Genetic polymorphism of opioid receptors and use of opioid substances by high school students of Cotonou and Parakou (Benin)

In Benin, schools become sometimes the hub for dealing and consuming psychoactive substances; opioids in particular. The objectives of this study are to identify the risk factors related to the use of opioids and investigate the genetic polymorphism of mu and delta opioid receptors of teenagers and young adults who consume opioids in schools. To accomplish this, 453 students participated in this study; R diversity 3.6.1 software in the RStudio environment was used to identify students who experience opioids through ASSIST V3.0 scoring. SNPs A118G on the OPRM gene (µ) and T921C on the OPRD gene (d), were searched by PCR on DNA extracts from peripheral blood of individuals. We identified 54 regular opioid users and 399 non users. This experience begins for most with the consumption of alcohol and tobacco and is facilitated by the proximity of marshlands, kiosks, and pubs near high schools and colleges. The aggressive advertisement combined with relative socio-cultural tolerance just worsen this behavioral deviance. We found no difference in the SNP frequencies of the OPRM (µ) and OPRD (d) genes between students opioids consumers and non-consumers.

Hydrogen Sulfide Inhibits Inflammatory Pain and Enhances the Analgesic Properties of Delta Opioid Receptors

Chronic inflammatory pain is present in many pathologies and diminishes the patient’s quality of life. Moreover, most current treatments have a low efficacy and significant side effects. Recent studies demonstrate the analgesic properties of slow-releasing hydrogen sulfide (H2S) donors in animals with osteoarthritis or neuropathic pain, but their effects in inflammatory pain and related pathways are not completely understood. Several treatments potentiate the analgesic actions of δ-opioid receptor (DOR) agonists, but the role of H2S in modulating their effects and expression during inflammatory pain remains untested. In C57BL/6J male mice with inflammatory pain provoked by subplantar injection of complete Freund’s adjuvant, we evaluated: (1) the antiallodynic and antihyperalgesic effects of different doses of two slow-releasing H2S donors, i.e., diallyl disulfide (DADS) and phenyl isothiocyanate (P-ITC) and their mechanism of action; (2) the pain-relieving effects of DOR agonists co-administered with H2S donors; (3) the effects of DADS and P-ITC on the oxidative stress and molecular changes caused by peripheral inflammation. Results demonstrate that both H2S donors inhibited allodynia and hyperalgesia in a dose-dependent manner, potentiated the analgesic effects and expression of DOR, activated the antioxidant system, and reduced the nociceptive and apoptotic pathways. The data further demonstrate the possible participation of potassium channels and the Nrf2 transcription factor signaling pathway in the pain-relieving activities of DADS and P-ITC. This study suggests that the systemic administration of DADS and P-ITC and local application of DOR agonists in combination with slow-releasing H2S donors are two new strategies for the treatment of inflammatory pain.

A Novel Multitarget Mu- and Delta-Opioid Receptors Agonist HAGD Has Peripherally Restrictive Potent Analgesia with Less Side Effects in Mice and Minimal Impact on Human Sperm Motility

ObjectivePain is a common clinical symptom. Although a variety of opioid analgesics have been developed, the side effects including negative impact on human sperm motility still hinder their application. Aim of this study is to develop a novel opioid analgesic, a multitarget peptide HAGD (H-Tyr-D-AIa-GIy-Phe-NH2) which has less side effects and minimal impact on sperm motility.MethodsThe peripheral antinociceptive effects of HAGD were appraised in a series of preclinical mice pain models, including the tail-flick test, carrageenan-induced inflammatory pain, acetic acid-induced writhing test and formalin test. In conditioned place preference experiment, open field test, gastrointestinal transit test and rotarod test, the side effects of HAGD in mice were assessed. The impacts of HAGD on sperm motility in vitro were investigated.ResultsHAGD produced equipotent antinociception compared with morphine. HAGD was stronger in terms of analgesia intensity in chemical stimulation pain of formalin test phase I. The antinociception was mediated by mu- and delta-opioid receptors. HAGD didn’t induce conditioned place preference and hyperlocomotion, but morphine did. Both HAGD and morphine had no impacts on motor coordination. HAGD had a limited side effect in gastrointestinal transit, while morphine inhibited gastrointestinal transit to a greater extent. However, HAGD had minimal impact on human sperm motility, whereas morphine declined sperm motility at concentrations of 1 × 10-7 mol/l and 1 × 10-8 mol/l at 3.5 h of incubation.Conclusion HAGD may be a better candidate for future development of novel multitarget opioid analgesics with less side effects and minimal impact on human sperm motility.

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, in mice, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, aside from largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs in a way that impacts somato-dendritic potassium currents or synaptic transmission. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, despite largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.