Activation Of Opioid Receptors Research Articles

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress.

Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also provide evidence that constitutive activity of κORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of κOR regulation that plays a critical role in reinstatement of drug seeking.

Inhibition of δ‐Opioid Receptors

Opioid addiction and abuse affects between 26 and 36 million people worldwide (Volkow, 2014), prompting researchers to try to design a drug that both has painkilling effects but does not create a dependency. Most opioid analgesics work through activation of mu opioid receptors (MOR). They naturally bind to opioid peptides, such as endomorphins 1 and 2, in order to regulate pain. Another important target is the delta opioid receptor (DOR). Inhibition of DOR has been shown to slow the development of addiction to MOR agonists in animal models of pain. DOR are proteins that transpermeate the cell membrane with seven alpha helices. Schiller and colleagues first reported an endomorphin analogue, DIPP‐NH2, that activates MOR and also inhibits DOR. DIPP‐NH2 is structurally similar to the natural endomorphins, so it can bind DOR through similar mechanisms. The DIPP‐NH2 interacts with the Met132, Tyr129, Val217, Ile277, and Trp284 on DOR. Moreover, one of the two methyl groups on DIPP‐NH2 engages Val281 and Ile277. Finally, a salt bridge forms between the DIPP‐NH2 N‐terminus and Asp128, and this salt bridge is crucial for opioid receptor ligand recognition. The Whitefish Bay High School SMART team (Students Modeling a Research Topic) is modeling DOR using 3D printing technology. DIPP‐NH2 may be the basis of a non‐addictive painkiller, which would be a significant advancement toward alleviating the major societal and financial problem of opioid addiction.Support or Funding InformationThis work was supported by the National Institutes of of Health Science Education Partnership Award (NIH‐SEPA 1R25OD010505‐01) and the National Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973).

MP83-19 CO-TREATMENT WITH L-METHADONE SIGNIFICANTLY INCREASES THE EFFICACY OF CYTOSTATIC DRUGS IN PROSTATE CANCER CELLS

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2017MP83-19 CO-TREATMENT WITH L-METHADONE SIGNIFICANTLY INCREASES THE EFFICACY OF CYTOSTATIC DRUGS IN PROSTATE CANCER CELLS Birgit Stadlbauer, Detlef Kozian, Christian Stief, and Alexander Buchner Birgit StadlbauerBirgit Stadlbauer More articles by this author , Detlef KozianDetlef Kozian More articles by this author , Christian StiefChristian Stief More articles by this author , and Alexander BuchnerAlexander Buchner More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2587AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In leukemia and glioblastoma cells, a significant increase of apoptosis rates has been observed in vitro under cytostatic therapy by activation of the µ-opioid receptor with methadone. This study investigated the effect of opioid receptor activation in prostate cancer cells in presence of different cytotoxic drugs. METHODS The prostate cancer cell lines PC-3, DU145 and LNCaP as well as control cell lines RCC-26 and A172 (renal cell carcinoma and glioblastoma) were incubated with different concentrations of the cytostatic drugs cabazitaxel and doxorubicin and the number of cells in apoptosis after 3 and 5 days was analyzed using flow cytometry (with annexin V-APC and 7AAD staining). In addition, the cells were incubated with various concentrations of L-methadone (0-100 µg/ml). Furthermore, gene expression analysis was performed using microarrays (Affymetrix GeneChip Prime View, ca. 49,000 transcripts) to detect changes in cell biology caused by methadone treatment. RESULTS Incubation of PC-3 cells with 10 nM cabazitaxel resulted in 53% apoptosis after 5 days. This rate remained constant under co-incubation with L-methadone. Incubation with 0.3 μM doxorubicin resulted in 37% apoptosis after 5 days. In this setting, co-incubation with L-methadone showed a dose-dependent increase of apoptosis rate up to 88% (2.4-fold increase). Control experiments with fentanyl and naloxone instead of methadone showed no influence on apoptosis rate. Comparable and partly even clearer results were achieved with DU145, LNCaP, RCC-26 and A172 cells: the cabazitaxel-induced apoptosis rates remained stable under L-methadone, the doxorubicin-induced apoptosis was significantly increased by L-methadone (up to 3.8-fold increase). Microarray analysis revealed 128 upregulated and 398 downregulated genes (≥2-fold change of expression level, p<0.05) caused by L-methadone in PC-3 cells. CONCLUSIONS Stimulation of the µ-opioid receptors by L-methadone enhances the therapeutic effect of cytostatic drugs in prostate carcinoma cells and in other tumor cell lines. The increase of cytostatic effect depends on the combination of cell line and cytostatic agent. The combination of L-methadone with certain cytotoxic drugs can be a promising new approach to increase the therapeutic efficacy in hormone-refractory prostate carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1114 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Birgit Stadlbauer More articles by this author Detlef Kozian More articles by this author Christian Stief More articles by this author Alexander Buchner More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge.

d-Pen2,d-Pen5 enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The in vitro activity was investigated showing a good affinity of 7a-c for μ- and δ-receptors. In vivo biological assays revealed that 7b is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i.c.v.) administration, whereas DPDPE was slightly active until 45 min. Compound 7b induced long lasting analgesia also after subcutaneous administration, whereas DPDPE was inactive.

Humoral immunity and autism spectrum disorders

Abnormal immune activation, particularly of a humoral nature, has consistently been described in the etiopathogenesis of autism spectrum disorders (ASD). In this journal, Mead and Ashwood (2015) reviewed immune abnormalities in autism and linked them to severity of classic autistic symptoms. However, there remains a lack of clarity as to how environmental risk factors in ASD may contribute to such immunophenotypes. The evidence presented herein highlights these immune deficits of a humoral nature in ASD. Moreover, aligned with prior research showing a link between chronic air pollution and suppression of humoral immunity, the author of this commentary has proposed that environmental exposure to pervasive air pollutants, particularly nitrous oxide (N2O), may target several anti-inflammatory biomarkers, including alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibition and stimulation of kappa opioid receptor (KOR) activity. Given that these physiological targets, in particular, may promote the oft-noted humoral immunophenotypes in ASD, including B cell survival and muted antibody responses, this correspondence supports an existing line of evidence that air pollution, and particularly exposure to environmental N2O, may be an important etiological risk factor in ASD.

Opioids: Modulators of angiogenesis in wound healing and cancer.

Opioids are potent drugs that are widely used to control wound or cancer pain. Increasing evidence suggest that opioids mediate clinically relevant effects that go beyond their classical role as analgesics. Of note, opioids appear to modulate angiogenesis - a process that is critical in wound healing and cancer progression. In this review, we focus on pro- and anti-angiogenic facets of opioids that arise from the activation of individual opioid receptors and the usage of individual concentrations or application routes. We overview the still incompletely elucidated mechanisms of these angiogenic opioid actions. Moreover, we describe plausible opioids effects, which - although not primarily studied in the context of vessel formation - may be related to the opioid-driven processes of angiogenesis. Finally we discuss the use of opioids as an innovative therapeutic avenue for the treatment of chronic wounds and cancer.

Antagonizing the different stages of kappa opioid receptor activation selectively and independently attenuates acquisition and consolidation of associative memories

Previous work from our laboratory has shown that nonspecific kappa opioid receptor (KOR) antagonism in primary somatosensory cortex (S1) can inhibit acquisition for the forebrain-dependent associative task, Whisker-Trace Eyeblink conditioning (WTEB). Although studies have demonstrated that KOR activation can alter stimuli salience, our studies controlled for these factors, demonstrating that KOR also plays a role in facilitating learning. KOR has two distinct phases of activation followed by internalization/downregulation, that each independently activate kinases and transcription factors known to mediate task acquisition and memory consolidation respectively. The current study demonstrated that antagonism of the initial phase of KOR activation in S1 via local injections of the g-protein inhibitor, pertussis toxin (PTX), blocked initial WTEB acquisition without affecting retention of the association. In contrast, KOR late phase antagonism in S1 via local injections of the GRK3-specific antagonist, guanidinonaltrindole (GNTI), blocked retention of the WTEB association without affecting task acquisition. Consistent with the known mechanism for KOR activation, KOR protein expression in S1 was found to be decreased following WTEB training, further supporting the involvement of neocortical KOR activation with learning. Prior studies have shown that task acquisition and memory consolidation are mediated by distinct molecular processes; however, little is known regarding a potential mechanism driving these processes. The current study suggests that neocortical KOR activation mediates activation of these processes with learning. This study provides the first evidence for a time- and learning-dependent property of neocortical KOR in facilitating acquisition and consolidation of associative memories, while elucidating an unexplored neocortical learning mechanism.

Role of central opioid on the antinociceptive effect of sulfated polysaccharide from the red seaweed Solieria filiformis in induced temporomandibular joint pain

This study aimed to investigate the effect of sulfated polysaccharide from red seaweed Solieria filiformis (Fraction F II) in the inflammatory hypernociception in the temporomandibular joint (TMJ) of rats. Male Wistar rats were pretreated (30min) with a subcutaneous injection (s.c.) of vehicle or FII (0.03, 0.3 or 3.0mg/kg) followed by intra-TMJ injection of 1.5% Formalin or 5-hydroxytryptamine (5-HT, 225μg/TMJ). In other set of experiments rats were pretreated (15min) with an intrathecal injection of the non-selective opioid receptors Naloxone, or μ-opioid receptor antagonist CTOP, or δ-opioid receptor Naltridole hydrochloride, or κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI) followed by injection of FII (s.c.). After 30min, the animals were treated with an intra-TMJ injection of 1.5% formalin. After TMJ treatment, behavioral nociception response was evaluated for a 45-min observation period, animals were terminally anesthetized and periarticular tissue, trigeminal ganglion and subnucleus caudalis (SC) were collected plasma extravasation and ELISA analysis. Pretreatment with F II significantly reduced formalin- and serotonin-induced TMJ nociception, inhibit the plasma extravasation and inflammatory cytokines release induced by 1.5% formalin in the TMJ. Pretreatment with intrathecal injection of Naloxone, CTOP, Naltridole or Nor-BNI blocked the antinociceptive effect of F II in the 1.5% formalin-induced TMJ nociception. In addition, F II was able to significantly increase the β-endorphin release in the subnucleus caudalis. The results suggest that F II has a potential antinociceptive and anti-inflammatory effect in the TMJ mediated by activation of opioid receptors in the subnucleus caudalis and inhibition of the release of inflammatory mediators in the periarticular tissue.

Effects of endogenous cardioprotective mechanisms on ischemia-reperfusion injury.

Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size. Sequences of brief episodes of nonlethal ischemia and reperfusion applied before (preconditioning - IPC) or after (postconditioning - POC) the coronary occlusion are well documented to reduce the ischemiareperfusion injury. These phenomena improve cardiac function by mobilizing the molecular and cellular mechanisms limiting reperfusion injury. The mechanisms underlying IPC or POC are still not clarified, but strong experimental evidence suggests that opioids may be the part of the endogenous cardioprotective response to I/R injury. Stimulation of opioid receptors activates related to POC mechanisms affecting protection to the ischemic myocardium, while the use of non-selective opioid receptor antagonist - naloxone reduces this effect. There is no consensus that the subtype of opioid receptor is responsible for the protection of the human heart muscle. Morphine may reduce cardiac preload by peripheral vasodilatation. Numerous studies show a direct cardioprotective effect of the opioid pathway in ischemic conditions. Opioids act via membrane receptors: μ, δ, κ. The predominant subtype in the human cardiac cells are μ- and δ - opioid receptors. It has been hypothetized that opioid receptor activation exerts cardioprotection in human heart muscle pathway what may give insight into the explanation of the protective mechanisms in the acute myocardial infarction.

Effects of endogenous cardioprotective mechanisms on ischemia-reperfusion injury

Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size. Sequences of brief episodes of nonlethal ischemia and reperfusion applied before (preconditioning — IPC) or after (postconditioning — POC) the coronary occlusion are well documented to reduce the ischemiareperfusion injury. These phenomena improve cardiac function by mobilizing the molecular and cellular mechanisms limiting reperfusion injury. The mechanisms underlying IPC or POC are still not clarified, but strong experimental evidence suggests that opioids may be the part of the endogenous cardioprotective response to I/R injury. Stimulation of opioid receptors activates related to POC mechanisms affecting protection to the ischemic myocardium, while the use of non-selective opioid receptor antagonist - naloxone reduces this effect. There is no consensus that the subtype of opioid receptor is responsible for the protection of the human heart muscle.Morphine may reduce cardiac preload by peripheral vasodilatation. Numerous studies show a direct cardioprotective effect of the opioid pathway in ischemic conditions. Opioids act via membrane receptors: μ, δ, κ. The predominant subtype in the human cardiac cells are μ- and δ – opioid receptors. It has been hypothetized that opioid receptor activation exerts cardioprotection in human heart muscle pathway what may give insight into the explanation of the protective mechanisms in the acute myocardial infarction.

Central μ-Opioidergic System Activation Evoked by Heavy and Severe-Intensity Cycling Exercise in Humans: a Pilot Study Using Positron Emission Tomography with 11C-Carfentanil.

The central opioid receptor system likely contributes to the mechanism underlying the changes in affect elicited by exercise. Our aim was to use positron emission tomography (PET) to test whether exercise intensity influences activation of the μ-opioid receptor system in the brain, and whether changes in opioid receptor activation correlate with exercise-induced changes in affect. 7 healthy young male subjects (23±2 years) performed 20-min constant-load cycling exercises at heavy (ExH) and severe-intensity (ExS), and PET was performed using [11C]carfentanil as a tracer before and after each exercise. Exercise elicited the μ-opioidergic system activation in the large areas of the limbic system, particularly in the insular cortex, and cerebellum. Of note, deactivation of the μ-opioidergic system in the pituitary gland was identified as a specific finding in ExS, which evoked a distinctive sensation of fatigue. Within these brain areas, μ-opioid receptor activation correlated positively with increased positive affect (R2=0.67-0.95) in ExH and negative affect (R2=0.63-0.77) in ExS. These findings suggest that central μ-opioidergic neurotransmission evoked by continuous exercise is discriminated by work intensity. Notably, we also observed a possible contribution of the central μ-opioidergic system to the development of the sensation of fatigue during exhaustive exercise.

Evaluation of Analgesic Activity of Papaver libanoticum Extract in Mice: Involvement of Opioids Receptors.

Papaver libanoticum is an endemic plant to Lebanese region (family Papaveraceae) that has not been investigated before. The present study aimed to explore the analgesic activity of dried ethanolic extract of Papaver libanoticum (PLE) using tail flick, hot plate, and acetic acid induced writhing models in mice. The involvement of opioid receptors in the analgesic mechanism was investigated using naloxone antagonism. Results demonstrated that PLE exhibited a potent dose dependent analgesic activity in all tested models for analgesia. The analgesic effect involved activation of opioid receptors in the central nervous system, where both spinal and supraspinal components might be involved. The time course for analgesia revealed maximum activity after three hours in both tail flick and hot plate methods, which was prolonged to 24 hours. Metabolites of PLE could be responsible for activation of opioid receptors. The EC50 of PLE was 79 and 50 mg/kg in tail flick and hot plate tests, respectively. The total coverage of analgesia by PLE was double that of morphine in both tests. In conclusion, PLE proved to have opioid agonistic activity with a novel feature of slow and prolonged effect. The present study could add a potential tool in the armaments of opioid drugs as a natural potent analgesic and for treatment of opioid withdrawal syndrome.

Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum

The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DAMGO (selective MORs agonist) in three different subregions of DS along the rostro-caudal axis were studied. Our results indicate that whereas administration of 10μM DAMGO into the rostral and caudal DS significantly reduced DA levels, in medial DS an increase in DA levels was observed. These data reveal a regional-dependent MOR modulation of DA release in DS, similar to that described in the ventral striatum. Our findings may lead to a better understanding of the nigrostriatal DA system regulation.

The Role of κ Opioid Receptor in Brain Ischemia.

Our previous studies indicated that highly selective κ opioid receptor agonists could protect the brain, indicating an important role of κ opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of κ opioid receptor agonists in brain ischemia in a middle cerebral artery occlusion mouse model. Animal model. Laboratory. The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice. Various doses of salvinorin A, a highly selective and potent κ opioid receptor agonist, were administered intranasally 10 minutes after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, IP) as a κ opioid receptor antagonist was administered in one group before administration of salvinorin A (50μg/kg) to investigate the specific role of κ opioid receptor. Infarct volume, κ opioid receptor expression, and Evans blue extravasation in the brain, and neurobehavioral outcome were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, interleukin-10, and tumor necrosis factor-α levels to investigate the role of apoptosis and inflammation. κ opioid receptor expression was elevated significantly in the ischemic penumbral area compared with that in the nonischemic area. Salvinorin A reduced infarct volume and improved neurologic deficits dose-dependently. Salvinorin A at the dose of 50 μg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier and decreased the expression of cleaved caspase-3, interleukin-10, and tumor necrosis factor-α in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. κ opioid receptors were up-regulated and played a critical role in brain ischemia and reperfusion. κ opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition.

B Lymphocytes Express Pomc mRNA, Processing Enzymes and β-Endorphin in Painful Inflammation.

Immune cell-derived beta-endorphin (END) and other opioid peptides elicit potent and clinically relevant inhibition of pain (analgesia) in inflamed tissue by activation of peripheral opioid receptors. Pro-opiomelanocortin (POMC) is the polypeptide precursor of END and is processed by prohormone convertases (PCs). This study aims to decipher the processing of POMC in lymphocyte subsets in a rat model of unilateral painful hindpaw inflammation. Lymphocytes, isolated from popliteal lymph nodes, were separated into B-cells, T-cells, T-helper cells and cytotoxic T-cells using magnetic cell sorting, and were examined by polymerase chain reaction, immunofluorescence and radioimmunoassay. At 2h of inflammation, POMC exon 2-3 mRNA was mostly expressed in B- but not in T-cells. Prohormone convertase 1 (PC1) mRNA and protein were upregulated in B-cells and T-helper cells. Prohormone convertase 2 (PC2) was expressed in T- and B-cells, both in inflamed and non-inflamed lymph nodes. END was expressed in B- but not in T-cells. We conclude that POMC, its processing enzymes and END are predominantly expressed in B-lymphocytes at 2h of paw inflammation.

Review: The Role of MOP and DOP Receptors in Treatment of Diarrheapredominant Irritable Bowel Syndrome.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a frequent functional disorder of the gastrointestinal (GI) tract affecting nearly one fifth of the worldwide population. IBS-D is associated with numerous symptoms including diarrhea, bloating, abdominal pain and discomfort, which significantly reduce patients' quality of life. Due to a complex and unclear pathogenesis, effective therapy against IBS-D has not been developed yet. Nowadays, treatment is focused on non-pharmacological (e.g. changes in diet and life style) and pharmacological (e.g. loperamide, ramosetron, rifaximin) approaches. The endogenous opioid system is responsible for the maintenance of homeostasis in the GI tract. Activation of the intestinal opioid receptors (ORs), in particular μ (MOP) and δ (DOP) results in reduction of epithelial secretion and increase of water/electrolyte absorption; moreover, opioids are strong analgesic agents. Thus, ligands of ORs are a promising target in IBS-D treatment. In this review, we discuss the role of ORs in the pathogenesis of IBS-D and the use of "classical" and novel, such as P-317, eluxadoline and biphalin MOP and DOP receptor ligands in preclinical and clinical trials.

Neurokinin 1 and opioid receptors: relationships and interactions in nervous system

Opioid receptors and neurokinin 1 receptor (NK1R) are found highly expressed in the central nervous system. The co-localization of these two kinds of receptors suggests that they might interact with each other in both the transmission and modulation of the pain signal. In this review, we explore the relationships between opioid receptors and NK1R. Substance P (SP) plays a modulatory role in the pain transmission by activating the NK1R. Opioid receptor activation can inhibit SP release. NK1R is found participating in the mechanisms of the side effects of the opioids, including opioid analgesic tolerance, hyperalgesia, anxiety behaviors of morphine reward and opioids related respiratory depression. A series of compounds such as NK1R antagonists and ligands works on both mu/delta opioid receptor (MOR/DOR) and NK1R were synthesized as novel analgesics that enhance the clinical pain management efficacy and reduce the dosage and side effects. The current status of these novel ligands and the limitations are discussed in this review. Although the working mechanisms of these ligands remained unclear, they could be used as research tool for developing novel analgesic drugs in the future.

The Pharmacology and Toxicology of the ‘Holy Trinity’

Combining opioids with benzodiazepines and skeletal muscle relaxants ('The Holy Trinity') has been reported to potentiate the 'high'. Through unique interactions with colocalized μ-opioid and GABAA receptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by μ1 -opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAA R to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAA R to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.

Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression.

Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.

Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain.

Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.