug seeking is not restricted to subjects experienced with cocaine self-administration. Self-administration history does, however, determine the effect of U69593 on amphetamine-produced drug seeking.

  14. Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone

    PubMed Central

    Mallik, Adiel; Chanda, Mona Lisa; Levitin, Daniel J.

    2017-01-01

    Music’s universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a μ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants’ responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music. PMID:28176798

  15. Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone.

    PubMed

    Mallik, Adiel; Chanda, Mona Lisa; Levitin, Daniel J

    2017-02-08

    Music's universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a μ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants' responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music.

  16. Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement

    PubMed Central

    Richard, Jocelyn M; Fields, Howard L

    2016-01-01

    Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement. PMID:27089981

  17. Conditioning Factors in the Relationship between Stress and Opioid Self-Administration in Rats

    DTIC Science & Technology

    1992-08-03

    correlation between swim -stress induced antinociception and [3Hlleu-enkephalin binding to brain homogenates in mice . Pharmacology Biochemistry and Beha vior...APPROVAL SHEET GRAOIJA TE EDUCATION TEACHING HOSPITALS WALTER REED ARMY MEDICAL CENTER NAVAL HOSPITAL. BETHESDA MALCOLM GROW AIR FORCE MEDICAL...CENTER WILFORD HALL AIR FORCE MEDICAL CENTER Title of Dissertation: "Conditioning Factors in the Relationship between Stress and Opioid Self

  18. Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin.

    PubMed

    Zhang, Ye; Irwin, Michael G; Lu, Yao; Mei, Bin; Zuo, You-Mei; Chen, Zhi-Wu; Wong, Tak-Ming

    2011-04-10

    The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the δ, κ or μ-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three δ, κ and μ opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning.

  19. Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system.

    PubMed

    Biscaia, Miguel; Fernández, Beatriz; Higuera-Matas, Alejandro; Miguéns, Miguel; Viveros, Maria-Paz; García-Lecumberri, Carmen; Ambrosio, Emilio

    2008-04-01

    Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.

  20. Antinociception induced by acute oral administration of sweet substance in young and adult rodents: the role of endogenous opioid peptides chemical mediators and μ(1)-opioid receptors.

    PubMed

    de Freitas, Renato Leonardo; Kübler, João Marcus Lopes; Elias-Filho, Daoud Hibraim; Coimbra, Norberto Cysne

    2012-04-01

    The present work aimed to investigate the effects of acute sucrose treatment on the perception of painful stimuli. Specifically, we sought to determine the involvement of the endogenous opioid peptide-mediated system as well as the role of the μ(1)-opioid receptor in antinociception organisation induced by acute sucrose intake. Nociception was assessed with the tail-flick test in rats (75, 150 and 250 g) of different ages acutely pre-treated with 500 μL of a sucrose solution (25, 50, 150 and 250 g/L) or tap water. Young and Adult rats (250 g) showed antinociception after treatment with 50 g/L (during 5 min) and 150 g/L and 250 g/L (during 20 min) sucrose solutions. Surprisingly, this antinociception was more consistent in mature adult rodents than in pups. To evaluate the role of opioid systems, mature adult rodents were pre-treated with different doses (0.25, 1 or 4 mg/kg) of the non-selective opioid receptor antagonist naloxone, the selective μ(1)-opioid receptor antagonist naloxonazine or vehicle followed by 250 g/L sucrose solution treatment. Sucrose-induced antinociception was reduced by pre-treatment with both naloxone and naloxonazine. The present findings suggest that sweet substance-induced hypo-analgesia is augmented by increasing sucrose concentrations in young and adult rodents. Acute oral sucrose treatment inhibits pain in laboratory animal by mediating endogenous opioid peptide and μ(1)-opioid receptor actions.

  1. Potent inhibition of alcohol self-administration in alcohol-preferring rats by a κ-opioid receptor antagonist.

    PubMed

    Cashman, John R; Azar, Marc R

    2014-07-01

    A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.

  2. Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

    ERIC Educational Resources Information Center

    Pinkston, Jonathan W.; Branch, Marc N.

    2004-01-01

    Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

  3. COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
    Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
    1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

  4. Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

    ERIC Educational Resources Information Center

    Pinkston, Jonathan W.; Branch, Marc N.

    2004-01-01

    Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

  5. COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
    Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
    1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

  6. ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate, Hughes, M. F., Kenyon, E. M., Edwards, B. C., Mitchell, C. T., Del Razo, L. M., and Thomas,
    D. J.

    The human carcinogen inorganic arsenic (iAs) is a pervasive environmental ...

  7. Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.

    PubMed

    Robledo-González, L E; Martínez-Martínez, A; Vargas-Muñoz, V M; Acosta-González, R I; Plancarte-Sánchez, R; Anaya-Reyes, M; Fernández Del Valle-Laisequilla, C; Reyes-García, J G; Jiménez-Andrade, J M

    2017-01-01

    The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund's adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15-day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints

  8. Video Teleconference Administration of the Repeatable Battery for the Assessment of Neuropsychological Status

    PubMed Central

    Galusha-Glasscock, Jeanine M.; Horton, Daniel K.; Weiner, Myron F.; Cullum, C. Munro

    2016-01-01

    Teleneuropsychology applications are growing, but a limited number of assessment tools have been studied in this context. The present investigation was designed to determine the feasibility and reliability of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) administration by comparing video teleconference (VTC) with face-to-face (FF) test conditions. Eighteen adult subjects over age 55 with and without cognitive impairment were administered Forms A and B of the RBANS in VTC and FF settings in counterbalanced fashion. Similar RBANS scores were obtained in both test conditions, with generally high correlations between administration methods. Results support the feasibility and reliability of remote administration of the RBANS via VTC. PMID:26446834

  9. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats

    PubMed Central

    Amitai, Nurith; Kuczenski, Ronald; Behrens, M. Margarita; Markou, Athina

    2011-01-01

    Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and γ-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction. PMID:21238466

  10. Repeated administration of histamine improves memory retrieval of inhibitory avoidance by lithium in mice.

    PubMed

    Zarrindast, Mohammad Reza; Parsaei, Leila; Ahmadi, Shamseddin

    2008-01-01

    The influence of repeated administration of histamine on lithium-induced state dependency has been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg), immediately after training (post-training), impaired inhibitory avoidance memory on the test day. Pre-test administration of lithium reversed amnesia induced by the drug given after training, with the maximum response at a dose of 10 mg/kg. Repeated intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) for 3 consecutive days followed by 5 days of no drug treatment improved memory retrieval of inhibitory avoidance by a pre-test lower dose (5 mg/kg i.p.) of lithium. In contrast, 3 days of i.c.v. injections of both the histamine H1 receptor antagonist pyrilamine (40 microg/mouse) and the histamine H2 receptor antagonist ranitidine (6.25 and 12.5 microg/mouse) prevented the improving effect of pre-test lithium (10 mg/kg i.p.) on memory retrieval. The results suggest that the repeated administration of histaminergic agents may induce a sensitization which affects the memory impairment induced by lithium.

  11. Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.

    PubMed

    Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna

    2016-02-15

    Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.

  12. Loss of the mu opioid receptor on different genetic backgrounds leads to increased bromodeoxyuridine labeling in the dentate gyrus only after repeated injection.

    PubMed

    Cominski, T P; Turchin, C E; Hsu, M S; Ansonoff, M A; Pintar, J E

    2012-03-29

    The endogenous opioid system is involved in various physiological processes, including neurogenesis in the dentate gyrus (DG) of the hippocampus. In the current study, we investigated the role of the mu opioid receptor (MOR-1) on DG neurogenesis and measured glucocorticoid levels following several injection paradigms to supplement the neurogenesis experiments. MOR-1 knockout (KO) mice on C57BL/6 and 129S6 backgrounds were injected with bromodeoxyuridine (BrdU) using either a single injection or two different repeated injection protocols and then sacrificed at different time points. The total number of BrdU and proliferating cell nuclear antigen (PCNA) positive cells in the DG is significantly increased in MOR-1 KO mice compared with wild type (WT) on both strains after repeated injection, but not after a single injection. Plasma corticosterone (CORT) levels increased similarly in MOR-1 KO and WT mice following both single and repeated injection, indicating that the stress response is activated following any injection protocol, but that the mechanism responsible for the increase in BrdU labeling in MOR-1 KO mice is CORT-level independent. Finally, WT 129S6 mice, independent of genotype, showed higher levels of plasma CORT compared with WT C57BL/6 mice in both noninjected controls and following injection at two separate time points; these levels were inversely correlated with low numbers of BrdU cells in the DG in 129S6 mice compared with C57BL/6 mice. In summary, these data demonstrate that loss of MOR-1 increases BrdU labeling in the DG independent of CORT levels, but only following a repeated injection, illustrating the capability of injection paradigms to influence cell-proliferative responses in a genotype-dependent manner.

  13. A ceramic drug delivery vehicle for oral administration of highly potent opioids.

    PubMed

    Forsgren, Johan; Jämstorp, Erik; Bredenberg, Susanne; Engqvist, Håkan; Strømme, Maria

    2010-01-01

    Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.

  14. Opioid dependence

    PubMed Central

    2011-01-01

    Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens. PMID:21929827

  15. Opioid Basics: Prescription Opioids

    MedlinePlus

    ... relievers for acute pain, and high daily doses. Addiction and Overdose Anyone who takes prescription opioids can ... in a primary care setting struggles with opioid addiction. 4,5,6 Once addicted, it can be ...

  16. Effect of acute ethanol administration on the release of opioid peptides from the midbrain including the ventral tegmental area.

    PubMed

    Jarjour, Samuel; Bai, Li; Gianoulakis, Christina

    2009-06-01

    Experimental evidence suggests that ethanol alters the activity of the endogenous opioid peptide systems in a dose and brain-region dependent manner. These alterations may influence the processes of ethanol reward and reinforcement. Thus, it was the objective of this study to investigate the response of the 3 major opioid peptide systems (endorphins, enkephalins, and dynorphins) to acute ethanol administration, at the level of the midbrain including the ventral tegmental area (midbrain/VTA), a region important for drug, including ethanol reinforcement. Using the in vivo microdialysis technique coupled with specific solid-phase radioimmunoassay for beta-endorphin, met-enkephalin, and dynorphin A(1-8,) changes in the extracellular concentration of theses peptides at the level of midbrain/VTA were determined at distinct time points following the administration of 0.0 (saline), 0.8, 1.2, 1.6, 2.0, and 2.4 g ethanol/kg B.Wt. A biphasic effect of ethanol on beta-endorphin release was found, with low to medium (1.2, 1.6, and 2.0 g) but not high (2.4 g) doses of ethanol, inducing a significant increase in the dialysate content of beta-endorphin. A late increase in the dialysate content of dynorphin A(1-8) was observed in response to the 1.2 g ethanol dose. However, none of the ethanol doses tested significantly altered the content of met-enkephalin in the dialysate. The present findings suggest that the ethanol-induced increase of beta-endorphin release at the level of midbrain/VTA may influence alcohol reinforcement.

  17. Activation of the opioid μ1, but not δ or κ, receptors is required for nicotine reinforcement in a rat model of drug self-administration.

    PubMed

    Liu, Xiu; Jernigan, Courtney

    2011-01-15

    There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the μ1, the δ, and the κ opioid receptors. Male Sprague-Dawley rats were trained in daily 1h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for μ1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for δ receptors, 0, 0.5 and 5mg/kg), and 5'-guanidinonaltrindole (GNTI, selective for κ receptors, 0, 0.25 and 1mg/kg). In each individual drug group, the 3 drug doses were tested by using a within-subject and Latin-Square design. The effects of these antagonists on food self-administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid μ1, but not the δ or the κ, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the μ1 receptors would be a promising target

  18. Activation of the opioid μ1, but not δ or κ, receptors is required for nicotine reinforcement in a rat model of drug self-administration

    PubMed Central

    Liu, Xiu; Jernigan, Courtney

    2010-01-01

    There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the μ1, the δ, and the κ opioid receptors. Male Sprague-Dawley rats were trained in daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for μ1 receptors, 0, 5, 15 mg/kg), naltrindole (selective for δ receptors, 0, 0.5, 5 mg/kg), and 5′-guanidinonaltrindole (GNTI, selective for κ receptors, 0, 0.25, 1 mg/kg). In each individual drug group, the 3 drug doses were tested by using a within-subject and Latin-Square design. The effects of these antagonists on food self-administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid μ1, but not the δ or the κ, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the μ1 receptors would be a promising target for

  19. Effects of Repeated Administration of Corticotropin-Releasing Factor on Schedule-Controlled Behavior in Rats

    DTIC Science & Technology

    1993-01-01

    alternate days for 10 days prior to performing on a multiple fixed-interval (FI) 60 s/fixed-ratio (FR) 20 schedule for food reinforcement . A daily...decrease in the number of earned reinforcements in the F1 and FR components, respectively. With repeated administration, CRF-induced suppression of...not result in a loss of reinforcements in the Fl component, whereas rats continued to lose 20% of the reinforcers in the FR component. After an 18-day

  20. Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A

    1997-01-01

    The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones

  1. Possible alteration of tryptophan metabolism following repeated administration of sertraline in the rat brain.

    PubMed

    Nakayama, Kazuhiko; Katsu, Hisatoshi; Ando, Tomomichi; Nakajo, Ryutaro

    2003-01-15

    The levels of tryptophan and the serotonin (5-HT) turnover were examined in various brain regions of rats after single or repeated treatment with the selective 5-HT uptake inhibitor, sertraline. A single administration of sertraline (10mg/kg, i.p.) increased tryptophan and 5-HT levels in all the brain regions investigated. The levels of 5-hydroxyindolacetic acid (5-HIAA) decreased in various brain regions. The 5-HIAA/5-HT ratio as turnover index was significantly decreased by a single administration of sertraline in all the brain regions investigated. Daily treatment with sertraline (10mg/kg) for 21 days did not affect tryptophan and 5-HT levels in various brain regions 1h after last injection. The 5-HT turnover was not changed in any of the brain regions investigated by a repeated administration of sertraline. In conclusion, the data show that the increase in tryptophan levels and the decrease in 5-HT turnover in rat brain are attenuated by repeated treatment of sertraline.

  2. Elimination of Progressive Mammary Cancer by Repeated Administrations of Chimeric Antigen Receptor-Modified T Cells

    PubMed Central

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-01-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease. PMID:24572294

  3. Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells.

    PubMed

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-05-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease.

  4. Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.

    PubMed

    Vlachou, Styliani; Guery, Sebastien; Froestl, Wolfgang; Banerjee, Deboshri; Benedict, Jessica; Finn, M G; Markou, Athina

    2011-05-01

    γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA(B) receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA(B) receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA(B) receptor agonists, GABA(B) receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. We examined whether the acute effects of the GABA(B) receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self-administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. These results showed that BHF177 selectively blocked nicotine self-administration and prevented cue-induced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA(B) receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans.

  5. Medications Development for Opioid Abuse

    PubMed Central

    Negus, S. Stevens; Banks, Matthew L.

    2013-01-01

    Here we describe methods for preclinical evaluation of candidate medications to treat opioid abuse and dependence. Our perspective is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effects, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) the states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and the effects of candidate medications. Effects of opioid medications on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications, and (2) continued development of nonopioids such as inhibitors of endocannabinoid catabolic enzymes or inhibitors of opioid-induced glial activation. PMID:23125072

  6. Intrathecal morphine versus intravenous opioid administration to impact postoperative analgesia in hepato-pancreatic surgery: a randomized controlled trial.

    PubMed

    Dichtwald, Sara; Ben-Haim, Menahem; Papismedov, Laila; Hazan, Shoshana; Cattan, Anat; Matot, Idit

    2017-04-01

    Inadequate analgesia following abdominal surgery may affect outcome. Data in patients undergoing liver surgery suggested that postoperative coagulopathy might delay epidural catheter removal. Thus, alternative analgesic techniques should be evaluated. We compared the analgesic efficacy of intraoperative intrathecal morphine [single injection 4 µg/kg before skin incision (ITM group, n = 23)] to intravenous opioids [iv remifentanil infusion during surgery followed by i.v. bolus of morphine, 0.15 mg/kg before the end of surgery (IVO group, n = 26)]. Forty-nine adult patients undergoing elective open resection of liver or pancreas lesions in the Tel Aviv Medical Center were randomized into the two analgesic protocols. Postoperatively both groups received i.v. morphine via a patient-controlled analgesia pump. Follow-up was till the 3rd postoperative day (POD). There was no significant difference in demographics and intraoperative data between groups. The primary outcome, pain scores on movement, was significantly worse in the IVO group when compared with the ITM group at various time points till POD3. In the secondary outcomes - need for rescue drugs - the IVO group required significantly more rescue morphine boluses. Complication related to the analgesia and recovery parameters were similar between groups. The findings suggest that a single dose of ITM before hepatic/pancreatic surgery may offer better postoperative pain control than i.v. opioid administration during surgery. This beneficial effect is maintained throughout the first three PODs and is not associated with a higher complication rate; neither did it influence recovery parameters. ITM provides an appropriate alternative to i.v. morphine during major abdominal surgery.

  7. Characteristics of Veterans Receiving Buprenorphine vs. Methadone for Opioid Use Disorder Nationally in the Veterans Health Administration

    PubMed Central

    Manhapra, Ajay; Quinones, Lantie; Rosenheck, Robert

    2016-01-01

    BACKGROUND The advent of buprenorphine as an alternative to methadone has dramatically shifted the landscape of opioid agonist therapy (OAT) for opioid use disorder (OUD). However, there is limited US national level data describing the differences between patients who are prescribed these two OAT options. METHODS From veterans with OUD diagnosis who used Veterans Health Administration services in 2012, we identified 3 mutually exclusive groups: those who received (1) buprenorphine only (n=5,670); (2) methadone only (n=6,252); or (3) both buprenorphine and methadone in the same year (n=2513). We calculated the bi-varate effect size differences (risk ratios and Cohen's d) for characteristics that differentiated these groups. Logistic regression analysis was then used to identify factors independently differentiating the groups. RESULTS Ten year increment in age (OR 0.67; 95% CI 0.64-0.70), urban residence (OR 0.26; 95% CI 0.25-0.33), and black race (OR 0.39; 95% CI 0.35-0.43) were strongly and negatively associated with odds of receiving buprenorphine compared to methadone, while medical and psychiatric comorbidities or receipt of other psychiatric medications did not demonstrate substantial differences between groups. CONCLUSIONS Differences between veterans receiving buprenorphine or methadone based OAT seems to be largely shaped by demographic characteristics rather than medical or psychiatric or service use characteristics. A clearer understanding of the reasons for racial differences could be helpful in assuring that black OUD patients are not denied the opportunity to receive buprenorphine if that is their preference. PMID:26804898

  8. Xendorphin B1, a novel opioid-like peptide determined from a Xenopus laevis brain cDNA library, produces opioid antinociception after spinal administration in amphibians

    PubMed Central

    Stevens, Craig W.; Tóth, Géza; Borsodi, Anna; Benyhe, Sándor

    2007-01-01

    Prodynorphins (PDYNs) from the African clawed frog (Xenopus leavis), originally described as ‘proxendorphins’, are novel members of the family of opioid-like precursor polypeptides and were recently discovered based on polymerase chain reaction (PCR) isolates from a Xenopus brain cDNA library. This amphibian prodynorphin was found in two isoforms, XenPDYN-A and XenPDYN-B, consisting of 247 and 279 amino acids, respectively. Each prepropeptide contains five potential opioid-like peptides, collectively named xendorphins. One of these, xendorphin B1 (XenPDYN-B sequence 96–111: YGGFIRKPDKYKFLNA), is a hexadecapeptide that displaced [3H]naloxone and the radiolabelled kappa opioid, [3H]dynorphin A (1–17), with nanomolar affinity from rat brain membranes. Using the acetic acid pain test, the present study examined the antinociceptive effects of spinally administered xendorphin B1 in amphibians. Xendorphin B1 produced a long-lasting and dose-dependent antinociceptive effect in the Northern grass frog (Rana pipiens) with an ED50 value of 44.5 nmol/frog. The antinociceptive effects of xendorphin B1 were significantly blocked by pretreatment with the non-selective opioid antagonist, naltrexone. This is the first report of the in vivo characterization of a non-mammalian prodynorphin-derived peptide and suggests that xendorphin peptides may play a role in the modulation of noxious information in vertebrates. PMID:17292806

  9. Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration.

    PubMed

    Schenk, S; Partridge, B; Shippenberg, T S

    2001-04-01

    Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effects of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was also sensitive to antagonism by kappa-opioid agonists. During a pretreatment phase, the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg) was administered prior to (1) 2 daily injections of cocaine (0.0 or 20.0 mg/kg), or (2) cocaine or saline administered via a yoking procedure. Cocaine pretreatment decreased the latency to acquisition of cocaine self-administration. However, prior administration of U69593 during the pretreatment phase failed to attenuate the development of this sensitized response to cocaine's reinforcing effect. In other groups, the effect of acute U69593 pretreatment on the maintenance of cocaine self-administration was examined during a 10 hr session. During training and testing, a stimulus was associated with each self-administered cocaine infusion for one group whereas responding of another group was reinforced by a cocaine infusion alone. On the test day, pretreatment with U69593 (0.32 mg/kg) decreased responding during each hour of the 10 hr session for the group that was reinforced with cocaine plus the cocaine-associated stimulus. U69593 failed to produce a long-lasting disruption of cocaine self-administration for rats that were trained and tested without the cocaine-associated stimulus. These data suggest that the acquisition and maintenance of cocaine self-administration are differentially sensitive to manipulations of kappa-opioid systems. Further, the disruption of cocaine self-administration by U69593 may be due to interactions with mechanisms that underlie facilitative effects of stimuli that have been associated with self-administered cocaine infusions.

  10. Developing Items to Measure Theory of Planned Behavior Constructs for Opioid Administration for Children: Pilot Testing.

    PubMed

    Vincent, Catherine; Riley, Barth B; Wilkie, Diana J

    2015-12-01

    The Theory of Planned Behavior (TpB) is useful to direct nursing research aimed at behavior change. As proposed in the TpB, individuals' attitudes, perceived norms, and perceived behavior control predict their intentions to perform a behavior and subsequently predict their actual performance of the behavior. Our purpose was to apply Fishbein and Ajzen's guidelines to begin development of a valid and reliable instrument for pediatric nurses' attitudes, perceived norms, perceived behavior control, and intentions to administer PRN opioid analgesics when hospitalized children self-report moderate to severe pain. Following Fishbein and Ajzen's directions, we were able to define the behavior of interest and specify the research population, formulate items for direct measures, elicit salient beliefs shared by our target population and formulate items for indirect measures, and prepare and test our questionnaire. For the pilot testing of internal consistency of measurement items, Cronbach alphas were between 0.60 and 0.90 for all constructs. Test-retest reliability correlations ranged from 0.63 to 0.90. Following Fishbein and Ajzen's guidelines was a feasible and organized approach for instrument development. In these early stages, we demonstrated good reliability for most subscales, showing promise for the instrument and its use in pain management research. Better understanding of the TpB constructs will facilitate the development of interventions targeted toward nurses' attitudes, perceived norms, and/or perceived behavior control to ultimately improve their pain behaviors toward reducing pain for vulnerable children.

  11. Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

    PubMed

    Macnamara, Claire L; Holmes, Nathan M; Westbrook, R Fred; Clemens, Kelly J

    2016-06-01

    Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Role of Serine Racemase in Behavioral Sensitization in Mice after Repeated Administration of Methamphetamine

    PubMed Central

    Horio, Mao; Kohno, Mami; Fujita, Yuko; Ishima, Tamaki; Inoue, Ran; Mori, Hisashi; Hashimoto, Kenji

    2012-01-01

    Background The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. Methodology/Principal Findings Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. Conclusions/Significance These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may

  13. Influence of repeated administration of cholecystokinin and secretin on the pancreas of the rat.

    PubMed

    Fölsch, U R; Winckler, K; Wormsley, K G

    1978-01-01

    Repeated injections of cholecystokinin (CCK) during a period of up to 3 weeks significantly increased the weight of the pancreas in rats. This was associated with an increase in the amount of protein per unit weight of DNA, suggesting hypertrophy of the acinar cells, and with increase in the total amount of pancreatic DNA, indicating additional hyperplasia of the gland. CCK administration also increased the pancreatic content of amylase and trypsin, but the content of lipase remained unchanged. The rate of secretion of the two enzymes increased in the CCK-treated rats, although it appeared that the functional capacity of the individual pancreatic acinar cells was not increased. CCK injections had no effect on the insulin content of the pancreas or on the composition of the partoid glands. Repeated injections of secretin in the doses used in this study had no effect on the pancreas.

  14. Effects of nicotine gum on repeated administration of the Stroop test.

    PubMed

    Provost, S C; Woodward, R

    1991-01-01

    Using a double-blind procedure, 24 non-smoking subjects chewed either 2 mg nicorette gum or a placebo for 20 min, before completing a Stroop test on three occasions. Colour-word reading and simple colour naming times were consistent across repeats, and were unaffected by nicotine. However, the time taken to name the colour of incongruous colour word stimuli declined across trials. This increase in speed across repeats was significantly greater in those subjects who had received nicotine. These data are consistent with previous reports of a decreased Stroop effect following nicotine administration, but are not compatible with a simple model which assumes that nicotine alters the way in which information is filtered by selective attentional mechanisms. The present results can be explained by postulating that nicotine influences either the rate at which colour naming become more automatic, or changes the way in which resources are allocated to non-automatic processes.

  15. Effects of repeated administration of methamphetamine on P3-like potentials in rats.

    PubMed

    Takeuchi, S; Jodo, E; Suzuki, Y; Matsuki, T; Niwa, S; Kayama, Y

    1999-06-01

    Effects of repeated administration of methamphetamine (MAP) on a component of the cortical event-related potential (ERP), P3-like potential which corresponds to the human P3b, were examined in rats performing an active discrimination task. Rats were trained to press a bar within 1200 ms after cessation of a target tone (1000 Hz) lasting for 800 ms, and to withhold an overt response to the standard tone (2000 Hz). The rats were given intracranial electrical stimulation to the medial forebrain bundle as a reward, only when they correctly responded to the target tone. ERPs before drug administration were recorded after the correct response ratio exceeded 85%. Thereafter, a daily dose of 4 mg/kg of MAP, or the same volume of saline in another group, was administered intraperitoneally 15 times. ERPs were recorded again 7-10 days after the last injection. In the rats which received MAP the amplitude of the P3-like potential decreased with no change in its latency, while the response latency of bar-pressing and the correct response ratio were not altered significantly. These results suggest some changes in catecholaminergic transmission induced by repeated MAP-administration affect a P3 generation mechanism. MAP-treated rats may be useful as an animal model to investigate neural mechanisms of MAP-psychosis and schizophrenia.

  16. Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats.

    PubMed

    Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

    2017-04-01

    Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

  17. Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

    PubMed Central

    Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

    2017-01-01

    Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis. PMID:28413513

  18. Repeated chlorpromazine administration increases a behavioural response of rats to 5-hydroxytryptamine receptor stimulation.

    PubMed Central

    Green, A R

    1977-01-01

    1 The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by L-tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5-hydroxytryptamine (5-HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and L-tryptophan administration 24 h after the final dose of chlorpromazine. 2 One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/L-tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and L-tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose. 3 Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioral responses to the suggested 5-HT agonist 5-methoxy N,N-dimethyltryptamine (2 mg/kg) on day 5. 4 Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5-hydroxytryptamine (5-HT) concentration on day 5, but no difference in the rate of brain 5-HT synthesis or the rate of 5-HT accumulation after tranylcypromine and L-tryptophan administration. 5. There is some evidence that chlorpromazine blocks 5-HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5-HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5-HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5-HT receptors. PMID:264797

  19. Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex.

    PubMed

    Wabno, Joanna; Hess, Grzegorz

    2013-05-01

    Alterations in the functions of brain gamma-aminobutyric acid (GABA) inhibitory system and a distortion in the balance between excitatory and inhibitory synaptic transmission have been hypothesized to be possible causes of mood disorders. Experimental evidence points to modifications of GABAergic transmission as a result of prolonged treatment with antidepressant drugs, however, the influence of the tricyclic antidepressant imipramine on inhibitory synaptic transmission in the rat cerebral cortex has not yet been investigated. Therefore, in the present study the effects of single and repeated administration of imipramine were evaluated ex vivo in slices of the rat frontal cortex using electrophysiological approach. In slices prepared 2 days after the last drug administration from animals receiving imipramine for 14 days (dose 10 mg/kg p.o., twice daily) the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II/III pyramidal neurons was decreased, while the mean amplitude of sIPSCs was increased. These effects were absent in slices obtained from rats which received imipramine once. Application of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN 082), a selective mGluR7 allosteric agonist, to the slice incubation medium resulted in a decrease in the mean frequency of sIPSCs in preparations obtained from repeated imipramine-treated animals, in contrast to slices originating from control rats where no AMN 082-induced effects were observed. Repeated imipramine treatment reduced protein density levels of the three tested GABAA receptor subunits: α 1, β 2 and γ 2. These data indicate that repeated treatment of normal rats with imipramine results in a modification of the release mechanism of GABA from presynaptic terminals and its modulation by mGluR7 receptors as well as in an alteration in GABAA receptor subunit protein levels in the rat cerebral cortex.

  20. Different dosing regimens of repeated ketamine administration have opposite effects on novelty processing in rats.

    PubMed

    Schumacher, Anett; Sivanandan, Brindan; Tolledo, Edgor Cole; Woldegabriel, Jacob; Ito, Rutsuko

    2016-08-01

    Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure.

    PubMed

    Caputi, Francesca Felicia; Palmisano, Martina; Carboni, Lucia; Candeletti, Sanzio; Romualdi, Patrizia

    2016-12-01

    The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ)-NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8mg/kg) or repeated (8mg/kg twice daily for seven days) MDMA exposure. MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure. Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up-regulation. Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse.

  2. Persistence and accumulation of micronucleated hepatocytes in liver of rats after repeated administration of diethylnitrosamine.

    PubMed

    Narumi, Kazunori; Ashizawa, Koji; Fujiishi, Yohei; Tochinai, Ryota; Okada, Emiko; Tsuzuki, Yasuhiro; Tatemoto, Hideki; Hamada, Shuichi; Kaneko, Kimiyuki; Ohyama, Wakako

    2013-08-15

    A repeat-dose micronucleus assay in adult rat liver was recently developed [Mutat. Res. 747 (2012) 234-239]. This assay demonstrated a high detectability of hepatocarcinogens at relatively low doses, as indicated by dose-dependent micronucleus induction. Because the adult rat liver is known to have a long life-span, this desirable property of the assay will be an advantage in detecting micronucleated hepatocytes (MNHEPs) that have persisted for long periods in the liver following repeated dosing. However, no data directly supporting the underlying mechanisms have been published to date. In the present study, we verified the mechanisms by means of pulse-labeling of micronucleated hepatocytes with the thymidine analog 5-ethynyl-2'-deoxyuridine (EdU). The rodent hepatocarcinogen diethylnitrosamine (DEN) was repeatedly administered orally to male Crl:CD (SD) rats (6 weeks old) for up to 2 weeks, and EdU was injected intraperitoneally on days 1, 7, or 14. Hepatocytes were isolated by use of a non-perfusion technique at 24h, 1 week, or 2 weeks after EdU injection and analyzed for EdU incorporation and micronucleus formation. The results of our study confirmed that MNHEPs labeled with EdU on the first day of DEN administration persisted until 2 weeks post-administration in the rat livers. However, the frequency of MHNEPs among EdU-labeled hepatocytes decreased over time. In addition, the number of terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL)-positive cells in the liver tissue increased, suggesting selective removal of micronucleated cells. Theoretical calculation of the cumulative MNHEP frequency on each of the days on which DEN was administered, taking into account the rate of loss, came out closer to the actual value observed in the liver micronucleus test. Taken together, these results indicate that although micronucleated cells induced in rat livers by administration of the genotoxic hepatocarcinogen DEN undergo selective removal, they

  3. Intermittent, chronic fenfluramine administration to rats repeatedly suppresses food intake despite substantial brain serotonin reductions.

    PubMed

    Choi, SuJean; Jonak, Elizabeth M; Simpson, Lynn; Patil, Vaishali; Fernstrom, John D

    2002-02-22

    The mechanisms by which fenfluramine suppresses food intake and body weight have been linked to its ability to enhance transmission across serotonin synapses in brain. This drug initially lowers body weight and suppresses food intake, yet after repeated administration food intake soon returns to normal and body weight no longer decreases. Fenfluramine also causes rapid and prolonged reductions in brain serotonin concentrations, which might account for its loss of appetite suppression. This possibility has been evaluated in rats by assessing if intermittent, chronic fenfluramine administration could suppress food intake during each treatment period, and if so, whether such an effect occurs in the presence of reduced brain serotonin levels. Rats were injected once daily with 10 mg/kg D,L-fenfluramine for 5 days, and then received no injections for the next 5 days. Control rats received only vehicle injections. This 10-day sequence was repeated five more times. During each period of fenfluramine administration, daily food intake dropped markedly the first 1-2 days of treatment, but returned to pretreatment values by day 5. Daily food intake was normal or slightly above normal during non-injection periods. Body weight dropped modestly during each period of fenfluramine administration, and rose during each subsequent period when injections had ceased. Serotonin concentrations and synthesis rates in several brain regions were markedly reduced at early, middle, and late periods of the experiment. Despite the long-term reduction in brain serotonin pools produced by fenfluramine, the drug continues to reduce food intake and body weight. Several possible interpretations of these findings are considered, based on the multiple mechanisms through which this drug has been proposed to modify synaptic serotonin transmission.

  4. Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain.

    PubMed

    Holdridge, Sarah V; Cahill, Catherine M

    2007-08-01

    Neuropathic (NP) pain is a debilitating chronic pain disorder considered by some to be inherently resistant to therapy with traditional analgesics. Indeed, micro opioid receptor (OR) agonists show reduced therapeutic benefit and their long term use is hindered by the high incidence of adverse effects. However, pharmacological and physiological evidence increasingly suggests a role for deltaOR agonists in modulating NP pain symptoms. In this study, we examined the antihyperalgesic and antiallodynic effects of the spinally administered deltaOR agonist, d-[Ala(2), Glu(4)]deltorphin II (deltorphin II), as well as the changes in deltaOR expression, in rats following chronic constriction injury (CCI) of the sciatic nerve. Rats with CCI exhibited cold hyperalgesia and mechanical allodynia over a 14-day testing period. Intrathecal administration of deltorphin II reversed cold hyperalgesia on day 14 and dose-dependently attenuated mechanical allodynia. The effects of deltorphin II were mediated via activation of the deltaOR as the effect was antagonized by co-treatment with the delta-selective antagonist, naltrindole. Western blotting experiments revealed no changes in deltaOR protein in the dorsal spinal cord following CCI. Taken together, these data demonstrate the antihyperalgesic and antiallodynic effectiveness of a spinally administered deltaOR agonist following peripheral nerve injury and support further investigation of deltaORs as potential therapeutic targets in the treatment of NP pain.

  5. Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

    PubMed

    Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C

    2009-10-01

    Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

  6. Self-Administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of mu receptor efficacy using labor supply analysis.

    PubMed

    Rowlett, James K; Rodefer, Joshua S; Spealman, Roger D

    2005-03-01

    Cocaine and heroin often are abused by self-administering the drugs in combination as a "speedball". We evaluated the extent to which intrinsic efficacy at the mu-opioid receptor influences combined cocaine-opioid self-administration and used the behavioral economic model termed "labor supply" to quantitatively evaluate the reinforcing effects of cocaine-opioid combinations. Rhesus monkeys (n = 8) were trained under a progressive-ratio schedule of i.v. cocaine injection in which the response requirement increased during the experimental session and the initial response requirement was varied. Combination of cocaine with heroin enhanced self-administration compared with the drugs individually, with ineffective doses of both drugs maintaining self-administration when combined. These effects also were observed with the high-efficacy mu agonist alfentanil and low-efficacy agonist nalbuphine. Using the labor supply economic model, combinations of heroin, alfentanil, or nalbuphine with relatively low doses of cocaine were found to increase the number of injections per session ("income") and total responses per session ("labor"). Combination of a relatively high dose of cocaine with either heroin or alfentanil, but not nalbuphine, also resulted in only a small reduction in income concomitant with increased labor, suggesting that heroin and alfentanil made cocaine consumption more resistant to increasing response costs, or more "inelastic." Collectively, these findings suggest that speedball self-administration may occur even with relatively low levels of intrinsic efficacy at mu-opioid receptors and that an inelastic relationship between drug consumption and labor may contribute to the persistence of speedball abuse.

  7. The influence of time of day of administration on duration of opioid labor analgesia.

    PubMed

    Scavone, Barbara M; McCarthy, Robert J; Wong, Cynthia A; Sullivan, John T

    2010-10-01

    Medications administered into the epidural or intrathecal space for labor analgesia may demonstrate variable effects dependent on time of day, and this may affect clinical research trials investigating the pharmacology of specific drugs. In this retrospective study, we evaluated the effect of time of day of administration of intrathecal fentanyl and systemic hydromorphone labor analgesia from data collected as part of a randomized clinical trial examining the influence of analgesia method on labor outcome. Six hundred ninety-two healthy parturients were randomized early in labor to receive combined spinal-epidural (intrathecal fentanyl 25 μg followed by a lidocaine and epinephrine containing epidural test dose) versus systemic (hydromorphone 1 mg IV and 1 mg IM) labor analgesia at first analgesia request. No further analgesics were administered until the patient requested additional analgesia (second analgesia request). Subjects were assigned to the daytime group (DAY) if initial analgesia (neuraxial or systemic) was administered between the hours of 07:01 and 23:00 and to the nighttime group (NIGHT) if it was administered between 23:01 and 07:00. Within each mode of analgesia study arm (neuraxial or systemic), the DAY and NIGHT groups were compared. The primary outcome variable was analgesia duration, defined as the time interval from administration of labor analgesia until the second analgesia request. Cervical dilation at first and second analgesia requests, pain score at first analgesia request, and average amount of pain between analgesia administration and second analgesia request were also compared between DAY and NIGHT groups. Rhythm analyses for duration of analgesia, cervical dilation, and pain scores were performed. There was no difference in the median duration of either neuraxial or systemic analgesia in DAY versus NIGHT subjects, and no harmonic variation was observed for analgesia duration. Rhythm analysis demonstrated a 24-h harmonic cycle for

  8. Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects.

    PubMed

    Zhang, G-F; Liu, W-X; Qiu, L-L; Guo, J; Wang, X-M; Sun, H-L; Yang, J-J; Zhou, Z-Q

    2015-06-01

    Current available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects.

  9. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    PubMed Central

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-01-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans. PMID:1637802

  10. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    PubMed

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-06-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans.

  11. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep.

    PubMed

    Huang, W L; Harper, C G; Evans, S F; Newnham, J P; Dunlop, S A

    2001-07-01

    Glucocorticoids regulate oligodendrocyte maturation and the myelin biosynthetic pathways. Synthetic glucocorticoids, the corticosteroids have been successfully used in clinical practice as a single course to enhance lung maturation and reduce mortality and morbidity in preterm infants with no long-term neurologic or cognitive side effects. However, a trend has arisen to use repeated courses despite an absence of safety data from clinical trials. We examined the effects of clinically appropriate, maternally administrated, repeated courses of corticosteroids on myelination of the corpus callosum using sheep as a large animal model. The corpus callosum is a major white matter tract that undergoes protracted myelination, underpins higher order cognitive processing and developmental damage to which is associated with, for example, cerebral palsy, mental retardation and attention deficit hyperactivity disorder. Pregnant ewes were given saline or betamethasone (0.5 mg/kg) at 104,111,118 and 124 days gestation, stages equivalent to the third trimester in humans. Lambs were delivered at 145 days (term), perfused and the corpus callosum examined light and electron microscopically. Total axon numbers were unaffected (P>0.05). However, myelination was significantly delayed. Myelinated axons were 5.7% in the experimental group and 9.2% in controls (P<0.05); conversely, unmyelinated axons were 88.3 and 83.7% (P<0.05). Myelinated axon diameter and myelin sheath thickness were also reduced (0.68 vs. 0.94 and 0.11 vs. 0.14 microm, P<0.05). Our data suggest that repeated prenatal corticosteroid administration delays myelination of the corpus callosum and that further safety data are needed to evaluate clinical practice.

  12. [Study on absorption and accumulation of mercury in rats by repeated administration of Yuhong ointment].

    PubMed

    Qiu, Heng; Sun, Xin-Min; Huang, Wen; Hu, Xiao-Jing; Wang, Qi; Mou, Ji-Zheng; Wang, Li-Xia

    2013-03-01

    To study in vivo mercury absorption and accumulation through repeated transdermal administration of Yuhong ointment containing calomel, in order to provide scientific evidences for clinical safe medication. A total of 100 SD rats were randomly classified into five groups: the control group, the Yuhong ointment group, the double-concentration Yuhong Ointment group, the quadruple-concentration Yuhong ointment group and the 1.6% calomel group. The rats were treated with the dosage of 0.04 g . cm-2 by repeated transdermal administration for 2, 4 weeks. After the drug discontinuance for 4 weeks, the levels of mercury in blood, urine, and tissues of heart, liver, brain and kidney were determined, respectively. Compared with the control group, the blood mercury level of the Yuhong ointment group show no obvious change after treatment for 4 weeks. However, the levels of mercury in blood and urine of other experimental groups increased significantly with time and the increase in dosage, and so did the level of mercury in major organ. At 4 weeks, all experimental groups showed increase in the content of mercury, and kidneys displayed the highest level, whereas brain displayed the lowest level After the drug discontinuance for 4 weeks, the mercury level in blood and urine of every dose group recovered to normal, with significant decline in the content of mercury in each organ. After transdermal administration in rats for 4 weeks, there was no obvious absorption of mercury in blood. Mercury was mainly accumulated in kidneys and excreted through urine. The results suggest that the patients' mercury content and kidney function indexes need to be monitored in long-term clinical use of Yuhong ointment.

  13. Acute and residual interactive effects of repeated administrations of oral methamphetamine and alcohol in humans

    PubMed Central

    Kirkpatrick, Matthew G.; Gunderson, Erik W.; Levin, Frances R.; Foltin, Richard W.; Hart, Carl L.

    2011-01-01

    Although methamphetamine and alcohol are commonly used together in a binge-like pattern, there is a dearth of empirical data investigating the repeated effects of this drug combination. The current study examined acute and residual mood, performance, and physiological effects of methamphetamine alone, alcohol alone, and the combination. Nine adult male volunteers completed this 20-day within-participant, residential laboratory study. During four 5-day blocks of sessions, participants were administered oral methamphetamine (0, 10 mg) combined with alcohol (0, 0.375, 0.75 g/kg) three times (day 2: AM, day 2: PM, and day 3: PM). Breath alcohol concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and repeatedly thereafter. Subjective and objective sleep measures were also assessed; residual effects were assessed on days 3–5 of each block. Following the first drug administration, the methamphetamine–alcohol combination produced greater elevations of heart rate and ratings of “good drug effect” compared to either drug alone. Methamphetamine attenuated alcohol-related performance decrements and feelings of intoxication, whereas alcohol attenuated methamphetamine-related sleep disruptions. By the third administration, many of these effects were significantly diminished, suggesting that participants developed tolerance. Few residual effects were observed. These data show that methamphetamine combined with alcohol produced a profile of effects that was different from the effects of either drug alone. The largely positive effects of the drug combination (i.e., greater euphoria, and fewer performance and sleep disruptions) might explain why these drugs are often used in combination. PMID:21748253

  14. Patterns of cocaine and opioid co-use and polyroutes of administration among street-based cocaine users in Montréal, Canada.

    PubMed

    Roy, Élise; Richer, Isabelle; Arruda, Nelson; Vandermeerschen, Jill; Bruneau, Julie

    2013-03-01

    Effective public health programs aimed at problematic cocaine users are challenged by the fact that they can have complex patterns of drug use with respect to polysubstance use and routes of drug administration. This study was carried out to explore the presence of subgroups of cocaine users on the basis of their concurrent use of opioids and their routes of cocaine and opioid administration, and to determine if subgroups could be differentiated in terms of sociodemographic factors and risk behaviours. Regular cocaine users (≥1 per week) were recruited in low-threshold services located in the Montréal downtown area. The following variables were examined: demographic characteristics, types of drug used, routes of drug administration, and condom use with occasional or commercial sexual partners. Latent class analysis and multinomial logistic regression modeling were carried out. 886 cocaine users were recruited (83.5% male: mean age 35.38 years). A 5-class model was identified: (1) "cocaine smokers" (CSs) (n = 161; membership probability (MP) = 0.183); (2) "cocaine smokers/sniffers" (CSSs) (n = 201; MP = 0.218); (3) "cocaine injectors" (CIs) (n = 207; MP = 0.231); (4) "cocaine-opioid injectors" (COIs) (n = 277; MP = 0.291); (5) "cocaine-opioid polyroute users" (COPs) (n = 40; MP = 0.077). Compared with COIs, other subtypes were significantly different in terms of either age, duration of cocaine use, ethnic background, homelessness, polydrug use or condom use. The heterogeneity of consumption patterns supports the importance of offering an array of interventions aimed at problematic cocaine users. These should include the provision of clean injecting and smoking material, the promotion of safe sexual behaviours and the prevention of initiation to drug injection. In the absence of specific treatment, cocaine users should have access to primary health care services and addiction treatment based on innovative behavioural and pharmacological approaches. Copyright

  15. Opioid intoxication

    MedlinePlus

    ... use of opioid-based drugs. These include morphine, heroin, oxycodone, and synthetic (man-made) opioid narcotics. Prescription ... United States, the most commonly abused opioids are heroin and methadone. People who become addicted to these ...

  16. Effect of oral administration of sodium bicarbonate on surface EMG activity during repeated cycling sprints.

    PubMed

    Matsuura, Ryouta; Arimitsu, Takuma; Kimura, Takehide; Yunoki, Takahiro; Yano, Tokuo

    2007-11-01

    The purpose of this study was to determine the effect of oral administration of sodium bicarbonate (NaHCO3) on surface electromyogram (SEMG) activity from the vastus lateralis (VL) during repeated cycling sprints (RCS). Subjects performed two RCS tests (ten 10-s sprints) interspersed with both 30-s and 360-s recovery periods 1 h after oral administration of either NaHCO3 (RCSAlk) or CaCO3 (RCSPla) in a random counterbalanced order. Recovery periods of 360 s were set before the 5th and 9th sprints. The rate of decrease in plasma HCO3- concentration during RCS was significantly greater in RCSAlk than in RCSPla, but the rates of decline in blood pH during the two RCS tests were similar. There was no difference between change in plasma lactate concentration in RCSAlk and that in RCSPla. Performance during RCSAlk was similar to that during RCSPla. There were no differences in oxygen uptake immediately before each cycling sprint (preVO2) and in SEMG activity between RCSAlk and RCSPla. In conclusion, oral administration of NaHCO3 did not affect SEMG activity from the VL. This suggests that the muscle recruitment strategy during RCS is not determined by only intramuscular pH.

  17. Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse

    PubMed Central

    Do, Phong H.; See, Ronald E.

    2011-01-01

    Rationale Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D2/D3 receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. Objectives We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Materials and methods Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10–14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Results Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. Discussion These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder. PMID:19779699

  18. Amplified reacquisition of nicotine self-administration in rats by repeated stress during abstinence.

    PubMed

    Yu, Guoliang; Chen, Hao; Sharp, Burt M

    2014-08-01

    Quitting smoking is often very challenging, leading to frequent relapse. Exposure to acute and chronic stress during abstinence increases the likelihood of relapse to smoking. In rodents, stress acutely reinstates nicotine seeking after extinction of nicotine self-administration (SA). However, whether reacquisition of nicotine taking is amplified by chronic stress during abstinence from nicotine SA has not been determined in animals. We sought to determine effects of repeated restraint stress during abstinence on reacquisition of nicotine SA. Rats acquired nicotine SA (23 h/day) under a fixed-ratio (FR) 5 schedule of reinforcement, which was followed by an abstinence phase. Restraint (0, 2, and 4 times) was administered during abstinence. Animals reacquired nicotine SA, first under a progressive ratio (PR) schedule, beginning immediately after the final stress, followed by an FR5 schedule. In another experiment, reacquisition (FR5) began 24 h after the final stress. No PR testing was conducted. Four restraint stress exposures during abstinence, but not only two, enhanced reacquisition of nicotine SA by increasing nicotine injections under a PR schedule beginning immediately after the final stress (p < 0.05) followed by increasing nicotine intake under an FR5 schedule (p < 0.05). This was observed even when the final stress and reacquisition trial were separated by 24 h. Moreover, repeated stress-induced nicotine taking during the behaviorally inactive phase (i.e., lights on) of the 24-h diurnal cycle. Chronic (i.e., repeated) stress during abstinence promotes reacquisition of nicotine SA and affects diurnal pattern of nicotine intake.

  19. Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference.

    PubMed

    Zarrindast, M-R; Nasehi, M; Rostami, P; Rezayof, A; Fazli-Tabaei, S

    2005-03-01

    The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.

  20. Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse.

    PubMed

    Feltenstein, Matthew W; Do, Phong H; See, Ronald E

    2009-12-01

    Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D(2)/D(3) receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10-14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder.

  1. Effects of repeated administration of methylphenidate on reproductive parameters in male rats.

    PubMed

    Montagnini, Bruno Garcia; Silva, Luiza Sienna; dos Santos, Alice Hartmann; Anselmo-Franci, Janete Aparecida; Fernandes, Glaura Scantamburlo Alves; Mesquita, Suzana de Fátima Paccola; Gerardin, Daniela Cristina Ceccatto

    2014-06-22

    Methylphenidate (MPH) is a psychostimulant drug which acts by blocking the dopamine and norepinephrine transporters and is the main drug used to treat attention deficit hyperactivity disorder in children and adolescents. During puberty, changes in neurotransmitter systems (including dopaminergic system) are engaged on the release of gonadal hormones and the development of cephalic structures responsible for reproductive function. This study investigated the effects of repeated treatment with methylphenidate during development on reproductive parameters of adult male rats. Wistar rats received MPH 2.5 mg/kg, MPH 5.0 mg/kg, or distilled water (gavage) from postnatal day (PND) 21 to PND 60. At PND 100, an increase in percentage of abnormal tail morphology sperm in MPH 2.5 and increase in testicular interstitial tissue volume in MPH groups as well as in the number of type A spermatogonia in MPH 5.0 group were observed. This study demonstrated that repeated administration of methylphenidate during periods corresponding childhood to early adulthood interfered on testicular function in rats at adult life. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Toxicity associated with repeated administration of artemether-lumefantrine in rats.

    PubMed

    Owumi, Solomon E; Gbadegesin, Michael A; Odunola, Oyeronke A; Adegoke, Ayodeji M; Uwaifo, Anthony O

    2015-03-01

    Chemotherapy remains an important approach in the fight against malaria. Artemether-lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum. Misuse in the form of multiple repeated doses of this anti-malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether-lumefantrine in rats. Graded doses of artemether-lumefantrine (1-5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether-lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ-glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether-lumefantrine treated rats were significantly higher (p < 0.05) than that of the negative control group indicating that repeated administration of artemether-lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross-section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced (p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused.

  3. The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration.

    PubMed

    Job, Martin O; Shen, Li L; Kuhar, Michael J

    2013-08-29

    CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.

  4. Penetration of prulifloxacin into gynaecological tissues after single and repeated oral administrations.

    PubMed

    Gorlero, Franco; Lorenzi, Paola; Rosignoli, Maria Teresa; Picollo, Rossella; Ruggieri, Alessandro; Barattè, Simona; Dionisio, Paolo

    2007-01-01

    This study aimed to evaluate the penetration into gynaecological tissues of ulifloxacin, the active metabolite of prulifloxacin, a once-daily fluoroquinolone administered once or in repeated doses. This was an open-label, randomised study that included 20 consenting female inpatients (age range 40-65 years) requiring total simple hysterectomy as a result of benign disease. Three groups of patients were enrolled: group A (four patients whose gynaecological tissue samples were used to set up the bioanalytical method); group B (eight patients treated 3 hours before surgery with one 600 mg tablet of prulifloxacin); group C (eight patients treated with prulifloxacin 600 mg once daily for 3 days and undergoing surgery 3 hours after the last dose). Patients to be treated with prulifloxacin were randomly allocated to group B or C. During surgery, samples of blood were collected jointly with healthy tissue removed from the endometrium, proximal fallopian tube, vaginal posterior fornix and portio vaginalis. Ulifloxacin concentrations in plasma and gynaecological tissues were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method. An intrastudy assessment of the bioanalytical method performance was also conducted for plasma and tissues using calibration and quality control data (spiked samples). Ulifloxacin mean concentrations were always higher in group C than in group B patients, both in plasma (0.76 vs 0.53 microg/mL) and in gynaecological tissues, namely fallopian tube (1.38 vs 0.81 microg/g), posterior fornix (1.48 vs 1.05 microg/g), portio vaginalis (1.46 vs 1.45 microg/g) and endometrium (2.20 vs 1.39 microg/g), as expected after repeated drug administrations. Tissue concentrations observed after repeated administrations were generally higher than the ulifloxacin minimum inhibitory concentrations for pathogens more frequently involved in gynaecological bacterial infections. The mean tissue/plasma ratios ranged between 1.5 and

  5. [Repeated perioperative administration of fructose and sorbitol in a female patient with hereditary fructose intolerance [HFI)].

    PubMed

    Sachs, M; Asskali, F; Förster, H; Encke, A

    1993-03-01

    The present paper reports on an adult female patient whose hereditary fructose intolerance (HFI) was at first not diagnosed and who, within the space of 2 years after repeated elective surgery and the perioperative administration of fructose and sorbitol, developed "hepatic and renal failure of unclear origin." At a later stage we were able to establish the diagnosis of HFI by means of a fructose tolerance test in both she and her brother, for whom intolerance to fruit and desserts had been known since early childhood. In addition, literature references to fatalities following the parenteral application of fructose and sorbitol were analyzed. During the course of fructose infusion in both the patient and her brother with HFI, the following metabolic changes were noted: hypoglycemia, elevated rise in the blood fructose concentration, hyperlactacidemia, elevated rise in the blood fructose concentration, hyperlactacidemia, and hyperammonemia. These metabolic changes proved to be reversible after discontinuing the fructose infusion. Analysis of the literature on the fatalities following parenteral fructose administration established that fruit and dessert intolerance was known for all collated patients with HFI, and that, clearly, no regular metabolic tests had been conducted.

  6. Association of increased postoperative opioid administration with non-small-cell lung cancer recurrence: a retrospective analysis.

    PubMed

    Maher, D P; Wong, W; White, P F; McKenna, R; Rosner, H; Shamloo, B; Louy, C; Wender, R; Yumul, R; Zhang, V

    2014-07-01

    Evidence suggests that opioid-sparing anaesthetic techniques might be associated with increased cancer-free postoperative survival. This could be related to suppression of natural killer cells by opioid analgesics in the perioperative period. This retrospective analysis tested the hypothesis that greater opioid use in the postoperative period is associated with a higher incidence of recurrences after surgery for lung cancer. The medical records of 99 consecutive patients who underwent video-assisted thoracoscopic surgery with lobectomy for Stage I or IIa biopsy-proven non-small-cell lung cancer (NSCLC) were reviewed. Perioperative information including patient characteristics, laboratory data, and surgical, anaesthetic, nursing, and pharmacy reports were collected. Doses of opioids administered intra-operatively and for the first 96 h after operation were converted into equianalgesic doses of oral morphine using a standard conversion table. Data were then compared with the National Cancer Registry's incidence of disease-free survival for 5 yr. A total of 99 patients with similar characteristics were included in the final analysis, 73 of whom were NSCLC recurrence-free at 5 yr and 26 had NSCLC recurrence within 5 yr. Total opioid dose during the 96 h postoperative period was 124 (101) mg of morphine equivalents in the cancer-free group and 232 mg (355) mg in the recurrence group (P=0.02). This retrospective analysis suggests an association between increased doses of opioids during the initial 96 h postoperative period with a higher recurrence rate of NSCLC within 5 yr. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress.

    PubMed

    Traini, Chiara; Evangelista, Stefano; Girod, Vincent; Faussone-Pellegrini, Maria Simonetta; Vannucchi, Maria Giuliana

    2017-04-01

    Otilonium bromide (OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome (IBS). Its efficacy has been attributed to the block of L- and T-type Ca(2+) channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress (WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP-, NK1r-, nNOS-, VIP-, and S100β-immunoreactivity (IR) and the increase in CGRP-, and CRF1r-IR. On the contrary, OB does not affect the increase in CRF2r-IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT-IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L-type Ca(2+) channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

    PubMed

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-19

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.

  9. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

    PubMed Central

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-01

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg−1 per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg−1 galantamine and 3.0 mg kg−1 donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

  10. Opioid-Independent Mechanisms Supporting Offset Analgesia and Temporal Sharpening of Nociceptive Information

    PubMed Central

    Martucci, K. T.; Eisenach, J. C.; Tong, C.; Coghill, R. C.

    2012-01-01

    The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed following administration of naloxone, a μ-opioid antagonist, and on a separate day, during and following intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real time computerized visual analog scale ratings (VAS, 1–10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered following naloxone administration, during remifentanil infusion, or following the termination of remifentanil infusion. Since thermal hyperalgesia was observed following both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals. PMID:22503222

  11. Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information.

    PubMed

    Martucci, K T; Eisenach, J C; Tong, C; Coghill, R C

    2012-06-01

    The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a μ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

  12. Increased Risk of Depression Recurrence after Initiation of Prescription Opioids in Non-Cancer Pain Patients

    PubMed Central

    Scherrer, Jeffrey F.; Salas, Joanne; Copeland, Laurel A.; Stock, Eileen M.; Schneider, F. David; Sullivan, Mark; Bucholz, Kathleen K.; Burroughs, Thomas; Lustman, Patrick J.

    2016-01-01

    Several studies have demonstrated chronic opioid analgesic use is associated with increased risk of new onset depression. It is not known if patients with remitted depression are at increased risk of relapse following exposure to opioid analgesics. A retrospective cohort design using patient data from the Veterans Health Administration (VHA; n=5,400), and Baylor Scott & White Health (BSWH; n=842) was performed with an observation period 2002–2012 in VHA and 2003–2012 in BSWH. Eligible patients had a diagnosis of depression at baseline and experienced a period of remission. Risk of depression recurrence was modeled in patients that either started an opioid or remained without opioid prescriptions before or during remission. Cox-proportional hazard models measured the association between opioid use and depression recurrence controlling for pain, and other confounders. Patients exposed to an opioid compared to those unexposed had a significantly greater risk of depression recurrence in both patient populations (VHA: HR=2.17; 95% CI:2.01–2.34; BSWH: HR=1.77; 95% CI:1.42–2.21). These results suggest opioid use doubles the risk of depression recurrence even after controlling for pain, psychiatric disorders and opioid misuse. Further work is needed to determine if risk increases with duration of use. Repeated screening for depression after opioid initiation may be warranted. PMID:26884282

  13. Attentional bias for prescription opioid cues among opioid dependent chronic pain patients.

    PubMed

    Garland, Eric L; Froeliger, Brett E; Passik, Steven D; Howard, Matthew O

    2013-12-01

    Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioid-related cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200. vs. 2,000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2,000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior.

  14. Pharmacogenomic considerations in opioid analgesia

    PubMed Central

    Vuilleumier, Pascal H; Stamer, Ulrike M; Landau, Ruth

    2012-01-01

    Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration. PMID:23226064

  15. Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

    PubMed Central

    Tsagareli, Merab G.; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

    2011-01-01

    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too. PMID:21845173

  16. Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

    PubMed

    Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

    2011-01-01

    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  17. The pharmacological basis of opioids

    PubMed Central

    Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Bianchi, Enrica

    2015-01-01

    Summary An opioid is a chemical that binds to opioid receptors, which are widely distributed in the central and peripheral nervous system and gastrointestinal tract. The different effects elicited by activation of these receptors are due to their specific neuronal and extraneuronal distribution. The painkiller effect of opioids is induced by the synergy of the two events, namely reduction of pain threshold and emotional detachment from pain. The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. There are opioid-like substances endogenously produced by the body. Naturally occurring peptides, called enkephalins, have opioid-like activities but are not derived from opium and exert opioid-like effects by interacting with opioid receptors on cell membranes. Yet, animals do contain the same morphine precursors and metabolites as opium poppy and are able to synthesize endogenous morphine alkaloid. Experimental and clinical studies show that opioids, at doses comparable to those of endogenous opioids, can activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. Whether endogenous opioids play a role in the acute pain necessary to the survival of the individual, remains an open question. PMID:26811699

  18. Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector.

    PubMed Central

    O'Neal, W. K.; Zhou, H.; Morral, N.; Langston, C.; Parks, R. J.; Graham, F. L.; Kochanek, S.; Beaudet, A. L.

    2000-01-01

    BACKGROUND: Certain gene therapy protocols may require multiple administrations of vectors to achieve therapeutic benefit to the patient. This may be especially relevant for vectors such as adenoviral vectors that do not integrate into the host chromosome. Because immunocompetent animal models used for gene transfer studies develop neutralizing antibodies to adenoviral vectors after a single administration, little is known about how repeat administrations of vectors might affect transgene expression and vector toxicity. MATERIALS AND METHODS: We used mice deficient in the membrane spanning region of immunoglobulin (IgM), which do not develop antibodies, to evaluate the effect of repeated intravenous administration of first-generation and helper-dependent adenoviral vectors expressing human alpha 1-antitrypsin (hAAT). The duration and levels of transgene expression were evaluated after repeated administration of vectors. Toxicity was assessed by measuring the level of liver enzymes in the serum and the degrees of hepatocyte hypertrophy and proliferation. RESULTS: We found that previous administration of first-generation adenoviral vectors can alter the response to subsequent doses. These alterations included an increase in transgene expression early (within 1 and 3 days), followed by a rapid drop in expression by day 7. In addition, previous administrations of first-generation vectors led to an increase in toxicity of subsequent doses, as indicated by a rise in liver enzymes and an increase in hepatocyte proliferation. In contrast to first-generation vectors, use of the helper-dependent adenovirus vector, Ad-STK109, which contained no viral coding regions, did not lead to increased toxicity after multiple administrations. CONCLUSIONS: We conclude that the response of the host to adenoviral vectors can be altered after repeated administration, compared with the response after the initial vector dose. In addition, these experiments provide further evidence for the

  19. Safety of Oral Dronabinol During Opioid Withdrawal in Humans

    PubMed Central

    Jicha, Crystal J.; Lofwall, Michelle R.; Nuzzo, Paul A.; Babalonis, Shanna; Elayi, Samy Claude; Walsh, Sharon L.

    2015-01-01

    Background Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Methods Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30mg qid. Double-blind placebo substitutions occurred for 21 hours before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Results Dronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg produced significant increases in heart rate beginning 1 hour after drug administration that lasted approximately two hours (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). Conclusion Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. PMID:26483357

  20. [Opioid overdose].

    PubMed

    Reingardiene, Dagmara; Vilcinskaite, Jolita

    2002-01-01

    The dangers of opioid overdose have been recognized for as long as the use of opium itself. When used correctly for medical purposes, opioids are remarkably safe and effective agents. However, excessive dosing, whether with therapeutic, suicidal, or euphoric intent, may results in significant toxicity. In a number of countries the use of heroin and other opioids in nonmedical contexts in associated with on increasing rate of overdose and often of fatal opioid overdose. This review article discusses opioid-receptor pharmacology, which is necessary for understanding of the signs and symptoms of opioid ingestion and management principles, clinical and toxic effects mediated with the opioids, the diagnosis and management guidelines in opioid intoxication, a clinical prediction rule to identify patients who can be safely discharge from hospital, the problems of the significant morbidity and mortality associated with opioid overdose.

  1. Attentional Bias For Prescription Opioid Cues Among Opioid Dependent Chronic Pain Patients

    PubMed Central

    Garland, Eric L.; Froeliger, Brett; Passik, Steven D.; Howard, Matthew O.

    2012-01-01

    Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioidrelated cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200 ms. vs. 2000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior. PMID:22968666

  2. Lack of response suppression follows repeated ventral tegmental cannabinoid administration: an in vitro electrophysiological study.

    PubMed

    Cheer, J F; Marsden, C A; Kendall, D A; Mason, R

    2000-01-01

    . To assess the role of GABA in cannabinoid-mediated excitation, HU210 was added in the presence of bicuculline. HU210 did not affect the initial bicuculline-induced increase in firing, suggesting different sites of action for the two compounds. Our data fail to support previously reported findings using repeated cannabinoid administration and cell preparations. The maintained increase in DA drive elicited by the potent cannabinoid agonist HU210 in the in vitro ventral tegmental circuit could explain some of the behavioural properties of cannabinoids, such as the lack of tolerance for the psychotropic effects of marijuana seen in human users.

  3. Opioid Receptors.

    PubMed

    Stein, Christoph

    2016-01-01

    Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.

  4. The effects of acute and repeated pyridostigmine bromide administration on response acquisition with immediate and delayed reinforcement.

    PubMed

    van Haaren, F; De Jongh, R; Hoy, J B; Karlix, J L; Schmidt, C J; Tebbett, I R; Wielbo, D

    1999-02-01

    This experiment was designed to assess the effects of acute and repeated administration of pyridostigmine bromide (a carbamate with prophylactic and therapeutic uses) on response acquisition. Experimentally naïve, male Sprague-Dawley rats were exposed to a situation in which lever presses were either immediately followed by food-pellet presentation or after a 16-s resetting delay. Different groups of rats received either one acute administration of pyridostigmine bromide (10 mg/kg, by gavage) or repeated pyridostigmine administration for 7 days (1.5 mg/kg/day, by gavage). Other groups were treated with distilled water for the same period of time. Both acute and repeated pyridostigmine bromide administration decreased serum cholinesterase levels by approximately 50%, but neither treatment affected brain cholinesterase levels in our assay. Acute and repeated drug administration produced the same behavioral effects. Subjects exposed to the 0-s delay conditions obtained many more food pellets than those exposed to the 16-s delay conditions. Administration of pyridostigmine bromide delayed the onset of responding in some, but not all, of the subjects in the treated groups, independent of the delay condition to which they were exposed. Many more responses were observed on an inoperative lever during the 16-s delay conditions than during the 0-s delay conditions, especially during the 16-s delay condition in which subjects had received acute vehicle administration. Whether or not these effects of small doses of pyridostigmine bromide on response acquisition are of central or peripheral origin will need to be determined in future studies, as response acquisition in the present experiment may have been affected by pyridostigmine's effects on gastrointestinal functioning and/or motor activity.

  5. Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

    PubMed Central

    Robledo-González, LE; Martínez-Martínez, A; Vargas-Muñoz, VM; Acosta-González, RI; Plancarte-Sánchez, R; Anaya-Reyes, M; Fernández del Valle-Laisequilla, C; Reyes-García, JG; Jiménez-Andrade, JM

    2017-01-01

    Background The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund’s adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. Methods Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15–day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. Results Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic

  6. Resolution of opioid-induced postoperative ileus in a newborn infant after methylnaltrexone.

    PubMed

    Garten, Lars; Degenhardt, Petra; Bührer, Christoph

    2011-03-01

    Transient impairment of bowel function is a frequent and distressing problem in neonates on opioid-induced analgesia. Methylnaltrexone, a peripheral-acting μ-opioid receptor antagonist, has been studied in adults for the treatment of opioid-induced constipation in advanced illness and has been suggested as a promising therapeutic concept for reducing postoperative ileus. Here, we report on a newborn infant on fentanyl analgesia after major abdominal surgery with aggravated ileus. After 8 days of quiescent bowel, the patient's intestinal dysmotility resolved within 15 minutes after intravenous administration of methylnaltrexone (0.15 mg/kg body weight). Methylnatrexone was repeated daily until cessation of fentanyl administration. There were no signs of pain or opioid withdrawal. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

    PubMed Central

    Quiding, H; Olsson, G L; Boreus, L O; Bondesson, U

    1992-01-01

    1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine. PMID:1540490

  8. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade.

    PubMed

    Gavva, Narender R; Bannon, Anthony W; Hovland, David N; Lehto, Sonya G; Klionsky, Lana; Surapaneni, Sekhar; Immke, David C; Henley, Charles; Arik, Leyla; Bak, Annette; Davis, James; Ernst, Nadia; Hever, Gal; Kuang, Rongzhen; Shi, Licheng; Tamir, Rami; Wang, Jue; Wang, Weiya; Zajic, Gary; Zhu, Dawn; Norman, Mark H; Louis, Jean-Claude; Magal, Ella; Treanor, James J S

    2007-10-01

    Capsaicin, the active ingredient in some pain-relieving creams, is an agonist of a nonselective cation channel known as the transient receptor potential vanilloid type 1 (TRPV1). The pain-relieving mechanism of capsaicin includes desensitization of the channel, suggesting that TRPV1 antagonism may be a viable pain therapy approach. In agreement with the above notion, several TRPV1 antagonists have been reported to act as antihyperalgesics. Here, we report the in vitro and in vivo characterization of a novel and selective TRPV1 antagonist, N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I (AMG 517), and compare its pharmacology with that of a closely related analog, tert-butyl-2-(6-([2-(acetylamino)-1,3-benzothiazol-4-yl]oxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate (AMG8163). Both AMG 517 and AMG8163 potently and completely antagonized capsaicin, proton, and heat activation of TRPV1 in vitro and blocked capsaicin-induced flinch in rats in vivo. To support initial clinical investigations, AMG 517 was evaluated in a comprehensive panel of toxicology studies that included in vivo assessments in rodents, dogs, and monkeys. The toxicology studies indicated that AMG 517 was generally well tolerated; however, transient increases in body temperature (hyperthermia) were observed in all species after AMG 517 dosing. To further investigate this effect, we tested and showed that the antipyretic, acetaminophen, suppressed the hyperthermia caused by TRPV1 blockade. We also showed that repeated administration of TRPV1 antagonists attenuated the hyperthermia response, whereas the efficacy in capsaicin-induced flinch model was maintained. In conclusion, these studies suggest that the transient hyperthermia elicited by TRPV1 blockade may be manageable in the development of TRPV1 antagonists as therapeutic agents. However, the impact of TRPV1 antagonist-induced hyperthermia on their clinical utility is still unknown.

  9. Opioid receptor heteromers in analgesia

    PubMed Central

    Costantino, Cristina M.; Gomes, Ivone; Stockton, Steven D.; Lim, Maribel P.; Devi, Lakshmi A.

    2013-01-01

    Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation. PMID:22490239

  10. Repeated oral administration of chitosan/DNA nanoparticles delivers functional FVIII with the absence of antibodies in hemophilia A mice.

    PubMed

    Dhadwar, S S; Kiernan, J; Wen, J; Hortelano, G

    2010-12-01

    Current treatment of hemophilia A is expensive and involves regular infusions of factor (F)VIII concentrates. The supply of functional FVIII is further compromised by the generation of neutralizing antibodies. Thus, the development of an alternative safe, cost effective, non-invasive treatment that circumvents immune response induction is desirable. To evaluate the feasibility of oral administration of chitosan nanoparticles containing FVIII DNA to provide sustainable FVIII activity in hemophilia A mice. Nanoparticles were characterized for morphology, DNA protection and transfection efficiency. Oral administration of nanoparticles containing canine FVIII in C57Bl/6 FVIII(-/-) hemophilia A mice was evaluated for biodistribution, plasma FVIII activity and phenotypic correction. Sustainable FVIII expression was elucidated after repeated nanoparticle administration. Immune responses to repeated oral nanoparticle administration were also investigated. Chitosan nanoparticles had a particle size range of 200-400 nm and protected DNA from endonuclease and pH degradation. In addition, nanoparticles transfected HEK 293 cells resulted in expression of eGFP, luciferase and FVIII. Hemophilia A mice that ingested chitosan nanoparticles demonstrated transient canine FVIII expression reaching > 100 mU 1 day after treatment, together with partial phenotypic correction. The delivered FVIII plasmid DNA was detected in the intestine and, to a lesser extent, in the liver. Importantly, repeated weekly administrations restored FVIII activity. Furthermore, inhibitors and non-neutralizing FVIII antibodies were not detectable. Repeat oral administration of FVIII DNA formulated in chitosan nanoparticles resulted in sustained FVIII activity in hemophilic mice, and thus may provide a non-invasive alternative treatment for hemophilia A. © 2010 International Society on Thrombosis and Haemostasis.

  11. Working together: Expanding the availability of naloxone for peer administration to prevent opioid overdose deaths in the Australian Capital Territory and beyond.

    PubMed

    Lenton, Simon; Dietze, Paul; Olsen, Anna; Wiggins, Nicole; McDonald, David; Fowlie, Carrie

    2015-07-01

    Since the mid-1990s, there have been calls to make naloxone, a prescription-only medicine in many countries, available to heroin and other opioid users and their peers and family members to prevent overdose deaths. In Australia there were calls for a trial of peer naloxone in 2000, yet at the end of that year, heroin availability and harm rapidly declined, and a trial did not proceed. In other countries, a number of peer naloxone programs have been successfully implemented. Although a controlled trial had not been conducted, evidence of program implementation demonstrated that trained injecting drug-using peers and others could successfully administer naloxone to reverse heroin overdose, with few, if any, adverse effects. In 2009 Australian drug researchers advocated the broader availability of naloxone for peer administration in cases of opioid overdose. Industrious local advocacy and program development work by a number of stakeholders, notably by the Canberra Alliance for Harm Minimisation and Advocacy, a drug user organisation, contributed to the rollout of Australia's first prescription naloxone program in the Australian Capital Territory (ACT). Over the subsequent 18 months, prescription naloxone programs were commenced in four other Australian states. The development of Australia's first take-home naloxone program in the ACT has been an 'ice-breaker' for development of other Australian programs. Issues to be addressed to facilitate future scale-up of naloxone programs concern scheduling and cost, legal protections for lay administration, prescribing as a barrier to scale-up; intranasal administration, administration by service providers and collaboration between stakeholders. © 2014 Australasian Professional Society on Alcohol and other Drugs.

  12. Regulation of gene expression in brain tissues of rats repeatedly treated by the highly abused opioid agonist, oxycodone: microarray profiling and gene mapping analysis.

    PubMed

    Hassan, Hazem E; Myers, Alan L; Lee, Insong J; Chen, Hegang; Coop, Andrew; Eddington, Natalie D

    2010-01-01

    Although oxycodone is the most often used opioid agonist, it remains one of the most understudied drugs. We used microarray analysis to better understand the global changes in gene expression in brain tissues of rats repeatedly treated with oxycodone. Many genes were significantly regulated by oxycodone (e.g., Fkbp5, Per2, Rt1.Dalpha, Slc16a1, and Abcg2). Validation of the microarray data by quantitative real-time-polymerase chain reaction (Q-PCR) indicated that there was a strong significant correlation (r = 0.979, p < 0.0000001) between the Q-PCR and the microarray data. Using MetaCore (a computational platform), many biological processes were identified [e.g., organic anion transport (p = 7.251 x 10(-4)) and regulation of immune response (p = 5.090 x 10(-4))]. Among the regulated genes, Abcg2 mRNA was up-regulated by 2.1-fold, which was further confirmed by immunoblotting (1.8-fold up-regulation). Testing the Abcg2 affinity status of oxycodone using an Abcg2 ATPase assay suggests that oxycodone behaves as an Abcg2 substrate only at higher concentrations (> or = 500 microM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up-regulation resulted in a significant (p < 0.05) decrease (approximately 2-fold) in brain/plasma ratios of mitoxantrone. These results highlight markers/mediators of neuronal responses and identify regulatory pathways involved in the pharmacological action of oxycodone. These results also identify genes that potentially modulate tolerance, dependence, immune response, and drug-drug interactions. Finally, our findings suggest that oxycodone-induced up-regulation of Abcg2 enhanced the efflux of the Abcg2 substrate, mitoxantrone, limiting its brain accumulation and resulting in an undesirable drug-drug interaction. Extrapolating these results to other Abcg2 substrates (e.g., daunorubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with

  13. Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine.

    PubMed

    Yang, Chun; Han, Mei; Zhang, Ji-Chun; Ren, Qian; Hashimoto, Kenji

    2016-05-30

    Clinical use of the rapid antidepressant drug ketamine is limited, due to psychotomimetic side effects. R-ketamine appears to be a potent, long-lasting and safer antidepressant, relative to S-ketamine (esketamine), since it is free of psychotomimetic side effects. Repeated, intermittent administration of esketamine (10mg/kg, once per week for 8-weeks), but not R-ketamine, caused loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex and hippocampus of mouse brains, regions associated with psychosis. This study suggests that repeated intermittent use of R-ketamine is safer than esketamine in the treatment of depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. The effect of repeated tryptophan administration on body weight, food intake, brain lipid peroxidation and serotonin immunoreactivity in mice.

    PubMed

    Coşkun, Sule; Ozer, Ciğdem; Gönül, Bilge; Take, Gülnur; Erdoğan, Deniz

    2006-06-01

    Tryptophan as a circulating precursor of serotonin (5-HT) may suppress food intake and body weight. Tryptophan administration can enhance the generation of reactive oxygen species (ROS) by inducing oxidative pathway in vivo and in vitro. We have examined the effect of repeated tryptophan administration on food consumption, body weight, brain lipid peroxidation and 5-HT immunoreactivity. Tryptophan was given at the dose of 100 mg/kg/24 hr in 0.2 ml saline solution i.p. for 7 days to mice. Control mice received 0.9% NaCL solution at the same manner and volume. Body weights were recorded at the beginning and end of the experiments. Thiobarbituric acid reactive substance (TBARS), the last product of lipid peroxidation, was measured spectrophotometrically. Brain 5-HT levels were determined by the immunohistochemical method. Our findings indicate that the tryptophan suppresses food intake significantly in mice. Body weight decreased and brain TBARS levels increased significantly by repeated tryptophan treatment. Immunohistochemical detection showed that 5-HT levels increased by tryptophan administration. There is a link between increased 5-HT level and oxidative stress by tryptophan administration on brain tissue. Tryptophan at repeated doses should be exercised carefully in clinical practice.

  15. Opioid Analgesics.

    PubMed

    Jamison, Robert N; Mao, Jianren

    2015-07-01

    Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  16. Opioid metabolism.

    PubMed

    Smith, Howard S

    2009-07-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

  17. Opioid Metabolism

    PubMed Central

    Smith, Howard S.

    2009-01-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. PMID:19567715

  18. Determination of co-administrated opioids and benzodiazepines in urine using column-switching solid-phase extraction and liquid chromatography-tandem mass spectrometry.

    PubMed

    Xiong, Lingjuan; Wang, Rong; Liang, Chen; Teng, Xiaomei; Jiang, Fengli; Zeng, Libo; Ye, Haiying; Ni, Chunfang; Yuan, Xiaoliang; Rao, Yulan; Zhang, Yurong

    2015-05-22

    Co-administration of opioids with benzodiazepines is very common around the world. A semi-automated method was developed for the determination of four opioids and two benzodiazepines as well as their metabolites (including glucuronide metabolites) in human urine, based on on-line column-switching-solid-phase extraction (CS-SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The CS-SPE was performed by loading 200μL of urine sample to an Oasis HLB cartridge. Detection was achieved using a LC-MS/MS system equipped with an electrospray ionization source (ESI). For unequivocal identification and confirmation, two selected reaction monitoring transitions were registered for each compound, and no co-elution of interferences was observed at the expected retention time. Significant ion suppressions were observed for most analytes during chromatographic runs, but isotope-labeled internal standards (ISs) were used and found to be useful to compensate for the determination error caused by the matrix effect. The assay's linearity ranged from 1-20ng/mL to 800-1000ng/mL for 23 compounds, except for lorazepam (LOR), whose linearity was in the range of 1-100ng/mL. This method showed to be precise and accurate. The relative standard deviation (RSD) % values of within-run precision, between-run precision and total precision were not greater than 10.4% (n=3), 12.9% (n=5) and 15.1% (n=15), respectively. Accuracy values were in the range of 87.5-110%. Limits of detection (LODs) ranged from 0.2ng/mL to 5ng/mL, and limits of quantification (LOQs) ranged from 1ng/mL to 20ng/mL. The method was applied to the assay of 12 samples from forensic cases, which exemplified the co-administration of benzodiazepines (BZDs) by some heroin abusers. This method was of high sensitivity, selectivity and reliability, minimum sample manipulation, semi-automation, and fairly high throughput (analysis time per sample was 20min). The method developed will be useful for the detection of co-administrated

  19. Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

    PubMed Central

    Watkins, Linda R.; Hutchinson, Mark R.; Ledeboer, Annemarie; Wieseler-Frank, Julie; Milligan, Erin D.; Maier, Steven F.

    2007-01-01

    Within the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the efficacy of morphine and other opioids for pain control. While glia have little-to-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs. PMID:17175134

  20. Naloxone Administration for Suspected Opioid Overdose: An Expanded Scope of Practice by a Basic Life Support Collegiate-Based Emergency Medical Services Agency

    ERIC Educational Resources Information Center

    Jeffery, Ryan M.; Dickinson, Laura; Ng, Nicholas D.; DeGeorge, Lindsey M.; Nable, Jose V.

    2017-01-01

    Opioid abuse is a growing and significant public health concern in the United States. Naloxone is an opioid antagonist that can rapidly reverse the respiratory depression associated with opioid toxicity. Georgetown University's collegiate-based emergency medical services (EMS) agency recently adopted a protocol, allowing providers to administer…

  1. Long-term risk of repeat occupational injury or illness incidents among veterans health administration nursing employees.

    PubMed

    Welch, Charles E

    2010-08-01

    This retrospective population-based study assessed the long-term risk of repeat reported occupational injury or illness incidents among Veterans Health Administration (VHA) nursing employees. Using fiscal year (FY) 2002 as the start date for the longitudinal surveillance of incidents, descriptive analyses included all VHA nursing employees (N = 25,697) who reported an initial (index) incident that occurred between FY 2002 and FY 2005. Adjusted for total administrative loss rates (e.g., attrition, disability, retirements), approximately half of the "surviving" index cases reported repeat incidents during an ensuing 3-year period. This total increased to approximately two thirds during a 6-year period. Compared to their nurse counterparts, practical nurses and nursing assistants had higher cumulative probabilities of multiple reported repeat occupational injury or illness incidents. Study findings suggest that reported levels of repeat occupational injury or illness incidents represent a complex interplay between environmental factors (e.g., location) and nursing staff demographics (e.g., level of education).

  2. Repeated cocaine administration suppresses HVA-Ca2+ potentials and enhances activity of K+ channels in rat nucleus accumbens neurons.

    PubMed

    Hu, Xiu-Ti; Basu, Somnath; White, Francis J

    2004-09-01

    The nucleus accumbens (NAc) is an important forebrain area involved in sensitization, withdrawal effects, and self-administration of cocaine. However, little is known about cocaine-induced alterations in the neuronal excitability and whole cell neuroplasticity in this region that may affect behaviors. Our recent investigations have demonstrated that repeated cocaine administration decreases voltage-sensitive sodium and calcium currents (VSSCs and VSCCs, respectively) in freshly dissociated NAc neurons of rats. In this study, current-clamp recordings were performed in slice preparations to determine the effects of chronic cocaine on evoked Ca(2+) potentials and voltage-sensitive K(+) currents in NAc neurons. Repeated cocaine administration with 3-4 days of withdrawal caused significant alterations in Ca(2+) potentials, including suppression of Ca(2+)-mediated spikes, increase in the intracellular injected current intensity required for generation of Ca(2+) potentials (rheobase), reduced duration of Ca(2+) plateau potentials, and abolishment of secondary Ca(2+) potentials associated with the primary Ca(2+) plateau potential. Application of nickel (Ni(2+)), which blocks low-voltage activated T-type Ca(2+) channels, had no impact on evoked Ca(2+) plateau potentials in NAc neurons, indicating that these Ca(2+) potentials are high-voltage activated (HVA). In addition, repeated cocaine pretreatment also hyperpolarized the resting membrane potential, increased the amplitude of afterhyperpolarization in Ca(2+) spikes, and enhanced the outward rectification observed during membrane depolarization. These findings indicate that repeated cocaine administration not only suppressed HVA-Ca(2+) potentials but also significantly enhanced the activity of various K(+) channels in NAc neurons. They also demonstrate an integrative role of whole cell neuroplasticity during cocaine withdrawal, by which the subthreshold membrane excitability of NAc neurons is significantly decreased.

  3. Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex.

    PubMed

    Kula, Joanna; Blasiak, Anna; Czerw, Anna; Tylko, Grzegorz; Sowa, Joanna; Hess, Grzegorz

    2016-04-01

    It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, β2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic

  4. G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal

    PubMed Central

    Terman, Gregory W; Jin, Wenzhen; Cheong, Young-Pyo; Lowe, Janet; Caron, Marc G; Lefkowitz, Robert J; Chavkin, Charles

    2003-01-01

    Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G-protein receptor kinase mediated receptor phosphorylation and subsequent β-arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G-protein receptor kinase 3 (GRK3) gene. Mice lacking GRK3 did not differ from wild-type littermates neither in their response latencies to noxious stimuli on the hot-plate test nor in their acute antinociceptive responses to fentanyl or morphine. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild-type littermate controls. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3-mediated desensitization. The results of these studies suggest that GRK3-mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3-dependent effects than morphine, a low efficacy agonist. PMID:14662727

  5. EFFECT OF EPISODIC WEEKLY NICOTINE ADMINISTRATION ON REPEATED ACQUISITION IN RATS.

    EPA Science Inventory

    Our prior research showed both tolerance and sensitization to nicotine?s effects on motor activity with weekly dosing. This experiment determined the generality of this finding to conditioned behavior. After extended training on a repeated acquisition/performance schedule all ra...

  6. EFFECT OF EPISODIC WEEKLY NICOTINE ADMINISTRATION ON REPEATED ACQUISITION IN RATS.

    EPA Science Inventory

    Our prior research showed both tolerance and sensitization to nicotine?s effects on motor activity with weekly dosing. This experiment determined the generality of this finding to conditioned behavior. After extended training on a repeated acquisition/performance schedule all ra...

  7. Effects of repeated oral corticosterone administration on performance and stress parameters of laying hens

    USDA-ARS?s Scientific Manuscript database

    The effects of repeated stress during rearing on performance and physiology of laying hens was studied using a corticosterone (Cort) model. 240 Hisex laying hens were reared in environmentally controlled battery cages. At 7, 11, and 15 wk of age they were exposed for 1 wk to the following treatments...

  8. Cyclization in opioid peptides.

    PubMed

    Piekielna, Justyna; Perlikowska, Renata; Gach, Katarzyna; Janecka, Anna

    2013-06-01

    Endogenous opioid peptides have been studied extensively as potential therapeutics for the treatment of pain. The major problems of using natural opioid peptides as drug candidates are their poor receptor specificity, metabolic instability and inability to reach the brain after systemic administration. A lot of synthetic efforts have been made to opioid analogs with improved pharmacological properties. One important structural modification leading to such analogs is cyclization of linear sequences. Intramolecular cyclization has been shown to improve biological properties of various bioactive peptides. Cyclization reduces conformational freedom responsible for the simultaneous activation of two or more receptors, increases metabolic stability and lipophilicity which may result in a longer half-life and easier penetration across biological membranes. This review deals with various strategies that have been employed to synthesize cyclic analogs of opioid peptides. Discussed are such bridging bonds as amide and amine linkages, sulfur-containing bonds, including monosulfide, disulfide and dithioether bridges, bismethylene bonds, monosulfide bridges of lanthionine and, finally, carbonyl and guanidine linkages. Opioid affinities and activities of cyclic analogs are given and compared with linear opioid peptides. Analgesic activities of analogs evaluated in the in vivo pain tests are also discussed.

  9. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone.

    PubMed

    Sullivan, Maria A; Bisaga, Adam; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Carpenter, Kenneth M; Mariani, John J; Levin, Frances R; Nunes, Edward V

    2015-02-01

    Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared behavioral naltrexone therapy (BNT) to compliance enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving adherence to oral naltrexone. A 24-week, randomized, placebo-controlled trial (n=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+placebo injection; (3) CE+XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X3(2)=9.19, p=0.027). For low-severity patients (≤ 6 bags/day), retention was highest in the BNT-XR-NTX group (60% at 6 months), as hypothesized. For high-severity (>6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone

    PubMed Central

    Sullivan, Maria A.; Bisaga, Adam; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Carpenter, Kenneth M.; Mariani, John J; Levin, Frances R.; Nunes, Edward V.

    2015-01-01

    Background Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared Behavioral Naltrexone Therapy (BNT) to Compliance Enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving aherence to oral naltrexone. Methods A 24-week, randomized, placebo-controlled trial (N=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+ placebo injection; (3) CE+ XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. Results Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X23 = 9.19, p = .027). For low-severity patients (<6 bags/day), retention was highest in the BNT-XRNTX group (60% at 6 months), as hypothesized. For high-severity (> 6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. Conclusion For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. PMID:25555621

  11. Repeated Administration of Korea Red Ginseng Extract Increases Non-Rapid Eye Movement Sleep via GABAAergic Systems.

    PubMed

    Lee, Chung-Il; Kim, Chung-Soo; Han, Jin-Yi; Oh, Eun-Hye; Oh, Ki-Wan; Eun, Jae Soon

    2012-10-01

    The current inquiry was conducted to assess the change in sleep architecture after long periods of administration to determine whether ginseng can be used in the therapy of sleeplessness. Following post-surgical recovery, red ginseng extract (RGE, 200 mg/ kg) was orally administrated to rats for 9 d. Data were gathered on the 1st, 5th, and 9th day, and an electroencephalogram was recorded 24 h after RGE administration. Polygraphic signs of unobstructed sleep-wake activities were simultaneously recorded with sleep-wake recording electrodes from 11:00 a.m. to 5:00 p.m. for 6 h. Rodents were generally tamed to freely moving polygraphic recording conditions. Although the 1st and 5th day of RGE treatment showed no effect on power densities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, the 9th day of RGE administration showed augmented α-wave (8.0 to 13.0 Hz) power densities in NREM and REM sleep. RGE increased total sleep and NREM sleep. The total percentage of wakefulness was only decreased on the 9th day, and the number of sleep-wake cycles was reduced after the repeated administration of RGE. Thus, the repeated administration of RGE increased NREM sleep in rats. The α-wave activities in the cortical electroencephalograms were increased in sleep architecture by RGE. Moreover, the levels of both α- and β-subunits of the γ-aminobutyric acid (GABA)A receptor were reduced in the hypothalamus of the RGE-treated groups. The level of glutamic acid decarboxylase was over-expressed in the hypothalamus. These results demonstrate that RGE increases NREM sleep via GABAAergic systems.

  12. Predominant D1 Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration.

    PubMed

    Hu, Zhenzhen; Oh, Eun-Hye; Chung, Yeon Bok; Hong, Jin Tae; Oh, Ki-Wan

    2015-03-01

    The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine- and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over-expression in mice. The levels of striatal CART mRNA were significantly increased on the 3(rd) day. CART peptides were over-expressed on the 5(th) day in the striata of behaviorally sensitized mice. A higher proportion of CART(+) cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both D1R and D2R antagonists, SCH 23390 (D1R selective) and raclopride (D2R selective), blocked cocaine induced-behavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over-expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both D1R and D2R knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the D1R-KO mice, but not in the D2R-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by D1R.

  13. Predominant D1 Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration

    PubMed Central

    Hu, Zhenzhen; Oh, Eun-Hye; Chung, Yeon Bok; Hong, Jin Tae

    2015-01-01

    The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine- and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over-expression in mice. The levels of striatal CART mRNA were significantly increased on the 3rd day. CART peptides were over-expressed on the 5th day in the striata of behaviorally sensitized mice. A higher proportion of CART+ cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both D1R and D2R antagonists, SCH 23390 (D1R selective) and raclopride (D2R selective), blocked cocaine induced-behavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over-expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both D1R and D2R knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the D1R-KO mice, but not in the D2R-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by D1R. PMID:25729269

  14. Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.

    PubMed

    Smith, Laura N; Jedynak, Jakub P; Fontenot, Miles R; Hale, Carly F; Dietz, Karen C; Taniguchi, Makoto; Thomas, Feba S; Zirlin, Benjamin C; Birnbaum, Shari G; Huber, Kimberly M; Thomas, Mark J; Cowan, Christopher W

    2014-05-07

    Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.

  15. Repeated Administration of Mercury Intensifies Brain Damage in Multiple Sclerosis through Mitochondrial Dysfunction

    PubMed Central

    Kahrizi, Farzad; Salimi, Ahmad; Noorbakhsh, Farshid; Faizi, Mehrdad; Mehri, Freshteh; Naserzadeh, Parvaneh; Naderi, Nima; Pourahmad, Jalal

    2016-01-01

    In this study we investigated the additive effect of mercury on the brain mitochondrial dysfunction in experimental autoimmune encephalomyelitis (EAE) model. Experimental animals (female C57BL/6 mice) are divided into four groups (n = 8); control, Hg, EAE, EAE with Hg. EAE model of MS induced by injecting myelin oligodendrocyte glycoprotein (MOG). Neurobehavioral alterations are recorded and then mice were sacrificed at day 28 and brain mitochondria were isolated and mitochondrial toxicity parameters including mitochondrial swelling, reactive oxygen species (ROS) formation, collapse of mitochondrial membrane potential (MMP) and cytochrome c release were measured. Our results showed that repeated treatment of mercury following induction of EAE in mice significantly increased the neurobehavioral scores, as well as mitochondrial toxicity through ROS formation, mitochondrial swelling, collapse of MMP and cytochrome c release. Our findings proved that repeated exposure with mercury accelerates progression of MS through mitochondrial damage related to oxidative stress and finally apoptosis. PMID:28243280

  16. Reducing malignant ascites accumulation by repeated intraperitoneal administrations of a Viscum album extract.

    PubMed

    Bar-Sela, Gil; Goldberg, Hadassah; Beck, Dan; Amit, Amnon; Kuten, Abraham

    2006-01-01

    Malignant ascites is a major problem in the management of advanced stages of certain malignancies. The possibility of reducing the accumulation of ascites by intraperitoneal injections of a Viscum album extract (Iscador M) was evaluated. Twenty-three patients, with end-stage malignancies of varying histology, requiring repeated peritoneal punctures, were eligible for analysis. The time-interval between the first two punctures was measured and defined as the baseline. Following each subsequent puncture, Iscador M 10 mg was injected intraperitoneally. The intervals between later punctures were compared to previous intervals. Following the first injection, the median time-interval between injections increased from 7 to 12 days, reaching 13 days after the second injection. No toxicity was observed. This phase II study suggests that installation of Iscador M into the peritoneal cavity may reduce the need for repeated punctures. A randomized trial is needed to confirm these promising preliminary results.

  17. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    PubMed

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  18. Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model.

    PubMed

    Ji, Fang; Wang, Zhenhong; Ma, Nan; Riley, John; Armstead, William M; Liu, Renyu

    2013-01-15

    Since herkinorin is the first non-opioid mu agonist derived from salvinorin A that has the ability to induce cerebral vascular dilatation, we hypothesized that herkinorin could have similar vascular dilatation effect via the mu and kappa opioid receptors and the cAMP pathway. The binding affinities of herkinorin to kappa and mu opioid receptors were determined by in-vitro competition binding assays. The cerebral arteries were monitored in piglets equipped with a closed cranial window and the artery responses were recorded before and every 30s after injection of artificial cerebrospinal fluid (CSF) in the presence or absence of the investigated drugs: herkinorion, norbinaltorphimine (NTP), a kappa opioid receptor antagonist, β-funaltrexamine (β-FNA), a mu opioid receptor antagonist, or Rp-8-Br-cAMPS (Rp-cAMPS), an inhibitor of protein kinase A (PKA). CSF samples were collected before and 10 min after herkinorin and NTP administration for the measurement of cAMP levels. Data were analyzed by repeated-measures analysis of variance. Our results show that herkinorin binds to both kappa and mu opioid receptors. Its vasodilation effect is totally abolished by NTP, but is not affected by β-FNA. The levels of cAMP in the CSF elevate after herkinorin administration, but are abolished with NTP administration. The cerebral vasodilative effect of herkinorin is also blunted by Rp-cAMPS. In conclusion, as a non-opioid kappa and mu opioid receptor agonist, herkinorin exhibits cerebral vascular dilatation effect. The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process.

  19. Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

    PubMed

    Salin-Pascual, R J; Granados-Fuentes, D; Galicia-Polo, L; Nieves, E; Gillin, J C

    1993-02-01

    The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

  20. Increased 5-HT Levels Following Repeated Administration of Nigella sativa L. (Black Seed) Oil Produce Antidepressant Effects in Rats

    PubMed Central

    Perveen, Tahira; Haider, Saida; Zuberi, Nudrat Anwar; Saleem, Sadia; Sadaf, Sana; Batool, Zehra

    2014-01-01

    The seeds of Nigella sativa L., commonly known as black seed or black cumin, and its extracts are used in folk medicine in the Middle East and in Asian countries for the promotion of good health and as a remedy for many ailments. These seeds have many acclaimed medicinal properties such as broncho-dilatory, immunopotentiating, analgesic, anti-inflammatory, and hypotensive. In the present study, the antidepressant activity following the repeated administration of Nigella sativa L. oil has been monitored using the forced swim test. Rats treated with Nigella sativa L. oil exhibited a significant increase in struggling time after oral administration of Nigella sativa L. oil (0.1 ml/kg/day) for four weeks. Nigella sativa L. oil increased brain 5-HT levels and decreased 5-HT turnover (5-HT/5-HIAA ratio). Levels of tryptophan increased significantly in the brain and plasma following the repeated administration of Nigella sativa L. oil. Nigella sativa L. oil showed a potential antidepressant-like effect. PMID:24634848

  1. Increased 5-HT Levels Following Repeated Administration of Nigella sativa L. (Black Seed) Oil Produce Antidepressant Effects in Rats.

    PubMed

    Perveen, Tahira; Haider, Saida; Zuberi, Nudrat Anwar; Saleem, Sadia; Sadaf, Sana; Batool, Zehra

    2014-01-01

    The seeds of Nigella sativa L., commonly known as black seed or black cumin, and its extracts are used in folk medicine in the Middle East and in Asian countries for the promotion of good health and as a remedy for many ailments. These seeds have many acclaimed medicinal properties such as broncho-dilatory, immunopotentiating, analgesic, anti-inflammatory, and hypotensive. In the present study, the antidepressant activity following the repeated administration of Nigella sativa L. oil has been monitored using the forced swim test. Rats treated with Nigella sativa L. oil exhibited a significant increase in struggling time after oral administration of Nigella sativa L. oil (0.1 ml/kg/day) for four weeks. Nigella sativa L. oil increased brain 5-HT levels and decreased 5-HT turnover (5-HT/5-HIAA ratio). Levels of tryptophan increased significantly in the brain and plasma following the repeated administration of Nigella sativa L. oil. Nigella sativa L. oil showed a potential antidepressant-like effect.

  2. Single dose and repeated administrations of liraglutide alter energy metabolism in the brains of young and adult rats.

    PubMed

    Prá, Morgana; Ferreira, Gabriela Kozuchovski; de Mello, Aline Haas; Schraiber, Rosiane de Bona; Cardoso, Larissa Colonetti; Souza, Luana da Rosa; da Rosa, Naiana; Fortunato, Jucélia Jeremias; Rezin, Gislaine Tezza

    2016-10-01

    Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue that was recently approved to treat obesity in some countries. Considering that liraglutide effects on brain energy metabolism are little known, we evaluated the effects of liraglutide on the energy metabolism. Animals received a single or daily injection of saline or liraglutide during 7 days (25, 50, 100, or 300 μg/kg i.p.). Twenty-four hours after the single or last injection, the rats were euthanized and the hypothalamus, prefrontal cortex, cerebellum, hippocampus, striatum, and posterior cortex were isolated. Our results demonstrated that a single dose of liraglutide in young rats increased the activity of complexes and inhibited creatine kinase activity. Repeated administrations of liraglutide in young rats reduced the activity of complexes and activated creatine kinase activity. In adult rats, a single dose of liraglutide reduced the activity of complex I and creatine kinase and increased the activity of complexes II and IV. Repeated administrations of liraglutide in adult rats increased the activity of complexes I and IV and reduced the activity of complex II and creatine kinase. We concluded that liraglutide may interfere in energy metabolism, because analysis of different times of administrations, concentrations, and level of brain development leads to divergent results.

  3. Effect of arthroscopic lavage and repeated intra-articular administrations of antibiotic in adult horses and foals with septic arthritis.

    PubMed

    Cousty, Matthieu; David Stack, John; Tricaud, Cyril; David, Florent

    2017-08-03

    To evaluate the effect of arthroscopic lavage and repeated intra-articular administration of antibiotic in adult horses and foals with septic arthritis. Retrospective clinical study. Adult horses and foals with septic arthritis (n = 62). Age, sex, cause of septic synovitis, joint involved, hospitalization time, and outcome were recorded. Arthroscopic lavage was performed at day 0 (D 0). Synovial fluid was collected every 48 hours prior to intra-articular administration of antibiotic, and until hospital discharge. Synovial nucleated cell count, total protein, and percentage of neutrophils were compared across time and between subjects with a favorable or unfavorable outcome. Synovial nucleated cell counts decreased progressively and were lower at all times compared to D 0. Percentages of neutrophils were lower than baseline at D 8 and 10, only. Total protein contents decreased progressively and were lower than baseline at D 2, 4, 6, 8, 10, and 14. When adult horses and foals with a favorable outcome were compared to those with an unfavorable outcome, the nucleated cell count was lower at D 10, 12, and 14 and the percentage of neutrophils was lower at D 4 only, but total protein content did not differ between groups at any time. Synovial nucleated cell counts and total protein concentrations decreased after arthroscopic lavage and repeated intra-articular administration of antibiotic in horses and foals with septic arthritis. Synovial nucleated cell count is limited as a monitoring tool during treatment of septic arthritis. © 2017 The American College of Veterinary Surgeons.

  4. Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration.

    PubMed

    Scatton, B

    1977-12-15

    Repeated treatment with haloperidol and sulpiride induced tolerance to the increases in homovanillic and dihydroxyphenyl acetic acids in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex of the rat. The threshold dose inducing this effect appeared to be lower in the striatum than in the limbic regions. Similar results were found in the frontal cortex by measuring dopamine utilization. Moreover, tolerance developed earlier in the striatum than in the limbic areas. The possible reasons are discussed for the differential development of tolerance in the various DA areas investigated.

  5. Repeated administration of trimethoprim/sulfadiazine in the horse--pharmacokinetics, plasma protein binding and influence on the intestinal microflora.

    PubMed

    Gustafsson, A; Båverud, V; Franklin, A; Gunnarsson, A; Ogren, G; Ingvast-Larsson, C

    1999-02-01

    Six healthy adult horses were given repeated administrations of trimethoprim/ sulfadiazine (TMP/SDZ) intravenously (i.v.) (2.5 mg/kg TMP and 12.5 mg/kg SDZ) and orally (p.o.) as a paste (5 mg/kg TMP and 25 mg/kg SDZ). Both formulations were given twice daily for 5 days, with a 3-week interval between i.v. and oral administration. The influence of the drug combination on the intestinal microflora was examined and the plasma concentrations, pharmacokinetic parameters and plasma protein binding were determined. There were no major changes in the bacterial intestinal flora and no clinical evidence of gastrointestinal disturbances following the i.v. and oral TMP/SDZ administration. An initial reduction in the number of coliform bacteria during the treatment was notable, though with no evident difference between i.v. and oral treatment. The minimum concentration during a dose interval at steady state (Cminss), the elimination half-life (t1/2beta) and the mean residence time (MRT) were significantly greater after oral administration compared to i.v. for both TMP and SDZ. The plasma protein binding was measured to be 20% for SDZ and 35% for TMP. Oral administration of TMP/SDZ in a dose of 30 mg/kg given twice daily in the form of paste appeared as a satisfactory method for obtaining plasma levels above MIC (minimum inhibitory concentration in vitro) values during the interdosing interval.

  6. New opioids.

    PubMed

    Mercadante, Sebastiano; Porzio, Giampiero; Gebbia, Vittorio

    2014-06-01

    Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. Therefore, there is a significant need for more effective treatment options. New opioids have been marketed in the past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: μ-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain.

  7. The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart.

    PubMed

    Korolenko, Tatyana A; Tuzikov, Fedor V; Johnston, Thomas P; Tuzikova, Natalia A; Kisarova, Yana A; Zhanaeva, Svetlana Ya; Alexeenko, Tatyana V; Zhukova, Natalia A; Brak, Ivan V; Spiridonov, Victor K; Filjushina, Elena E; Cherkanova, Marina S; Monoszon, Anna A

    2012-11-01

    The effects of repeated administration of poloxamer 407 (P-407) on lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subfractions, as well as the effect on liver and heart proteases, were studied. Repeated administration of P-407 to male CBA mice resulted in a model of atherosclerosis with increased diastolic blood pressure; there was a drastic increase in total serum cholesterol and especially TG. A novel small-angle X-ray scattering method for the determination of the fractional and subfractional composition of LP-C and LP-TG was used. In chronically P-407-treated mice, P-407 significantly increased atherogenic low-density lipoprotein C (LDL-C) fractions, as well as intermediate-density lipoprotein C (IDL-C), and LDL₁₋₃-C subfractions, and very-low-density lipoprotein-C (VLDL-C) fractions, as well as VLDL₁₋₂-C and VLDL₃₋₅-C subfractions), to a lesser extent, the total anti-atherogenic high-density lipoprotein C (HDL-C) fraction, as well as HDL₂-C and HDL₃-C subfractions. Additionally, we demonstrated an increase in the serum chitotriosidase activity, without significant changes in serum matrix metalloprotease (MMP) activity. Morphological changes observed in P-407-treated mice included atherosclerosis in the heart and storage syndrome in the liver macrophages. P-407 significantly increased the activity of cysteine, aspartate proteases, and MMPs in the heart, and only the activity of cathepsin B and MMPs in the liver of mice. Thus, repeated administration of P-407 to mice induced atherosclerosis secondary to sustained dyslipidemia and formation of foamy macrophages in liver, and also modulated the activity of heart and liver proteases.

  8. Adaptation of the pancreas to repeated caerulein administration in rats. A morphological and functional study.

    PubMed

    Tomaszewska, R; Dembiński, A; Warzecha, Z; Konturek, S J; Ceranowicz, P; Konturek, P K; Stachura, J

    1997-01-01

    We studied the ability of the pancreas in the aspect of histological, biochemical and functional changes (pancreatic blood flow, serum and pancreatic amylase levels, DNA and RNA content and pancreatic mass) to recover from repeated episodes of caerulein-induced acute pancreatitis. The experiment was carried out in three animal groups: group I receiving one infusion of caerulein, group II receiving two infusions of caerulein at the interval of 10 days, and group III with three infusions every 10 days. It was found that histological signs of acute pancreatitis after the first caerulein infusion showed regression after 3 days, and the process of regeneration was almost completed after 10 days. The content of DNA and RNA correlated with the histological picture. At this time interval also the level of amylase was returning to normal. Each subsequent infusion of caerulein resulted in less enhanced tissue destruction, but regeneration started later. Pancreatic blood flow was decreased each time after induction of pancreatitis, whereas normalization was more rapid. The present findings indicate that the pancreas adapts to repeated injury, which is manifested by decreased severity of changes, but the process of regeneration is delayed.

  9. Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

    SciTech Connect

    Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

    1988-01-01

    Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with (/sup 3/H)DA, modulation of (/sup 3/H)-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in (/sup 3/H)spiperone binding assays. 31 references, 2 figures, 1 table.

  10. Repeated Administrations of Rituximab along with Steroids and Immunosuppressive Agents in Refractory Steroid-resistant Nephrotic Syndrome.

    PubMed

    Fujinaga, Shuichiro; Sakuraya, Koji

    2017-01-15

    A recent randomized control trial in children with steroid-resistant nephrotic syndrome revealed that two doses of rituximab did not reduce proteinuria. A 14-month-old boy developed refractory steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. The patient achieved complete remission 11 months after disease onset following eight doses of rituximab combined with steroids and cyclosporine. Long-lasting B cell depletion with repeated rituximab administrations may be required to achieve complete remission in patients with steroid-resistant nephrotic syndrome and massive proteinuria.

  11. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

    PubMed

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2013-09-01

    This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.

  12. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts

    PubMed Central

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2014-01-01

    This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  13. Delayed administration of D-Ala2-D-Leu5-enkephalin, a delta-opioid receptor agonist, improves survival in a rat model of sepsis.

    PubMed

    Tang, Cheng Wu; Feng, Wen Ming; Du, Hui Min; Bao, Ying; Zhu, Ming

    2011-01-01

    Sepsis is the major cause of death in intensive care units, despite enormous efforts in the development of antimicrobial therapies. Sepsis is mediated by early [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and late [e.g., high-mobility group box 1 protein (HMGB1)] proinflammatory cytokines. HMGB1, which is secreted into extracellular milieu by activated macrophages or passively released by destroyed macrophages, stimulates intensive inflammatory responses. D-Ala2-D-Leu5-enkephalin (DADLE), a synthetic δ-opioid receptor agonist, has been shown to protect rats from sepsis. Here we elucidated the mechanism for protective effect of DADLE against sepsis. Sepsis was established in Sprague-Dawley rats by means of cecal ligation and puncture (CLP). In this model, the serum levels of TNF-α and IL-1β were increased after 2-3 h, while those of HMGB1 were increased after 18 h. Administration of DADLE (5 mg/kg) concurrently with CLP improved survival, which was associated with the decreases in the serum levels of TNF-α, IL-1β and HMGB1. Importantly, DADLE administrated 4 h after CLP showed comparable protective effect as the concurrent administration, with decreased serum HMGB1 levels. Moreover, peritoneal macrophages isolated from rats were challenged with lipopolysaccharide (LPS). Concurrent or delayed DADLE administration at 10(-6) M suppressed the LPS-induced cell death. DADLE also suppressed the release of HMGB1 from macrophages that was induced by LPS, TNF-α or interferon-γ. In conclusion, DADLE protects rats from sepsis probably by decreasing the serum level of HMGB1. We propose DADLE as a candidate for septic shock therapy, even if it is administered after the onset of sepsis.

  14. Effects of Repeated Oral Administration of Pazufloxacin Mesylate and Meloxicam on the Antioxidant Status in Rabbits

    PubMed Central

    Khan, Adil Mehraj; Rampal, Satyavan

    2014-01-01

    Prolonged antibiotic and antiinflammatory therapy for complicated infections exposes the body to xenobiotics that can produce several adverse effects for which oxidative damage is the proposed underlying mechanism. In this context, we evaluated the effect of pazufloxacin, a fluoroquinolone antimicrobial, and meloxicam, a nonsteroidal antiinflammatory drug, on antioxidant parameters and lipid peroxidation in rabbits after oral administration for 21 d. Reduced glutathione levels were significantly decreased in rabbits (n = 4 per group) given pazufloxacin, meloxicam, or their combination. In addition, glutathione peroxidase activity was induced in the rabbits treated with pazufloxacin only. Administration of pazufloxacin and meloxicam, as single agents as well as in combination, produced significant lipid peroxidation compared with levels in untreated controls. In conclusion, both pazufloxacin and meloxicam potentially can induce oxidative damage in rabbits. PMID:25199097

  15. Pharmacokinetics of repeated oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Souza, Marcy J; Gerhardt, Lillian; Cox, Sherry

    2013-07-01

    To determine the pharmacokinetics of tramadol hydrochloride (30 mg/kg) following twice-daily oral administration in Hispaniolan Amazon parrots (Amazona ventralis). 9 healthy adult Hispaniolan Amazon parrots. Tramadol hydrochloride was administered to each parrot at a dosage of 30 mg/kg, PO, every 12 hours for 5 days. Blood samples were collected just prior to dose 2 on the first day of administration (day 1) and 5 minutes before and 10, 20, 30, 60, 90, 180, 360, and 720 minutes after the morning dose was given on day 5. Plasma was harvested from blood samples and analyzed by high-performance liquid chromatography. Degree of sedation was evaluated in each parrot throughout the study. No changes in the parrots' behavior were observed. Twelve hours after the first dose was administered, mean ± SD concentrations of tramadol and its only active metabolite M1 (O-desmethyltramadol) were 53 ± 57 ng/mL and 6 ± 6 ng/mL, respectively. At steady state following 4.5 days of twice-daily administration, the mean half-lives for plasma tramadol and M1 concentrations were 2.92 ± 0.78 hours and 2.14 ± 0.07 hours, respectively. On day 5 of tramadol administration, plasma concentrations remained in the therapeutic range for approximately 6 hours. Other tramadol metabolites (M2, M4, and M5) were also present. On the basis of these results and modeling of the data, tramadol at a dosage of 30 mg/kg, PO, will likely need to be administered every 6 to 8 hours to maintain therapeutic plasma concentrations in Hispaniolan Amazon parrots.

  16. Repeated carbon nanotube administrations in male mice cause reversible testis damage without affecting fertility

    PubMed Central

    Bai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, Bing

    2010-01-01

    Soluble carbon nanotubes are promising materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, however, their effects on male reproduction have not been examined. Here we show that repeated intravenous injections of water-soluble multi-walled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress, and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired after 60 and 90 days. The quantity, quality, and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice. PMID:20693989

  17. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility

    NASA Astrophysics Data System (ADS)

    Bai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, Bing

    2010-09-01

    Soluble carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reproduction have not been examined. Here, we show that repeated intravenous injections of water-soluble multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired at 60 and 90 days. The quantity, quality and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice.

  18. Inhibition of rat brain monoamine oxidase by repeated administration of pirlindol

    SciTech Connect

    Verevkina, I.V.; Asnina, V.V.; Gorkin, V.Z.; Mashovskii, M.D.

    1985-10-01

    Since pirlindol, like other antidepressants, is used for a long time and since its therapeutic effect usually appears 5-7 days or more after the beginning of treatment, the authors investigate its action on activity of MAO of types A and B in rat brain when administered repeatedly. MAO activity was determined in 50% homogenates of rat brain, made up in 10 mM phosphate buffer, pH 7.4, containing 2% detergent Triton X-100. It is shown that an important role in the antidepressant effect of pirlindol is played by its property of selectively blocking deamination of neurotrans mitters such as serotonin and noradrenalin in the human brain.

  19. Comparative toxicity of silicon dioxide, silver and iron oxide nanoparticles after repeated oral administration to rats.

    PubMed

    Yun, Jun-Won; Kim, Seung-Hyun; You, Ji-Ran; Kim, Woo Ho; Jang, Ja-June; Min, Seung-Kee; Kim, Hee Chan; Chung, Doo Hyun; Jeong, Jayoung; Kang, Byeong-Cheol; Che, Jeong-Hwan

    2015-06-01

    Although silicon dioxide (SiO2), silver (Ag) and iron oxide (Fe2O3) nanoparticles are widely used in diverse applications from food to biomedicine, in vivo toxicities of these nanoparticles exposed via the oral route remain highly controversial. To examine the systemic toxicity of these nanoparticles, well-dispersed nanoparticles were orally administered to Sprague-Dawley rats daily over a 13-week period. Based on the results of an acute toxicity and a 14-day repeated toxicity study, 975.9, 1030.5 and 1000 mg kg(-1) were selected as the highest dose of the SiO2 , Ag and Fe2O3 nanoparticles, respectively, for the 13-week repeated oral toxicity study. The SiO2 and Fe2O3 nanoparticles did not induce dose-related changes in a number of parameters associated with the systemic toxicity up to 975.9 and 1000 mg kg(-1) , respectively, whereas the Ag nanoparticles resulted in increases in serum alkaline phosphatase and calcium as well as lymphocyte infiltration in liver and kidney, raising the possibility of liver and kidney toxicity induced by the Ag nanoparticles. Compared with the SiO2 and Fe2O3 nanoparticles showing no systemic distribution in all tissues tested, the Ag concentration in sampled blood and organs in the Ag nanoparticle-treated group significantly increased with a positive and/or dose-related trend, meaning that the systemic toxicity of the Ag nanoparticles, including liver and kidney toxicity, might be explained by extensive systemic distribution of Ag originating from the Ag nanoparticles. Our current results suggest that further study is required to identify that Ag detected outside the gastrointestinal tract were indeed a nanoparticle form or ionized form. Copyright © 2015 John Wiley & Sons, Ltd.

  20. Predictors of Repeat Epinephrine Administration for Emergency Department Patients with Anaphylaxis.

    PubMed

    Campbell, Ronna L; Bashore, Curtis J; Lee, Sangil; Bellamkonda, Venkatesh R; Li, James T C; Hagan, John B; Lohse, Christine M; Bellolio, M Fernanda

    2015-01-01

    Risk factors that predict which patients with anaphylaxis might require repeat doses of epinephrine are poorly understood. The objective of this study was to identify risk factors associated with the need for multiple doses of epinephrine during an anaphylactic reaction. Patients were included if they met diagnostic criteria for anaphylaxis on presentation to the emergency department (ED) at our academic medical center between April 2008 and February 2014. Data were collected on allergic history, presenting signs and symptoms, anaphylaxis management, and disposition. Univariable and multivariable analyses were performed to estimate associations between possible risk factors and the need for multiple doses. Of 582 ED patients with anaphylaxis, 45 (8%) required multiple doses of epinephrine. By multivariable analysis, factors associated with the need for repeat doses were a history of anaphylaxis (odds ratio [OR], 2.5 [95% CI, 1.3-4.7]; P = .005), the presence of flushing or diaphoresis (OR, 2.4 [95% CI, 1.3-4.5]; P = .007), and the presence of dyspnea (OR, 2.2 [95% CI, 1.0-5.0]; P = .046). Patients who received more than 1 dose were more likely to be admitted to the general medical floor (OR, 2.8 [95% CI, 1.1-7.2]; P = .03) or intensive care unit (OR, 7.6 [95% CI, 3.7-15.6]; P < .001). Patients with a history of anaphylaxis, flushing or diaphoresis, or dyspnea may require multiple doses of epinephrine to treat anaphylactic reactions. Patients who require more than 1 dose are more likely to be admitted to the hospital, thus increasing health care resource utilization. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  1. [Repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910) by oral administration to rats].

    PubMed

    Inui, T; Fujiwara, T; Susami, M; Hishida, N; Kuwamura, Y; Kuse, H; Kawai, Y; Kudow, S

    1997-11-01

    Four-, 13- and 52-week repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910), a thyrotropin-releasing hormone(TRH) analogue, were carried out in rats. Through the three studies, TA-0910 solution was administered orally at doses of 3, 30 and 300 mg/kg/day. The animals receiving TA-0910 showed hyperlocomotion, grooming and wet dog shaking which were attributable to the central effects similar to those of TRH, but there was no death nor obvious deterioration of health caused by the treatment. Body weights decreased in males of 300 mg/kg group, and food consumption was on the upward trend in females in 300 mg/kg group. In 13- and 52-week studies, females receiving 300 mg/kg showed elongated estrous cycle, although it was not an evident change. Blood examinations revealed increases in erythrocyte count, hemoglobin and hematocrit in 300 mg/kg group. Reductions in serum(plasma) proteins and lipids, and drug-metabolizing enzyme activity of the liver were regarded as non-specific changes, as they were sporadic and slight in 300 mg/kg group. Salivary gland and adrenal weights increased in 300 mg/kg group. For the thyroid, weights increased in 300 mg/kg group in the 4- and 13-week studies, and increases of microfollicles and cell debris were observed microscopically in each treated group in the 52-week study. These changes seemed to be related with hormonal action of TA-0910, but the effects on animals were judged slight from plasma TSH and thyroid hormone levels after 4 weeks of dosing. The non-toxic dose was estimated to be 30 mg/kg/day, through the rat repeated dose toxicity studies. All the above changes were alleviated or abolished by 4-week recovery period.

  2. Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain.

    PubMed

    Sartor, Oliver; Reid, Robert H; Bushnell, David L; Quick, Donald P; Ell, Peter J

    2007-02-01

    Samarium Sm 153 lexidronam (Sm-153) is an effective and well-tolerated treatment for painful bone metastases. The purpose of the analysis was to assess the safety and efficacy of repeated doses of Sm-153 in patients with metastatic bone pain. Data were collected prospectively for 202 patients administered 1.0 mCi/kg of Sm-153. Particular emphasis was placed on analysis of data from 55 patients receiving > or = 2 doses. Pain scores, adverse events, and hematologic parameters were assessed after each dose. Mild, transient suppression of platelets and white blood cell counts was the most common adverse event after treatment. Nadirs were approximately half of baseline at 4 weeks after dosing with recovery by Week 8 in 90% of patients. Temporary grade 3 thrombocytopenia occurred in 11%, 12%, and 17% of patients after the first, second, and third drug administration, respectively. Grade 3 leukopenia occurred in less than 7% of patients independent of the number of administrations. Significant decreases in pain scores (P < .001) were observed at Week 4 after each of the first 3 doses and maintained at Week 8 after the first 2 doses (P < .003) but not the third. Decreases in pain scores were observed in 70%, 63%, and 80% of patients, respectively, at Week 4 after the first 3 administrations. Repeated dosing of 1.0 mCi/kg of Sm-153 was both safe and effective and is a reasonable treatment option in patients whose bone pain responds and then recurs after an initial dose provided that adequate hematologic function is present at the time of drug administration. (c) 2007 American Cancer Society.

  3. Brief overdose education is sufficient for naloxone distribution to opioid users.

    PubMed

    Behar, Emily; Santos, Glenn-Milo; Wheeler, Eliza; Rowe, Christopher; Coffin, Phillip O

    2015-03-01

    While drug users are frequently equipped with naloxone for lay opioid overdose reversal, the amount of education needed to ensure knowledge of indications and administration is unknown. We administered four instruments, assessing comfort and knowledge around opioid overdose and naloxone administration, to opioid users receiving naloxone for the first time (N=60) and upon returning for a refill (N=54) at community distribution programs. Participants completed the instruments prior to receiving naloxone; first-time recipients repeated the instruments immediately after the standardized 5-10min education. Comfort with recognition of, response to, and administration of naloxone for an overdose event significantly increased after brief education among first-time recipients (p<0.05). Knowledge of appropriate responses to opioid overdose was high across all assessments; 96% of participants could identify at least one acceptable action to assess and one acceptable action to care for an opioid overdose. Facility with naloxone administration was high across all assessments and significantly increased for intranasal administration after education for first-time recipients (p<0.001). First-time recipients (before and after education) and refillers demonstrated a high level of knowledge on the Brief Overdose Recognition and Response Assessment, correctly identifying a mean of 13.7 out of 16 overdose scenarios. Opioid users seeking naloxone in San Francisco have a high level of baseline knowledge around recognizing and responding to opioid overdose and those returning for refills retain that knowledge. Brief education is sufficient to improve comfort and facility in recognizing and managing overdose. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Mechanism of nephrotoxicity induced by repeated administration of cadmium chloride in rats

    SciTech Connect

    Sudo, Jun-ichi; Hayashi, Taiji; Kimura, Shin-ichi

    1996-07-01

    To explore the mechanism of Cd nephrotoxicity, CdCl{sub 2} was subcutaneously injected to rats, at 3 mg Cd/kg body weight once a day, for 8 d. In the liver, Cd bound to metallothioneins (MTs-Cd) rose from d 1 after the initiation of CdCl{sub 2} administration, and reached a plateau after the administration ceased. In the plasma, MTs-Cd rose from d 4, peaked on d 8, and gradually fell thereafter. In the kidney`s leucine aminopeptidase (LAP) and N-acetyl {beta}-D-glucosaminidase (NAG) fell during d 6-20, and Cd bound to cellular membranes (Mem-Cd) rose from d 1 and reached a plateau during d 6-20. The Mem-Cd levels were significantly correlated with the reduction in the LAP and NAG activity; the values of MTs-Cd plus Mem-Cd were almost equivalent to those of total Cd. These findings showed that the hepatic synthesis of MTs-Cd occurred followed by its release into plasma; the extent of renal injury was aggravated as the plasma level of MTs-Cd rose; and a greater part of the renal Cd distributed intracellularly as the MTs-binding form, while the residual Cd distributed as the cellular membrane-binding form. Also, it was suggested that Cd that occurred as the cullular membrane-binding form in the kidneys was involved in manifestation of renal injury. 29 refs., 9 figs., 1 tab.

  5. Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

    PubMed Central

    Gonzales, Edson Luck T.; Yang, Sung Min; Choi, Chang Soon; Mabunga, Darine Froy N.; Kim, Hee Jin; Cheong, Jae Hoon; Ryu, Jong Hoon; Koo, Bon-Nyeo; Shin, Chan Young

    2015-01-01

    Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner. PMID:25995824

  6. Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

    PubMed

    Harris, Ruth B S

    2016-12-23

    Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period.

  7. Development and validation of a 6-item working alliance questionnaire for repeated administrations during psychotherapy.

    PubMed

    Falkenström, Fredrik; Hatcher, Robert L; Skjulsvik, Tommy; Larsson, Mattias Holmqvist; Holmqvist, Rolf

    2015-03-01

    Recently, researchers have started to measure the working alliance repeatedly across sessions of psychotherapy, relating the working alliance to symptom change session by session. Responding to questionnaires after each session can become tedious, leading to careless responses and/or increasing levels of missing data. Therefore, assessment with the briefest possible instrument is desirable. Because previous research on the Working Alliance Inventory has found the separation of the Goal and Task factors problematic, the present study examined the psychometric properties of a 2-factor, 6-item working alliance measure, adapted from the Working Alliance Inventory, in 3 patient samples (ns = 1,095, 235, and 234). Results showed that a bifactor model fit the data well across the 3 samples, and the factor structure was stable across 10 sessions of primary care counseling/psychotherapy. Although the bifactor model with 1 general and 2 specific factors outperformed the 1-factor model in terms of model fit, dimensionality analyses based on the bifactor model results indicated that in practice the instrument is best treated as unidimensional. Results support the use of composite scores of all 6 items. The instrument was validated by replicating previous findings of session-by-session prediction of symptom reduction using the Autoregressive Latent Trajectory model. The 6-item working alliance scale, called the Session Alliance Inventory, is a promising alternative for researchers in search for a brief alliance measure to administer after every session.

  8. Hepatotoxicity assessment of Mn-doped ZnS quantum dots after repeated administration in mice

    PubMed Central

    Yang, Yanjie; Lv, Shuang-Yu; Yu, Bianfei; Xu, Shuang; Shen, Jianmin; Zhao, Tong; Zhang, Haixia

    2015-01-01

    Doped ZnS quantum dots (QDs) have a longer dopant emission lifetime and potentially lower cytotoxicity compared to other doped QDs. The liver is the key organ for clearance and detoxification of xenobiotics by phagocytosis and metabolism. The present study was designed to synthesize and evaluate the hepatotoxicity of Mn-doped ZnS QDs and their polyethylene glycol-coated counterparts (1 mg/kg and 5 mg/kg) in mice. The results demonstrated that daily injection of Mn-doped ZnS QDs and polyethylene glycol-coated QDs via tail vein for 7 days did not influence body weight, relative liver weight, serum aminotransferases (alanine aminotransferase and aspartate aminotransferase), the levels of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), or malondialdehyde in the liver. Analysis of hepatocyte ultrastructure showed that Mn-doped ZnS QDs and polyethylene glycol-coated QDs mainly accumulated in mitochondria at 24 hours after repeated intravenous injection. No damage to cell nuclei or mitochondria was observed with either of the QDs. Our results indicate that Mn-doped ZnS QDs did not cause obvious damage to the liver. This study will assist in the development of Mn-doped ZnS QDs-based bioimaging and biomedical applications in the future. PMID:26396512

  9. Cardiac troponin T following repeated administration of pyridoxal isonicotinoyl hydrazone in rabbits.

    PubMed

    Adamcová, M; Machácková, J; Gersl, V; Pelouch, V; Simůnek, T; Klimtová, I; Hrdina, R; Ponka, P

    2002-01-01

    Pyridoxal isonicotinoyl hydrazone (PIH) is a new tridentate Fe-chelating agent that should be very promising in many pathological states resulting from both an iron-overload and formation of free radicals. The aim of our study was to investigate the effect of PIH on the cardiovascular system focusing to the regulatory protein -- cardiac troponin T (cTnT). The study was carried out in two groups of Chinchilla male rabbits: 1) PIH (50 mg/kg dissolved in 10 % Cremophor i.p., once a week, 10 administrations, n=8) and 2) Cremophor (2 ml/kg i.p. in the same schedule, n=7). Plasma concentrations of cTnT (as a marker of myocardial damage) were measured using a commercial kit (Roche). cTnT was within the physiological range (i.e. < 0.1 microg/l) during the whole experiment in the Cremophor group. In the PIH group, the cTnT levels were not significantly increased when compared with the control group or with the initial values (except with those before the 5th administration). Furthermore, we analyzed the cytosolic and myofibrillar fraction of cTnT in the left ventricular myocardium. Using SDS-PAGE and Western blot we resolved three isoforms. The profiling of TnT did not differ significantly between the PIH-treated group and the Cremophor-treated group. Our data concerning cTnT support the opinion that the possible cardiotoxicity of PIH is very low.

  10. Synergism in immunotoxicological effects due to repeated combined administration of arsenic and lead in mice.

    PubMed

    Bishayi, B; Sengupta, M

    2006-03-01

    Arsenic and lead are considered potent human hazards because of their neoplastic outcomes; increasing epidemiologic evidence indicates a link between heavy metal exposure and health risk. Since health risks of singly administered metals are well-established, in the present study we determined whether simultaneous repeated multimetal (arsenic + lead) exposure influences the development of immunotoxicity in mice exposed (in vivo) to lead acetate (10 mg/kg b.w.) and sodium arsenite (0.5 mg/kg b.w.) simultaneously. We report that in vivo multimetal exposure alters cell morphology, inhibits cell adhesion, nitric oxide release, intracellular killing ability, chemotactic migration, myeloperoxidase release, bacterial clearance from blood and spleen and increases DNA fragmentation. On measuring bacterial density in blood and spleen after 0, 24, 48 and 72 h post infection (with Staphylococcus aureus MC524) in control and multimetal treated groups, bacterial load showed delayed clearance from blood and spleen in the multimetal exposed group. We also found that in vivo exposure to the multimetal caused a decrease in cell adhesion, indicated by a fall in absorbance at 570 nm with respect to control. Exposure to multimetal led to morphological changes in macrophages, since more deformed cells were obtained in repeated combined exposure to arsenic and lead compared to control. Nitric oxide, which has a potent microbicidal activity in macrophages, was found to be released in fewer amounts in the multimetal exposed group from that of control group. It was observed that the viability of bacteria gradually decreased in control macrophage with time, whereas, in macrophages of multimetal exposed mice, the viability of S. aureus gradually increased. Chemotactic migration of splenic macrophages significantly decreased in the multimetal exposed group from that of control. Lysosomal enzyme release from splenic macrophages decreased upon simultaneous exposure to arsenic and lead, as is

  11. Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat

    PubMed Central

    Cox, Brittney M.; Shah, Mrudang M.; Cichon, Teri; Tancer, Manuel E.; Galloway, Matthew P.; Thomas, David M.; Perrine, Shane A.

    2015-01-01

    Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10 mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light–dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light–dark box test at the same dose. Additionally, 10 mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10 mg/kg), but not low (5 mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior. PMID:24121061

  12. Repeated administration of angiotensin II reduces its dipsogenic effect without affecting saline intake

    PubMed Central

    Vento, Peter J.; Daniels, Derek

    2010-01-01

    Angiotensin II (AngII) acts at central type I (AT1) receptors to increase intake of water and saline. In vitro studies demonstrated rapid desensitization of the AT1 receptor after AngII exposure and behavioural studies in rats suggest that exposure to AngII decreases the dipsogenic potency of subsequent AngII. Nevertheless, the effect of repeated AngII injections on saline intake remains untested and a reliable paradigm for examining this purported behavioural desensitization has not emerged from the literature. To address these issues, we established a reliable approach to study AngII-induced dipsetic desensitization and used this approach to test the requirement of central AT1 receptors and the specificity of the effect for water intake. Rats given a treatment regimen of three injections of AngII (300 ng, icv), each separated by 20 min, drank less water than control rats after a subsequent test injection of AngII. The effect was relatively short lasting, dependent on the dose and timing of AngII, and was almost completely blocked by the AT1 receptor antagonist losartan. In further testing, when rats were given access to both water and 1.5% saline, animals that received an AngII treatment regimen drank less water than controls, but saline intake was unaffected. These data support previous suggestions that AngII-induced water and saline intakes are separable. Given the role of G protein uncoupling in desensitization of the AT1 receptor, these data are consistent with the emerging hypothesis that AT1 receptor G protein-dependent intracellular signalling pathways are more relevant for water, but not saline intake. PMID:20228119

  13. Dependence and addiction during chronic opioid therapy.

    PubMed

    Juurlink, David N; Dhalla, Irfan A

    2012-12-01

    The use of opioids for chronic noncancer pain has increased dramatically over the past 25 years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.

  14. Preventing Risky Drinking in Veterans Treated with Prescription Opioids

    DTIC Science & Technology

    2015-04-01

    toxicology tests, opioid overdoses, and ratings of depression and pain. Repeated measures analyses will compare the IPI and SC conditions on...opioid medication, pain treatment , risky drinking, prevention, brief intervention, monitoring, adaptive interventions, benzodiazepines, overdose, follow...biological measures of heavy drinking, urine toxicology tests to assess other drug use, opioid overdoses, depression , and pain. Objectives and

  15. Effects of repeated-low level sodium chlorate administration on ruminal and fecal coliforms in sheep.

    PubMed

    Arzola, Claudio; Copado, Ramon; Epps, Sharon V R P; Rodriguez-Almeida, Felipe; Ruiz-Barrera, Oscar; Rodriguez-Muela, Carlos; Corral-Luna, Agustin; Castillo-Castillo, Yamicela; Diaz-Plascencia, Daniel

    2014-01-01

    Abstract The objective of this study was to evaluate the efficacy of oral sodium chlorate administration on reducing total coliform populations in ewes. A 30% sodium chlorate product or a sodium chloride placebo was administered to twelve lactating Dorper X Blackbelly or Pelibuey crossbred ewes averaging 65 kg body weight. The ewes were adapted to diet and management. Ewes were randomly assigned (4/treatment) to one of three treatments which were administered twice daily by oral gavage for five consecutive days: a control (TC) consisting of 3 g sodium chloride/animal/d, a T3 treatment consisting of 1.8 g of sodium chlorate/animal/d, and a T9 treatment consisting of 5.4 g sodium chlorate/animal/d; the latter was intended to approximate a lowest known effective dose. Ruminal samples collected by stomach tube and freshly voided fecal samples were collected daily beginning 3 days before treatment initiation and for 6 days thereafter. Contents were cultured quantitatively to enumerate total coliforms. There were no significant differences in total coliform numbers (log10 cfu/g) in the feces between treatments (P = 0.832). There were differences (P < 0.02) in ruminal coliform counts (log10 cfu/mL) between treatments (4.1, 4.3 and 5.0 log10/mL contents in TC, T3 and T9 Treatments, respectively) which tended to increase from the beginning of treatment until the 5th day of treatment (P < 0.05). Overall, we did not obtain the expected results with oral administration of sodium chloride at the applied doses. By comparing the trends in coliform populations in the rumen contents in all treatments, there was an increase over the days. The opposite trend occurred in the feces, due mainly to differences among rumen contents and feces in ewes administered the T9 treatment (P = 0.06). These results suggest that the low chlorate doses used here were suboptimal for the control of coliforms in the gastrointestinal tract of ewes.

  16. Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats.

    PubMed

    Maldonado-Devincci, Antoniette M; Alipour, Kent K; Michael, Laura A; Kirstein, Cheryl L

    2010-10-01

    Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a "bender" in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28-31, PND 35-38 and PND 42-45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46-59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of elucidating the

  17. Repeated Binge Ethanol Administration During Adolescence Enhances Voluntary Sweetened Ethanol Intake in Young Adulthood in Male and Female Rats

    PubMed Central

    Maldonado-Devincci, Antoniette M.; Alipour, Kent K.; Michael, Laura A.; Kirstein, Cheryl L.

    2014-01-01

    Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a “bender” in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28–31, PND 35–38 and PND 42–45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46–59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of

  18. Cue-Induced Craving to Paraphernalia and Drug Images in Opioid Dependence

    PubMed Central

    McHugh, R. Kathryn; Fulciniti, Francesca; Mashhoon, Yasmin; Weiss, Roger D.

    2016-01-01

    Background and Objectives Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence. Methods Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N=50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving. Results Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group. Discussion and Conclusions These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type. Scientific Significance Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further understand cue-induced craving in this population. PMID:26848719

  19. Screening for Homelessness in the Veterans Health Administration: Monitoring Housing Stability through Repeat Screening

    PubMed Central

    Fargo, Jamison D.; Montgomery, Ann Elizabeth; Roberts, Christopher B.; Culhane, Dennis P.; Kane, Vincent

    2015-01-01

    Objective This study examined veterans' responses to the Veterans Health Administration's (VHA's) universal screen for homelessness and risk of homelessness during the first 12 months of implementation. Methods We calculated the baseline annual frequency of homelessness and risk of homelessness among all veterans who completed an initial screen during the study period. We measured changes in housing status among veterans who initially screened positive and then completed a follow-up screen, assessed factors associated with such changes, and identified distinct risk profiles of veterans who completed a follow-up screen. Results More than 4 million veterans completed an initial screen; 1.8% (n=77,621) screened positive for homelessness or risk of homelessness. Of those who initially screened positive for either homelessness or risk of homelessness and who completed a second screen during the study period, 85.0% (n=15,060) resolved their housing instability prior to their second screen. Age, sex, race, VHA eligibility, and screening location were all associated with changes in housing stability. We identified four distinct risk profiles for veterans with ongoing housing instability. Conclusion To address homelessness among veterans, efforts should include increased and targeted engagement of veterans experiencing persistent housing instability. PMID:26556940

  20. Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors.

    PubMed

    Berger, Anthony L; Williams, Angela M; McGinnis, Molly M; Walker, Brendan M

    2013-03-01

    Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappa-opioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system.

  1. Opioid Abuse and Addiction

    MedlinePlus

    ... oxycodone, hydrocodone, fentanyl, and tramadol. The illegal drug heroin is also an opioid. Some opioids are made ... NAS). Opioid abuse may sometimes also lead to heroin use, because some people switch from prescription opioids ...

  2. Opioid Basics: Fentanyl

    MedlinePlus

    ... Basics Understanding the Epidemic Overdose Prevention Prescription Opioids Heroin Fentanyl Data Opioid Data Analysis Drug Overdose Death Data Prescribing Data Prescription Opioid Overdose Data Heroin Overdose Data Synthetic Opioid Data Fentanyl Encounters Data ...

  3. Use of the novel atypical opioid tapentadol in goats (Capra hircus): pharmacokinetics after intravenous, and intramuscular administration.

    PubMed

    Lavy, E; Lee, H-K; Mabjeesh, S J; Sabastian, C; Baker, Y; Giorgi, M

    2014-10-01

    The objective of the present study was to assess the pharmacokinetics of the novel atypical drug tapentadol (TAP) after intravenous (I.V.) and intramuscular (I.M.) injections in clinically healthy goats. A 2 × 2 cross-over design study was carried out. Six local adult Nubian nonlactating, nonpregnant female goats, were given 5 mg/kg body weight of TAP by I.V. and I.M. routes. The concentrations of TAP in plasma were evaluated using a validated HPLC method. Transient adverse effects were noticed in some animals, especially after I.V. administration (tremors and ataxia). Three days after drug administration, severe hair loss was also recorded. The plasma concentrations after the two routes of administration were best described by a bi-compartmental model. After I.M. injection, TAP showed a very fast absorption (Tmax  = 0.17 h) and a short half-life (1.29 h). The I.M. bioavailability was quite high, despite being variable (87.8 ± 35.6%). This is the first pharmacokinetic study of TAP in goats but due to its unknown safety profile and efficacy, it is premature to recommend the use of this drug in clinical ovine practice.

  4. Low-dose repeated caffeine administration for circadian-phase-dependent performance degradation during extended wakefulness.

    PubMed

    Wyatt, James K; Cajochen, Christian; Ritz-De Cecco, Angela; Czeisler, Charles A; Dijk, Derk-Jan

    2004-05-01

    To investigate whether the effectiveness of a novel high-frequency low-dose caffeine regimen in counteracting the deterioration of performance during extended wakefulness is related to its interaction with homeostatic or circadian signals modulating performance and sleep propensity. Double-blind, placebo-controlled, parallel-group design in a 29-day forced desynchrony paradigm in which the period of the sleep-wake cycle was scheduled to be 42.85 hours, i.e., far removed from the circadian range. This design allowed for separate estimation of the sleep homeostatic, circadian, and caffeine contributions to performance deficits or improvements. Private suite of a general clinical research center, in the absence of time of day information. Sixteen healthy normal-sleeping men (aged 18-30 years) Caffeine (0.3 mg per kg per hour) or placebo was administered hourly during the 28.57-hour wake episodes. Plasma caffeine concentrations rose in an exponential saturating manner during wakefulness. Rising caffeine levels markedly attenuated wake-dependent deterioration of a number of measures of cognitive performance, particularly at the circadian performance nadir. Moreover, caffeine enhanced the ability of subjects to remain consistently awake for extended periods, holding subjects back from completing the full transition to sleep, but at the expense of increasing subjective sleepiness. High-frequency low-dose caffeine administration is effective in countering the detrimental performance effects of extended wakefulness. These data are in accordance with the hypothesis that adenosine is a mediator of performance decrements associated with extended wakefulness and may lead to new strategies to use caffeine in situations in which neurobehavioral functioning is affected by sleep loss.

  5. Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

    PubMed

    Leri, Francesco; Zhou, Yan; Goddard, Benjamin; Cummins, Erin; Kreek, Mary Jeanne

    2006-07-01

    Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

  6. Absorption and dosage of theophylline in the horse after single and repeated administration of a microencapsulated preparation.

    PubMed

    Roncada, P; Tomasi, L; Montesissa, C; Grossi, G; Stracciari, G L; Anfossi, P

    1995-01-01

    The kinetics of 2 formulations of theophylline were studied in horses. In an initial cross-over study (Phase I) serum concentration-time curves were determined for granulated and microencapsulated theophylline after a single oral administration (5 mg/kg bwt). In Phase II microencapsulated theophylline was administered at 5 mg/kg bwt/12 h for 10 days at feeding time, as in normal clinical practice. Although no significant differences between the 2 preparations were found with respect to the main kinetic parameters, the microencapsulated form was more evenly and completely absorbed from the digestive tract; furthermore, after the repeated treatment, its trough-peak serum concentrations were always within the therapeutic window and no toxic effects were observed in treated animals.

  7. Repeated Methamphetamine Administration Differentially Alters Fos Expression in Caudate-Putamen Patch and Matrix Compartments and Nucleus Accumbens

    PubMed Central

    Jedynak, Jakub P.; Cameron, Courtney M.; Robinson, Terry E.

    2012-01-01

    Background The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (“sensitization”) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix. Methodology/Principal Findings In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. Conclusions/Significance These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine. PMID:22514626

  8. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    NASA Technical Reports Server (NTRS)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

  9. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    NASA Technical Reports Server (NTRS)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

  10. Effects of repeated cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain.

    PubMed

    Iida, K; Iwata, E; Asanuma, M; Asanuma, S N; Gómez-Vargas, M; Miyazaki, I; Nakanishi, T; Ogawa, N

    1998-02-01

    To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities of transcription factors to the TPA (12-O-tetradecanoylphorbol-13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in rats treated with IDPN alone. The levels of D1-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D1-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia.

  11. The evolution of vertebrate opioid receptors

    PubMed Central

    Stevens, Craig W.

    2011-01-01

    The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely-related proteins belonging to the large superfamily of G-protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This review presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptors arose by gene duplication, that there is a vector of opioid receptor divergence, and that MOR shows evidence of rapid evolution. PMID:19273128

  12. Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal grey of rats.

    PubMed

    Tortorici, V; Vanegas, H

    2000-11-01

    Non-opioid analgesics have been shown to elicit antinociception by an action upon central nervous system structures, in addition to their well known action upon peripheral tissues. Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain-modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail-flick reflex. Since these effects involve an activation of endogenous opioidergic systems, the possibility that metamizol induces opioid tolerance was investigated. Microinjection of metamizol into the ventrolateral PAG in awake rats induced antinociception, as demonstrated in the heat-elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2 days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol-tolerant rats were also tolerant to morphine microinjection into the same PAG site, and displayed signs of opioid withdrawal upon systemic administration of naloxone. These and other results suggest that metamizol activates endogenous opioid systems and that nonopioid analgesics may, by an action upon the central nervous system, lead to opioid tolerance and the risk of opioid withdrawal.

  13. Possible involvement of endogenous opioid system located downstream of α7 nicotinic acetylcholine receptor in mice with physical dependence on nicotine.

    PubMed

    Ueno, Keiko; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Wakida, Naoki; Yamamoto, Chizuko; Maeda, Takehiko; Ozaki, Masanobu; Kishioka, Shiroh

    2014-01-01

    We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice. We evaluated increased serum corticosterone (SCS) as an indicator of NIC withdrawal, as it is a quantitative indicator of naloxone (opioid receptor antagonist, NLX)-precipitated morphine withdrawal in mice. In this study, NLX precipitated an SCS increase in mice receiving repeated NIC, by a dose-dependent mechanism, and correlated with the dose and number of days of repeated NIC administration. When an opioid receptor antagonist (naltrexone) was concomitantly administered with repeated NIC, the NLX-precipitated SCS increase was not elicited. Concomitant administration of the α7 nicotinic acetylcholine receptor (nAChR) antagonist (methyllycaconitine) with repeated NIC, but not the α4β2 nAChR antagonist (dihydro-β-erythroidine), did not elicit an SCS increase by NLX. Thus, a physical dependence on NIC was in part mediated by the activation of the endogenous opioid system, located downstream of α7 nAChR.

  14. Repeated daclizumab administration to delay the introduction of calcineurin inhibitors in heart transplant patients with postoperative renal dysfunction.

    PubMed

    Sánchez Lázaro, Ignacio J; Almenar Bonet, Luis; Martínez Dolz, Luis; Buendía Fuentes, Francisco; Navarro Manchón, Josep; Agüero Ramón-Llin, Jaime; Vicente Sánchez, José Luis; Salvador Sanz, Antonio

    2011-03-01

    Daclizumab is an interleukin-2 receptor antagonist which is used for induction therapy in heart transplant patients. It has few side effects and is associated with a low infection rate. Postoperative renal failure after heart transplantation is common and potentially fatal. The administration of calcineurin inhibitors in the postoperative period can aggravate the situation. We report the cases of six patients who underwent heart transplantation and developed acute renal failure in the immediate postoperative period. All were administered daclizumab weekly to avoid the introduction of calcineurin inhibitors and to facilitate recovery of renal function. Calcineurin inhibitors were introduced only once renal function had improved. Renal function recovered in all cases and there was a low complication rate. The administration of repeated doses of daclizumab to patients who experience acute postoperative renal failure after heart transplantation may provide an alternative therapeutic approach that enables calcineurin inhibitors to be avoided and, consequently, renal function to recover. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  15. Clenbuterol Distribution and Residues in Goat Tissues After the Repeated Administration of a Growth-Promoting Dose.

    PubMed

    Zhao, Zhen; Yao, Ting; Qin, Yuchang; Yang, Xiaowei; Li, Jun; Li, Junguo; Gu, Xu

    2015-01-01

    This study was conducted to investigate the deposition and depletion process of clenbuterol (CL) in goat tissues, plasma and urine after the repeated administration of a growth-promoting dose. The experiment was conducted in 24 goats (21 treated and 3 controls). Treated animals were administered orally in a dose of 16 µg/kg body mass once daily for 21 consecutive days and randomly sacrificed on days 0.25, 1, 3, 7, 14, 21 and 28 of the withdrawal period. CL in goat tissues was extracted with organic solvents and determined using liquid chromatography tandem mass spectrometry. The depletion rates of tissue differed significantly. The highest concentrations of CL in all tissues are detected on day 0.25 of treatment discontinuation. After administration had been discontinued for 28 days, CL still residues in all tissues, especially, in whole eye, where the concentrations reach 363.29 ± 31.60 μg/kg. These findings confirmed that the whole eye, which are rich in pigment, showed a much higher concentration than any other studied tissue during the withdrawal period. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Reduction in voluntary ethanol intake following repeated oral administration of Jodina rhombifolia lyophilized aqueous extract in male Wistar rats.

    PubMed

    Teves, Mauricio Roberto; Wendel, Graciela Haydée; Pelzer, Lilian Eugenia

    2015-02-23

    The leaves of Jodina rhombifolia (Hook. & Arn.) Reissek (SANTALACEAE) is utilized in Argentine folk medicine for the treatment of alcoholism. To evaluate the antialcoholic activity of Jodina rhombifolia lyophilized aqueous extract (JRLE) in male Wistar rats. Rats were housed individually in standard plastic cages with wood chip bedding. Throughout the duration of experiment, ethanol was offered in the standard home-cage; two-bottle free-choice regimen between an ethanolic solution (20% in tap water, v/v) and tap water with unlimited access for 24h per day for 10 consecutive days. Rats were administrated intragastrically twice daily (1 ml/200 g) for 10 consecutive days, with the control vehicle (distilled water) or one of the doses of JRLE (125, 250 and 500 mg/Kg weight). Body weight, ethanol, water and food intake were measured every day at the same hour during the 10 days of experimentation. The reducing effect of JRLE on daily ethanol intake was evidenced from the first day of treatment and persisted throughout the entire treatment period. The treatment did not significantly affect daily water intake neither the body weight gain. Daily food intake was higher in rat groups treated with JRLE. The results obtained in the present preliminary study show that repeated administration of JRLE, markedly reduces ethanol voluntary intake in male Wistar rats. The reduction of consumption was of remarkable magnitude and stable during the treatment 10-days. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Permanent relief from intermittent cold stress-induced fibromyalgia-like abnormal pain by repeated intrathecal administration of antidepressants.

    PubMed

    Nishiyori, Michiko; Uchida, Hitoshi; Nagai, Jun; Araki, Kohei; Mukae, Takehiro; Kishioka, Shiroh; Ueda, Hiroshi

    2011-09-21

    Fibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS). In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief. These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

  18. A three-month repeated oral administration study of a low viscosity grade of hydroxypropyl methylcellulose in rats.

    PubMed

    Obara, S; Muto, H; Shigeno, H; Yoshida, A; Nagaya, J; Hirata, M; Furukawa, M; Sunaga, M

    1999-02-01

    The toxicity of the lowest viscosity grade of hydroxypropyl methylcellulose (HPMC) that is currently commercially available was investigated by means of a three-month repeated oral administration study in male and female Crj:CD (SD) IGS rats at doses of 505, 1,020 and 2,100 mg/kg/day. Body weights of males and females in the 2,100 mg/kg group were lower than those of the control group on and after day 28 of administration, but the differences were not statistically significant. The degree of suppression of body weight gain in males was higher than that in females. This tendency was similar to the results in other toxicity studies of HPMC that have been reported. Males in the 2,100 mg/kg group showed a tendency (not significant) for decreased food consumption and urine volume. Examinations of general signs, hematology, blood chemistry, ophthalmology, absolute and relative organ weights, autopsy and histopathology revealed only a few, apparently coincidental, statistically significant differences from the control, and no evidence of any dose-dependent changes was found. It was concluded that the lowest viscosity grade of HPMC showed extremely low toxicity under the conditions of this study, as has been found for higher viscosity grades.

  19. Opioid pharmacology.

    PubMed

    Trescot, Andrea M; Datta, Sukdeb; Lee, Marion; Hansen, Hans

    2008-03-01

    Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of distribution) of opioids have been known for some time. However, the metabolism has, until recently, been poorly understood, and there has been recent interest in the role of metabolites in modifying the pharmacodynamic response in patients, in both analgesia and adverse effects. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages and disadvantages of various opioids in the management of chronic pain are discussed. This review looks at the structure, chemistry, and metabolism of opioids in an effort to better understand the side effects, drug interactions, and the individual responses of patients receiving opioids for the treatment of intractable pain. Mu receptor agonists and agonist-antagonists have been used throughout recent medical history for the control of pain and for the treatment of opiate induced side effects and even opiate withdrawal syndromes.

  20. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.

    PubMed

    Schiavon, Angélica Pupin; Bonato, Jéssica Mendes; Milani, Humberto; Guimarães, Francisco Silveira; Weffort de Oliveira, Rúbia Maria

    2016-01-04

    Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice.

  1. Opioid research in amphibians: an alternative pain model yielding insights on the evolution of opioid receptors

    PubMed Central

    Stevens, Craig W.

    2011-01-01

    This review summarizes the work from our laboratory investigating mechanisms of opioid analgesia using the Northern grass frog, Rana pipiens. Over the last dozen years, we have accumulated data on the characterization of behavioral effects after opioid administration on radioligand binding by using opioid agonist and antagonist ligands in amphibian brain and spinal cord homogenates, and by cloning and sequencing opioid-like receptor cDNA from amphibian central nervous system (CNS) tissues. The relative analgesic potency of mu, delta, and kappa opioids is highly correlated between frogs and other mammals, including humans. Radioligand binding studies using selective opioid agonists show a similar selectivity profile in amphibians and mammals. In contrast, opioid antagonists that are highly selective for mammalian mu, delta, and kappa opioid receptors were not selective in behavioral and binding studies in amphibians. Three opioid-like receptor cDNAs were cloned and sequenced from amphibian brain tissues and are orthologs to mammalian mu, delta, and kappa opioid receptors. Bioinformatics analysis of the three types of opioid receptor cDNAs from all vertebrate species with full datasets gave a pattern of the molecular evolution of opioid receptors marked by the divergence of mu, delta, and kappa opioid receptor sequences during vertebrate evolution. This divergence in receptor amino acid sequence in later-evolved vertebrates underlies the hypothesis that opioid receptors are more type-selective in mammals than in nonmammalian vertebrates. The apparent order of receptor type evolution is kappa, then delta, and, most recently, the mu opioid receptor. Finally, novel bioinformatics analyses suggest that conserved extracellular receptor domains determine the type selectivity of vertebrate opioid receptors. PMID:15464208

  2. Opioid research in amphibians: an alternative pain model yielding insights on the evolution of opioid receptors.

    PubMed

    Stevens, Craig W

    2004-10-01

    This review summarizes the work from our laboratory investigating mechanisms of opioid analgesia using the Northern grass frog, Rana pipiens. Over the last dozen years, we have accumulated data on the characterization of behavioral effects after opioid administration on radioligand binding by using opioid agonist and antagonist ligands in amphibian brain and spinal cord homogenates, and by cloning and sequencing opioid-like receptor cDNA from amphibian central nervous system (CNS) tissues. The relative analgesic potency of mu, delta, and kappa opioids is highly correlated between frogs and other mammals, including humans. Radioligand binding studies using selective opioid agonists show a similar selectivity profile in amphibians and mammals. In contrast, opioid antagonists that are highly selective for mammalian mu, delta, and kappa opioid receptors were not selective in behavioral and binding studies in amphibians. Three opioid-like receptor cDNAs were cloned and sequenced from amphibian brain tissues and are orthologs to mammalian mu, delta, and kappa opioid receptors. Bioinformatics analysis of the three types of opioid receptor cDNAs from all vertebrate species with full datasets gave a pattern of the molecular evolution of opioid receptors marked by the divergence of mu, delta, and kappa opioid receptor sequences during vertebrate evolution. This divergence in receptor amino acid sequence in later-evolved vertebrates underlies the hypothesis that opioid receptors are more type-selective in mammals than in nonmammalian vertebrates. The apparent order of receptor type evolution is kappa, then delta, and, most recently, the mu opioid receptor. Finally, novel bioinformatics analyses suggest that conserved extracellular receptor domains determine the type selectivity of vertebrate opioid receptors.

  3. Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects.

    PubMed

    Röshammar, Daniel; Hai, Trinh Ngoc; Friberg Hietala, Sofia; Van Huong, Nguyen; Ashton, Michael

    2006-05-01

    To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects. Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM. A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V(ss)/F and t(1/2)(z) were found to be 56.4 (29-84) l/h, 6,000 (3,500-8,500) l and 11.7 (8.3-15.7) days, respectively. Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.

  4. Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism

    PubMed Central

    2015-01-01

    Given its profound analgesic nature, neuraxial opioids are frequently used for pain management. Unfortunately, the high incident rate of itch/pruritus after spinal administration of opioid analgesics reported in postoperative and obstetric patients greatly diminishes patient satisfaction and thus the value of the analgesics. Many endeavors to solve the mystery behind neuraxial opioid-induced itch had not been successful, as the pharmacological antagonism other than the blockade of mu opioid receptors remains elusive. Nevertheless, as the characteristics of all opioid receptor subtypes have become more understood, more studies have shed light on the potential effective treatments. This review discusses the mechanisms underlying neuraxial opioid-induced itch and compares pharmacological evidence in nonhuman primates with clinical findings across diverse drugs. Both nonhuman primate and human studies corroborate that mixed mu/kappa opioid partial agonists seem to be the most effective drugs in ameliorating neuraxial opioid-induced itch while retaining neuraxial opioid-induced analgesia. PMID:25861787

  5. Effects of chronic and repeated repeated coritcosterone administration in rearing chickens on physiology, the onset of lay and egg production in hens.

    USDA-ARS?s Scientific Manuscript database

    A corticosterone (CORT) model was used to study the effects of repeated stress during rearing phase on physiology and performance of hens’ in subsequent laying period. Two hundred and seventy Hy-line laying birds were reared in environmentally controlled battery cages. At 7, 11, and 15 wk of age bir...

  6. The effect of repeated nicotine administration on the performance of drug-naive rats in a five-choice serial reaction time task.

    PubMed

    Blondel, A; Simon, H; Sanger, D J; Moser, P

    1999-11-01

    Nicotine improves cognitive performance both in animals and in humans, particularly in tests involving attentional processes. The five-choice serial reaction time task (5-CSRTT) is widely used as a model of attentional performance in rats, and previous studies have demonstrated effects of nicotine in this task on measures such as improved reaction time. Using a modified version of this task (in which rats were required to respond to the disappearance of one of five stimulus lights), we evaluated the effects of repeated nicotine administration (0.3 mg/kg, intraperitoneally, on three occasions over 7 days) in drug-naive rats. After the first administration, nicotine increased accuracy and reduced inappropriate responding (anticipatory responses and responses during time-out) compared to performance following vehicle administration on the preceding day. However, with repeated administration the improvement in accuracy disappeared, and other effects became apparent. Thus, after the third administration the main effects of nicotine were to increase inappropriate responding and to reduce reaction times. A fourth administration 1-2 weeks later produced similar results to the third administration, suggesting that the effects of nicotine were now constant. Despite the general increase in inappropriate responding, there was no impairment in accuracy. In contrast to the response to repeated nicotine, the performance of the rats on the 3 vehicle days remained constant. These data demonstrate that the administration of nicotine to drug-naive subjects improves performance in the 5-CSRTT but that with repeated administration this effect disappears and is replaced by a profile in which inappropriate and impulsive responding predominate.

  7. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    PubMed

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  8. Paradoxical reaction of raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis.

    PubMed

    Barreira, Rebeca Iglesias; García, Belén Bardán; López, Mónica Granero; Legazpi, Iria Rodríguez; Díaz, Hortensia Álvarez; Penín, Isaura Rodríguez

    2012-10-01

    To report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement. In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5-1 ng/kg/min (6 hours per day, for 5 days every 6-8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased. Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient. This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.

  9. Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids

    PubMed Central

    Adler-Neal, Adrienne L.; Wells, Rebecca E.; Stagnaro, Emily; May, Lisa M.; Eisenach, James C.; McHaffie, John G.; Coghill, Robert C.

    2016-01-01

    Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline

  10. Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

    PubMed

    Zeidan, Fadel; Adler-Neal, Adrienne L; Wells, Rebecca E; Stagnaro, Emily; May, Lisa M; Eisenach, James C; McHaffie, John G; Coghill, Robert C

    2016-03-16

    Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results

  11. Lymphatic Filariasis Control in Tanzania: Effect of Repeated Mass Drug Administration with Ivermectin and Albendazole on Infection and Transmission

    PubMed Central

    Simonsen, Paul E.; Pedersen, Erling M.; Malecela, Mwelecele N.; Derua, Yahya A.; Magesa, Stephen M.

    2010-01-01

    Background In most countries of sub-Saharan Africa the control of lymphatic filariasis (LF) is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole, in order to interrupt transmission. Here we present the first detailed study on the effect of 3 repeated MDAs with this drug combination, as implemented by the Tanzanian National Lymphatic Filariasis Elimination Programme (NLFEP). Methodology/Principal Findings Infection and transmission was monitored during a five-year period (one pre-intervention and four post-intervention years) in a highly endemic community (Kirare village) in north-eastern Tanzania. The vectors were Anopheles gambiae, An. funestus and Cx. quinquefasciatus. After start of intervention, human microfilaraemia initially decreased rapidly and statistically significant (prevalence by 21.2% and 40.4%, and mean intensity by 48.4% and 73.7%, compared to pre-treatment values after the first and second MDA, respectively), but thereafter the effect levelled off. The initial decrease in microfilaraemia led to significant decreases in vector infection and vector infectivity rates and thus to a considerable reduction in transmission (by 74.3% and 91.3% compared to pre-treatment level after first and second MDA, respectively). However, the decrease in infection and infectivity rates subsequently also levelled off, and low-level transmission was still noted after the third MDA. The MDAs had limited effect on circulating filarial antigens and antibody response to Bm14. Conclusion/Significance Critical issues that may potentially explain the observed waning effect of the MDAs in the later study period include the long intervals between MDAs and a lower than optimal treatment coverage. The findings highlight the importance of ongoing surveillance for monitoring the progress of LF control programmes, and it calls for more research into the long-term effect of repeated ivermectin/albendazole MDAs (including the significance of

  12. Amphiphysin I but not dynamin I nor synaptojanin mRNA expression increased after repeated methamphetamine administration in the rat cerebrum and cerebellum.

    PubMed

    Hamamura, Mitsuko; Okouchi, Jiro; Ozawa, Hidetoshi; Kimuro, Yoshihiko; Iwaki, Akiko; Fukumaki, Yasuyuki

    2013-07-01

    Dopamine increases/decreases synaptic vesicle recycling and in schizophrenia the proteins/mRNA is decreased. We isolated cDNA clone, similar to amphiphysin 1 (vesicle protein) mRNA from the neocortex of rats injected repeatedly with methamphetamine using polymerase chain reaction (PCR) differential display. This clone is highly homologous to the 3' region of the human amphiphysin gene. PCR extension study using a primer specific for the rat amphiphysin 1 gene and a primer located within the clone revealed that it is the 3' UTR region of the rat amphiphysin 1 gene. Furthermore, in situ hybridization revealed that amphiphysin 1 mRNA is expressed in the cerebrum, medial thalamus, hippocampus and cerebellum. In the cerebellum, amphiphysin mRNA expression was confined to upper granule cell layer. Repeated methamphetamine administration increased amphiphysin I mRNA expression in both anterior part of the cerebrum, and the cerebellum. However, the repeated administration did not alter mRNA expression of the other vesicle proteins, synaptotagmin I, synapsin I, synaptojanin and dynamin I, we conclude that the repeated administration selectively increased amphiphysin 1 mRNA expression. Thus, amphiphysin 1 does not work as synaptic recycling, but it is suggested, as a part of pathogenesis of brain tissue injury (under Ca²⁺ and Mg²⁺ devoid environment) in repeated methamphetamine-injected states, the gene regulate actin-asssembly, learning, cell stress signaling and cell polarity.

  13. Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine.

    PubMed

    Schenk, S; Partridge, B

    1997-09-26

    Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-D-aspartate (NMDA) (0.6, 1.25 or 2.5 microg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.

  14. Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials

    PubMed Central

    Gan, Tong J; Singla, Neil; Daniels, Stephen E; Hamilton, Douglas A; Lacouture, Peter G; Reyes, Christian RD; Carr, Daniel B

    2017-01-01

    Purpose Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac. Patients and methods Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose. Results Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPβCD-diclofenac versus placebo for the 0–24 through 0–120 hour time periods (P<0.0001), as well as versus ketorolac for the 0–72 through 0–120 hour time periods (P<0.05). HPβCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0–24 hour period onward. When compared to ketorolac, HPβCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0–72 through 0–120 hours) and opioid dose number among patients ≥65 years old (0–24 through 0

  15. Clinical outcomes of cardiac arrest patients according to opioid use history.

    PubMed

    Kim, Eun Young; Suh, Hee Jung; Seo, Ga Jin; Choi, Sun Hui; Huh, Jin Won; Hong, Sang-Bum; Koh, Younsuck; Lim, Chae-Man

    2016-10-01

    Opioid analgesics are potent respiratory depressants. The purpose of this study was to describe the effects of opioids administered within 24hours before cardiac arrest on clinical outcomes. We retrospectively collected the cardiac arrest data of noncancer patients who were admitted to the general ward of Asan Medical Center from January 2008 to August 2012. We investigated the proportion of these patients who received opioids within 24hours of a cardiac arrest event, as well as the cardiac arrest characteristics, survival rates, and opioid administration patterns. Of the 193 patients identified, 58 (30%) had been administered opioids within the previous 24hours (the opioid group), whereas the remaining 135 (70%) had not been administered opioids (the nonopioid group). The survival rate did not differ significantly between these 2 groups. In the opioid group, as-needed opioid administration was associated with a lower 24-hour survival rate than regular opioid administration (9 [33.3%] of 27 patients vs 20 [64.5%] of 31 patients; P=.030). In multivariate logistic regression analysis, as-needed opioid administration was negatively associated with 24-hour survival. Opioid administration within 24hours before cardiac arrest per se was not associated with adverse outcomes. However, administration of opioid analgesics on an as-needed basis was associated with poorer survival outcomes than regular dosing. Greater attention should be paid to patients who receive as-needed opioid administration in the general ward. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

    PubMed

    de Boer, Johannes D; Berkhout, Lea C; de Stoppelaar, Sacha F; Yang, Jack; Ottenhoff, Roelof; Meijers, Joost C M; Roelofs, Joris J T H; van't Veer, Cornelis; van der Poll, Tom

    2015-10-15

    Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

  17. Intracerebroventricular opioids for intractable pain

    PubMed Central

    Raffa, Robert B; Pergolizzi, Joseph V

    2012-01-01

    When pain is refractory to systemic opioid and non-opioid analgesic therapy and palliative chemoradiation or ablative or stimulant neurosurgical procedures are not possible, palliative treatment becomes limited, particularly if the patient wishes to be at home at the end of life. Intracerebroventricular (ICV) infusion of morphine in the home setting might be presented as an option. The present article reviews the basic and clinical evidence of the efficacy and safety of ICV administration of opioids. Information was gathered from various bibliographic sources, including PubMed and others, and summarized and evaluated to assess the efficacy and safety of ICV opioids for pain relief. Results from ICV infusion of morphine into terminally ill patients refractory to other pain treatments have been reported since the early 1980s. Good efficacy has been achieved for the vast majority of patients, without serious development of analgesic tolerance. There have also been a low incidence of adverse effects, such as constipation and respiratory depression, and a significant retention of alertness associated with this route of administration. Intracerebroventricular infusion of opioid analgesics thus appears to be a safe and effective therapy for the palliative treatment of refractory pain. PMID:22295988

  18. Trends in receipt of single and repeat courses of antenatal corticosteroid administration among preterm and term births: A retrospective cohort study.

    PubMed

    Grzeskowiak, Luke E; Grivell, Rosalie M; Mol, Ben W

    2017-07-10

    To investigate trends in receipt and timing of antenatal corticosteroid (ACS) administration over a ten-year interval. Retrospective cohort study of all live births from 2006 to 2015 occurring at a tertiary level teaching hospital in Adelaide, Australia. We analysed temporal trends in the receipt of single courses and repeat doses of ACSs, according to administration timing prior to birth. The main outcome measures were receipt of a single course of ACS and whether administration was 'Optimal' (≥24 h to administration of repeat doses. Among 47 105 live births, 4191 (8.9%) received any ACS, while 1009 (2.1%) received at least one repeat dose. From 2006/7 to 2014/15, receipt of a single course (relative risk (RR) 1.33; 95%CI 1.21, 1.47) or repeat dose of ACS (RR 1.24; 95%CI 1.01, 1.55) increased. Among women giving birth between 23-34 weeks gestation, receipt of any ACS increased from 75 to 84%, while an optimally timed single course of ACS increased from 20.4 to 31.0% (RR 1.40; 95%CI 1.24, 1.87). From 2006/7 to 2014/15, the greatest increase in ACS administration was evident among infants born 35-36 and ≥37 weeks gestation by caesarean section (RR 1.94; 95%CI 1.48, 2.55 and RR 2.55; 95%CI 1.86, 3.50, respectively). While frequently used, less than half of ACS administration prior to preterm birth was optimally timed. The impact of suboptimal ACS timing on neonatal outcomes requires further investigation. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  19. The mu opioid receptor: A new target for cancer therapy?

    PubMed

    Singleton, Patrick A; Moss, Jonathan; Karp, Daniel D; Atkins, Johnique T; Janku, Filip

    2015-08-15

    Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor. © 2015 American Cancer Society.

  20. Opioid System Modulates the Immune Function: A Review

    PubMed Central

    Liang, Xuan; Liu, Renyu; Chen, Chunhua; Ji, Fang; Li, Tianzuo

    2016-01-01

    Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function. PMID:26985446

  1. Opioid System Modulates the Immune Function: A Review.

    PubMed

    Liang, Xuan; Liu, Renyu; Chen, Chunhua; Ji, Fang; Li, Tianzuo

    Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function.

  2. Opioid Use in Fibromyalgia: A Cautionary Tale.

    PubMed

    Goldenberg, Don L; Clauw, Daniel J; Palmer, Roy E; Clair, Andrew G

    2016-05-01

    Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration-approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  3. The effects of opioids on the lung.

    PubMed

    Radke, Joshua B; Owen, Kelly P; Sutter, Mark E; Ford, Jonathan B; Albertson, Timothy E

    2014-02-01

    The term opioid refers to a broad class of medications that are used most frequently for their analgesic effects. Along with this effect, they also produce euphoria, and it is for this reason that they have been used illicitly, as well as medicinally, for thousands of years. While the most well-known complications of opioid use and misuse include respiratory and central nervous system depression, there are many other toxicities that have been associated with these drugs. Many complications can occur with multiple different opioids, such as non-cardiogenic pulmonary edema, while many of the complications are unique to the opioid used as well as the route of administration. This review focuses on the pulmonary complications associated with opioid use and abuse, but opioids can affect nearly every organ system. Their effects on the pulmonary system can be direct, such as causing granulomatous change, but they can also work indirectly. For example, opioids cause respiratory depression by decreasing sensitivity of peripheral chemoreceptors to carbon dioxide and decreasing activity in the central respiratory centers. Opioids have also been reported to affect the immune system, and place users at increased risk for many different infectious complications. Patients can have a wide array of signs and symptoms, sometimes making it difficult to recognize opioids as a cause for a patient's clinical picture. Due to the sedative effects of opioids, patients are also often not able to provide a reliable history. Knowledge of the possible toxicities of opioids can help prepare a physician to recognize the many complications associated with opioid use.

  4. Effects of co-administration of 2-arachidonylglycerol (2-AG) and a selective μ-opioid receptor agonist into the nucleus accumbens on high-fat feeding behaviors in the rat

    PubMed Central

    Parker, Kyle E.; McCall, Jordan G.; McGuirk, Sophia R.; Trivedi, Seema; Miller, Dennis K.; Will, Matthew J.

    2015-01-01

    Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well-characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the µ-opioid receptor agonist DAla2,N,Me-Phe4,Gly-ol5-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub-threshold dose of 2-AG (0 or 0.25µg/0.5µl/side) and DAMGO (0, 0.025µg or 0.25µg/0.5µl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2hr-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2- AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding. PMID:26100333

  5. Effects of co-administration of 2-arachidonylglycerol (2-AG) and a selective µ-opioid receptor agonist into the nucleus accumbens on high-fat feeding behaviors in the rat.

    PubMed

    Parker, Kyle E; McCall, Jordan G; McGuirk, Sophia R; Trivedi, Seema; Miller, Dennis K; Will, Matthew J

    2015-08-27

    Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well-characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the μ-opioid receptor agonist DAla(2),N,Me-Phe(4),Gly-ol(5)-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub-threshold dose of 2-AG (0 or 0.25 μg/0.5 μl/side) and DAMGO (0, 0.025 μg or 0.25 μg/0.5 μl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2h-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2-AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. The Impact of Repeated Rounds of Mass Drug Administration with Diethylcarbamazine Plus Albendazole on Bancroftian Filariasis in Papua New Guinea

    PubMed Central

    Weil, Gary J.; Kastens, Will; Susapu, Melinda; Laney, Sandra J.; Williams, Steven A.; King, Christopher L.; Kazura, James W.; Bockarie, Moses J.

    2008-01-01

    Background This study employed various monitoring methods to assess the impact of repeated rounds of mass drug administration (MDA) on bancroftian filariasis in Papua New Guinea, which has the largest filariasis problem in the Pacific region. Methodology/Principal Findings Residents of rural villages near Madang were studied prior to and one year after each of three rounds of MDA with diethylcarbamazine plus albendazole administered per World Health Organization (WHO) guidelines. The mean MDA compliance rate was 72.9%. Three rounds of MDA decreased microfilaremia rates (Mf, 1 ml night blood by filter) from 18.6% pre-MDA to 1.3% after the third MDA (a 94% decrease). Mf clearance rates in infected persons were 71%, 90.7%, and 98.1% after 1, 2, and 3 rounds of MDA. Rates of filarial antigenemia assessed by card test (a marker for adult worm infection) decreased from 47.5% to 17.1% (a 64% decrease) after 3 rounds of MDA. The filarial antibody rate (IgG4 antibodies to Bm14, an indicator of filarial infection status and/or exposure to mosquito-borne infective larvae) decreased from 59.3% to 25.1% (a 54.6% decrease). Mf, antigen, and antibody rates decreased more rapidly in children <11 years of age (by 100%, 84.2%, and 76.8%, respectively) relative to older individuals, perhaps reflecting their lighter infections and shorter durations of exposure/infection prior to MDA. Incidence rates for microfilaremia, filarial antigenemia, and antifilarial antibodies also decreased significantly after MDA. Filarial DNA rates in Anopheles punctulatus mosquitoes that had recently taken a blood meal decreased from 15.1% to 1.0% (a 92.3% decrease). Conclusions/Significance MDA had dramatic effects on all filariasis parameters in the study area and also reduced incidence rates. Follow-up studies will be needed to determine whether residual infection rates in residents of these villages are sufficient to support sustained transmission by the An. punctulatus vector. Lymphatic filariasis

  7. The impact of repeated rounds of mass drug administration with diethylcarbamazine plus albendazole on bancroftian filariasis in Papua New Guinea.

    PubMed

    Weil, Gary J; Kastens, Will; Susapu, Melinda; Laney, Sandra J; Williams, Steven A; King, Christopher L; Kazura, James W; Bockarie, Moses J

    2008-01-01

    This study employed various monitoring methods to assess the impact of repeated rounds of mass drug administration (MDA) on bancroftian filariasis in Papua New Guinea, which has the largest filariasis problem in the Pacific region. Residents of rural villages near Madang were studied prior to and one year after each of three rounds of MDA with diethylcarbamazine plus albendazole administered per World Health Organization (WHO) guidelines. The mean MDA compliance rate was 72.9%. Three rounds of MDA decreased microfilaremia rates (Mf, 1 ml night blood by filter) from 18.6% pre-MDA to 1.3% after the third MDA (a 94% decrease). Mf clearance rates in infected persons were 71%, 90.7%, and 98.1% after 1, 2, and 3 rounds of MDA. Rates of filarial antigenemia assessed by card test (a marker for adult worm infection) decreased from 47.5% to 17.1% (a 64% decrease) after 3 rounds of MDA. The filarial antibody rate (IgG(4) antibodies to Bm14, an indicator of filarial infection status and/or exposure to mosquito-borne infective larvae) decreased from 59.3% to 25.1% (a 54.6% decrease). Mf, antigen, and antibody rates decreased more rapidly in children <11 years of age (by 100%, 84.2%, and 76.8%, respectively) relative to older individuals, perhaps reflecting their lighter infections and shorter durations of exposure/infection prior to MDA. Incidence rates for microfilaremia, filarial antigenemia, and antifilarial antibodies also decreased significantly after MDA. Filarial DNA rates in Anopheles punctulatus mosquitoes that had recently taken a blood meal decreased from 15.1% to 1.0% (a 92.3% decrease). MDA had dramatic effects on all filariasis parameters in the study area and also reduced incidence rates. Follow-up studies will be needed to determine whether residual infection rates in residents of these villages are sufficient to support sustained transmission by the An. punctulatus vector. Lymphatic filariasis elimination should be feasible in Papua New Guinea if MDA can be

  8. Repeated citalopram administration counteracts kainic acid-induced spreading of PSA-NCAM-immunoreactive cells and loss of reelin in the adult mouse hippocampus.

    PubMed

    Jaako, Külli; Aonurm-Helm, Anu; Kalda, Anti; Anier, Kaili; Zharkovsky, Tamara; Shastin, Dmitri; Zharkovsky, Alexander

    2011-09-01

    Systemic or intracerebral administration of kainic acid in rodents induces neuronal death followed by a cascade of neuroplastic changes in the hippocampus. Kainic acid-induced neuroplasticity is evidenced by alterations in hippocampal neurogenesis, dispersion of the granule cell layer and re-organisation of mossy fibres. Similar abnormalities are observed in patients with temporal lobe epilepsy and, therefore, kainic acid-induced hippocampal neuroplasticity might mimic pathological mechanisms leading to the formation of 'epileptic brain' in patients with temporal lobe epilepsy. Previous studies have demonstrated that selective serotonin re-uptake inhibitor antidepressants might reduce the severity of seizures in epileptic patients and reduce neuronal death in laboratory animal models of kainic acid-induced neurotoxicity. In the present study, we investigated whether kainic acid-induced neuroplasticity in mice is modulated by the repeated administration of citalopram, a selective serotonin reuptake inhibitor. We found that at the histopathological level, repeated citalopram treatment counteracted the kainic acid-induced neuronal loss and dispersion of young granule neurons expressing the polysialylated neural cell adhesion molecule within the granule cell layer of the hippocampus. Citalopram also counteracted the downregulation of reelin on both mRNA and protein levels induced by kainic acid administration. Our findings indicate that repeated administration of citalopram is able to prevent kainic acid-induced abnormal brain plasticity and thereby prevent the formation of an epileptic phenotype.

  9. Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats.

    PubMed

    Erb, Suzanne; McPhee, Matthew; Brown, Zenya J; Kupferschmidt, David A; Song, Lifang; Lovejoy, David A

    2014-08-01

    The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

  10. Relationship of opioid prescription sales and overdoses, North Carolina.

    PubMed

    Modarai, F; Mack, K; Hicks, P; Benoit, S; Park, S; Jones, C; Proescholdbell, S; Ising, A; Paulozzi, L

    2013-09-01

    In the United States, fatal drug overdoses have tripled since 1991. This escalation in deaths is believed to be driven primarily by prescription opioid medications. This investigation compared trends and patterns in sales of opioids, opioid drug overdoses treated in emergency departments (EDs), and unintentional overdose deaths in North Carolina (NC). Our ecological study compared rates of opioid sales, opioid related ED overdoses, and unintentional drug overdose deaths in NC. Annual sales data, provided by the Drug Enforcement Administration, for select opioids were converted into morphine equivalents and aggregated by zip code. These opioid drug sales rates were trended from 1997 to 2010. In addition, opioid sales were correlated and compared to opioid related ED visits, which came from a Centers for Disease Control and Prevention syndromic surveillance system, and unintentional overdose deaths, which came from NC Vital Statistics, from 2008 to 2010. Finally, spatial cluster analysis was performed and rates were mapped by zip code in 2010. Opioid sales increased substantially from 1997 to 2010. From 2008 to 2010, the quarterly rates of opioid drug overdoses treated in EDs and opioid sales correlated (r=0.68, p=0.02). Specific regions of the state, particularly in the southern and western corners, had both high rates of prescription opioid sales and overdoses. Temporal trends in sales of prescription opioids correlate with trends in opioid related ED visits. The spatial correlation of opioid sales with ED visit rates shows that opioid sales data may be a timely way to identify high-risk communities in the absence of timely ED data. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain.

    PubMed

    Shurman, Joseph; Koob, George F; Gutstein, Howard B

    2010-07-01

    Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.

  12. Prescription Opioids during Pregnancy

    MedlinePlus

    ... brand names ConZip®, Ryzolt®, Ultram®) The street drug heroin also is an opioid. What problems can opioids ... to buy them illegally. People often start using heroin after becoming addicted to prescription opioids. Sometimes opioids ...

  13. Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

    PubMed Central

    Kinsey, Steven G.; Wise, Laura E.; Ramesh, Divya; Abdullah, Rehab; Selley, Dana E.; Cravatt, Benjamin F.

    2013-01-01

    The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug–induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 (≥16 mg/kg) for 6 days displayed decreased CB1 receptor density and function in the brain, as assessed in [3H]SR141716A binding and CP55,940 [(−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding assays, respectively. In contrast, normal CB1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ9-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid

  14. Rewarding effects of electrical stimulation of the insular cortex: decayed effectiveness after repeated tests and subsequent increase in vertical behavioral activity and conditioned place aversion after naloxone administration.

    PubMed

    García, Raquel; Zafra, Maria A; Puerto, Amadeo

    2015-02-01

    The insular cortex has been associated with various aversive and rewarding sensory, regulatory, and learning processes. The objective of this study was to examine the characteristics of the reinforcement induced by electrical stimulation of this brain area in rats. Results obtained confirm that electrical stimulation of the insular cortex may induce conditioned place and flavor preferences but the learning acquired is not transferred in a reversal test. Unexpectedly, they also demonstrate that this rewarding effect diminishes after repeated tests. In follow-up experiments, locomotor activity tests revealed an increased number of rearings (a sensitization index) in stimulated animals. Furthermore, in these same animals, administration of low doses of naloxone, an opiate antagonist, developed place aversion toward the maze compartment for which the animals had previously shown preference. These results are interpreted in relation to the effects induced by the repeated administration of natural and artificial rewarding stimuli.

  15. Effects of Repeated 3,4-Methylenedioxymethamphetamine Administration on Neurotransmitter Efflux and Sensory-Evoked Discharge in the Ventral Posterior Medial ThalamusS⃞

    PubMed Central

    Starr, M. A.; Page, M. E.

    2012-01-01

    3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may “distort,” rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits. PMID:21984836

  16. Prescription opioid epidemic and infant outcomes.

    PubMed

    Patrick, Stephen W; Dudley, Judith; Martin, Peter R; Harrell, Frank E; Warren, Michael D; Hartmann, Katherine E; Ely, E Wesley; Grijalva, Carlos G; Cooper, William O

    2015-05-01

    Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS). We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics. Of 112,029 pregnant women, 31,354 (28%) filled ≥ 1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67-2.60]) were associated with greater risk of developing NAS. Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS. Copyright © 2015 by the American Academy of Pediatrics.

  17. Prescription Opioid Epidemic and Infant Outcomes

    PubMed Central

    Dudley, Judith; Martin, Peter R.; Harrell, Frank E.; Warren, Michael D.; Hartmann, Katherine E.; Ely, E. Wesley; Grijalva, Carlos G.; Cooper, William O.

    2015-01-01

    BACKGROUND AND OBJECTIVES: Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS). METHODS: We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics. RESULTS: Of 112 029 pregnant women, 31 354 (28%) filled ≥1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67–2.60]) were associated with greater risk of developing NAS. CONCLUSIONS: Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS. PMID:25869370

  18. Assessing the impact of the extended-release/long-acting opioid an-algesics risk evaluation and mitigation strategies on opioid prescrip-tion volume.

    PubMed

    Divino, Victoria; Cepeda, M Soledad; Coplan, Paul; Maziere, Jean-Yves; Yuan, Yingli; Wade, Rolin L

    The Food and Drug Administration approved the extended-release/long-acting (ER/LA) opioid analgesics risk evaluation and mitigation strategies (REMS) in July 2012 to educate healthcare providers and patients about safe and appropriate opioid analgesic use. The authors evaluated the impact of the REMS on ER/LA opioid analgesic utilization, overall and stratified by patient characteristics and prescriber type associated with greater expected need for analgesia. Retrospective repeated cross-sectional study. QuintilesIMS's National Prescription Audit™ and LifeLink™ patient-level longitudinal prescription databases measured prescription volumes, projected to national estimates. Changes were assessed in ER/LA opioid analgesic prescriptions dispensed from the 2-year pre-REMS implementation (July 2010 to June 2012) to the 18-month post-REMS implementation (July 2013 to December 2014) periods (with 12-month transitional implementation period in between). Average quarterly ER/LA opioid prescription volume significantly decreased by 4.3 percent from Preimple-mentation to the Active Period (5.58 vs 5.34 million, p < 0.001). Differences in prescription volume change were observed between age, gender, and payer types. Prescription volume either significantly decreased or remained stable from Preimplementation to the Active Period among most provider specialties evaluated. The largest volume decreases were observed for dentists (-48.5 percent) and emergency medicine specialists (-25.5 percent) (both p < 0.001). The largest increases were observed for nurse practitioners (+33.7 percent) and physician assistants (+31.2 percent; both p < 0.001), whose overall prescribing of nonopioid medications also increased. A significant decrease in dispensed ER/LA opioid prescriptions was observed following REMS implementation compared to Preimplementation. The impact on volume varied by patient characteristics and prescriber specialty. The REMS program, in conjunction with other healthcare

  19. The skeletal muscle response to the repeated administration of suxamethonium and its interaction with edrophonium in anaesthetised man.

    PubMed Central

    Sugai, N; Hughes, R; Payne, J P

    1975-01-01

    Tetanic and single twitch contractions of the adductor pollicis muscle in man were recorded during repeated injections of suxamethonium (0.2 mg/kg or 0.1 mg/kg) every 15 minutes. 2 Tachyphylaxis to suxamethonium developed rapidly in every patient studied when single twitch contractions were observed but tetanic contractions later showed an increasingly prolonged recovery with repeated injections. 3 Edrophonium administered at the point of 50% recovery of the tetanic contractions in patients given suxamethonium (0.2 mg/kg) repeatedly first potentiated the blockade but when the tachyphylaxis had developed fully on the single twitch, usually after the third or fourth injection, the blockade of the tetanic contractions was reversed. 4 These findings indicate that the tachyphylaxis and the change in the nature of the blockade produced by suxamethonium in man take place at the same time and might be part of the same phenomenon. PMID:1234012

  20. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    PubMed

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

  1. Interplay between RAS and opioids: opening the Pandora of complexities.

    PubMed

    Bali, Anjana; Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2014-08-01

    Angiotensin and endogenous opioids are important bioactive neuropeptides, which are widely distributed in the brain and peripheral regions to produce diverse biological and neurobiological activities. An endogenous opioid system includes proopiomelanocortin-derived enkephalin, dynorphin and endorphin that act on their specific receptors such as delta (δ), kappa (κ) and mu (μ) receptors. Research evidence demonstrates significant positive as well as negative interactions between renin angiotensin system (RAS) and endogenous opioids in the brain and periphery. The diverse actions of Ang II are possibly mediated indirectly through endogenous opioids, while opioids are also shown to activate RAS components suggesting the up-regulation of each system in concern with each other. On the contrary, there are reports suggesting a negative correlation between RAS and opioid system. Research evidence also supports the notion that Ang II acts as anti-opioid peptide to decrease the actions of opioids. Moreover, opioids-induced decline in angiotensin release and functioning has also been reported. Co-administration of ACE inhibitors with opioids exhibits significant interactions possibly due to decreased metabolism of opioids leading to potentiation of their actions. The present review describes the complexities of positive and negative interactions between RAS and opioids along with possible mechanisms responsible for these interactions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Delta-Opioid Receptor Analgesia Is Independent of Microglial Activation in a Rat Model of Neuropathic Pain

    PubMed Central

    Rojewska, Ewelina; Makuch, Wioletta; Starowicz, Katarzyna; Przewlocka, Barbara

    2014-01-01

    The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10–20 µg), DAMGO (1–2 µg) and U50,488H (25–50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10–20 µg), deltorphin II (1.5–15 µg) and SNC80 (10–20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain. PMID:25105291

  3. Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

    PubMed

    Mika, Joanna; Popiolek-Barczyk, Katarzyna; Rojewska, Ewelina; Makuch, Wioletta; Starowicz, Katarzyna; Przewlocka, Barbara

    2014-01-01

    The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

  4. Repeated administration of a mild acute toxic dose of di-n-butyltin dichloride at intervals of 3 weeks induces severe lesions in pancreas and liver of rats.

    PubMed

    Merkord, J; Weber, H; Kröning, G; Hennighausen, G

    2001-08-01

    Di-n-butyltin dichloride (DBTC) induced thymus atrophy, bile duct lesions, pancreatitis, and liver lesions in rats. Depending on dose [6 and 8 mg/kg intravenous (i.v.) DBTC] and time (1-24 weeks), the lesions in pancreas developed to a pancreatic fibrosis and the lesions in liver to liver cirrhosis. A single i.v. administration of 4 mg/kg DBTC induces a mild interstitial pancreatitis after 2-4 days followed by a restitutio ad integrum after 21-28 days. In the present study, the lesions of biliopancreatic duct, pancreas, and liver of rats after repeated administration of 4 mg/kg DBTC i.v. at intervals of 3 weeks have been investigated. The histopathological changes of pancreas and liver were examined by light microscopy 1,4, and 7 days and 2,3,4,6,9, and 12 weeks after administration of DBTC. Furthermore, pathobiochemical parameters of pancreatitis (amylase and lipase activity in serum), liver lesions (alkaline phosphatase activity and bilirubin in serum), and of fibrosis (hyaluronic acid in serum) were studied. Repeated administration of rats with DBTC (4 mg/kg i.v.) at intervals of 3 weeks induced an acute interstitial pancreatitis and after 9-12 weeks, a pancreatic fibrosis and liver lesions (intrahepatic bile duct hyperplasia, inflammation in periportal tract, and necrosis). In serum, elevated levels of alkaline phosphatase, bilirubin, and hyaluronic acid were found. This study demonstrates that the organotin compound induces toxic effects on pancreas and liver of rats by repeated administration of lower doses at long intervals. The risk of exposure to organotin at long intervals should be considered.

  5. Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

    PubMed

    Setnik, Beatrice; Bramson, Candace; Bass, Almasa; Levy-Cooperman, Naama; Malhotra, Bimal; Matschke, Kyle; Sommerville, Kenneth W; Wolfram, Gernot; Geoffroy, Pierre

    2015-12-01

    ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2  h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2  h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2  h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

  6. [Misuse of opioid analgesics. An internet analysis].

    PubMed

    Krüger, R; Meißner, W; Zimmer, A

    2014-10-01

    Apart from the prescribed administration and indications for pain relief, opioids are also used for unintended purposes. Information for misuse is circulated on the internet. In order to analyze the abuse of opioids and opiates,which are only available by prescription, defined search keywords were entered into the search engine of a German language internet forum on drugs in 2010 and 2013 and the results were evaluated. Items to be assessed and analyzed were the frequency of naming various substances and (in the first analysis only) aspects of their incorporation as well as user reports on various aspects of use (e.g. drug procurement, administration, effects and side effects). Tramadol was the most frequently quoted opioid followed by codeine, tilidine, morphine and oxycodone. Other opioids were named in only 10 % of the entries. Oral intake was the most frequently mentioned mode of administration followed by parenteral and nasal routes. These findings can support caregivers to identify unintended use of opioids and to increase awareness of the most frequently used opioids and modes of administration.

  7. ACCUMULATION AND TISSUE DISPOSITION OF PARTICLE ASSOCIATED ELEMENTS IN THE RAT AFTER REPEATED INTRATRACHAEL ADMINISTRATION OF SOURCE PARTICLES

    EPA Science Inventory

    The goal of this study was to determine the fate of source particle tracer elements following repeated intratracheal instillation (IT) to rats. PM samples comprised Mt. St. Helens ash (MSH) with no water-soluble metals, and oil flyash emission PM (EPM) with water-leachable solubl...

  8. ACCUMULATION AND TISSUE DISPOSITION OF PARTICLE ASSOCIATED ELEMENTS IN THE RAT AFTER REPEATED INTRATRACHAEL ADMINISTRATION OF SOURCE PARTICLES

    EPA Science Inventory

    The goal of this study was to determine the fate of source particle tracer elements following repeated intratracheal instillation (IT) to rats. PM samples comprised Mt. St. Helens ash (MSH) with no water-soluble metals, and oil flyash emission PM (EPM) with water-leachable solubl...

  9. Opioid overuse pain syndrome (OOPS): the story of opioids, prometheus unbound.

    PubMed

    Mehendale, Anand W; Goldman, Mark P; Mehendale, Rachel P

    2013-01-01

    Throughout history, opioids have effectively alleviated pain but not without the risk of addiction and death. Seductive and dangerous, full of promise and destruction, opioids are both revered and feared by Western culture. Their exponential use in "developed countries" is now an enormous public health problem and requires us to harness their properties with scientific rigor and adequate safeguards. The use of opioids for the treatment of chronic nonterminal pain (CNTP) has been a relatively new phenomenon which has coincided with the proclamation by the Joint Commission on Accreditation of Health Care Organization in 2000 that pain assessment be the "fifth vital sign," notwithstanding the fact that pain is a symptom and not a sign.(1) Nonetheless, this resulted in a culture of a marked increase in use of opioids for acute and chronic pain management. Consequently, there are many unintended outcomes which include opioid-induced hyperalgesia increased diversion, addiction, and death. Understandably, this has resulted in many regulatory responses from such agencies such as the Drug Enforcement Administration (DEA) and state medical boards. This article proposes a clinically relevant paradigm of opioid overuse pain syndrome. The goal of this article is to inform the clinicians of the complicated neurobiology of opioids. It is our hope that scientists rather than government regulators dictate the appropriate response to the epidemic of over prescription of opioids. A similar designation of "medication overuse headache" has resulted in near extinction of excessive use of opioids in the field of headache medicine.

  10. Spinal opioids in the home and hospice setting.

    PubMed

    Smith, D E

    1990-06-01

    The outpatient management of spinal opioids presents multiple challenges to the home infusion pharmacist. These include compounding, Schedule II prescription control, dispensing for long-term infusion or injection, reimbursement, and the management of opioids in the home. Although spinal opioids such as meperidine, fentanyl, and methadone have been used to control intractable pain, preservative-free morphine is the preferred opioid for epidural and intrathecal injection. Commercial products, including Astromorph (Astra) and Duramorph (Elkins Sinn), are available but relatively expensive when compared with morphine prepared in the pharmacy or morphine with preservatives. Local anesthetics, including bupivacaine, have been combined with preservative-free morphine in the home setting. Spinal opioids can be administered intermittently, by continuous infusion, or patient-controlled analgesia pump. Extensive clinical experience indicates that the home administration of spinal opioids is safe and effective. There is a need for additional research on stability, storage and use of various opioids administered in the home environment.

  11. Neonatal opioid withdrawal syndrome.

    PubMed

    Sutter, Mary Beth; Leeman, Lawrence; Hsi, Andrew

    2014-06-01

    Neonatal opioid withdrawal syndrome is common due to the current opioid addiction epidemic. Infants born to women covertly abusing prescription opioids may not be identified as at risk until withdrawal signs present. Buprenorphine is a newer treatment for maternal opioid addiction and appears to result in a milder withdrawal syndrome than methadone. Initial treatment is with nonpharmacological measures including decreasing stimuli, however pharmacological treatment is commonly required. Opioid monotherapy is preferred, with phenobarbital or clonidine uncommonly needed as adjunctive therapy. Rooming-in and breastfeeding may decease the severity of withdrawal. Limited evidence is available regarding long-term effects of perinatal opioid exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Pharmacokinetics of Repeated Sodium Salicylate Administration to Laying Hens: Evidence for Time Dependent Increase in Drug Elimination from Plasma and Eggs

    PubMed Central

    Poźniak, Błażej; Grabowski, Tomasz; Motykiewicz-Pers, Karolina; Bobrek, Kamila; Rak, Lech; Bobusia, Katarzyna; Gaweł, Andrzej; Świtała, Marcin

    2015-01-01

    Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (Cmin, C16h) and elimination half-life (T1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB) increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment. PMID:25893240

  13. Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

    PubMed

    Lane, E L; Cheetham, S C; Jenner, P

    2005-01-01

    BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

  14. Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial.

    PubMed

    Rodrigues-Junior, Valnês S; Cintra, Luciana; Machado, Pablo; Dadda, Adílio; Basso, Luiz Augusto; Mafra, Ana Carolina Cintra Nunes; Campos, Alexandre Holthausen; Campos, Maria Martha; Santos, Diógenes Santiago

    2017-08-23

    IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration. Diarrhea and alopecia were the clinical signs observed in animals dosed with IQG-607 for 90 days. Long-term treatment with IQG-607 did not induce evident alterations of blood cell counts or any hematological parameters. Importantly, the repeated schedule of administration of IQG-607 resulted in increased cholesterol levels, increased glucose levels, decrease in the globulin levels, and increased creatinine levels over the time. Most necropsy and histopathological alterations of the organs from IQG-607-treated groups were also observed for the untreated group. In addition, pharmacokinetic parameters were evaluated. IQG-607 represents a potential candidate molecule for anti-tuberculosis drug development programs. Its promising in vivo activity and mild to moderate toxic events detected in this study suggest that IQG-607 represents a candidate for clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Comparison of Capillary and Venous Plasma Drug Concentrations After Repeated Administration of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole

    PubMed Central

    De Meulder, Marc; Ariyawansa, Jay; Savitz, Adam

    2016-01-01

    Abstract Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open‐label, parallel‐group study was performed to compare finger‐stick‐based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger‐stick‐based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography–tandem mass spectrometry methods. Finger‐stick‐based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary–venous differences were observed for extended‐release and long‐acting intramuscular formulations and for aripiprazole, a drug with a long half‐life, compared with drugs administered as an immediate‐release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger‐stick‐based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations. PMID:27363344

  16. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function

    PubMed Central

    Gao, Jun; Qin, Rongyin; Li, Ming

    2016-01-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. PMID:25586399

  17. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

    PubMed

    Gao, Jun; Qin, Rongyin; Li, Ming

    2015-04-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems.

  18. Delivery systems of opioid analgesics for pain relief: a review.

    PubMed

    Leppert, Wojciech; Krajnik, Malgorzata; Wordliczek, Jerzy

    2013-01-01

    Chronic pain is usually treated with pharmacological measures using opioids alone or in combination with adjuvant analgesics that play an important role in the treatment of pain not fully responsive to opioids administered alone, especially in neuropathic, bone and visceral colicky pain. The important part of the chronic pain treatment is the appropriate use of non-pharmacological measures along with psychosocial and spiritual support. Opioids may be administered by different routes; the most common and most convenient for majority of treated patients are oral and transdermal. However, in certain circumstances such as inability to swallow, lack of analgesic efficacy and intractable opioid-induced adverse effects parenteral routes (subcutaneous, intravenous) might be more useful. When these routes fail, in some patients intrathecal administration of opioids is required. Recently, more patients have been treated with short-acting opioids for breakthrough pain with sublingual, buccal and intranasal routes of opioid administration that may provide efficacy superior to oral and comparable to intravenous routes. Alternative routes comprise rectal, inhaled and topical administration of opioids. This article discusses various routes of opioid administration.

  19. Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review.

    PubMed

    Bicket, Mark C; Long, Jane J; Pronovost, Peter J; Alexander, G Caleb; Wu, Christopher L

    2017-08-02

    Prescription opioid analgesics play an important role in the treatment of postoperative pain; however, unused opioids may be diverted for nonmedical use and contribute to opioid-related injuries and deaths. To quantify how commonly postoperative prescription opioids are unused, why they remain unused, and what practices are followed regarding their storage and disposal. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched from database inception to October 18, 2016, for studies describing opioid oversupply for adults after a surgical procedure. The primary outcome-opioid oversupply-was defined as the number of patients with either filled but unused opioid prescriptions or unfilled opioid prescriptions. Two reviewers independently screened studies for inclusion, extracted data, and assessed the study quality. Six eligible studies reported on a total of 810 unique patients (range, 30-250 patients) who underwent 7 different types of surgical procedures. Across the 6 studies, 67% to 92% of patients reported unused opioids. Of all the opioid tablets obtained by surgical patients, 42% to 71% went unused. Most patients stopped or used no opioids owing to adequate pain control, and 16% to 29% of patients reported opioid-induced adverse effects. In 2 studies examining storage safety, 73% to 77% of patients reported that their prescription opioids were not stored in locked containers. All studies reported low rates of anticipated or actual disposal, but no study reported US Food and Drug Administration-recommended disposal methods in more than 9% of patients. Postoperative prescription opioids often go unused, unlocked, and undisposed, suggesting an important reservoir of opioids contributing to nonmedical use of these products, which could cause injuries or even deaths.

  20. Effects of amphetamine on the human brain opioid system--a positron emission tomography study.

    PubMed

    Guterstam, Joar; Jayaram-Lindström, Nitya; Cervenka, Simon; Frost, J James; Farde, Lars; Halldin, Christer; Franck, Johan

    2013-05-01

    Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

  1. Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects.

    PubMed

    Neves, Gilda; Borsoi, Milene; Antonio, Camila B; Pranke, Mariana A; Betti, Andresa H; Rates, Stela M K

    2017-01-01

    Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

  2. Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine.

    PubMed

    Herrold, Amy A; Persons, Amanda L; Napier, T Celeste

    2013-08-01

    Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal-enriched tyrosine phosphatase isoform 61 (STEP61 ) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates, and stimulants. STEP61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5, were evaluated via a protein cross-linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP) harvested 1 day after acute, or fourteen days after repeated morphine (8 mg/kg) or methamphetamine (1 mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP61 levels decreased and GluA2 surface expression increased. Pre-treatment with a mGlu5-selective negative allosteric modulator, blocked methamphetamine-induced behavioral sensitization and changes in mPFC GluA2 and STEP61 . These data reveal (i) region-specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (ii) that mGlu5 is necessary for methamphetamine-induced alterations in mPFC GluA2 and STEP61 .

  3. Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord.

    PubMed

    Shi, L; Tang, G P; Gao, S J; Ma, Y X; Liu, B H; Li, Y; Zeng, J M; Ng, Y K; Leong, K W; Wang, S

    2003-07-01

    Gene delivery into the spinal cord provides a potential approach to the treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis, and spinal muscular atrophy. These disorders progress over long periods of time, necessitating a stable expression of functional genes at therapeutic levels for months or years. We investigated in this study the feasibility of achieving prolonged transgene expression in the rat spinal cord through repeated intrathecal administration of plasmid DNA complexed with 25 kDa polyethylenimine (PEI) into the lumbar subarachnoid space. With a single injection, DNA/PEI complexes could provide transgene expression in the spinal cord 40-fold higher than naked plasmid DNA. The transgene expression at the initial level persisted for about 5 days, with a low-level expression being detectable for at least 8 weeks. When repeated dosing was tested, a 70% attenuation of gene expression was observed following reinjection at a 2-week interval. This attenuation was associated with apoptotic cell death and detected even using complexes containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene expression was detected after repeated intrathecal injections, even in those rats receiving three doses, administered 2 weeks apart. Lumbar puncture is a routine and relatively nontraumatic clinical procedure. Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord disorders.

  4. Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

    PubMed Central

    Darwish, Mona; Ma, Yuju; Tracewell, William; Robertson, Philmore; Webster, Lynn R.

    2017-01-01

    Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated. PMID:27330154

  5. Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

    PubMed

    Darwish, Mona; Bond, Mary; Ma, Yuju; Tracewell, William; Robertson, Philmore; Webster, Lynn R

    2017-01-01

    To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA ® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Randomized, double-blind, placebo-controlled, crossover study. One study site in the United States; adult nondependent, recreational opioid users. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was "at the moment" drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Mean maximum effect (E max ) for "at the moment" drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P  <   0.001). Drug liking for intact hydrocodone ER was comparable to placebo (E max : 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective "at the moment" drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

  6. Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats.

    PubMed

    Calcagnoli, Federica; Kreutzmann, Judith C; de Boer, Sietse F; Althaus, Monika; Koolhaas, Jaap M

    2015-01-01

    Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro-social effects of intracerebroventricular (icv) OXT administration in male rats. The present study tested whether similar behavioral effects are induced when OXT is delivered intranasally. Heart-rate and blood-pressure responses were telemetrically monitored to investigate whether peripheral physiological effects were provoked after intranasal OXT administration. Intranasal OXT administration in resident animals reduced offensive aggression and increased social exploration toward an unfamiliar male intruder. Using a partner-preference test, intranasal OXT also strengthened the bonding between the male resident and its female partner. No changes in cardiovascular (re)activity were found, indicating an absence of direct peripheral physiological effects after intranasal OXT treatment. In conclusion, although the precise route and mechanisms of nose-to-brain transport/communication remain to be elucidated, our data demonstrated intranasal OXT to be an effective application method for suppressing intermale aggression and enhancing social affiliation.

  7. Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B.

    PubMed

    Willing, Alison E; Garbuzova-Davis, Svitlana N; Zayko, Olga; Derasari, Hiranya M; Rawls, Ashley E; James, Chris R; Mervis, Ron F; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Sanberg, Paul R

    2014-01-01

    Sanfilippo syndrome type III B (MPS III B) is an inherited disorder characterized by a deficiency of α-N-acetylglucosaminidase (Naglu) enzyme leading to accumulation of heparan sulfate in lysosomes and severe neurological deficits. We have previously shown that a single administration of human umbilical cord mononuclear cells (hUCB MNCs) into Naglu knockout mice decreased behavioral abnormalities and tissue pathology. In this study, we tested whether repeated doses of hUCB MNCs would be more beneficial than a single dose of cells. Naglu mice at 3 months of age were randomly assigned to either a Media-only group or one of three hUCB MNC treatment groups--single low dose (3 × 10(6) cells), single high dose (1.8 × 10(7) cells), or multiple doses (3 × 10(6) cells monthly for 6 months) delivered intravenously; cyclosporine was injected intraperitoneally to immune suppress the mice for the duration of the study. An additional control group of wild-type mice was also used. We measured anxiety in an open field test and cognition in an active avoidance test prior to treatment and then at monthly intervals for 6 months. hUCB MNCs restored normal anxiety-like behavior in these mice (p < 0.001). The repeated cell administrations also restored hippocampal cytoarchitecture, protected the dendritic tree, decreased GM3 ganglioside accumulation, and decreased microglial activation, particularly in the hippocampus and cortex. These data suggest that the neuroprotective effect of hUCB MNCs can be enhanced by repeated cell administrations.

  8. Repeated Administrations of Human Umbilical Cord Blood Cells Improve Disease Outcomes in a Mouse Model of Sanfilippo Syndrome Type III B.

    PubMed

    Willing, Alison E; Garbuzova-Davis, Svitlana N; Zayko, Olga; Derasari, Hiranya M; Rawls, Ashley E; James, Chris R; Mervis, Ron F; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Sanberg, Paul R

    2013-12-30

    Sanfilippo syndrome type III B (MPS III B) is an inherited disorder characterized by a deficiency of ?-N-acetylglucosaminidase (Naglu) enzyme leading to accumulation of heparan sulfate in lysosomes and severe neurological deficits. We have previously shown that a single administration of human umbilical cord mononuclear cells (hUCB MNC) into Nagluknockout mice decreased behavioral abnormalities and tissue pathology. In this study, we tested whether repeated doses of hUCB MNCs would be more beneficial than a single dose of cells. Naglumice at 3 months of age were randomly assigned to either a Media only group, or one of three hUCB MNC treatment groups - single low dose (3x10(6) cells), single high dose (1.8x10(7) cells) or multiple doses (3x10(6) cells monthly for 6 months) delivered intravenously (i.v.); cyclosporine was injected i.p. to immune suppress the mice for the duration of the study. An additional control group of wild type mice was also used. We measured anxiety in an open field test and cognition inactive avoidance test prior to treatment and then at monthly intervals for 6 months. hUCB MNCs restored normal anxiety-like behavior in these mice (p < 0.001). The repeated cell administrations also restored hippocampal cytoarchitecture, protected the dendritic tree, decreased GM3 ganglioside accumulation and decreased microglial activation, particularly in hippocampus and cortex. These data suggest that the neuroprotective effect of hUCB MNCs can be enhanced by repeated cell administrations.

  9. Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions

    PubMed Central

    Rosenblum, Andrew; Marsch, Lisa A.; Joseph, Herman; Portenoy, Russell K.

    2009-01-01

    Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic non-cancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainty about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice. PMID:18837637

  10. Opioids and the treatment of chronic pain: controversies, current status, and future directions.

    PubMed

    Rosenblum, Andrew; Marsch, Lisa A; Joseph, Herman; Portenoy, Russell K

    2008-10-01

    Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainty about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

  11. Non-opioid actions of opioid peptides.

    PubMed

    Wollemann, Mária; Benyhe, Sándor

    2004-06-04

    Beside the well known actions of opioid peptides on mu-, delta- and kappa-opioid receptors, increasing amount of pharmacological and biochemical evidence has recently been published about non-opioid actions of various opioid peptides. These effects are not abolished by naloxone treatments. Such non-opioid effects are observed both in nervous tissues and in the cellular elements of the immune system. Peptides exhibiting non-opioid effects include beta-endorphin, dynorphin A, nociceptin/OFQ, endomorphins, hemorphins and a number of Proenkephalin A derived peptides, such as Met-enkephalin, Met-enkephalin-Arg-Phe (MERF) and bovine adrenal medullary peptide (BAM22). Non-opioid actions are exerted through different neuronal receptors, e.g., dynorphin hyperalgesia through NMDA receptor, Met-enkephalin induced regulation of cell growth through zeta receptors, pain modulation by nociceptin through ORL-1 or NOP receptors, while BAM22 acts through sensory neuron specific G protein-coupled receptors (SNSR). We have investigated Met-enkephalin-Arg-Phe (MERF) and its analogues by the means of direct and indirect radioligand binding assays. It has been found that in addition to kappa(2) and delta-opioid receptors, MERF can act also through sigma(2)- or probably via FMRF-NH(2) receptors in rat cerebellum. A role of functionally assembling heterodimer receptors in mediating the non-conventional actions of these peptide ligands can not be excluded as well.

  12. Brain regional acetylcholinesterase activity and muscarinic acetylcholine receptors in rats after repeated administration of cholinesterase inhibitors and its withdrawal

    SciTech Connect

    Kobayashi, Haruo . E-mail: hk1664@iwate-u.ac.jp; Suzuki, Tadahiko; Sakamoto, Maki; Hashimoto, Wataru; Kashiwada, Keiko; Sato, Itaru; Akahori, Fumiaki; Satoh, Tetsuo

    2007-03-15

    Activity of acetylcholinesterase (AChE) and specific binding of [{sup 3}H]quinuclidinyl benzilate (QNB), [{sup 3}H]pirenzepine (PZP) and [{sup 3}H]AF-DX 384 to muscarinic acetylcholine receptor (mAChR) preparations in the striatum, hippocampus and cortex of rats were determined 1, 6 and 11 days after the last treatment with an organophosphate DDVP, a carbamate propoxur or a muscarinic agonist oxotremorine as a reference for 7 and 14 days. AChE activity was markedly decreased in the three regions 1 day after the treatment with DDVP for 7 and 14 days with a gradual recovery 6 to 11 days, and much less decreased 1, 6 and 11 days after the treatment with propoxur for 7 days but not for 14 days in the hippocampus and cortex. The binding of [{sup 3}H]-QNB, PZP and AF-DX 384 in the three regions was generally decreased by the treatment with DDVP for 7 and 14 days. Such down-regulations were generally restored 6 or 11 days after the treatment for 7 but not for 14 days. The down-regulation or up-regulation as measured by [{sup 3}H]-QNB, PZP and AF-DX 384 was observed 1, 6 or 11 days after treatment with propoxur for 7 days and/or 14 days. Repeated treatment with oxotremorine produced similar effects except AChE activity to DDVP. These results suggest that repeated inhibition of AChE activity may usually cause down-regulation of mAChRs with some exception in the hippocampus when a reversible antiChE propoxur is injected.

  13. Changes in Risk of Immediate Adverse Reactions to Iodinated Contrast Media by Repeated Administrations in Patients with Hepatocellular Carcinoma

    PubMed Central

    Fujiwara, Naoto; Tateishi, Ryosuke; Akahane, Masaaki; Taguri, Masataka; Minami, Tatsuya; Mikami, Shintaro; Sato, Masaya; Uchino, Kouji; Enooku, Kenichiro; Kondo, Yuji; Asaoka, Yoshinari; Yamashiki, Noriyo; Goto, Tadashi; Shiina, Shuichiro; Yoshida, Haruhiko; Ohtomo, Kuni; Koike, Kazuhiko

    2013-01-01

    Background To elucidate whether repeated exposures to iodinated contrast media increase the risk of adverse reaction. Materials and Methods We retrospectively reviewed 1,861 patients with hepatocellular carcinoma who visited authors’ institution, a tertiary referral center, between 2004 and 2008. We analyzed cumulative probability of adverse reactions and risk factors. We categorized all symptoms into hypersensitivity reactions, physiologic reactions, and other reactions, according to the American College of Radiology guidelines, and evaluated each category as an event. We estimated the association between hazard for adverse reactions and the number of cumulative exposures to contrast media. We also evaluated subsequent contrast media injections and adverse reactions. Results There were 23,684 contrast media injections in 1,729 patients. One hundred and thirty-two patients were excluded because they were given no contrast media during the study period. Adverse reactions occurred in 196 (0.83%) patients. The cumulative incidence at 10th, 20th, and 30th examination was 7.9%, 15.2%, and 24.1%, respectively. Presence of renal impairment was found to be one of risk factors for adverse reactions. The estimated hazard of overall adverse reaction gradually decreased until around 10th exposure and rose with subsequent exposures. The estimated hazard of hypersensitivity showed V-shaped change with cumulative number of exposures. The estimated hazard of physiologic reaction had a tendency toward decreasing and that of other reaction had a tendency toward increasing. Second adverse reaction was more severe than the initial in only one among 130 patients receiving subsequent injections. Conclusion Repeated exposures to iodinated contrast media increase the risk of adverse reaction. PMID:24098420

  14. Inhibition of verotoxin (VT) 2 absorption into systemic blood from intestine by repeated administration of bovine immune colostral antibody against VT2 in mice.

    PubMed

    Tetsurou, Seita; Kuribayashi, Takashi; Fukuyama, Masafumi; Yamaguchi, Seiji; Yamamoto, Shizuo

    2015-12-01

    Whether absorption of verotoxin (VT) 2 from the intestine in mice is inhibited by administration bovine immune colostral antibody against VT2 was investigated. Three-week-old mice were administered VT2 solution at 477.8 ng/mL or 955.6 ng/mL, and bovine immune colostral antibody against VT2 was then administered three times. Whey without antibody against VT2 was administered to control mice. Serum levels of VT2 were measured by fluorescence enzyme immunoassay. Serum levels of VT2 in mice administered VT2 solution at 477.8 ng/mL and bovine immune colostral antibody against VT2 scarcely changed. By contrast, serum levels of VT2 in control mice increased and peaked 12 hours after administration. Peak values were 15.4 ± 5.04 ng/mL. Furthermore, serum levels of VT2 at 12 hours and 16 hours in control mice were significantly higher than in mice administered bovine colostral antibody against VT2. Serum levels of VT2 in mice administered antibody at 955.6 ng/mL showed no significant differences between repeated administration of bovine immune colostral antibody and controls. These results suggest that absorption of VT2 from the intestine was inhibited by repeated administration of bovine immune colostral antibody against VT2 at early stages of Escherichia coli O157:H7 infection, whereas VT2 in the intestine remained at low levels. Copyright © 2014. Published by Elsevier B.V.

  15. Development of Antihuman IgG Antibodies and Hematologic Deficits but Not Clinical Abnormalities in C57BL/6 Mice after Repeated Administration of Human Intravenous Immunoglobulin

    PubMed Central

    Loeffler, David A; Smith, Lynnae M; Klaver, Andrea C; Brzezinski, Heather A; Morrison, Essie I; Coffey, Mary P; Steficek, Barbara A; Cook, Susan S

    2012-01-01

    Intravenous immunoglobulin (IvIg) preparations consist of purified human immunoglobulins collected from large numbers of healthy persons and are used to treat autoimmune, immunodeficiency, and inflammatory disorders. Studying the effects of IvIg effects in experimental animal models might clarify its mechanisms of action in these disorders, but whether ‘serum sickness’ or other abnormalities occur after repeated IvIg administration to immunocompetent animals is unknown. In the current study, male C57BL/6 mice (8 to 10 wk old; n = 27) received IvIg (1 g/kg IP) weekly for 6 wk. They were observed for clinical abnormalities, and body weight, temperature, renal function, hematologic parameters, and serum antihuman IgG antibodies were measured before and during treatment. Postmortem evaluations were performed on kidney, spleen, liver, and heart. No clinical or histologic abnormalities were noted despite a transient increase in BUN. Mean antibody levels to human IgG on days 21 and 43 after IvIg administration were increased by 23-fold compared with pretreatment levels. 88% and 89% of the mice were antibody responders on those days. Unexpectedly, hemoglobin, hematocrit, and RBC, WBC, lymphocyte, and platelet counts decreased after IvIg administration. These findings suggest that although it does not produce serum sickness, repeated IvIg administration to immunocompetent mice induces a strong humoral immune response and hematologic deficits of unknown etiology. These factors could cause the effects of IvIg preparations in mouse models of human disease to differ from their effects in the human disorders. PMID:22330649

  16. Development of antihuman IgG antibodies and hematologic deficits but not clinical abnormalities in C57BL/6 mice after repeated administration of human intravenous immunoglobulin.

    PubMed

    Loeffler, David A; Smith, Lynnae M; Klaver, Andrea C; Brzezinski, Heather A; Morrison, Essie I; Coffey, Mary P; Steficek, Barbara A; Cook, Susan S

    2012-02-01

    Intravenous immunoglobulin (IvIg) preparations consist of purified human immunoglobulins collected from large numbers of healthy persons and are used to treat autoimmune, immunodeficiency, and inflammatory disorders. Studying the effects of IvIg effects in experimental animal models might clarify its mechanisms of action in these disorders, but whether 'serum sickness' or other abnormalities occur after repeated IvIg administration to immunocompetent animals is unknown. In the current study, male C57BL/6 mice (8 to 10 wk old; n = 27) received IvIg (1 g/kg IP) weekly for 6 wk. They were observed for clinical abnormalities, and body weight, temperature, renal function, hematologic parameters, and serum antihuman IgG antibodies were measured before and during treatment. Postmortem evaluations were performed on kidney, spleen, liver, and heart. No clinical or histologic abnormalities were noted despite a transient increase in BUN. Mean antibody levels to human IgG on days 21 and 43 after IvIg administration were increased by 23-fold compared with pretreatment levels. 88% and 89% of the mice were antibody responders on those days. Unexpectedly, hemoglobin, hematocrit, and RBC, WBC, lymphocyte, and platelet counts decreased after IvIg administration. These findings suggest that although it does not produce serum sickness, repeated IvIg administration to immunocompetent mice induces a strong humoral immune response and hematologic deficits of unknown etiology. These factors could cause the effects of IvIg preparations in mouse models of human disease to differ from their effects in the human disorders.

  17. The effects of repeated administration of camphor-crataegus berry extract combination on blood pressure and on attentional performance - a randomized, placebo-controlled, double-blind study.

    PubMed

    Erfurt, L; Schandry, R; Rubenbauer, S; Braun, U

    2014-09-25

    The present study investigated the effects of repeated administration of Korodin(®), a combination of camphor and crataegus berry extract, on blood pressure and attentional functioning. This study was conducted based on a randomized, placebo-controlled, double-blind design. 54 persons participated (33 female, 21 male) with a mean age of 24.3 years. Blood pressure and body mass index were in the normal range. Participants received 20 drops of either Korodin(®) or a placebo for four times with interjacent time intervals of about 10 min. Blood pressure was measured sphygmomanometrically before and after each administration. Attentional performance was quantified by using two paper-and-pencil tests, the d2 Test of Attention and Digit Symbol Test. Greater increases in blood pressure occurred after the four Korodin(®) administrations in comparison to the four placebo administrations. The performance in two parameters of d2 Test of Attention was consistently superior after the intake of Korodin(®). The excellent tolerability and safety of Korodin(®), even after a total consumption of 80 drops, was confirmed. Copyright © 2014 Elsevier GmbH. All rights reserved.

  18. Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats

    PubMed Central

    Carvalho, A. F.; Reyes, B. A. S.; Ramalhosa, F.; Sousa, N.

    2014-01-01

    Recent studies demonstrate a differential trajectory for cannabinoid receptor expression in cortical and sub-cortical brain areas across postnatal development. In the present study, we sought to investigate whether chronic systemic exposure to a synthetic cannabinoid receptor agonist causes morphological changes in the structure of dendrites and dendritic spines in adolescent and adult pyramidal neurons in the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) in the nucleus accumbens (Acb). Following systemic administration of WIN 55,212-2 in adolescent (PN 37–40) and adult (P55–60) male rats, the neuronal architecture of pyramidal neurons and MSN was assessed using Golgi–Cox staining. While no structural changes were observed in WIN 55,212-2-treated adolescent subjects compared to control, exposure to WIN 55,212-2 significantly increased dendritic length, spine density and the number of dendritic branches in pyramidal neurons in the mPFC of adult subjects when compared to control and adolescent subjects. In the Acb, WIN 55,212-2 exposure significantly decreased dendritic length and number of branches in adult rat subjects while no changes were observed in the adolescent groups. In contrast, spine density was significantly decreased in both the adult and adolescent groups in the Acb. To determine whether regional developmental morphological changes translated into behavioral differences, WIN 55,212-2-induced aversion was evaluated in both groups using a conditioned place preference paradigm. In adult rats, WIN 55,212-2 administration readily induced conditioned place aversion as previously described. In contrast, adolescent rats did not exhibit aversion following WIN 55,212-2 exposure in the behavioral paradigm. The present results show that synthetic cannabinoid administration differentially impacts cortical and sub-cortical neuronal morphology in adult compared to adolescent subjects. Such differences may underlie the disparate development

  19. Effect of repeated administration with subtoxic doses of acetaminophen to rats on enterohepatic recirculation of a subsequent toxic dose.

    PubMed

    Ghanem, Carolina I; Ruiz, María L; Villanueva, Silvina S M; Luquita, Marcelo; Llesuy, Susana; Catania, Viviana A; Bengochea, Laura A; Mottino, Aldo D

    2009-05-15

    Development of resistance to toxic effects of acetaminophen (APAP) was reported in rodents and humans, though the mechanism is only partially understood. We examined in rats the effect of administration with subtoxic daily doses (0.2, 0.3, and 0.6g/kg, i.p.) of APAP on enterohepatic recirculation and liver toxicity of a subsequent i.p. toxic dose of 1g/kg, given 24h after APAP pre-treatment. APAP and its major metabolite APAP-glucuronide (APAP-Glu) were determined in bile, urine, serum and liver homogenate. APAP pre-treatment was not toxic, as determined by serum markers of liver damage and neither induced oxidative stress as demonstrated by assessment of ROS generation in liver or glutathione species in liver and bile. APAP pre-treatment induced a partial shift from biliary to urinary elimination of APAP-Glu after administration with the toxic dose, and decreased hepatic content and increased serum content of this conjugate, consistent with a marked up-regulation of its basolateral transporter Mrp3 relative to apical Mrp2. Preferential secretion of APAP-glu into blood decreased enterohepatic recirculation of APAP, thus attenuating liver exposition to the intact drug, as demonstrated 6h after administration with the toxic dose. The beneficial effect of interfering the enterohepatic recirculation was alternatively tested in animals receiving activated charcoal by gavage to adsorb APAP of biliary origin. The data indicated decreased liver APAP content and glutathione consumption. We conclude that selective up-regulation of Mrp3 expression by APAP pre-treatment may contribute to development of resistance to APAP hepatotoxicity, at least in part by decreasing its enterohepatic recirculation.

  20. Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures.

    PubMed

    Umpierre, Anthony D; Bennett, Isaiah V; Nebeker, Lismore D; Newell, Thomas G; Tian, Bruce B; Thomson, Kyle E; White, H Steve; White, John A; Wilcox, Karen S

    2016-05-01

    More efficient or translationally relevant approaches are needed to model acquired temporal lobe epilepsy (TLE) in genetically tractable mice. The high costs associated with breeding and maintaining transgenic, knock-in, or knock-out lines place a high value on the efficiency of induction and animal survivability. Herein, we describe our approaches to model acquired epilepsy in C57BL/6J mice using repeated, low-dose kainate (KA) administration paradigms. Four paradigms (i.p.) were tested for their ability to induce status epilepticus (SE), temporal lobe pathology, and the development of epilepsy. All four paradigms reliably induce behavioral and/or electrographic SE without mortality over a 7d period. Two of the four paradigms investigated produce features indicative of TLE pathology, including hippocampal cell death, widespread astrogliosis, and astrocyte expression of mGluR5, a feature commonly reported in TLE models. Three of the investigated paradigms were able to produce aberrant electrographic features, such as interictal spiking in cortex. However, only one paradigm, previously published by others, produces spontaneous recurrent seizures over an eight week period. Presentation of spontaneous seizures is rare (N=2/14), with epilepsy preferentially developing in animals having a high number of seizures during SE. Overall, repeated, low-dose KA administration improves the efficiency and pathological relevance of a systemic KA insult, but does not produce a robust epilepsy phenotype under the experimental paradigms described herein.

  1. The effects of beta alanine plus creatine administration on performance during repeated bouts of supramaximal exercise in sedentary men.

    PubMed

    Okudan, N; Belviranli, M; Pepe, H; Gökbel, H

    2015-11-01

    The aim of this study was to investigate the effects of beta alanine and/or creatine supplementation on performance during repeated bouts of supramaximal exercise in sedentary men. Forty-four untrained healthy men (aged 20-22 years, weight: 68-72 kg, height: 174-178 cm) participated in the present study. After performing the Wingate Test (WAnT) for three times in the baseline exercise session, the subjects were assigned to one of four treatment groups randomly: 1) placebo (P; 10 g maltodextrose); 2) creatine (Cr; 5 g creatine plus 5 g maltodextrose); 3) beta-alanine (β-ALA; 1,6 g beta alanine plus 8,4 g maltodextrose); and 4) beta-alanine plus creatine (β-ALA+Cr; 1,6 g beta alanine plus 5 g creatine plus 3,4 g maltodextrose). Participants were given the supplements orally twice a day for 22 consecutive days, then four times a day for the following 6 days. After 28 days, the second exercise session was applied during which peak power (PP) and mean power (MP) were measured and fatigue index (FI) was calculated. PP and MP decreased and FI increased in all groups during exercise before and after the treatment. During the postsupplementation session PP2 and PP3 increased in creatine supplemented group (from 642.7±148.6 to 825.1±205.2 in PP2 and from 522.9±117.5 to 683.0±148.0 in PP3, respectively). However, MP increased in β-ALA+Cr during the postsupplementation compared to presupplementation in all exercise sessions (from 586.2±55.4 to 620.6±49.6 in MP1, from 418.1±37.2 to 478.3±30.3 in MP2 and from 362.0±41.3 to 399.1±3 in MP3, respectively). FI did not change with beta alanine and beta alanine plus creatine supplementation during the postsupplementation exercise session. Beta-alanine and beta alanine plus creatine supplementations have strong performance enhancing effect by increasing mean power and delaying fatigue Index during the repeated WAnT.

  2. Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.

    PubMed

    Zhou, ZhiQiang; Zhang, GuangFen; Li, XiaoMin; Liu, XiaoYu; Wang, Nan; Qiu, LiLi; Liu, WenXue; Zuo, ZhiYi; Yang, JianJun

    2015-04-01

    Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. To test this hypothesis, ketamine's antidepressant-like effects were evaluated by the forced swimming test. Ketamine-induced stereotyped behaviors and hyperactivity actions and the function of PV interneurons were also assessed. We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects. Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.

  3. Region-specific effects of isoflurane anesthesia on Fos immunoreactivity in response to intravenous cocaine challenge in rats with a history of repeated cocaine administration.

    PubMed

    Kufahl, Peter R; Peartree, Natalie A; Heintzelman, Krista L; Chung, Maggie; Neisewander, Janet L

    2015-01-12

    We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos immunoreactivity in rats under isoflurane anesthesia. Given that Fos expression is a marker of neural activation, the results suggested that isoflurane is appropriate for imaging cocaine effects under anesthesia. However, most imaging research in this area utilizes subjects with a history of repeated cocaine exposure and this drug history may interact with anesthetic use differently from acute cocaine exposure. Thus, this study further examined Fos expression under isoflurane in rats with a history of repeated i.v. cocaine administration. Rats received daily injections of either saline or cocaine (2mg/kg, i.v.) across 7 consecutive days, followed by 5 days of no drug exposure. On the test day, rats were either nonanesthetized or anesthetized under isoflurane and were given an acute challenge of cocaine (2mg/kg, i.v.). Additional saline-exposed controls received a saline challenge. Ninety min after the drug challenge, the rats were perfused under isoflurane anesthesia and their brains were processed for Fos protein immunohistochemistry. We found that challenge injections of cocaine following a regimen of repeated cocaine exposure resulted in Fos expression in the prefrontal cortex and striatum roughly equivalent to that found in rats who had received the cocaine challenge after a history of vehicle injections. Additionally, isoflurane anesthesia resulted in a heterogeneous attenuation of cocaine-induced Fos expression, with the most robust effect in the orbital cortex but no effect in the nucleus accumbens core (NAcC). These results indicate that cocaine-induced Fos is preserved in the NAcC under isoflurane, suggesting that isoflurane can be used in imaging studies involving cocaine effects in this region. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. 14C-NaVP and 14C-PEV repeated dose study in rat. Pharmacokinetic study in rats after repeated oral administrations of 14C-valproic acid sodium salt and 14C-valproic acid pivaloyl oxymethyl ester.

    PubMed

    Bertolino, M; Acerbi, D; Canali, S; Giachetti, C; Poli, G; Ventura, P; Zanolo, G

    1998-01-01

    The absorption, excretion and tissue distribution of radioactivity after repeated oral equimolar doses of 14C-valproic acid sodium salt (NaVP) or 14C-valproic acid pivaloyl oxymethyl ester (PEV) was investigated in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 microg eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 microg eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting from 4 h onwards, radioactivity levels after PEV treatment were higher than those after NaVP (AUCtau = 113.3 h.microg eq./ml after PEV vs 71.9 h.microg eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivity recovered (0-432 h interval) in urine accounted for 79.3% (PEV) and 56.1% (NaVP) while, in faeces accounted for 9.1% (PEV) and 26.1% (NaVP) of total administered dose (14 days). The difference is attributable to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excreted in expired air, as observed in single dose studies. Radioactivity excreted in bile (0-8 h interval of the last 14th day) accounted for 5.1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observed after PEV administration is probably due to an inhibition of the glucuronation of valproic acid (or other metabolites) caused by the pivalic acid. Due to the presence of the enterohepatic recycle, the radioactivity levels in intestine, 0.5 and 2 h after administration, were higher after NaVP administration

  5. Participation of opioid peptides in sucking-induced oxytocin and prolactin secretions in lactating goats.

    PubMed

    Bruna, F A; de Di Nasso, E G; Soaje, M; Deis, R P; Carón, R W

    2010-10-01

    The role of opioid peptides in the secretion of oxytocin (OT) and prolactin (PRL) induced by sucking was studied in goats. Seven goats were isolated with their kids (four singletons and three twins) in individual corrals 3-4 weeks after parturition. On day 1 of the experiment, the kids were separated from the does for 7 h and were weighed before and 15 min after being reunited with their mothers to assess the amount of milk obtained by sucking. The does were blood-sampled 10 min before and at the end of the sucking period. On day 2, a similar protocol was followed, but naloxone was given immediately after the first blood sample. On day 3, the protocol was repeated but saline vehicle was injected instead of naloxone. On day 5, the naloxone experiment was repeated as on day 2. Milk ejection was evaluated as the difference in the weight of the kids before and after sucking for 15 min, and the maternal serum levels of OT and PRL were measured by radioimmunoassay. A significant decrease in the weight gain of the kids was obtained when the mothers were treated with naloxone on day 2. Consistently, serum levels of OT and PRL induced by sucking were significantly reduced; indicating that sucking-induced OT secretion for milk ejection in lactating goats is facilitated by opioid peptides. In a second experiment performed in the same animals 10 days later, the administration of OT, immediately after naloxone administration, prevented the decrease in the weight gain induced by naloxone, suggesting that the effect of the opioid antagonist on milk ejection in goats is a result of a reduced OT secretion. The results of this study confirm the importance of sucking-induced OT secretion for milk ejection in lactating goats, and indicate that OT and PRL secretion are regulated by opioid peptides in this species.

  6. Repeated cocaine administration alters the expression of genes in corticolimbic circuitry after a 3-week withdrawal: a DNA macroarray study.

    PubMed

    Toda, Shigenobu; McGinty, Jacqueline F; Kalivas, Peter W

    2002-09-01

    Addiction to psychostimulants elicits behavioral and biochemical changes that are assumed to be mediated by alterations of gene expression in the brain. The changes in gene expression after 3 weeks of withdrawal from chronic cocaine treatment were evaluated in the nucleus accumbens core and shell, dorsal prefrontal cortex and caudate using a complementary DNA (cDNA) array. The level of mRNA encoded by several genes was identified as being up- or down-regulated in repeated cocaine versus saline subjects. The results from the cDNA array were subsequently confirmed at the protein level with immunoblotting. Of particular interest, parallel up-regulation in protein and mRNA was found for the adenosine A1 receptor in the accumbens core, neuroglycan C in the accumbens shell, and the GluR5 glutamate receptor subtype in dorsal prefrontal cortex. However, there was an increase in TrkB protein in the nucleus accumbens core of cocaine-treated rats without a corresponding alteration in mRNA. These changes of gene expression in corticolimbic circuitry may contribute to the psychostimulant-induced behavioral changes associated with addiction.

  7. Ovarian response to repeated administration of alternating exogenous gonadotropin regimens in the ocelot (Leopardus pardalis) and tigrinus (Leopardus tigrinus).

    PubMed

    da Paz, Regina Celia Rodrigues; Dias, Eduardo Antunes; Adania, Cristina Harumi; Barnabe, Valquíria Hippólito; Barnabe, Renato Campanarut

    2006-10-01

    Exogenous gonadotropins are used to stimulate ovarian follicular growth and ovulation in mammalian species, including wild cats. However, successes in application of assisted reproduction techniques in nondomestic felids have been sparse. Our objectives were to assess the effectiveness of alternating gonadotropin regimens on ovarian responses. Five adult female ocelots and four adult female tigrinus were treated four to six times, using alternating eCG/hCG and pFSH/pLH at 4-month intervals. Laparoscopies were done to assess follicular development and to collect oocytes from matures follicles. The average number of follicles and corpus luteum (CL) per stimulation was higher in ocelots (7.0 +/- 0.8; mean +/- S.E.M.) than in tigrinus (2.5 +/- 0.4; P < 0.05), but the percentage of mature oocytes did not differ between the two species (mean range, 54-55%). Within species, both gonadotropin regimens were equally effective in inducing follicular growth and oocyte maturation. The total number of ovarian structures and oocyte maturation percentages did not decrease in either species with sequential stimulations. In summary, female ocelots and tigrinus continued to respond to repeated alternating ovarian stimulation protocols. In conclusion, the use of alternating gonadotropin regimens may permit more intensive reproductive management in these endangered cats.

  8. Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats

    PubMed Central

    Hingne, Priyanka M.; Sluka, Kathleen A.

    2008-01-01

    Repeated daily application transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the anti-hyperalgesia produced by TENS. Since N-Methyl-D-Aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minute daily at high frequency (100 Hz), low frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg-0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation, and before and after TENS treatment for 4 days. On day 1 TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4 TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4 demonstrating that tolerance did not develop. Vehicle treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. Perspective Tolerance observed to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan. PMID:18061543

  9. Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice.

    PubMed

    Dai, Xu; Cui, Shi-gang; Li, Shi-rong; Chen, Qiang; Wang, Rui

    2007-08-22

    The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to deltorphin I analgesia, and this effect was dose dependent. However, melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the MT(2) receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor.

  10. Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder

    PubMed Central

    Lewis, Alan S.; Qayyum, Zheala; Koslosky, Kourtney; Picciotto, Marina R.; Volkmar, Fred R.

    2016-01-01

    Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted. PMID:25982311

  11. Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder.

    PubMed

    Van Schalkwyk, Gerrit I; Lewis, Alan S; Qayyum, Zheala; Koslosky, Kourtney; Picciotto, Marina R; Volkmar, Fred R

    2015-09-01

    Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted.

  12. Consistency of maternal telephone administration of the asthma control test using postpartum recall compared to repeated measures during pregnancy.

    PubMed

    Xu, Ronghui; Li, Mofei; Johnson, Diana L; Luo, Yunjun; Chambers, Christina D

    2017-05-01

    Suboptimal asthma control during pregnancy may impact perinatal outcomes. U.S. guidelines recommend questionnaires to assess asthma control including the Asthma Control Test (ACT). It is unknown in a research setting to what extent recall differs by the time between symptom occurrence and the administration of the questionnaire. Between 2009-2014, 196 pregnant asthmatic women were recruited by the Organization of Teratology Information Specialists (OTIS) MotherToBaby Pregnancy Studies. Participants were administered the ACT at enrollment, gestational weeks 20 and 32, and shortly after delivery. The same women were also administered the ACT retrospectively at approximately 6 months postpartum. The Pearson correlation coefficients between the in-pregnancy and retrospective continuous ACT scores for the 1st, 2nd and 3rd trimesters were: 0.67 (95% CI: 0.58, 0.74), 0.61 (0.52, 0.70) and 0.65 (0.56, 0.72), respectively. When dichotomized into well-controlled asthma (ACT score ≥ 20) versus otherwise, the chi-square test for all three trimesters resulted in p values <0.0001. Cohen's Kappa statistics for the same dichotomized scores were 0.51, 0.45 and 0.40 for each trimester respectively. There was no evidence that adverse outcome of pregnancy (recall bias) influenced postpartum responses. The retrospectively recalled ACT score obtained postpartum was substantially different compared to in-pregnancy administration of the same questionnaire which could reflect test-retest variability as well as attenuation of recall. Documentation of the magnitude and direction of these differences could be useful in interpretation of the impact of asthma control when the ACT is used in retrospective case-control studies for pregnancy outcomes.

  13. Wearable Biosensors to Detect Physiologic Change During Opioid Use.

    PubMed

    Carreiro, Stephanie; Wittbold, Kelley; Indic, Premananda; Fang, Hua; Zhang, Jianying; Boyer, Edward W

    2016-09-01

    Opioid analgesic use is a major cause of morbidity and mortality in the US, yet effective treatment programs have a limited ability to detect relapse. The utility of current drug detection methods is often restricted due to their retrospective and subjective nature. Wearable biosensors have the potential to improve detection of relapse by providing objective, real time physiologic data on opioid use that can be used by treating clinicians to augment behavioral interventions. Thirty emergency department (ED) patients who were prescribed intravenous opioid medication for acute pain were recruited to wear a wristband biosensor. The biosensor measured electrodermal activity, skin temperature and locomotion data, which was recorded before and after intravenous opioid administration. Hilbert transform analyses combined with paired t-tests were used to compare the biosensor data A) within subjects, before and after administration of opioids; B) between subjects, based on hand dominance, gender, and opioid use history. Within subjects, a significant decrease in locomotion and increase in skin temperature were consistently detected by the biosensors after opioid administration. A significant change in electrodermal activity was not consistently detected. Between subjects, biometric changes varied with level of opioid use history (heavy vs. nonheavy users), but did not vary with gender or type of opioid. Specifically, heavy users demonstrated a greater decrease in short amplitude movements (i.e. fidgeting movements) compared to non-heavy users. A wearable biosensor showed a consistent physiologic pattern after ED opioid administration and differences between patterns of heavy and non-heavy opioid users were noted. Potential applications of biosensors to drug addiction treatment and pain management should be studied further.

  14. Neonatal opioid withdrawal and antenatal opioid prescribing.

    PubMed

    Turner, Suzanne D; Gomes, Tara; Camacho, Ximena; Yao, Zhan; Guttmann, Astrid; Mamdani, Muhammad M; Juurlink, David N; Dhalla, Irfan A

    2015-01-01

    The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown. We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy. The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p < 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p < 0.001). The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy.

  15. Neonatal opioid withdrawal and antenatal opioid prescribing

    PubMed Central

    Gomes, Tara; Camacho, Ximena; Yao, Zhan; Guttmann, Astrid; Mamdani, Muhammad M.; Juurlink, David N.; Dhalla, Irfan A.

    2015-01-01

    Background The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown. Methods We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy. Results The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p < 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p < 0.001). Interpretation The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy. PMID:25844370

  16. Medication-Assisted Treatment For Opioid Addiction in Opioid Treatment Programs. Treatment Improvement Protocol (TIP) Series 43

    ERIC Educational Resources Information Center

    Tinkler, Emily; Vallejos Bartlett, Catalina; Brooks, Margaret; Gilbert, Johnatnan Max; Henderson, Randi; Shuman, Deborah, J.

    2005-01-01

    TIP 43 provides best-practice guidelines for medication-assisted treatment of opioid addiction in opioid treatment programs (OTPs). The primary intended audience for this volume is substance abuse treatment providers and administrators who work in OTPs. Recommendations in the TIP are based on both an analysis of current research and determinations…

  17. Treating Opioid-Induced Constipation in Older Adults: New Options.

    PubMed

    Sani, Halima; Mahan, Rebecca J

    2015-10-01

    Numerous factors, such as changes in gastrointestinal physiology, reduced mobility, decreased liquid and nutritional intake, and certain comorbidities, predispose older adults to constipation. Use of opioid medications further compounds this problem. Unlike other side effects associated with opioid use, patients do not develop tolerance to constipation and other opioid-induced bowel dysfunctions. Although opioid-induced constipation has a prevalence rate of 80% in this population, it remains highly undertreated. Despite this problem, there have been limited therapeutic options available for older adults suffering from opioid-induced constipation. On September 16, 2014, a new oral agent, naloxegol, a peripherally acting muopioid receptor antagonist (PAMORA), approved by the Food and Drug Administration, provides new hope for patients. This paper explores clinical complications associated with opioid-induced constipation in older adults, analyzes the efficacy and safety of laxatives and PAMORAs, and defines the future role of naloxegol in this vulnerable population.

  18. Opioid Analgesics Administered for Pain in the Inpatient Pediatric Setting.

    PubMed

    Walco, Gary A; Gove, Nancy; Phillips, Jennifer; Weisman, Steven J

    2017-06-24

    This study aimed to describe utilization of opioid medications among infants, children, and adolescents on the inpatient setting. These data are needed to guide clinical trials and improve research methodologies, as well as to inform more about possible sources of opioid misuse in the United States. A retrospective chart review was conducted covering a span of 1 year, with a special focus on the prescription of opioids for long-term treatment of chronic pain. Opioid medications were prescribed for <5 days in most (75%) patients. Among those who were prescribed opioids for >14 days, the focus was often for reasons other than pain. These data indicate that models of chronic pain that may be utilized in clinical trials of longer-term opioid usage in pediatrics are exceedingly limited. In addition, the patterns of utilization indicate that opioid administration among pediatric inpatients is not a likely contributory factor to concerns about opioid misuse in the United States. This article presents data on the administration of opioids in a major children's hospital, with a special eye toward usage beyond treatment for short-term acute pain. These data are important to better inform discussions of research strategies for chronic pain, as well as concerns for misuse in the pediatric population. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  19. The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam.

    PubMed

    Jelovac, N; Sikiric, P; Rucman, R; Petek, M; Perovic, D; Marovic, A; Anic, T; Seiwerth, S; Mise, S; Pigac, B; Duplancie, B; Turkovic, B; Dodig, G; Prkacin, I; Stancic-Rokotov, D; Zoricic, I; Aralica, G; Sebecic, B; Ziger, T; Slobodnjak, Z

    1999-09-30

    A novel gastric pentadecapeptide BPC 157 with different beneficial activities and anticonvulsant effect interacting with GABAergic system could improve diazepam efficacy coadministered (10 microg/kg, 10 ng/kg i.p.) with diazepam (5.0 mg/kg i.p.) twice daily for 10 days, since diazepam chronic medication would otherwise predispose for diazepam- tolerance/withdrawal development (shorter latency to convulsion after convulsant). In diazepam chronically treated mice, it attenuated diazepam tolerance (provoked by later acute administration of diazepam together with convulsant) and postponed physical dependence/withdrawal effects (provoked by later administration of isoniazid). In tolerance assay, at 42 h after the end of conditioning regimen, shorter preconvulsive latencies than in healthy (non-diazepam conditioned) mice following isoniazid (800 mg/kg i.p.) (as hallmark of tolerance) were observed if diazepam (5.0 mg/kg i.p.) was again given acutely to mice previously conditioned with diazepam alone (use of picrotoxin 3.0 mg/kg i.p., as convulsant, with acute application of diazepam in previously diazepam conditioned mice did not lead to tolerance hallmark). This was completely avoided in diazepam+BPC 157 10 microg or diazepam+BPC 157 10 ng chronically treated animals. In physical dependence assay (isoniazid challenge assessed at 6, 14, 42 and 72 h after conditioning medication), when compared to diazepam non-conditioned healthy mice, in diazepam conditioned mice residual anticonvulsive activity was not present already at the earliest post-conditioning interval (i.e., not different latency to isoniazid-convulsions), whereas shorter preconvulsive latencies (as physical dependence/withdrawal hallmark) were noted in diazepam conditioned mice following isoniazid challenge at 42 h and at 72 h after end of conditioning treatment. In diazepam+BPC 157 10 microg- conditioned mice, a residual anticonvulsive activity (i.e., longer latency to isoniazid convulsion) was noted at 6 h

  20. Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors.

    PubMed

    Pacheco, Daniela da Fonseca; Romero, Thiago Roberto Lima; Duarte, Igor Dimitri Gama

    2014-05-08

    It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.

  1. Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects.

    PubMed

    Mathias, Stefan; Zihl, Josef; Steiger, Axel; Lancel, Marike

    2005-04-01

    Aging is associated with dramatic reductions in sleep continuity and sleep intensity. Since gaboxadol, a selective GABA(A) receptor agonist, has been demonstrated to improve sleep consolidation and promote deep sleep, it may be an effective hypnotic, particularly for elderly patients with insomnia. In the present study, we investigated the effects of subchronic gaboxadol administration on nocturnal sleep and its residual effects during the next days in elderly subjects. This was a randomized, double-blind, placebo-controlled, balanced crossover study in 10 healthy elderly subjects without sleep complaints. The subjects were administered either placebo or 15 mg gaboxadol hydrochloride at bedtime on three consecutive nights. Sleep was recorded during each night from 2300 to 0700 h and tests assessing attention (target detection, stroop test) and memory function (visual form recognition, immediate word recall, digit span) were applied at 0900, 1400, and 1700 h during the following days. Compared with placebo, gaboxadol significantly shortened subjective sleep onset latency and increased self-rated sleep intensity and quality. Polysomnographic recordings showed that it significantly decreased the number of awakenings, the amount of intermittent wakefulness, and stage 1, and increased slow wave sleep and stage 2. These effects were stable over the three nights. None of the subjects reported side effects. Next-day cognitive performance was not affected by gaboxadol. Gaboxadol persistently improved subjective and objective sleep quality and was devoid of residual effects. Thus, at the employed dose, it seems an effective hypnotic in elderly subjects.

  2. Muscarinic receptor plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate

    SciTech Connect

    Pintor, A.; Fortuna, S.; Volpe, M.T.; Michalek, H.

    1988-01-01

    Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of /sup 3/H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax, which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity.

  3. Opioids, Pain, the Brain, and Hyperkatifeia: A Framework for the Rational Use of Opioids for Pain

    PubMed Central

    Shurman, Joseph; Koob, George F.; Gutstein, Howard B.

    2010-01-01

    Objective Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. Results In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek “katifeia” for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Conclusions Repeated engagement of opponent processes without time for the brain’s emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability. PMID:20545871

  4. Repeated systemic administration of the cinnamon essential oil possesses anti-anxiety and anti-depressant activities in mice.

    PubMed

    Sohrabi, Reyhaneh; Pazgoohan, Nasim; Seresht, Hasan Rezaei; Amin, Bahareh

    2017-06-01

    The present study aimed to evaluate the putative antidepressant and anti-anxiety effects of the cinnamon essential oil when administered acute (for 3 doses) and sub-acute (for 14 days) to mice. In an acute experimental study, forced swim test (FST) was conducted to evaluate the antidepressant-like behavior of animals treated with the intraperitoneal (IP) essential oil of cinnamon in triple doses (0.5, 1, and 2 mg/kg). In a sub-acute study (14 days in 24-hr intervals) antidepressant-like effects of essential oil (0.5, 1, and 2 mg/kg) with the same route were assessed in FST and tail suspension test (TST). Anti-anxiety and motor activities were evaluated using elevated plus-maze (EPM) and open field tests, respectively. Determination of different constituents within the sample oil was via gas chromatography-mass spectrometry (GC-MS) analysis. Repetitive administration of cinnamon essential oil (0.5, 1, 2 mg/kg) during 14 days significantly decreased the time of immobility in both FST and TST as compared to the control group. Mice treated with oil at the dose of 2 mg/kg spent a longer time and had more entries into the open arms of EPM as compared with the vehicle-treated ones. According to GC-MS analysis, 46 chemical compounds were identified in the studied cinnamon essential oil with the main constituent being trans-cinnamaldehyde (87.32%). Cinnamon essential oil might be used as an adjunctive therapy in improving symptoms of depressive and anxiety disorders. However, dose-response effects need further evaluation. Trans-cinnamaldehyde might be responsible for the beneficial effect observed.

  5. Repeated systemic administration of the cinnamon essential oil possesses anti-anxiety and anti-depressant activities in mice

    PubMed Central

    Sohrabi, Reyhaneh; Pazgoohan, Nasim; Seresht, Hasan Rezaei; Amin, Bahareh

    2017-01-01

    Objective(s): The present study aimed to evaluate the putative antidepressant and anti-anxiety effects of the cinnamon essential oil when administered acute (for 3 doses) and sub-acute (for 14 days) to mice. Materials and Methods: In an acute experimental study, forced swim test (FST) was conducted to evaluate the antidepressant-like behavior of animals treated with the intraperitoneal (IP) essential oil of cinnamon in triple doses (0.5, 1, and 2 mg/kg). In a sub-acute study (14 days in 24-hr intervals) antidepressant-like effects of essential oil (0.5, 1, and 2 mg/kg) with the same route were assessed in FST and tail suspension test (TST). Anti-anxiety and motor activities were evaluated using elevated plus-maze (EPM) and open field tests, respectively. Determination of different constituents within the sample oil was via gas chromatography–mass spectrometry (GC–MS) analysis. Results: Repetitive administration of cinnamon essential oil (0.5, 1, 2 mg/kg) during 14 days significantly decreased the time of immobility in both FST and TST as compared to the control group. Mice treated with oil at the dose of 2 mg/kg spent a longer time and had more entries into the open arms of EPM as compared with the vehicle-treated ones. According to GC-MS analysis, 46 chemical compounds were identified in the studied cinnamon essential oil with the main constituent being trans-cinnamaldehyde (87.32%). Conclusion: Cinnamon essential oil might be used as an adjunctive therapy in improving symptoms of depressive and anxiety disorders. However, dose-response effects need further evaluation. Trans-cinnamaldehyde might be responsible for the beneficial effect observed. PMID:28868126

  6. Opioids and endocrine dysfunction

    PubMed Central

    Hester, Joan

    2012-01-01

    The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic-pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized. The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable. If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist. PMID:26516462

  7. Indications for Opioid Antagonists.

    PubMed

    Coppes, O J Michael; Sang, Christine N

    2017-06-01

    As opioids have become more common in clinical practice for the treatment of both acute and chronic pain, so too has the need for a deeper understanding of the clinical applications of opioid antagonists. The purpose of this review is to present both the longstanding and potential new indications for the use of drugs that block the effects of opioid receptors. There is a growing body of data demonstrating the modulation of pain by opioid antagonists. Additional clinical studies that show their direct antinociceptive effects and/or enhancement of the analgesic potency of opioid agonists are warranted. We briefly discuss the well-established role that these agents play in the reversal of life-threatening opioid toxicity and explore both existing and expanding clinical applications, including their apparent paradox that they may themselves be associated with analgesia.

  8. Cellular Composition of the Spleen and Changes in Splenic Lysosomes in the Dynamics of Dyslipidemia in Mice Caused by Repeated Administration of Poloxamer 407.

    PubMed

    Goncharova, N V; Shurlygina, A V; Mel'nikova, E V; Karmatskikh, O L; Avrorov, P A; Loktev, K V; Korolenko, T A

    2015-11-01

    We studied the effect of dyslipidemia induced by poloxamer 407 (300 mg/kg twice a week for 30 days) on cellular composition of the spleen and splenocyte lysosomes in mice. Changes in blood lipid profile included elevated concentrations of total cholesterol, aterogenic LDL, and triglycerides most pronounced in 24 h after the last poloxamer 407 injection; gradual normalization of lipid profile was observed in 4 days (except triglycerides) and 10 days. The most pronounced changes in the spleen (increase in organ weight and number of cells, inhibition in apoptosis, and reduced accumulation of vital dye acridine orange in lysosomes) were detected on day 4; on day 10, the indices returned to normal. Cathepsin D activity in the spleen also increased at these terms. The relationship between changes in the cellular composition of the spleen and dynamics of serum lipid profile in mice in dyslipidemia caused by repeated administrations of relatively low doses of poloxamer 407 is discussed.

  9. The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance.

    PubMed

    Sakamoto, Kazuhiro; Matsumura, Shigenobu; Okafuji, Yoko; Eguchi, Ai; Yoneda, Takeshi; Mizushige, Takafumi; Tsuzuki, Satoshi; Inoue, Kazuo; Fushiki, Tohru

    2015-01-01

    The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement.

  10. Quantitative mapping shows that serotonin rather than dopamine receptor mRNA expressions are affected after repeated intermittent administration of MDMA in rat brain.

    PubMed

    Kindlundh-Högberg, Anna M S; Svenningsson, Per; Schiöth, Helgi B

    2006-09-01

    Ecstasy, (+/-)-3,4-methylenedioxy-metamphetamine (MDMA), is a popular recreational drug among young people. The present study aims to mimic MDMA intake among adolescents at dance clubs, taking repeated doses in the same evening on an intermittent basis. Male Sprague-Dawley rats received either 3x1 or 3x5 mg/kg/day (3 h apart) every seventh day during 4 weeks. We used real-time RT-PCR to determine the gene expression of serotonin 5HT1A, 5HT1B, 5HT2A, 5HT2C, 5HT3, 5HT6 receptors and dopamine D1, D2, D3 receptors in seven brain nuclei. The highest dose of MDMA extensively increased the 5HT1B-receptor mRNA in the cortex, caudate putamen, nucleus accumbens, and hypothalamus. The 5HT2A-receptor mRNA was reduced at the highest MDMA dose in the cortex. The 5HT2C mRNA was significantly increased in a dose-dependent manner in the cortex and the hypothalamus, as well as the 5HT3-receptor mRNA was in the hypothalamus. The 5HT6 mRNA level was increased in the forebrain cortex and the amygdala. Dopamine receptor mRNAs were only affected in the hypothalamus. In conclusion, this study provides evidence for a unique implication of serotonin rather than dopamine receptor mRNA levels, in response to repeated intermittent MDMA administration. We therefore suggest that serotonin regulated functions also primarily underlie repeated MDMA intake at rave parties.

  11. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  12. Effects of chronic and repeated corticosterone administration in rearing chickens on physiology, the onset of lay and egg production of hens.

    PubMed

    Shini, S; Shini, A; Huff, G R

    2009-08-04

    A corticosterone model was used to study the effects of chronic and repeated stress during the rearing phase on physiology, the onset of lay and performance of laying hens in the subsequent laying period. Two hundred and seventy Hy-line brown layer pullets were reared in environmentally controlled battery cages. At 7, 11, and 15 weeks of age birds were exposed for 1 week to the following treatments in drinking water: corticosterone dissolved in ethanol, ethanol, or untreated water. One week following each treatment, and at 35 weeks of age endocrine, metabolic and haematological tests were conducted. Body weight was measured throughout the study, and egg production was recorded daily throughout the laying period. Plasma corticosterone levels and heterophil to lymphocyte (H/L) ratio were increased after each corticosterone delivery, showing the effectiveness of the treatment. When corticosterone delivery was interrupted, plasma corticosterone and H/L ratio were significantly reduced. Exposing birds to repeated and long-term corticosterone treatment significantly affected BW (P<0.01), and relative organ weights (P<0.01). Corticosterone delivery also resulted in increased blood levels of glucose (GLU), cholesterol (CHOL), and triglyceride (TRG). Administration of corticosterone during the rearing phase delayed the onset of lay and decreased egg production at 35 weeks of age. These results demonstrate that oral corticosterone treatment affects hen physiology, reduces performance, and may model the effects of production stressors.

  13. 78 FR 28865 - Request for Comment on the Federal Guidelines for Opioid Treatment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-16

    ... HUMAN SERVICES Substance Abuse and Mental Health Services Administration Request for Comment on the Federal Guidelines for Opioid Treatment AGENCY: Substance Abuse and Mental Health Services Administration... address ONLY: Substance Abuse and Mental Health Services Administration, Attention: DPT Federal...

  14. Opioid analgesia in neonates following cardiac surgery.

    PubMed

    Hammer, Gregory B; Golianu, Brenda

    2007-03-01

    Pain in the newborn is complex, involving a variety of receptors and mechanisms within the developing nervous system. When pain is generated, a series of sequential neurobiologic changes occur within the central nervous system. If pain is prolonged or repetitive, the developing nervous system could be permanently modified, with altered processing at spinal and supraspinal levels. In addition, pain is associated with a number of adverse physiologic responses that include alterations in circulatory (tachycardia, hypertension, vasoconstriction), metabolic (increased catabolism), immunologic (impaired immune response), and hemostatic (platelet activation) systems. This "stress response" associated with cardiac surgery in neonates could be profound and is associated with increased morbidity and mortality. Neonates undergoing cardiac operations are exposed to extensive tissue damage related to surgery and additional painful stimulation related to endotracheal and thoracostomy tubes that may remain in place for variable periods of time following surgery. In addition, postoperatively neonates endure repeated procedural pain from suctioning of endotracheal tubes, placement of vascular catheters, and manipulation of wounds (eg, sternal closure) and dressings. The treatment and/or prevention of pain are widely considered necessary for humanitarian and physiologic reasons. Improved clinical and developmental outcomes underscore the importance of providing adequate analgesia for newborns who undergo major surgery, mechanical ventilation, and related procedures in the intensive care unit. This article reviews published information regarding opioid administration and associated issues of tolerance and abstinence syndromes (withdrawal) in neonates with an emphasis on those having undergone cardiac surgery.

  15. Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

    PubMed Central

    Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.

    2017-01-01

    Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954

  16. Parenteral opioids for maternal pain management in labour

    PubMed Central

    Ullman, Roz; Smith, Lesley A; Burns, Ethel; Mori, Rintaro; Dowswell, Therese

    2014-01-01

    Background Parenteral opioids are used for pain relief in labour in many countries throughout the world. Objectives To assess the acceptability, effectiveness and safety of different types, doses and modes of administration of parenteral opioids given to women in labour. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 April 2011) and reference lists of retrieved studies. Selection criteria We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient controlled analgesia) for women in labour. We looked at studies comparing an opioid with another opioid, placebo, other non-pharmacological interventions (TENS) or inhaled analgesia. Data collection and analysis At least two review authors independently assessed study eligibility, collected data and assessed risk of bias. Main results We included 57 studies involving more than 7000 women that compared an opioid with placebo, another opioid administered intramuscularly or intravenously or compared with TENS to the back. The 57 studies reported on 29 different comparisons, and for many outcomes only one study contributed data. Overall, the evidence was of poor quality regarding the analgesic effect of opioids, satisfaction with analgesia, adverse effects and harm to women and babies. There were few statistically significant results. Many of the studies had small sample sizes, and low statistical power. Overall findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour, although up to two-thirds of women who received opioids reported moderate or severe pain and/or poor or moderate pain relief one or two hours after administration. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We

  17. [Development of physical dependence on nicotine and endogenous opioid system--participation of α7 nicotinic acetylcholine receptor].

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Yamamoto, Chizuko

    2014-10-01

    Nicotine (NIC) regulates various cellular functions acting on the nicotinic acetylcholine receptor (nAChR). And nAChR consists of ligand-gated cation channels with pentameric structure and composed of α and β subunits. In the central nervous system, α 4 β 2 and α 7 nAChRs are the most abundantly expressed as nAChR subtypes. There are several lines of evidence indicating that systemic administration of NIC elicits the release of endogenous opioids, such as, endorphins, enkephalins and dynorphins, in the brain. NIC exerts numerous acute effects, for example, antinociceptive effects and the activating effects of the hypothalamic-pituitary-adrenal (HPA) axis. In these effects, NIC-induced antinociception, but not HPA axis activation, was inhibited by opioid receptor antagonist, naloxone (NLX), and was also suppressed in morphine tolerated mice, indicating the participation of the endogenous opioid system in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception was antagonized by both α 4 β 2 and α 7 nAChR antagonists, while NIC-induced HPA axis activation was antagonized by α 4 β 2 nAChR antagonist, but not by α 7 nAChR antagonist. These results suggest that the endogenous opioid system may not be located on the downstream of α 4 β 2 nAChR. On the other hand, NIC has substantial physical dependence liability. NLX elicits NIC withdrawal after repeated NIC administration evaluated by corticosterone increase as a withdrawal sign, and NLX-precipitated NIC withdrawal is inhibited by concomitant administration of other opioid receptor antagonist, naltrexone, indicating the participation of endogenous opioid system in the development of physical dependence on NIC. NLX-precipitated NIC withdrawal was also inhibited by concomitant administration of an α 7 nAChR antagonist, but not an α 4 β 2 nAChR antagonist. Taken together, these findings suggest that the endogenous opioid system may be located on the downstream of α 7

  18. Repeated ketamine administration alters N-methyl-d-aspartic acid receptor subunit gene expression: Implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

    PubMed Central

    Lipsky, Robert H

    2015-01-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. PMID:25245072

  19. Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.

    PubMed

    Xu, Ke; Lipsky, Robert H

    2015-02-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.

  20. Opioid Prescribing at Hospital Discharge Contributes to Chronic Opioid Use.

    PubMed

    Calcaterra, Susan L; Yamashita, Traci E; Min, Sung-Joon; Keniston, Angela; Frank, Joseph W; Binswanger, Ingrid A

    2016-05-01

    Chronic opioid therapy for chronic pain treatment has increased. Hospital physicians, including hospitalists and medical/surgical resident physicians, care for many hospitalized patients, yet little is known about opioid prescribing at hospital discharge and future chronic opioid use. We aimed to characterize opioid prescribing at hospital discharge among 'opioid naïve' patients. Opioid naïve patients had not filled an opioid prescription at an affiliated pharmacy 1 year preceding their hospital discharge. We also set out to quantify the risk of chronic opioid use and opioid refills 1 year post discharge among opioid naïve patients with and without opioid receipt at discharge. This was a retrospective cohort study. From 1 January 2011 to 31 December 2011, 6,689 opioid naïve patients were discharged from a safety-net hospital. Chronic opioid use 1 year post discharge. Twenty-five percent of opioid naïve patients (n = 1,688) had opioid receipt within 72 hours of discharge. Patients with opioid receipt were more likely to have diagnoses including neoplasm (6.3% versus 3.5%, p < 0.001), acute pain (2.7% versus 1.0 %, p < 0.001), chronic pain at admission (12.1% versus 3.3%, p < 0.001) or surgery during their hospitalization (65.1% versus 18.4%, p < 0.001) compared to patients without opioid receipt. Patients with opioid receipt were less likely to have alcohol use disorders (15.7% versus 20.7%, p < 0.001) and mental health disorders (23.9% versus 31.4%, p < 0.001) compared to patients without opioid receipt. Chronic opioid use 1 year post discharge was more common among patients with opioid receipt (4.1% versus 1.3%, p < 0.0001) compared to patients without opioid receipt. Opioid receipt was associated with increased odds of chronic opioid use (AOR = 4.90, 95% CI 3.22-7.45) and greater subsequent opioid refills (AOR = 2.67, 95% CI 2.29-3.13) 1 year post discharge compared to no opioid receipt. Opioid receipt at hospital

  1. Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy Mu Opioid Receptor (MOR) Agonist/Delta Opioid Receptor (DOR) Antagonist Ligands

    PubMed Central

    Mosberg, Henry I.; Yeomans, Larisa; Harland, Aubrie A.; Bender, Aaron M.; Sobczyk-Kojiro, Katarzyna; Anand, Jessica P.; Clark, Mary J.; Jutkiewicz, Emily M.; Traynor, John R.

    2013-01-01

    We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance. PMID:23419026

  2. Neuroprotective actions of GR89696, a highly potent and selective kappa-opioid receptor agonist.

    PubMed Central

    Birch, P. J.; Rogers, H.; Hayes, A. G.; Hayward, N. J.; Tyers, M. B.; Scopes, D. I.; Naylor, A.; Judd, D. B.

    1991-01-01

    1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention. PMID:1657267

  3. The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities.

    PubMed

    Leppert, Wojciech

    2012-01-01

    Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal symptoms such as constipation, anorexia, nausea, vomiting, gastro-oesophageal reflux, delayed digestion, abdominal pain, bloating, hard stool and incomplete evacuation that significantly deteriorate patients' quality of life and compliance. Approximately one third of patients treated with opioids do not adhere to the opioid regimen or simply quit the treatment due to OIBD. Several strategies are undertaken to prevent or treat OIBD. Traditional oral laxatives are used but their effectiveness is limited and they display adverse effects. Other possibilities comprise opioid switch or changing the administration route. New therapies target opioid receptors in the gut that seem to be the main source of OIBD. One is a combination of an opioid and opioid antagonist (oxycodone/naloxone) in prolonged-release tablets, and another is a purely peripherally acting opioid receptor antagonist (methylnaltrexone) available in subcutaneous injections. The aim of this article is to review the pathomechanism and possible treatment strategies of OIBD.

  4. A review of opioid prescription in a teaching hospital in Colombia

    PubMed Central

    Moyano, Jairo; Figueras, Albert

    2012-01-01

    Introduction: Review of opioid prescriptions in a hospital provides valuable information to health care professionals which may contribute to proper pain management; opioid utilization studies may help uncover factors that can be improved for better prescribing. To evaluate the use of opioid analgesics in a university hospital, a review of opioids prescribed in hospitalized patients was developed. Methods: Information was obtained from the pharmacy database and medical records. The study period was 1 month. Results: Medical records of 1156 patients admitted in July 2009 were analyzed. The most widely prescribed opioid was tramadol; the preferred administration route was intravenous; the main indication was severe pain; and major prescribers were from surgical departments. Discussion: Underutilization of potent opioids for acute and chronic pain seems to occur. Conclusion: Most prescribers prefer weak opioids, given intravenously to treat acute and chronic pain, while some patients may benefit from the prescription of more potent opioids. PMID:23049273

  5. Oral Administration of Recombinant Lactococcus lactis Expressing HSP65 and Tandemly Repeated P277 Reduces the Incidence of Type I Diabetes in Non-Obese Diabetic Mice

    PubMed Central

    Ma, Yanjun; Liu, Jingjing; Hou, Jing; Dong, Yuankai; Lu, Yong; Jin, Liang; Cao, Rongyue; Li, Taiming; Wu, Jie

    2014-01-01

    Diabetes mellitus type 1 (DM1) is an autoimmune disease that gradually destroys insulin-producing beta-cells. We have previously reported that mucosal administration of fusion protein of HSP65 with tandem repeats of P277 (HSP65-6P277) can reduce the onset of DM1 in non-obese diabetic (NOD) mice. To deliver large amounts of the fusion protein and to enhance long-term immune tolerance effects, in the present study, we investigated the efficacy of using orally administrated L. lactis expressing HSP65-6P277 to reduce the incidence of DM1 in NOD mice. L. lactis strain NZ9000 was engineered to express HSP65-6P277 either constitutively or by nisin induction. After immunization via gavage with the recombinant L. lactis strains to groups of 4-week old female NOD mice for 36 weeks, we observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis. Immunologic analysis showed that treatment with recombinant L. lactis induced HSP65- and P277- specific T cell immuno-tolerance, as well as antigen-specific proliferation of splenocytes. The results revealed that the DM1-preventing function was in part caused by a reduction in the pro-inflammatory cytokine IFN-γ and an increase in the anti-inflammatory cytokine IL-10. Orally administered recombinant L. lactis delivering HSP65-6P277 may be an effective therapeutic approach in preventing DM1. PMID:25157497

  6. Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury.

    PubMed

    Vaquero, Jesús; Zurita, Mercedes; Rico, Miguel A; Bonilla, Celia; Aguayo, Concepción; Fernández, Cecilia; Tapiador, Noemí; Sevilla, Marta; Morejón, Carlos; Montilla, Jesús; Martínez, Francisco; Marín, Esperanza; Bustamante, Salvador; Vázquez, David; Carballido, Joaquín; Rodríguez, Alicia; Martínez, Paula; García, Coral; Ovejero, Mercedes; Fernández, Marta V

    2017-03-01

    Cell therapy with mesenchymal stromal cells (MSCs) offers new hope for patients suffering from spinal cord injury (SCI). Ten patients with established incomplete SCI received four subarachnoid administrations of 30 × 10(6) autologous bone marrow MSCs, supported in autologous plasma, at months 1, 4, 7 and 10 of the study, and were followed until the month 12. Urodynamic, neurophysiological and neuroimaging studies were performed at months 6 and 12, and compared with basal studies. Variable improvement was found in the patients of the series. All of them showed some degree of improvement in sensitivity and motor function. Sexual function improved in two of the eight male patients. Neuropathic pain was present in four patients before treatment; it disappeared in two of them and decreased in another. Clear improvement in bladder and bowel control were found in all patients suffering previous dysfunction. Before treatment, seven patients suffered spasms, and two improved. Before cell therapy, nine patients suffered variable degree of spasticity, and 3 of them showed clear decrease at the end of follow-up. At this time, nine patients showed infra-lesional electromyographic recordings suggesting active muscle reinnervation, and eight patients showed improvement in bladder compliance. After three administrations of MSCs, mean values of brain-derived neurotrophic factor, glial-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin 3 and 4 showed slight increases compared with basal levels, but without statistically significant difference. Administration of repeated doses of MSCs by subarachnoid route is a well-tolerated procedure that is able to achieve progressive and significant improvement in the quality of life of patients suffering incomplete SCI. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  7. Repeated restraint and nerve growth factor administration in male and female mice: effect on sympathetic and cardiovascular mediators of the stress response.

    PubMed

    Manni, Luigi; Di Fausto, Veronica; Fiore, Marco; Aloe, Luigi

    2008-02-01

    Chronic stress and increased sympathetic nerve activity have been associated with cardiovascular disorders such as hypertension, myocardial infarction and stroke. The aim of this study was to investigate the role of nerve growth factor (NGF) on the expression of tyrosine hydroxylase (TH), vascular-endothelial growth factor (VEGF) and leptin receptor (OB-R) in brain, adrenal and cardiovascular tissues of adult male and female mice following a chronic stress procedure. It was found that daily restraint for 10 consecutive days alters TH levels in hypothalamic and brainstem areas related to sympathetic activation, in both male and female mice. Chronic stress procedure also modifies heart and aorta VEGF levels in male mice, and adrenal glands TH in female mice. The NGF administration in stressed mice reverted the stress-induced up-regulation of TH levels in male and female mice hypothalamic nuclei and in male locus coeruleus. Administration of NGF in stressed animals also down-regulated OB-R levels in the hypothalamus of both male and female mice and in the female aorta. Our findings indicate that repeated restraint in mice has an effect on TH and VEGF protein content at different brain and peripheral sites involved in the sympathetic and cardio-vascular response to stressful stimuli. NGF administration is able to counteract some of these stress-induced changes. Since NGF is known to be up-regulated during stress, a possible functional significance of our observations is that the circulating NGF released during and following stress may serve to prevent possible deficits and/or damage linked to stress-induced sympathetic and cardiovascular activation.

  8. Effects of repeated social defeat on adolescent mice on cocaine-induced CPP and self-administration in adulthood: integrity of the blood-brain barrier.

    PubMed

    Rodríguez-Arias, Marta; Montagud-Romero, Sandra; Rubio-Araiz, Ana; Aguilar, María A; Martín-García, Elena; Cabrera, Roberto; Maldonado, Rafael; Porcu, Francesca; Colado, María Isabel; Miñarro, José

    2017-01-01

    Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference and quantitative analysis of claudin-5, laminin, collagen-IV and IgG immunoreactivity took place 3 weeks after RSD. Mice socially defeated during adolescence developed conditioned place preference and exhibited reinstated preference with a non-effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine self-administration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin-5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen-IV expression) in the nucleus accumbens and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen-IV expression in the hippocampus was more pronounced in RSD mice. In summary, our findings suggest that stress and cocaine can increase the long-term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB.

  9. Expression of amphetamine-induced behavioral sensitization after short- and long-term withdrawal periods: participation of mu- and delta-opioid receptors.

    PubMed

    Magendzo, Karin; Bustos, Gonzalo

    2003-03-01

    Repeated amphetamine administration results in behavioral sensitization, an enduring behavioral transformation expressed after short and long periods of withdrawal. To investigate the participation of the opioid system in amphetamine-induced behavioral sensitization, we studied the effect of naloxone, an opioid receptor antagonist, on the expression of behavioral sensitization tested after short- (2 days) and long-term (14 days) withdrawal periods. In addition, using quantitative competitive RT-PCR, we examined the levels of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) mRNA in the nucleus accumbens shell (NAcSh) and ventral tegmental area (VTA) of behaviorally sensitized rats, at these two withdrawal times. This study showed that whereas naloxone did not modify the expression of behavioral sensitization tested after 2 days of withdrawal, it completely blocked the expression when tested after 14 days of withdrawal. DOR and MOR mRNA levels were not modified in the NAcSh of rats expressing behavioral sensitization after 2 or 14 days of withdrawal. Conversely, DOR and MOR mRNA levels were elevated in the VTA of animals expressing behavioral sensitization after 2 days of withdrawal. However, whereas DOR mRNA returned to control levels, MOR mRNA levels remained elevated in animals expressing behavioral sensitization after 14 days of withdrawal. These results indicate a striking difference between the role played by opioid receptors in the expression of amphetamine-induced behavioral sensitization, when tested after short- or long-term withdrawal periods. In addition, our results support the notion that repeated amphetamine-induced changes in opioid receptor expression may contribute to the perpetuation of psychostimulant abuse and/or relapse.

  10. Overview of genetic analysis of human opioid receptors.

    PubMed

    Spampinato, Santi M

    2015-01-01

    The human μ-opioid receptor gene (OPRM1), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies. The μ-opioid receptor (MOR), encoded by OPRM1, contributes to regulate the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic polymorphisms of opioid receptors are candidates for the variability of clinical opioid effects. The non-synonymous polymorphism A118G of the OPRM1 has been repeatedly associated with the efficacy of opioid treatments for pain and various types of dependence. Genetic analysis of human opioid receptors has evidenced the presence of numerous polymorphisms either in exonic or in intronic sequences as well as the presence of synonymous coding variants that may have important effects on transcription, mRNA stability, and splicing, thus affecting gene function despite not directly disrupting any specific residue. Genotyping of opioid receptors is still in its infancy and a relevant progress in this field can be achieved by using advanced gene sequencing techniques described in this review that allow the researchers to obtain vast quantities of data on human genomes and transcriptomes in a brief period of time and with affordable costs.

  11. Compulsivity in opioid dependence.

    PubMed

    Tolomeo, Serenella; Matthews, Keith; Steele, Douglas; Baldacchino, Alex

    2017-09-14

    This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n=24), ii) heroin users stabilised on methadone maintenance treatment (n=48), iii) abstinent participants with a history of opioid dependence due to heroin use (n=24) and iv) healthy controls (n=50). Compulsivity was measured using Intra/Extra-Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT). Structural Magnetic Resonance Imaging (MRI) data were also obtained. As hypothesised, compulsivity was negatively associated with impulsivity (p<0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group, compared to the other opioid dependent groups. In addition, self-reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. Our findings are consistent with Volkow & Koob's addiction models and underline the important role of compulsivity versus impulsivity in opioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Opioid-induced Cardioprotection

    PubMed Central

    Tanaka, Katsuya; Kersten, Judy R.; Riess, Matthias L.

    2014-01-01

    Ischemic heart disease and myocardial infarction continue to be leading causes of cardiovascular morbidity and mortality. Activation of opioid, adenosine, bradykinin, adrenergic and other G-protein coupled receptors have been found to be cardioprotective. κ- and/or δ-opioid receptor activation is involved in direct myocardial protection, while the role of μ-opioid receptors seems less clear. In addition, differential affinities to the three opioid-receptor subtypes by various agonists and cross-talk among different G-protein coupled receptors render conclusions regarding opioid-mediated cardioprotection challenging. The present review will focus on the protective effects of endogenously released opioid peptides as well as exogenously administered opioids such as morphine, fentanyl, remifentanil, butorphanol, and methadone against myocardial ischemia/reperfusion injury. Receptor heterodimerization and cross-talk as well as interactions with other cardioprotective techniques will be discussed. Implications for opioid-induced cardioprotection in humans and for future drug development to improve myocardial salvage will be provided. PMID:24502571

  13. Opioid dependence and pregnancy.

    PubMed

    Winklbaur, Bernadette; Jung, Erika; Fischer, Gabriele

    2008-05-01

    The management of opioid dependence during pregnancy has received considerable attention over the past three decades. Recent peer-reviewed literature in the fields of pregnancy and opioid dependence and neonatal abstinence syndrome has been evaluated and discussed. Pregnant opioid-dependent women must be carefully managed to minimize harm to the fetus; therefore, standardized care for maternal health is required. In a multidisciplinary care system opioid maintenance therapy is the recommended treatment approach during pregnancy. Equivalent attention must be given to the treatment of neonatal abstinence syndrome, which occurs in 55-94% of neonates after intrauterine opioid exposure with a 60% likelihood of requiring treatment; heterogeneous rating scales as well as heterogeneous treatment approaches are often responsible for extended hospital stays. Interpretation of available literature is confounded by several methodological flaws. In general, there is still a lack of evidence-based study designs for pharmacological treatment of these patients as well as neonatal abstinence syndrome.

  14. The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.

    PubMed

    Galante, Julieta; Adamska, Ligia; Young, Alan; Young, Heather; Littlejohns, Thomas J; Gallacher, John; Allen, Naomi

    2016-02-28

    Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

  15. Impaired recovery of brain muscarinic receptor sites following an adaptive down-regulation induced by repeated administration of diisopropyl fluorophosphate in aged rats

    SciTech Connect

    Pintor, A.; Fortuna, S.; De Angelis, S.; Michalek, H. )

    1990-01-01

    Potential age-related differences in the recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor binding sites (mAChRs) following reduction induced by repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. Male 3- and 24-month old rats were s.c. injected with DFP on alternate days for 2 weeks and killed 48 hr and 7, 14, 21, 28 and 35 days after the last treatment. In the hippocampus and striatum, but not in the cerebral cortex, of control rats there as a significant age-related decline of ChE activity and maximal density of 3H-QNB binding sites (Bmax). The repeated administration of DFP during the first week caused a syndrome of cholinergic stimulation both in aged and young rats. The syndrome was more pronounced, in terms of intensity and duration in aged than in young animals resulting in 40 and 12% mortality, respectively; during the second week the syndrome attenuated in the two age-groups. The percentage inhibition of brain ChE at the end of DFP treatment did not differ between young and surviving aged rats. The down-regulation of mACRs was present in the three brain regions of both young and age rats (from 20 to 40%). Factorial analysis of variance showed significant differences for age, recovery rate, and significant interaction between age and recovery rate, both for ChE and mAChRs in young rats the three brain areas.

  16. Antidepressant-like effects of the novel kappa opioid antagonist MCL-144B in the forced-swim test.

    PubMed

    Reindl, J D; Rowan, K; Carey, A N; Peng, X; Neumeyer, J L; McLaughlin, J P

    2008-01-01

    Previous studies have demonstrated that kappa opioid receptor (KOR) antagonists reduce stress- and depression-like behaviors. We hypothesized that administration of a novel opioid mixed agonist/antagonist capable of antagonist activity at the KOR would attenuate forced-swim stress (FSS)-induced immobility, an animal model of depression-like behavior. C57Bl/6J mice were exposed to antinociceptive and repeated FSS testing after pretreatment with a graded dose of a novel bivalent morphinan compound, bis(N-cyclobutylmethylmorphinan-3-yl) sebacoylate dihydrochloride (MCL-144B). MCL-144B demonstrated dose- and time-dependent antinociception and KOR-mediated antagonism. In support of the hypothesis, pretreatment with MCL-144B dose-dependently attenuated stress-induced antinociception and immobility in the forced-swim test.

  17. ΔFosB induction correlates inversely with CB₁ receptor desensitization in a brain region-dependent manner following repeated Δ⁹-THC administration.

    PubMed

    Lazenka, Matthew F; Selley, Dana E; Sim-Selley, Laura J

    2014-02-01

    Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB

  18. Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

    PubMed

    Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W

    2008-08-01

    Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting

  19. Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

    PubMed Central

    Mall, Christine; Sckisel, Gail D.; Proia, David A.; Mirsoian, Annie; Grossenbacher, Steven K.; Pai, Chien-Chun Steven; Chen, Mingyi; Monjazeb, Arta M.; Kelly, Karen; Blazar, Bruce R.; Murphy, William J.

    2016-01-01

    ABSTRACT Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30–60 min after 4–5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation. PMID:27057446

  20. Error correction in latent inhibition and its disruption by opioid receptor blockade with naloxone.

    PubMed

    Leung, Hiu T; Killcross, A S; Westbrook, R Frederick

    2013-11-01

    Latent inhibition refers to the retardation in the development of conditioned responding when a pre-exposed stimulus is used to signal an unconditioned stimulus. This effect is described by error-correction models as an attentional deficit and is commonly used as an animal model of schizophrenia. A series of experiments studied the role of error-correction mechanism in latent inhibition and its interaction with the endogenous opioid system. Systemic administration of the competitive opioid receptor antagonist naloxone before rats were pre-exposed to a target stimulus prevented latent inhibition of its subsequent fear conditioning; it was without effect on a non-pre-exposed stimulus and did not produce state-dependent learning (Experiments 1a and 1b). Naloxone did not reverse the latent inhibitory effect already accrued to a pre-exposed target. However, it did prevent the enhancement of latent inhibition by a long retention interval interpolated between its initial exposure and re-exposure (Experiment 2) or by a novel stimulus compounded with the pre-exposed target during re-exposure (Experiment 3). These results provide evidence that attentional loss in latent inhibition is instructed by an opioid-mediated error signal which diminishes with repeated stimulus exposures but recovers with the passage of time or reintroduction of novelty.