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The neurosteroid 3α,5α-THP is a potent GABAA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation. [ABSTRACT FROM AUTHOR]

Chronic kidney disease–associated pruritus is itching directly related to kidney disease that cannot be explained by any other condition. Despite technological advances in the different aspects of dialysis sessions and the best treatment for chronic kidney disease patients, it is still a common problem in our patients. The many complex physiological mechanisms involved, the different hypotheses made over the years on the aetiology of the condition, and the great clinical variability may partially explain the limited knowledge about this problem and the difficulties in treating it. The presence of all these factors leads to the persistence of unpleasant symptoms, which must affect the disease burden and quality of life of kidney patients. Through the presentation of an illustrative clinical case, the aim of this review article is to highlight the need for adequate diagnosis and an improved approach to all aspects of chronic kidney disease–associated pruritus, in view of the heavy burden of the disease and the huge impact on the patient's quality of life. [ABSTRACT FROM AUTHOR]

The time of stress exposure relative to the moment of immunization affects the direction of the immunoregulatory effect of stress. In case of stress exposure preceding immunization, rotation stress stimulated the production of antibodies, while immobilization depressed it. After antigen injection, these types of stress had no significant effect on the formation of antibody-producing cells. Acute cold stress did not affect the number of antibody-forming cells before immunization, but stimulated the humoral response after it. At the same time, the effect of stress on the production of antibodies was leveled by blockade of opioid receptors with naloxone for rotation and immobilization, but was not canceled for acute cold stress. A similar pattern was revealed when analyzing the effect of stress exposure on cytokine production. Cold stress before antigen administration to mice had almost no effect on the production of IL-2, IL-4, IFNγ, while rotational and immobilization stress naloxone-dependently modulated the synthesis of IL-2 and IL-4. On the contrary, in animals subjected to stress after antigen administration, only cold stress significantly modulated the production of IL-2 and IL-4. [ABSTRACT FROM AUTHOR]

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Opioid receptors mediate antinociceptive effects. Methanolic fractions from sugarcane varieties (MFSCf) were evaluated in classic nociception models. Interactions between bioactive compounds and the µ-opioid receptor (µOR) through docking analysis were also studied. Five methanolic fractions of sugarcane juice were obtained and analysed by LC-ESI-MS/MS. The fractions and standards of phenolic compounds were evaluated in a nociception model using the formalin test. All MFSCfs exhibited antinociceptive activity in the first phase of the formalin test. Docking analyses corroborates with the in vivo test results, suggesting that the phenolic substances are able to activate µOR. These results, for the first time, implicate phenolic constituents from sugarcane juice and other phenolic compounds in the activation of µOR. The antinociceptive activity of fractions from sugarcane juice suggests the potential pharmacological use of this species, widely cultivated in Brazil. [ABSTRACT FROM AUTHOR]

Alcohol consumption leads to significant neurochemical and neurobiological changes, contributing to the development of alcohol use disorders (AUDs), which exhibit sex- and age-dependent variations according to clinical data. However, preclinical studies often neglect these factors when investigating alcohol consumption patterns. In this study, we present data on male and female rats continuously exposed to a 20 % ethanol solution for one month. The animals were divided into two groups based on their age at the onset of drinking (8 and 12 weeks old). Interestingly, 12-week-old males consumed significantly less alcohol than both 12-week-old females and 8-week-old animals, indicating that alcohol consumption patterns vary with sex and age in our model. Additionally, to advance in the study of the neurobiological alterations induced by ethanol intake in the mesocorticolimbic system (MCLS) that may participate in its reinforcing properties and the maintenance of alcohol drinking behavior, we measured catalase activity—an enzyme involved in alcohol metabolism and related to ethanol reinforcement—in the nucleus accumbens (NAc) of these animals. Furthermore, we measured the levels of mu (MOR), kappa (KOR), delta (DOR), and nociceptin (NOP) opioid receptors in the NAc, as the endogenous opioidergic system plays a pivotal role in regulating the MCLS and alcohol reinforcement. MOR levels were lower in high alcohol-consuming groups (8-week-old males and all females). Both DOR and NOP levels decreased with age, whereas KOR levels remained unchanged. Our findings suggest that the age at onset of alcohol consumption critically influences alcohol intake, particularly in males. Additionally, females consistently showed higher alcohol intake regardless of age, highlighting inherent sex-specific differences. The dynamic changes in catalase activity and opioid receptor expression suggest the involvement of these factors in modulating alcohol consumption. • Adult male rats consume less alcohol than female rats and adolescent male rats. • Catalase activity correlates with alcohol intake levels. • MOR expression inversely correlates with alcohol intake levels. [ABSTRACT FROM AUTHOR]

Benedicte Nobile,1,2 Emilie Olie,1– 3 Nicolas Ramoz,4 Jonathan Dubois,1,2 Sebastien Guillaume,1– 3 Philip Gorwood,4 Philippe Courtet1– 3 1Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France; 2IGF, University of Montpellier, CNRS, INSERM, Montpellier, France; 3FondaMental Foundation, Créteil, France; 4Inserm UMRS1266, Institute of Psychiatry and Neuroscience of Paris, Paris, FranceCorrespondence: Benedicte Nobile Email benedicte.nobile@gmail.comBackground: Growing evidences suggest that depression with suicidal ideation (SI) could be a specific phenotype with its own characteristics. Moreover, opioid system deregulation might be implicated in suicidal behaviour (SB). The aim of this study was to determine whether the A118G polymorphism (rs1799971) in ORPM1 (the gene encoding opioid receptor mu 1) is associated with suicidal depression (ie, moderate to severe depression with SI) in a large cohort of outpatients with depression.Methods: GENESE is a large, prospective, naturalistic cohort of French adult outpatients with depression (DSM-IV criteria), treated and followed for 6 weeks. Depression severity was assessed with the Hospital Anxiety and Depression Scale (HADS), and SI with the suicidal item of the Montgomery–Åsberg Depression Rating Scale (MADRS-SI). From this cohort, patients with moderate or severe depression (HADS-D subscale score > 11) were selected and classified as without SI (MADRS-SI < 2), or with SI (MADRS-SI ≥ 2).Results: The AA/AG genotypes of the A118G polymorphism were significantly associated with suicidal depression in the non-adjusted (OR = 2.32, 95% CI = [1.28; 4.18]; p-value = 0.005) and in the adjusted models (OR = 2.54, 95% CI = [1.35; 4.78]; p-value = 0.004).Conclusion: Outpatients with depression harbouring the A allele are at higher risk of SI (and possibly SB) than those carrying the G allele. More studies are needed to better understand the link between this polymorphism and SB.Keywords: suicide, suicidal ideation, opioid system, A118G, OPRM1

Introduction: Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (V̇O2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release after a session of exercise. Methods: We studied 64 healthy lean men who performed a maximal incremental cycling test for V̇O2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA; in minutes per week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional positron emission tomography scan also after a 1-h session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training. Results: Higher self-reported MVPA level predicted greater opioid release after high-intensity interval training, and both V̇O2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely after exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability. Conclusions: We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioral responses associated with long-term exercise. [ABSTRACT FROM AUTHOR]

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders.

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non‐steroidal anti‐inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis‐ (±) ‐acetate of 4‐chloro‐6‐ (naphthalene‐1‐yl) ‐tetrahydro‐2h‐pyran −2‐yl) methyl2‐ (2‐ [2,6‐dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid‐induced abdominal writhing, formalin, tail flick, capsaicin‐ and glutamate‐induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid‐induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin‐induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor‐binaltorphimine, naltrindole, methylnaltrexone, 7‐nitroindazole, L‐NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF‐α, IL‐1β and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice. [ABSTRACT FROM AUTHOR]

• miR-133b-3p targeting P2X4R down-regulated in CPSP rats. • Overexpressing miR-133b-3p reversed allodynia by down-regulating P2X4R in CPSP rats. • Gabapentin decreased miR-133b-3p and blocked the allodynia in CPSP rats. • miR-133b-3p in CPSP patients decreased in plasma compared to control patients. Central poststroke pain (CPSP) is a neuropathic pain syndrome that usually occurs after cerebrovascular accidents. Currently, the pathogenesis of CPSP is not fully understood. Purinergic P2X4 receptor (P2X4R) is implicated in neuropathic pain including CPSP. Herein, we demonstrated that the levels of microRNA-133b-3p (miR-133b-3p), which targets P2X4R transcripts, were significantly downregulated in the ventral posterolateral nucleus of the thalamus (VPL), cerebrospinal fluid (CSF), and plasma of CPSP rats. The expression levels of miR-133b-3p negatively correlated with the severity of allodynia. Genetic knockdown of P2X4R in the VPL protected CPSP rats against allodynia. Similarly, genetic overexpression of miR-133b-3p in the VPL reversed the allodynia established in CPSP rats via downregulation of P2X4R expression. Treatment using gabapentin in CPSP rats significantly restored the decreased miR-133b-3p expression in the VPL, CSF, and plasma and blocked allodynia in CPSP rats. The administration of an miR-133b-3p inhibitor into the VPL abolished the antiallodynic activity of gabapentin. This mechanism was associated with P2X4R expression and involved the endogenous opioid system. Human patients with CPSP showed decreased plasma levels of miR-133b-3p compared with those of control participants. Logistic regression analysis of our patient cohort showed that determining plasma levels of miR-133b-3p may be useful for CPSP diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Non-suicidal self-injury (NSSI) is a type of behavioral pathology seen not only in a variety of clinical conditions but also among non-clinical populations, particularly adolescents and young adults. With the exception of rare genetic conditions that give rise to self-harming behaviors, the etiology of NSSI and the events that trigger specific episodes of this behavior remain poorly understood. This review presents the features of an important, extensively studied animal model of NSSI, namely spontaneously occurring self-injurious behavior (SIB) in rhesus macaque monkeys. We compare and contrast rhesus monkey SIB with NSSI with respect to form, prevalence rates, environmental and biological risk factors, behavioral correlates, proposed functions, and treatment modalities. Many parallels between rhesus monkey SIB and NSSI are demonstrated, which supports the validity of this animal model across several domains. Determining the etiology of spontaneously occurring SIB in monkeys, its underlying biological mechanisms, and which pharmacological agents are most effective for treating the disorder may aid in identifying potential risk factors for the occurrence of NSSI in humans and developing medications for severe cases that are resistant to conventional psychotherapeutic approaches.

Non-suicidal self-injury (NSSI) is a type of behavioral pathology seen not only in a variety of clinical conditions but also among non-clinical populations, particularly adolescents and young adults. With the exception of rare genetic conditions that give rise to self-harming behaviors, the etiology of NSSI and the events that trigger specific episodes of this behavior remain poorly understood. This review presents the features of an important, extensively studied animal model of NSSI, namely spontaneously occurring self-injurious behavior (SIB) in rhesus macaque monkeys. We compare and contrast rhesus monkey SIB with NSSI with respect to form, prevalence rates, environmental and biological risk factors, behavioral correlates, proposed functions, and treatment modalities. Many parallels between rhesus monkey SIB and NSSI are demonstrated, which supports the validity of this animal model across several domains. Determining the etiology of spontaneously occurring SIB in monkeys, its underlying biological mechanisms, and which pharmacological agents are most effective for treating the disorder may aid in identifying potential risk factors for the occurrence of NSSI in humans and developing medications for severe cases that are resistant to conventional psychotherapeutic approaches. [ABSTRACT FROM AUTHOR]

• Ketamine modulates anterior cingulate cortex (ACC) activity over minutes and hours. • Changes in ACC activity correlate with ketamine's antidepressant effects. • Ketamine's effects on anhedonia depend on modulation of dorsal and subgenual ACC. • Ketamine's action on ACC may reduce emotional pain and rumination. • Rodent and non-human primate studies are key to understanding ketamine's effects. The subdivisions of the anterior cingulate cortex (ACC) – including subgenual, perigenual and dorsal zones – are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network. [ABSTRACT FROM AUTHOR]

Popular medicine has been using oleoresin from several species of copaíba tree for the treatment of various diseases and its clinical administration potentially causes antinociception. Electrical stimulation of ventrolateral (vlPAG) and dorsolateral (dlPAG) columns of the periaqueductal gray matter also causes antinociception. The aim this study was to verify the antinociceptive effect of oleoresin extracted from Copaifera langsdorffii tree and to test the hypothesis that oleoresin-induced antinociception is mediated by µ 1 - and κ-opioid receptors in the vlPAG and dlPAG. Nociceptive thresholds were determined by the tail-flick test in Wistar rats. The copaíba tree oleoresin was administered at different doses (50, 100 and 200 mg/kg) through the gavage technique. After the specification of the most effective dose of copaíba tree oleoresin (200 mg/kg), rats were pretreated with either the µ 1 -opioid receptor selective antagonist naloxonazine (at 0.05, 0.5 and 5 µg/ 0.2 µl in vlPAG, and 5 µg/ 0.2 µl in dlPAG) or the κ-opioid receptor selective antagonist nor-binaltorphimine (at 1, 3 and 9 nmol/ 0.2 µl in vlPAG, and 9 nmol/ 0.2 µl in dlPAG). The blockade of µ 1 and κ opioid receptors of vlPAG decreased the antinociception produced by copaíba tree oleoresin. However, the blockade of these receptors in dlPAG did not alter copaíba tree oleoresin-induced antinociception. These data suggest that vlPAG µ 1 and κ opioid receptors are critically recruited in the antinociceptive effect produced by oleoresin extracted from Copaifera langsdorffii. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Pavlovian-to-instrumental transfer (PIT) quantifies the extent to which a stimulus that has been associated with reward or punishment alters operant behaviour. In alcohol dependence (AD), the PIT effect serves as a paradigmatic model of cue-induced relapse. Preclinical studies have suggested a critical role of the opioid system in modulating Pavlovian-instrumental interactions. The A118G polymorphism of the OPRM1 gene affects opioid receptor availability and function. Furthermore, this polymorphism interacts with cue-induced approach behaviour and is a potential biomarker for pharmacological treatment response in AD. In this study, we tested whether the OPRM1 polymorphism is associated with the PIT effect and relapse in AD.Methods: Using a PIT task, we examined three independent samples: young healthy subjects (N = 161), detoxified alcohol-dependent patients (N = 186) and age-matched healthy controls (N = 105). We used data from a larger study designed to assess the role of learning mechanisms in the development and maintenance of AD. Subjects were genotyped for the A118G (rs1799971) polymorphism of the OPRM1 gene. Relapse was assessed after three months.Results: In all three samples, participants with the minor OPRM1 G-Allele (G+ carriers) showed increased expression of the PIT effect in the absence of learning differences. Relapse was not associated with the OPRM1 polymorphism. Instead, G+ carriers displaying increased PIT effects were particularly prone to relapse.Conclusion: These results support a role for the opioid system in incentive salience motivation. Furthermore, they inform a mechanistic model of aberrant salience processing and are in line with the pharmacological potential of opioid receptor targets in the treatment of AD. [ABSTRACT FROM AUTHOR]

The endogenous opioid system is strongly involved in the modulation of pain. However, the potential role of this system in perceiving painful facial expressions from others has not been sufficiently explored as of yet. To elucidate the contribution of the opioid system to the perception of painful facial expressions, we conducted a double‐blind, within‐subjects pharmacological functional magnetic resonance imaging (fMRI) study, in which 42 participants engaged in an emotion discrimination task (pain vs. disgust expressions) in two experimental sessions, receiving either the opioid receptor antagonist naltrexone or an inert substance (placebo). On the behavioral level, participants less frequently judged an expression as pain under naltrexone as compared to placebo. On the neural level, parametric modulation of activation in the (putative) right fusiform face area (FFA), which was correlated with increased pain intensity, was higher under naltrexone than placebo. Regression analyses revealed that brain activity in the right FFA significantly predicted behavioral performance in disambiguating pain from disgust, both under naltrexone and placebo. These findings suggest that reducing opioid system activity decreased participants' sensitivity for facial expressions of pain, and that this was linked to possibly compensatory engagement of processes related to visual perception, rather than to higher level affective processes, and pain regulation. The behavioral and neural findings of this psychopharmacological fMRI study shed light on a causal role of the opioid system in the discrimination of painful facial expressions, paving the way for further exploration of clinical implications in the domains of pain diagnosis and treatment, on the one hand, and future research on the relationship between basic socio‐perceptual processing and empathy, on the other. [ABSTRACT FROM AUTHOR]

Social isolation stress (SIS) as a chronic model of early-life stress could induce proconvulsant effects in mice. In the current study, we evaluated the role of opioid receptors (OPRs) agonists and antagonists in pro-conversant effects of SIS and the common pathway between delta-opioid receptors (DORs) and nitric oxide (NO) in stress-induced seizure. For reaching to this goal, we used pentylenetetrazol (PTZ) model of clonic-seizure to measure seizure threshold and administrated selective and non-selective OPRs agonists and antagonists in both social condition (SC) and isolated condition (IC) animals. In the next step, we administrated sub effective dose of naltrindole (NLT, 0.3 mg/kg) with sub-effective doses of nitric oxide synthesis (NOS) inhibitors including L-NAME (10 mg/kg), aminoguanidine (50 mg/kg) and 7-NI (15 mg/kg). Also, we co-administrated sub-effective dose of SNC80 (0.5 mg/kg) with sub-effective dose of l-arg (25 mg/kg) to assess the seizure threshold. In addition, we measured nitrite levels of hippocampus following administration of mentioned drugs in both SC and IC mice. Our findings showed that L-NAME and 7-NI (but not AG) increased anti-convulsant activity of NLT and l-arg increased proconvulsant effects of SNC80 in IC animals. Nitrite assay showed that co-administration of NLT plus sub-effective doses of L-NAME and 7-NI (but not AG) decreased and co-administration of SNC80 with sub-effective dose of l-arg increased nitrite levels of hippocampus in IC mice. This study suggests the role of n-NOS in anti-convulsant effects of NLT and pro-convulsant effects of SNC80 in stress-induced seizure.

Animal venoms are an almost inexhaustible source for promising molecules with biological activity and the venom of Phoneutria nigriventer spider is a good example of this. Among several other toxins obtained from this venom, PnTx4(6–1), also called δ-Ctenitoxin-Pn1a, was isolated and initially described as an insect toxin that binds to the site 3 of sodium channels in cockroach nerve cord synaptosomes (Periplaneta americana) and slows down sodium current inactivation in isolated axons of this animal. This toxin did not cause any apparent toxicity to mice when intracerebroventricularly injected (30 μg). Subsequently, it was demonstrated that PnTx4(6–1) has an antinociceptive effect in three different pain models: inflammatory, induced by carrageenan; nociceptive, induced by prostaglandin E2 and neuropathic, induced by sciatic nerve constriction. Using diverse antagonists from receptors, it was shown that the cannabinoid system, via the CB1 receptor, and the opioid system, through the μ and δ receptors, are both involved in the antinociceptive effect of PnTx4(6–1). In the present work, it was synthesized a peptide, named PnAn13, based on the amino acid sequence of PnTx4(6–1) in order to try to reproduce or increase the analgesic effect of the toxin. As it was seen for the toxin, PnAn13 had antinociceptive activity, when intrathecally injected, and this effect involved the cannabinoid and opioid systems. In addition, when it was evaluated the peripheral effect of PnAn13, via intraplantar administration, this peptide was able to reverse the hyperalgesic threshold, evoked by prostaglandin E2. Therefore, using different pharmacological tools, it was shown the participation of cannabinoid and opioid systems in this effect.

Decades of studies on alcohol dependence showed that it is a very complex and multifactorial disorder. Several receptor systems are involved in development and susceptibility to alcohol abuse; however, there are some which play a crucial role in its pathogenesis, e.g. dopaminergic or opioid system. In this paper, an effort is made to explain the role of endogenous opioid system activity in alcohol dependence. To achieve the goal, we use a unique model is used which shows mice lines that are divergently selected for high (HA) and low (LA) stress-induced analgesia. This process allowed for selecting individuals characterised by hyperactive (HA) or hypoactive (LA) opioid system. Basing on the performed experiments, we proved that delta opioid receptors play a critical role in the development of addiction. The most notable achievement is an unspecific reaction of mice with the hyperactive opioid system to naloxone – an unspecific opioid system antagonist, which is currently approved in the pharmacotherapy of dependent patients.

Investigations on the use of medicinal plants are appealing to researchers. In Iranian traditional medicine, Ferula szowitsiana is used as an analgesic. This study investigates the effect of the extract of aerial parts of Ferula szowitsiana on an experimental model of chemical pain induced by subplantar injection of formalin. The Ferula szowitsiana hydroalcoholic extract was prepared with ethanol, Tween 80 and saline at a ratio of 8:1:1 serving as a solvent. Wistar Rats in the weight range of 200-250 g were divided into 10 groups randomly (n=7) according to treatment applied as follows: control; solvent (intraperitoneal, i.p.); solvent (intrathecal, i.t.); extract (50, 100, 200, 400 mg/kg i.p.); extract (80 μg/10 μL i.t); naloxone (2 mg/kg i.p.); extract (400 mg/kg) and naloxone (i.p.). To study the chemical pain, subplantar administration of formalin was performed in all groups. The results showed that the extract could reduce chemical pain in the neurogenic and inflammatory phase dose dependently as compared to the control group. The magnitude of the response after intrathecal administration of a dose of 80 μg/10μL was comparable to that observed with 400 mg/kg of extract administered via the intraperitoneal route. The administration of naloxone as an opioid receptor antagonist reversed the analgesic effect of the extract completely. According to the results, it seems that at least a significant part of the analgesic effect of Ferula szowitsiana extract is exerted through its effect on the central nervous system, and the analgesic effect of the extract in acute and inflammatory chemical pain is due to its effect on the opioid system.

Aim: To evaluate the analgesic activity of Zingiberis rhizoma-based carbon dots (ZR-CDs). Materials & methods: Novel ZR-CDs were prepared via a facile, green pyrolysis method. Microstructure, optical and functional group properties were characterized. Acetic acid writhing, hot-plate and tail-immersion tests were performed using mice to evaluate the analgesic activity of ZR-CDs, followed by a preliminary study on the analgesic mechanism. Results: ZR-CDs with a quantum yield of 5.2% had a diameter ranging from 2.23 to 3.77 nm. Remarkable analgesic effect of ZR-CDs was observed against both thermal and chemical stimulus tests, possibly mediated by an opioid-like mechanism and the regulation of 5-hydroxytryptamine levels. Conclusion: ZR-CDs have a promising potential for biomedical application in relieving pain-related diseases. [ABSTRACT FROM AUTHOR]

The adrenergic system, because of its reported implication in pain mechanisms, may be a potential target for chronic pain treatment. We previously demonstrated that β2-adrenoceptors (β2-ARs) are essential for neuropathic pain treatment by antidepressant drugs, and we showed that agonists of β2-ARs, that is, β2-mimetics, had an antiallodynic effect per se following chronic administration. To further explore the downstream mechanism of this action, we studied here the role of the opioid system. We used behavioral, genetic, and pharmacological approaches to test whether opioid receptors were necessary for the antiallodynic action of a short acting (terbutaline) and a long-acting (formoterol) β2-mimetic. Using the Cuff model of neuropathic pain in mice, we showed that chronic treatments with terbutaline (intraperitoneal) or formoterol (orally) alleviated mechanical hypersensitivity. We observed that these β2-mimetics remained fully effective in μ-opioid and in κ-opioid receptor deficient mice, but lost their antiallodynic action in δ-opioid receptor deficient mice, either female or male. Accordingly, we showed that the δ-opioid receptor antagonist naltrindole induced an acute relapse of allodynia in mice with neuropathic pain chronically treated with the β2-mimetics. Such relapse was also observed following administration of the peripheral opioid receptor antagonist naloxone methiodide. These data demonstrate that the antiallodynic effect of long-term β2-mimetics in a context of neuropathic pain requires the endogenous opioid system, and more specifically peripheral δ-opioid receptors. [ABSTRACT FROM AUTHOR]

The anatomo-physiological disruptions inherent to different categories of the Fetal Alcohol Spectrum Disorder do not encompass all the negative consequences derived from intrauterine ethanol (EtOH) exposure. Preclinical, clinical and epidemiological studies show that prenatal EtOH exposure also results in early programming of alcohol affinity. This affinity has been addressed through the examination of how EtOH prenatally exposed organisms recognize and prefer the drug's chemosensory cues and their predisposition to exhibit heightened voluntary EtOH intake during infancy and adolescence. In altricial species these processes are determined by the interaction of at least three factors during stages equivalent to the 2nd and 3rd human gestational trimester: (i) fetal processing of the drug's olfactory and gustatory attributes present in the prenatal milieu; (ii) EtOH's recruitment of central reinforcing effects that also imply progressive sensitization to the drug's motivational properties; and (iii) an associative learning process involving the prior two factors. This Pavlovian learning phenomenon is dependent upon the recruitment of the opioid system and studies also indicate a significant role of EtOH's principal metabolite (acetaldehyde, ACD) which is rapidly generated in the brain via the catalase system. The central and rapid accumulation of this metabolite represents a major factor involved in the process of fetal alcohol programming. According to recent investigations, it appears that ACD exerts early positive reinforcing consequences and antianxiety effects (negative reinforcement). Finally, this review also acknowledges human clinical and epidemiological studies indicating that moderate and binge-like drinking episodes during gestation result in neonatal recognition of EtOH's chemosensory properties coupled with a preference towards these cues. As a whole, the studies under discussion emphasize the notion that even subteratogenic EtOH exposure during fetal life seizes early functional sensory and learning capabilities that pathologically shape subsequent physiological and behavioral reactivity towards the drug. [ABSTRACT FROM AUTHOR]

• The opioid system has a key role in modulating neural systems dysregulated in MDD. • Opioids have effects on reward processing and emotional regulation in rodent models. • The impact of opioid ligands on neuroplasticity may suggest antidepressant activity. • Effects mediated by different opioid receptors are complex and context-dependent. • More studies are needed to fill knowledge gaps and identify therapeutic targets. Major depressive disorder (MDD) is a heterogeneous clinical syndrome involving distinct pathological processes. Core features of MDD include anhedonia, reduced motivation, increased anxiety, negative affective bias, cognitive impairments, and dysregulated neuroplasticity mechanisms. There are multiple biological hypotheses related to MDD, including dysfunction of the opioid system. Although opium was abandoned as an antidepressant after the introduction of monoaminergic drugs, there has been renewed interest in targeting the opioid system for MDD. In this review, we discuss the preclinical support of this idea using a neurocircuitry- and molecular neuroplasticity-based approach. This article highlights how the opioid system potently modulates mesolimbic circuitry underlying motivation and reward processing, limbic circuitry underlying fear and anxiety responses, cortical and hippocampal circuitry underlying a variety of cognitive functions, as well as broad functional and structural plasticity mechanisms. Ultimately, a more thorough understanding of how the opioid system modulates these core functional domains may lead to novel treatment strategies and molecular targets in the treatment of MDD. [ABSTRACT FROM AUTHOR]

While our recent studies have suggested that effective acupoints display neurogenic inflammation and can be identified as neurogenic spots (Neuro-Sps), the optimal stimulation conditions and the underlying mechanisms remain uncharacterized. We developed a combined mechano-electrical acupuncture device (MEA) and examined the effects of acupuncture at Neuro-Sps on systolic blood pressure (BP) in a rat model of immobilization-induced hypertension (IMH) and the mediation of endogenous opioid systems in its effect. Cutaneous neurogenic spots were found mostly in the forelimb. Electrical and mechanical acupuncture of Neuro-Sps increased 22-kHz ultrasonic vocalizations (USVs), c-Fos expression and cell excitability in the midbrain and synergistically alleviated the development of hypertension following immobilization stress, which was prevented by administration of the opioid antagonist naloxone into the rostral ventrolateral medulla (rVLM). These findings suggest that mechanical and electrical stimulation at Neuro-Sps suppresses the development of hypertension via mediation of the endogenous opioid system. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) is a sensory, emotional, and persistent disturbing experience caused by a lesion or disease of the somatosensory system which can lead when chronic to comorbidities such as anxiety and depression. Available treatments (pharmacotherapy, neurostimulation) have partial and unpredictable response; therefore, it seems necessary to find a new therapeutical approach that could alleviate most related symptoms and improve patients 'emotional state'. Posterior Insula seems to be a potential target of neurostimulation for pain relief. However, its effects on pain-related anxiety and depression remain unknown. Using rats with spared nerve injury (SNI), this study aims to elucidate the correlation between NP and anxio-depressive disorders, evaluate potential analgesic, anxiolytic, and antidepressant effects of right posterior insula stimulation (IS) using low (LF-IS, 50 Hz) or high (HF-IS, 150 Hz) frequency and assess endogenous opioid involvement in these effects. Results showed positive correlation between NP, anxiety, and depression. LF-IS reversed anhedonia and despair-like behavior through pain alleviation, whereas HF-IS only reduced anhedonia, all effects involving endogenous opioids. These findings support the link between NP and anxio-depressive disorders. Moreover, IS appears to have analgesic, anxiolytic and antidepressant effects mediated by the endogenous opioid system, making it a promising target for neurostimulation. [Display omitted] • Positive correlation is observed between neuropathic pain, anxiety, and depression. • Spared nerve injury induces pain, anhedonia, and despair-like behaviors. • Insular stimulation at 50 Hz reduced pain, anhedonia and despair. • Insular stimulation at 150 Hz only reduced anhedonia. • Insular stimulation effects on pain and anhedonia are mediated by opioid system. [ABSTRACT FROM AUTHOR]

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (

Background: The development of analgesic and anti-inflammatory drugs plays a crucial role in modern medicine, aiming to alleviate pain and reduce inflammation in patients. Opioids and nonsteroidal anti-inflammatory drugs are groups of drugs conventionally used to treat pain and inflammation, but a wide range of adverse effects and ineffectiveness in some pathological conditions leads us to search for new drugs with analgesic and anti-inflammatory properties., Objectives: In this regard, the authors intend to investigate the ((2s,6s)-6-ethyl-tetrahydro-2h-pyran- 2-yl) methanol compound (LS20) on pain and acute inflammation., Methods: Male Swiss mice were evaluated using acetic acid-induced abdominal writhing, formalin, and tail-flick as models of nociceptive evaluation and edema paw, air pouch and cell culture as models of inflammatory evaluation besides the rotarod test for assessment of motor impairment., Results: The compound showed an effect on the acetic acid-induced abdominal writhing, formalin and tail-flick tests. Studying the mechanism of action, reversion of the antinociceptive effect of the compound was observed from previous intraperitoneal administration of selective and non-selective opioid antagonists on the tail flick test. In addition, the compound induced an antiedematogenic effect and reduced leukocyte migration and the production of pro-inflammatory cytokines in the air pouch model. LS20 was able to maintain cell viability, in addition to reducing cell production of TNF-α and IL-6., Conclusion: In summary, the LS20 compound presented an antinociceptive effect, demonstrating the participation of the opioid system and an anti-inflammatory effect related to the inhibition of pro-inflammatory cytokine production. The compound also demonstrated safety at the cellular level., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an ad libitum (Adlib) or a 50% restricted (FR) diet. The pups' hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted-IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.

Spirulina platensis is a “super-food” and has attracted researchers’ attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3–300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

• A hypodopaminergic model is commonly proposed to underly relapse to alcohol drinking. • Addiction leads to highly dynamic changes in dopamine and opioid systems. • Existing data support both hypo- and hyperdopaminergic states during abstinence. • A revised model of opioid-dopamine interaction is proposed in protracted abstinence. A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder. Paradoxically, blockade of mu-opioid receptors (MORs) intended to suppress dopamine release and alcohol reward is a widely used treatment for preventing relapse in alcohol use disorder (AUD). To elucidate this apparent discrepancy, we systematically survey the literature on experimental studies in AUD subjects and animal models, which assessed striatal dopamine levels and D1, D2-like receptor, dopamine transporter and MOR via positron emission tomography (PET) and ex vivo receptor binding assays. The reported evidence indicates a changing dopaminergic signaling over time, which is associated with concomitant alterations in MOR, thus suggesting a highly dynamic regulation of the reward system during abstinence. Such a view can reconcile the various evidences from in vivo and postmortem studies, but makes developing an effective pharmacological intervention that specifically targets either dopamine receptors or the transporter system a daunting task. [ABSTRACT FROM AUTHOR]

Because of the involvement in motivational processes, opioid receptors are potential targets for apathy treatment in schizophrenia. We therefore searched for associations between the opioid receptor gene polymorphisms (OPRM1 (rs1799971) and OPRD1 (rs1042114, rs533123)) and apathy measured with the Apathy Evaluation Scale-S in a group of 284 schizophrenia patients. We analyzed individual genotypes, haplotypes, and the digenic interaction and observed nominally significant associations of rs1042114 genotypes and the rs1042114*rs1799971 interaction with behavioral apathy scores. The associations, however, did not withstand correction for multiple comparisons. Thus, the results did not provide enough evidence for the opioid receptor gene effects on apathy in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention. [ABSTRACT FROM AUTHOR]

The opioid system regulates affective processing, including pain, pleasure, and reward. Restricting the role of this system to hedonic modulation may be an underestimation, however. Opioid receptors are distributed widely in the human brain, including the more "cognitive" regions in the frontal and parietal lobes. Nonhuman animal research points to opioid modulation of cognitive and decision-making processes. We review emerging evidence on whether acute opioid drug modulation in healthy humans can influence cognitive function, such as how we choose between actions of different values and how we control our behavior in the face of distracting information. Specifically, we review studies employing opioid agonists or antagonists together with experimental paradigms of reward-based decision making, impulsivity, executive functioning, attention, inhibition, and effort. Although this field is still in its infancy, the emerging picture suggests that the mu-opioid system can influence higher-level cognitive function via modulation of valuation, motivation, and control circuits dense in mu-opioid receptors, including orbitofrontal cortex, basal ganglia, amygdalae, anterior cingulate cortex, and prefrontal cortex. The framework that we put forward proposes that opioids influence decision making and cognitive control by increasing the subjective value of reward and reducing aversive arousal. We highlight potential mechanisms that might underlie the effects of mu-opioid signaling on decision making and cognitive control and provide directions for future research. [ABSTRACT FROM AUTHOR]

Background. Numerous studies have investigated the association between the OPRM1 A118G polymorphism (rs1799971) and alcohol dependence, but the results have been inconsistent. The endogenous opioid system has been implicated in the development of alcohol dependence for its prominent role in the central rewarding mechanism. Objectives. The aim of this study was to evaluate the role of the A118G polymorphism of the OPRM1 gene in the pathogenesis of alcohol dependence syndrome (ADS). Material and methods. The OPRM1 (rs1799971) polymorphism was investigated in an association study of a group of ADS patients (n = 177) and in subgroups (delirium tremens and/or seizures, age at onset <26 years, dissocial alcoholics, positive familial history of alcoholism, delirium tremens, and seizures). The control group consisted of healthy volunteers, with matched gender and age, and with psychiatric disorders excluded (n = 162). Results. Our research shows that there are differences in the genotypes and alleles of the OPRM1 polymorphism in the case-control study. Furthermore, we observed associations in our homogeneous subgroups -- in the group of patients with ADS and accompanying delirium tremens and/or seizures at the genotype level, as well as in the subgroup of patients under 26 years of age with an early onset of dependence. Conclusions. It is strongly possible that the G allele described in numerous studies can be associated with a response to treatment, but not typology, or the very predisposition toward alcoholism. It is necessary to carry out further research which would embrace a larger group of patients; it should be divided into other homogeneous subgroups, including, e.g., naltrexone pharmacotherapy. [ABSTRACT FROM AUTHOR]

Abstract Cognitive and emotional impairment are a serious consequence of stress exposure and are core features of neurological and psychiatric conditions that involve memory disorders. Indeed, acute and chronic stress are high-risk factors for the onset of post-traumatic stress disorder (PTSD) and Alzheimer's disease (AD), two devastating brain disorders associated with memory dysfunction. Besides the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, stress response also involves the activation of the opioid system in brain regions associated with stress regulation and memory processing. In this context, it is possible that stress-induced memory disorders may be attributed to alterations in the interaction between the neuroendocrine stress system and the opioid system. In this review, we: (1) describe the effects of acute and chronic stress on memory, and the modulatory role of the opioid system, (2) discuss the contribution of the opioid system to the pathophysiology of PTSD and AD, and (3) present evidence of current and potential therapies that target the opioid receptors to treat PTSD- and AD-associated symptoms. Highlights • Acute and chronic stress exert opposite effects on episodic, emotional, and stimulus-response memories • Divergent effects of stress on memory are controlled by activation of the opioid system • Endogenous opioids in the limbic system are a critical neural substrate in the pathophysiology of Alzheimer's Disease (AD) and posttraumatic stress disorder (PTSD) • Opioid system is a therapeutic target for treating memory dysfunction in AD and PTSD [ABSTRACT FROM AUTHOR]

Abstract Mice selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA) are a unique model for studying the genetic background of this phenomenon. HA and LA miceshow substantial differences in the magnitude of the antinociceptive response to stress and when treated with exogenous opioids. However, the direct cause underplaying this distinctive feature has not yet been identified. The current study was designed to investigate the possibility that disturbances in G-protein signaling could explain the divergent response to opioid agonists. Supraspinal and spinal opioid sensitivity was assessed in vivo with intraperitoneal morphine and subsequent thermal stimulus exposure. The level of opioid receptor-mediated G-protein activation was investigated by means of DAMGO and morphine-stimulated [35S]GTPγS assay in the brain and spinal cord homogenates from HA and LA mice. Morphine (3–249 μmol/kg, i.p) was over 6 - and 3 - times more potent in HA than LA mice in the hot plate and tail-flick assays, respectively. Additionally, HA mice showed elevated β - endorphin levels in the brain. Enhanced efficacy of agonist-stimulated [35S]GTPγS binding was detected in opioid receptor-rich limbic regions of HA mice like the hypothalamus and hippocampus. Increased G-protein activity also emerged in the thalamus, periaqueductal gray matter and prefrontal cortex. In conclusion, the magnitude of the antinociceptive response to opioids in HA and LA mice is correlated with alterations in G-protein activation in brain regions responsible for integration and descending modulation of nociceptive information as well as at sites governing the emotional response to stressful stimuli. Highlights • Bidirectional selection for SSIA induced alterations in G-protein activity. • HA mice show enhanced G-protein activity in structures involved in pain modulation. • High morphine sensitivity correlates with altered μ - opioid receptor function. • HA mice show elevated β - endorphin levels. [ABSTRACT FROM AUTHOR]

Cognition and pain share common neural substrates and interact reciprocally: chronic pain compromises cognitive performance, whereas cognitive processes modulate pain perception. In the present study, we established a non-drug-dependent rat model of context-based analgesia, where two different contexts (dark and bright) were matched with a high (52°C) or low (48°C) temperature in the hot-plate test during training. Before and after training, we set the temperature to the high level in both contexts. Rats showed longer paw licking latencies in trials with the context originally matched to a low temperature than those to a high temperature, indicating successful establishment of a context-based analgesic effect in rats. This effect was blocked by intraperitoneal injection of naloxone (an opioid receptor antagonist) before the probe. The context-based analgesic effect also disappeared after optogenetic activation or inhibition of the bilateral infralimbic or prelimbic sub-region of the prefrontal cortex. In brief, we established a context-based, non-drug dependent, placebo-like analgesia model in the rat. This model provides a new and useful tool for investigating the cognitive modulation of pain. [ABSTRACT FROM AUTHOR]

Muscarinic receptors are also involved in the cholinergic anti-inflammatory function through a central mechanism, as well as a peripheral one, which was recently evidenced. The selective M1 agonist, McN-A-343, showed high anti-inflammatory potential in experimental acetic acid colitis. The opioid pathway also shows an attenuating effect on inflammation in the colitis models through the activation of µ and к receptors, what may show the interconnection of these pathways in the anti-inflammatory effect. The allosteric sites of the M1 and M4 muscarinic receptors have been the target of several pharmacological investigations. Dynorphin, an endogenous opioid kappa receptor agonist, is a negative allosteric agent of M1 muscarinic receptors. The hypothesis pointed out here is that the kappa antagonist, norbinaltomiphine (nor-BNI), also acts as a negative allosteric modulator in M1 receptors, since previous studies show that the simultaneous administration of nor-BNI and McN-A-343 during experimental colitis in mice causes reversal of the anti-inflammatory effect of the M1 agonist. Other kappa antagonists appear to act as negative allosteric modulators at M1. Furthermore, nor-BNI combines many of the common structural features of allosteric modulators of muscarinic receptors. Added to this is the fact that McN-A-343 needs bitopic binding, both in the orthosteric and allosteric sites of the M1 receptor, for its effective action. [ABSTRACT FROM AUTHOR]