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This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2019 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Learn More >IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibit IL-31 production remain unexploited. IL-31 production by helper T cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.
Learn More >Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.
Learn More >The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.
Learn More >To evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) and moderate to severe depression.
Learn More >Pain is one of the cardinal signs accompanying inflammation. The prostaglandins (PGs), synthetized from arachidonic acid by cyclooxygenase (COX)-2, are major bioactive lipids implicated in inflammation and pain. However, COX-2 is also able to metabolize other lipids, including the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), to give glycerol ester (PG-G) and ethanolamide (PG-EA) derivatives of the PGs. Consequently, COX-2 can be considered as a hub not only controlling PG synthesis, but also PG-G and PG-EA synthesis. As they were more recently characterized, these endocannabinoid metabolites are less studied in nociception compared to PGs. Interestingly R-profens, previously considered as inactive enantiomers of nonsteroidal anti-inflammatory drugs (NSAIDs), are substrate-selective COX inhibitors. Indeed, R-flurbiprofen can selectively block PG-G and PG-EA production, without affecting PG synthesis from COX-2. Therefore, we compared the effect of R-flurbiprofen and S-flurbiprofen in models of inflammatory pain triggered by local administration of lipopolysaccharides (LPS) and carrageenan in mice. Remarkably, the effects of flurbiprofen enantiomers on mechanical hyperalgesia seem to depend on (i) the inflammatory stimuli, (ii) the route of administration, and (iii) the timing of administration. We also assessed the effect of administration of the PG-Gs, PG-EAs, and PGs on LPS-induced mechanical hyperalgesia. Our data support the interest of studying the nonhydrolytic endocannabinoid metabolism in the context of inflammatory pain.
Learn More >Lidocaine continuous subcutaneous infusion (L-CSCI) for neuropathic pain in hospice patients has limited evidence for its safety and efficacy, and guidelines are lacking. This study assesses a series of patients admitted to a hospice over a six-month period that had neuropathic pain and received L-CSCI. The primary outcome was improvement in patient-rated distress from pain following L-CSCI titration. Also assessed were changes in oral morphine equivalent dose (OME), frequency of breakthrough medication, functional status, adverse effects and perception of response. Fifteen patients received L-CSCI for an average of 6.7 days (range 1-92). Average pain distress score decreased by 2 or more in six patients. Positive responses to L-CSCI were documented in the clinical notes of 10 patients. Opioid down-titration occurred in four patients. Lidocaine levels were performed in 3 patients but did not change management. Five patients experienced adverse effects attributable to lidocaine and all responded to simple measures. In conclusion, L-CSCI can help manage neuropathic pain in hospice patients, particularly in those who cannot swallow oral medications. Further systematic research is warranted to establish efficacy and tolerability, and to inform guideline development.
Learn More >Anti-inflammatory and antinociceptive effects of the selective cannabinoid CB receptor agonist ABK5.
Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB and CB, and Δ-tetrahydrocannabinol activates both of them, providing an analgesic effect but also psychoactive side effects. The psychoactive side effects are considered to be caused by activation of CB, but not CB. ABK5 is a CB subtype selective agonist that has a very different structure from known cannabinoid receptor agonists. Here, we report anti-inflammatory effects of ABK5 using the T-cell line Jurkat cells, and antinociceptive effect in an inflammatory pain model in rats. Production of the cytokines IL-2 and TNF-α was measured in stimulated Jurkat cells and MOLT-4 cells, and CXCL12-mediated chemotaxis of Jurkat cells was evaluated by a transwell migration assay. Anti-inflammatory and antinociceptive effects of ABK5 were also evaluated in a hindpaw CFA model in rats. ABK5 significantly decreased production of IL-2 and TNF-α measured as both mRNA and protein levels, and reduced chemotaxis towards CXCL12. It also attenuated edema and increased mechanical threshold in the hindpaw of CFA-treated rats. These results suggest that ABK5 is a good lead compound for the development of potential anti-inflammatory and analgesic agents.
Learn More >The quality of subgroup analyses (SGAs) in chronic non-cancer pain trials is uncertain. The purpose of this study was to address this issue. We conducted a comprehensive search in MEDLINE and EMBASE from January 2012 to September 2018 to identify eligible trials. Two pairs of reviewers assessed the quality of the SGAs and the credibility of subgroup claims using the 10 criteria developed by Sun et al. in 2012. The associations between the quality of the SGAs and the studies' characteristics including risk of bias, funding sources, sample size, and the latest impact factor, were assessed using multivariable logistic regression. Our search retrieved 3,401 articles of which 66 were eligible. The total number of SGAs was 177 of which 52 (29.4%) made a subgroup claim. Of these, only 15 (8.5%) were evaluated as being of high quality. Among the 30 SGAs that claimed subgroup effects using an appropriate method of performing interaction tests, the credibility of only 5 were assessed as high. None of the subgroup claims met all the credibility criteria. No significant association was found between the quality of SGAs and the studies' characteristics. The quality of the SGAs performed in chronic pain trials was poor. To enhance the quality of SGAs, scholars should consider the developed criteria when designing and conducting trials, particularly those which need to be specified a .
Learn More >The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in trigeminal activation.
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