Susceptibility to Pentylenetetrazole-Induced Seizures in Mice with Distinct Activity of the Endogenous Opioid System.

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.

Guanidine-to-piperidine switch affords high affinity small molecule NPFF ligands with preference for NPFF1-R and NPFF2-R subtypes.

The Neuropeptide FF (NPFF) receptor system is known to modulate opioid actions and has been shown to mediate opioid-induced hyperalgesia and tolerance. The lack of subtype selective small molecule compounds has hampered further exploration of the pharmacology of this receptor system. The vast majority of available NPFF ligands possess a highly basic guanidine group, including our lead small molecule, MES304. Despite providing strong receptor binding, the guanidine group presents a potential pharmacokinetic liability for in vivo pharmacological tool development. Through structure-activity relationship exploration, we were able to modify our lead molecule MES304 to arrive at guanidine-free NPFF ligands. The novel piperidine analogues 8b and 16a are among the few non-guanidine based NPFF ligands known in literature. Both compounds displayed nanomolar NPFF-R binding affinity approaching that of the parent molecule. Moreover, while MES304 was non-subtype selective, these two analogues presented new starting points for subtype selective scaffolds, whereby 8b displayed a 15-fold preference for NPFF1-R, and 16a demonstrated an 8-fold preference for NPFF2-R. Both analogues showed no agonist activity on either receptor subtype in the in vitro functional activity assay, while 8b displayed antagonistic properties at NPFF1-R. The calculated physicochemical properties of 8b and 16a were also shown to be more favorable for in vivo tool design. These results indicate the possibility of developing potent, subtype selective NPFF ligands devoid of a guanidine functionality.

Analgesic and Anti-Inflammatory Potential of the New Tetrahydropyran Derivative (2s,6s)-6-ethyl-tetrahydro-2h-pyran-2-yl) Methanol.

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. OBJECTIVE: 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 proinflammatory cytokine production. The compound also demonstrated safety at the cellular level.

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Copaifera langsdorffii Desf. tree oleoresin-induced antinociception recruits µ1- and κ -opioid receptors in the ventrolateral columns of the periaqueductal gray matter.

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 µ1- 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 µ1-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 µ1 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 µ1 and κ opioid receptors are critically recruited in the antinociceptive effect produced by oleoresin extracted from Copaifera langsdorffii.

Accumbal µ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics.

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.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats.

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 ß-endorphin (ß-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.

Effect of Stress on the Production of Antibodies and IL-2, IL-4, and IFNγ Depending on the Time of Antigen Administration and Evaluation of the Role of Opioid Receptors.

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.

Chronic Kidney Disease-Associated Pruritus and Quality of Life: Learning from Our Patients.

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.

Acetic acid-induced pain elicits stress-, and camouflage-related responses in zebrafish: Modulatory effects of opioidergic drugs on neurobehavioral phenotypes.

While pain results from the activation of nociceptors following noxious stimuli, mounting evidence links pain- and stress-related responses in mammals. In zebrafish, the activation of hypothalamic-pituitary-interrenal (HPI) axis may also regulate body pigmentation (the camouflage response). Here, we aimed to investigate a putative relationship between pain-, stress-, and camouflage-related parameters in adult zebrafish. To answer this question, we assessed whether intraperitoneal acetic acid injection can activate the HPI axis, measuring whole-body cortisol and the camouflage response as physiological endpoints in the presence or absence of morphine or naloxone, an opioid antagonist. Acetic acid induced a stereotypic circling behavior in the top of the tank, accompanied by abdominal writhing-like response, a specific phenotype that reflects local nociceptive effect. Both whole-body cortisol levels and camouflage response increased in the acetic acid group, while morphine prevented these responses, and naloxone antagonized morphine-induced effects. Moreover, we observed positive correlations between representative behavioral, physiological and skin coloration endpoints, and a "pain index" was proposed to summarize phenotypic profile of zebrafish under different pharmacological manipulations. Collectively, these findings suggest a coordinated activation of pain, camouflage- and stress-related pathways following acetic acid injection in zebrafish. Our data also support that camouflage response represents a novel and relevant biomarker for future probing pain and stress neurobiology, with a robust sensitivity to opioidergic drugs.

The Role of The Rostral Ventromedial Medulla in Stress Responses.

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.

Low-Dose Naltrexone in Rheumatological Diseases.

Background: Naltrexone has been approved for alcohol and opioid abuse by the FDA. At low-dose naltrexone (LDN) has been used in several diseases including chronic pain and autoimmune conditions, including rheumatic disorders. Aim: To review the use of LDN in rheumatic diseases: systemic sclerosis (SSc), dermatomyositis (DM), Sjögren's syndrome (SS), rheumatoid arthritis (RA), and fibromyalgia (FM). Methods: PubMed and Embase databases were searched for articles on LDN and rheumatic diseases between 1966 and August 2022. Results: Seven studies in FM have been identified: in this disease LDN has showed beneficial effects on pain and well-being. In SS, two articles with 3 cases description showed that LDN may be of help in the pain treatment. LDN relieved pruritus in scleroderma (a case description with a series of 3 patients) and dermatomyositis (description of 3 patients in two articles). In RA a study using Norwegian Prescription Database showed that LDN was associated to reduction in the use of analgesic and DMARDs. No serious side effects were detected. Conclusion: This review shows that LDN is a promising and safe therapy to be used in some rheumatic disease. However, the data is limited and needs to be reproduced in larger studies.

Etiopathogenesis of chronic kidney disease-associated pruritus: putting the pieces of the puzzle together.

Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice.

The Role of Mu Opioid Receptors in High Fat Diet-Induced Reward and Potentiation of the Rewarding Effect of Oxycodone.

Excessive high fat diet (HFD) consumption can induce food addiction, which is believed to involve the communication between the hypothalamus and mesolimbic dopaminergic neurons, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc). These brain areas are densely populated with opioid receptors, raising the possibility that these receptors, and particularly mu opioid receptors (MORs), are involved in rewards elicited by palatable food. This study sought to investigate the involvement of MORs in HFD-induced reward and if there is any difference between male and female subjects in this response. We also assessed if exposure to HFD would alter the rewarding action of oxycodone, a relatively selective MOR agonist. The place conditioning paradigm was used as an animal model of reward to determine if short-time (STC, 2 h) or long-time (LTC, 16 h) conditioning with HFD induces reward or alters the rewarding action of oxycodone. Male and female C57BL/6J mice as well as MOR knockout and their wildtype littermates of both sexes were tested for basal place preference on day 1 and then conditioned with an HFD in one chamber and a regular chow diet (RCD) in another chamber for 2 h on alternate days. Three sets of STC were used, followed by a set of LTC. Each set of conditioning consisted of two conditioning with RCD and two conditioning with HFD. Mice were tested for place preference after each set of STC and again after LTC. Controls were conditioned with RCD in both conditioning chambers. Following the last place preference test, mice were treated with oxycodone and conditioned in the HFD-paired chamber and with saline in the RCD-paired chamber for one hour once a day to explore the possibility if the HFD could alter oxycodone reward. The result showed that HFD induced conditioned place preference (CPP) in male but not female subjects. However, oxycodone conditioning elicited reward in both male and female mice of the HFD group but not the control group, showing that prior conditioning with HFD potentiated the rewarding action of oxycodone. The latter response was mediated via MORs, as it was blunted in MOR knockout mice. Similarly, HFD-induced CPP was blunted in male MOR knockout mice, suggesting sexual dimorphism in this response.

Flavonoids and fractions from Saccharum officinarum L. juice: antinociceptive agents and molecular docking evaluations with µ-opioid receptor.

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.

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system.

The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1ß, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 µg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.

The opioid system in depression.

Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.

The role of kappa opioid receptors in immune system - An overview.

Opioids are one of the most effective anti-nociceptive agents used in patients with cancer pain or after serious surgery in most countries. The endogenous opioid system participates in pain perception, but recently its role in inflammation was determined. κ-opioid receptors (KOP receptors), a member of the opioid receptor family, are expressed in the central and peripheral nervous system as well as on the surface of different types of immune cells, e.g. T cells, B cells and monocytes. In this review, we focused on the involvement of KOP receptors in the inflammatory process and described their function in a number of conditions in which the immune system plays a key role (e.g. inflammatory bowel disease, arthritis, subarachnoid hemorrhage, vascular dysfunction) and inflammatory pain. We summed up the application of known KOP ligands in pathophysiology and we aimed to shed new light on KOP receptors as important elements during inflammation.

Evidence of alterations of Beta-endorphin levels and Mu-opioid receptor gene expression in bipolar disorder.

Despite the well-recognized effects of endogenous opioids on mood and behavior, research on its role in bipolar disorder (BD) is still limited to small or anecdotal reports. Considering that Beta-endorphins (ß-END) and Mu-opioid receptors (MOR), in particular, have a crucial activity in affective modulation, we hypothesized their alteration in BD. A cross-sectional study was conducted. We compared: (1) BD type I (BD-I) patients (n = 50) vs healthy controls (n = 27), (2) two BD-I subject subgroups: manic (MAN; n = 25) vs depressed (DEP; n = 25) subjects. Plasma levels of ß-END and MOR gene expression in peripheral blood mononuclear cells were analyzed using ELISA Immunoassay qRT-PCR. We found that subjects with BD exhibited a significant upregulation of MOR gene expression and a decrease of ß-END (p<0.0001 for both). MAN display higher MOR levels than DEP (p<0.001) and HC (p<0.0001). Plasma levels of ß-END were lower in DEP compared to MAN (p<0.05) and HC (p<0.0001). The main limitations are the cross-sectional design and the lack of a group of euthymic subjects. Although preliminary, our results suggest a dysregulation of the endogenous opioid systems in BD. In particular, both MAN and DEP showed a reduction of ß-END levels, whereas MAN was associated with MOR gene overexpression.