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Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of enkephalinergic neurons in the brains of reptiles has been understudied. This study reports the organization of the methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) neuronal systems in the central nervous system of the gecko Hemidactylus frenatus using an immunofluorescence labeling method. Although M-ENK and L-ENK-immunoreactive (ir) fibers extended throughout the pallial and subpallial subdivisions, including the olfactory bulbs, M-ENK and L-ENK-ir cells were found only in the dorsal septal nucleus. Enkephalinergic perikarya and fibers were highly concentrated in the periventricular and lateral preoptic areas, as well as in the anterior and lateral subdivisions of the hypothalamus, while enkephalinergic innervation was observed in the hypothalamic periventricular nucleus, infundibular recess nucleus and median eminence. The dense accumulation of enkephalinergic content was noticed in the pars distalis of the hypophysis. In the thalamus, the nucleus rotundus and the dorsolateral, medial, and medial posterior thalamic nuclei contained M-ENK and L-ENK-ir fibers, whereas clusters of M-ENK and L-ENK-ir neurons were observed in the pretectum, mesencephalon, and rhombencephalon. The enkephalinergic fibers were also seen in the area X around the central canal, as well as the dorsal and ventral horns. The widespread distribution of enkephalin-containing neurons within the central nervous system implies that enkephalins regulate a variety of functions in the gecko, including sensory, behavioral, hypophysiotropic, and neuroendocrine functions. [ABSTRACT FROM AUTHOR]

Endogenous opioids are found in the central nervous system and multiple peripheral organs and affect the hypothalamus–pituitary–gonad axis at several levels in vertebrates. However, the influence of these opioid peptides on fish spermatogenesis is poorly studied. This investigation examined the impact of the opioid peptide dynorphin-A (DYN) on the pituitary–testicular axis in the tilapia Oreochromis mossambicus. Intraperitoneal injections of 5 µg DYN/day/fish for 21 days did not affect the early developmental stages of germ cells, but caused a significant decrease in the numbers of secondary spermatocytes and early and late spermatids compared with the controls. Although the mean area of the lobule was significantly decreased, there was a significant increase in the areas of the lumen and the interstitium in the DYN-treated group relative to controls. These results were concomitant with significantly lower serum levels of 11-ketotestosterone (11-KT) and luteinizing hormone (LH) in DYN-treated fish than in controls. However, the serum level of cortisol was significantly higher in the DYN-treated fish group. Overall, these results, for the first time, indicate that DYN interferes with spermatogenesis at the late stage of meiosis, leading to impairment in spermiogenesis, possibly mediated through the suppression of 11-KT secretion in the testis and LH release from the pituitary. This study also suggests that DYN may bring about this inhibitory effect via activation of the stress axis in teleosts. [ABSTRACT FROM AUTHOR]

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone—an opioid antagonist—may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail–cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of μ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of μ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the μ opioid receptor increased the CD8 effector and central memory T-cell populations. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and opioid use disorder (OUD) comprise twin plagues causing considerable morbidity and mortality worldwide. As interactions between TBI and OUD are to our knowledge uncharted, we review the possible mechanisms by which TBI may stimulate the development of OUD and discuss the interaction or crosstalk between these two processes. Central nervous system damage due to TBI appears to drive adverse effects of subsequent OUD and opioid use/misuse affecting several molecular pathways. Pain, a neurological consequence of TBI, is a risk factor that increases the likelihood of opioid use/misuse after TBI. Other comorbidities including depression, anxiety, posttraumatic stress disorder, and sleep disturbances are also associated with deleterious outcomes. We examine the hypothesis that a TBI "first hit" induces a neuroinflammatory process involving microglial priming, which, on a second hit related to opioid exposure, exacerbates neuroinflammation, modifies synaptic plasticity, and spreads tau aggregates to promote neurodegeneration. As TBI also impairs myelin repair by oligodendrocytes, it may reduce or degrade white matter integrity in the reward circuit resulting in behavioral changes. Along with approaches focused on specific patient symptoms, understanding the CNS effects following TBI offers a promise of improved management for individuals with OUD. [ABSTRACT FROM AUTHOR]

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, β-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 β-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. [ABSTRACT FROM AUTHOR]

Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer's patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients. The study shows, by using hematopoietic chimeric mice, that mucosal immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis including visceral sensitivity and normal behavior in mice. [ABSTRACT FROM AUTHOR]

Cocaine predictive cues and contexts exert powerful control over behaviour and can incite cocaine seeking and taking. This type of conditioned behaviour is encoded within striatal circuits, and these circuits and behaviours are, in part, regulated by opioid peptides and receptors expressed in striatal medium spiny neurons. We previously showed that augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP), while opioid receptor antagonists attenuate expression of cocaine CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. To address this, we generated mice with a targeted deletion of enkephalin from dopamine D2‐receptor expressing medium spiny neurons and tested them in a cocaine CPP paradigm. Low striatal enkephalin levels did not attenuate acquisition of CPP. However, expression of preference, assessed after acute administration of the opioid receptor antagonist naloxone, was blocked in females, regardless of genotype. When saline was paired with the cocaine context during extinction sessions, females, regardless of genotype, extinguished preference faster than males, and this was prevented by naloxone when paired with the cocaine context. We conclude that while striatal enkephalin is not necessary for acquisition, expression, or extinction of cocaine CPP, expression and extinction of cocaine preference in females is mediated by an opioid peptide other than striatal enkephalin. The unique sensitivity of females to opioid antagonists suggests sex should be a consideration when using these compounds in the treatment of cocaine use disorder. [ABSTRACT FROM AUTHOR]

The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides' opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [35S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP. [ABSTRACT FROM AUTHOR]

Cruor, the main component responsible for the red color of mammalian blood, contains 90% haemoglobin, a protein considered to be a rich source of bioactive peptides. The aim of the present study is to assess the potential of human hemoglobin as a source of bioactive peptides, compared with bovine hemoglobin, which has been extensively studied in recent years. More specifically, the study focused on the α137–141 fragment of bovine haemoglobin (TSKYR), a small (653 Da) hydrophilic antimicrobial peptide. In this work, the potential of human hemoglobin to contain bioactive peptides was first investigated in silico in comparison with bovine hemoglobin-derived peptides using bioinformatics tools. The blast results showed a high identity, 88% and 85% respectively, indicating a high similarity between the α and β chains. Peptide Cutter software was used to predict cleavage sites during peptide hydrolysis, revealing major conservation in the number and location of cleavage sites between the two species, while highlighting some differences. Some peptides were conserved, notably our target peptide (TSKYR), while others were specific to each species. Secondly, the two types of hemoglobin were subjected to similar enzymatic hydrolysis conditions (23 °C, pH 3.5), which showed that the hydrolysis of human hemoglobin followed the same reaction mechanism as the hydrolysis of bovine hemoglobin, the 'zipper' mechanism. Concerning the peptide of interest, α137–141, the RP-UPLC analyses showed that its identification was not affected by the increase in the initial substrate concentration. Its production was rapid, with more than 60% of the total α137–141 peptide production achieved in just 30 min of hydrolysis, reaching peak production at 3 h. Furthermore, increasing the substrate concentration from 1% to 10% (w/v) resulted in a proportional increase in α137–141 production, with a maximum concentration reaching 687.98 ± 75.77 mg·L−1, approximately ten-fold higher than that obtained with a 1% (w/v) concentration. Finally, the results of the UPLC-MS/MS analysis revealed the identification of 217 unique peptides in bovine hemoglobin hydrolysate and 189 unique peptides in human hemoglobin hydrolysate. Of these, 57 peptides were strictly common to both species. This revealed the presence of several bioactive peptides in both cattle and humans. Although some had been known previously, new bioactive peptides were discovered in human hemoglobin, such as four antibacterial peptides (α37–46 PTTKTYFPHF, α36–45 FPTTKTYFPH, α137–141 TSKYR, and α133–141 STVLTSKYR), three opioid peptides (α137–141 TSKYR,β31–40 LVVYPWTQRF,β32–40, VVYPWTQRF), an ACE inhibitor (β129–135 KVVAGVA), an anticancer agent (β33–39 VVYPWTQ), and an antioxidant (α137–141 TSKYR). To the best of our knowledge, these peptides have never been found in human hemoglobin before. [ABSTRACT FROM AUTHOR]

Introduction: Renal colic is one of the most common urological emergencies, and is usually caused by ureteral colic spasms. Pain management in renal colic remains the central focus of emergency treatment. The purpose of this meta-analysis is to identify the efficacy and safety of ketamine versus opioids in the treatment of patients with renal colic. Methods: We searched PubMed, EMBASE, Cochrane Library, and Web of Science databases for published randomized controlled trials (RCTs) that referred to the use of ketamine and opioids for patients with renal colic. The methodology was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The mean difference (MD) or odds ratio (OR) with a 95% confidence interval (CI) was used to analyze the data. The results were pooled using a fixed-effects model or random-effects model. The primary outcome measure was patient-reported pain scores 5, 15, 30, and 60 min after drug administration. The secondary outcome measure was side effects. Results: The data analysis revealed that ketamine was similar to opioids in pain intensity at the time of 5 min post-dose (MD = − 0.40, 95% CI − 1.82 to 1.01, P = 0.57), 15 min post-dose (MD = − 0.15, 95% CI − 0.82 to 0.52, P = 0.67), 30 min post-dose (MD = 0.38, 95% CI − 0.25 to 1.01, P = 0.24). Also, the pain score of ketamine was better than that of opioids at 60 min after administration (MD = − 0.12, 95% CI − 0.22 to − 0.02, P = 0.02). As for safety, the ketamine group was linked to a significant decrease in the incidence of hypotensive (OR = 0.08, 95% CI 0.01–0.65, P = 0.02). The two groups did not statistically differ in the incidence of nausea, vomiting, and dizziness. Conclusions: Compared with opioids, ketamine showed a longer duration of analgesia in renal colic, with satisfactory safety. Trial Registration: The PROSPERO registration number is CRD42022355246. [ABSTRACT FROM AUTHOR]

Enkephalins are small opioid peptides whose binding conformations are catalyzed by phospholipid membranes. Binding to opioid receptors is determined by the orientation of tyrosine and phenylalanine side chains. In this work, we investigate the effects of different charged phospholipid headgroups on the insertion of the tyrosine side chain into a lipid bilayer using a combination of 2D IR spectroscopy, anharmonic DFT calculations, and third order response function modeling. The insertion is probed by using the ∼1515 cm−1 tyrosine ring breathing mode, which we found exhibits rich vibrational dynamics on the picosecond timescale. These dynamics include rapid intramolecular vibrational energy redistribution (IVR), where some of the energy ends up in a dark state that shows up as an anharmonically shifted combination band. The waiting-time dependent 2D IR spectra also show an unusual line shape distortion that affects the extraction of the frequency–frequency correlation function (FFCF), which is the dynamic observable of interest that reflects the tyrosine side chain's insertion into the lipid bilayer. We proposed three models to account for this distortion: a hot-state exchange model, a local environment dependent IVR model, and a coherence transfer model. A qualitative analysis of these models suggests that the local environment dependent IVR rate best explains the line shape distortion, while the coherence transfer model best reproduced the effects on the FFCF. Even with these complex dynamics, we found that the tyrosine ring mode's FFCF is qualitatively correlated with the degree of insertion expected from the different phospholipid headgroups. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are defined as neurodevelopmental disorders, which are highly variable in nature and do not form a uniform picture, either in terms of symptomatology or depth of the disturbance. Diagnosis of ASD is made for children who show signs of impairment in social interaction, communication and cognitive skills. The exact cause of autism spectrum disorders has not been determined to date. Although there is no cure for ASD, a variety interventions have been proposed. The most commonly used restrictive dietary intervention is the gluten-free casein-free diet (GFCF), which is based on the opioid excess theory. This paper summarizes and discusses research on the core elements of the opioid excess theory in ASD: increased levels of opioid peptides in body fluids in ASD patients, increased intestinal permeability, altered peptidase activity and the effectiveness of GFCF diet in alleviating symptoms of ASD. Furthermore, we discuss the difficulties and their causes in conducting research with ASD patients. The assumptions of the opioid excess theory have neither been definitively confirmed nor disproved. Research in this area should continue, taking into account the highest possible quality standards and the specific needs and abilities of patients with ASD and their families. [ABSTRACT FROM AUTHOR]

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain. [ABSTRACT FROM AUTHOR]

Introduction: Oxidative stress and inflammation are major factors contributing to the progressive death of dopaminergic neurons in Parkinson's disease (PD). Recent studies have demonstrated that morphine's biosynthetic pathway, coupled with nitric oxide (NO) release, is evolutionarily conserved throughout animals and humans. Moreover, dopamine is a key precursor for morphine biosynthesis. Method: The present study evaluated a series of preclinical experiments to evaluate the effects of low-level morphine treatment upon neuro-immune tissues exposed to rotenone and 6-OHDA as models of PD, followed by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay and cell/tissue computer-assisted imaging analyses to assess cell/neuronal viability. Results: Morphine at normal physiological concentrations (i.e., 10−6 M and 10−7 M) provided neuroprotection, as it significantly inhibited rotenone and 6-OHDA dopaminergic insults; thereby, reducing and/or forestalling cell death in invertebrate ganglia and human nerve cells. To ensure that morphine caused this neuroprotective effect, naloxone, a potent opiate receptor antagonist, was employed and the results showed that it blocked morphine's neuroprotective effects. Additionally, co-incubation of NO synthase inhibitor L-NAME also blocked morphine's neuroprotective effects against rotenone and 6-OHDA insults. Conclusions: Taken together, the present preclinical study showed that while morphine can attenuate lipopolysaccharide-induced inflammation and cell death, both naloxone and L-NAME can abolish this effect. Preincubation of morphine precursors (i.e., L-3,4-dihydroxyphenylalanine, reticuline, and trihexyphenidyl [THP] at physiological concentrations) mimics the observed morphine effect. However, high concentrations of THP, a precursor of the morphine biosynthetic pathway, induced cell death, indicating the physiological importance of morphine biosynthesis in neural tissues. Thus, understanding the morphine biosynthetic pathway coupled with a NO signaling mechanism as a molecular target for neuroprotection against oxidative stress and inflammation in other preclinical models of PD is warranted. [ABSTRACT FROM AUTHOR]

Pregnancy-induced anti-nociception is a continuous dialogue between increased levels of endogenous opioids, activation of spinal kappa and delta receptors as well as altered hormonal concentrations. Pain of labour is a multi-factorial subjective algesic experience. It has two components: visceral and somatic. Understanding the interplay between various factors can help in developing newer pain-relieving strategies during labour. Labour pain is an excellent model of acute pain, which is highest on the pain rating scale when compared to other painful life experiences. The two major pathways that attenuate nociceptive inputs in the dorsal horn consist of local control from inhibitory interneurons and the descending inhibitory system from the supra-spinal level. Pain inhibitory neurotransmitters, such as serotonin, noradrenaline, glycine, and GABA, play an important role in pain modulation at the inhibitory interneurons and the descending pain inhibitory system. Labour pain is a nociceptive experience that not only involves inhibitory neurotransmitters but other contributing factors such as hormonal levels, previous experiences, stress, and socioeconomic factors. Visceral/peripheral factors are also important for the subjective experience of pain. Therefore, more studies are warranted to understand the role of pain inhibitory neurotransmitters in central and peripheral modulation of labour pain. [ABSTRACT FROM AUTHOR]

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G protein-biased delta-opioid receptor agonists, and in vivo studies have demonstrated that they exert several beneficial effects via the central nervous system. The most unique and attractive advantage of rubiscolin-6 over other oligopeptides is its oral availability. Therefore, it can be considered a promising candidate for the development of a novel and safe drug. In this review, we show the therapeutic potential of rubiscolin-6, mainly focusing on its effects when orally administered based on available evidence. Additionally, we present a hypothesis for the pharmacokinetics of rubiscolin-6, focusing on its absorption in the intestinal tract and ability to cross the blood–brain barrier. [ABSTRACT FROM AUTHOR]

The mu opioid receptor (MOR) is central to hedonic balance and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states. To investigate this hypothesis, we tested whether neurons expressing MOR in the Hb (Hb-MOR neurons) promote negative affect. Using Oprm1 -Cre knockin mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of Hb-MOR neuron stimulation for approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze, and marble burying), and despair-like behavior (tail suspension). Optostimulation of Hb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus, Hb-MOR neurons project to the dorsal raphe nucleus. Optostimulation of Hb-MOR/interpeduncular nucleus terminals triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of Hb-MOR/dorsal raphe nucleus terminals increased levels of anxiety with no effect on other behaviors, revealing 2 dissociable pathways controlling negative affect. Together, the data demonstrate that Hb neurons expressing MOR facilitate aversive states via 2 distinct Hb circuits, contributing to despair-like behavior (Hb-MOR/interpeduncular nucleus) and anxiety (Hb-MOR/dorsal raphe nucleus). The findings support the notion that inhibition of these neurons by either endogenous or exogenous opioids may relieve negative affect, a mechanism that would have implications for hedonic homeostasis and addiction. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) remains the leading cause of mortality in the world, highlighting an urgent need for the development of novel, more effective approaches for the treatment of AMI. Remote postconditioning (RPost) of the heart could be a useful approach. It was demonstrated that RPost triggers infarct size reduction, improves contractile function of the heart in reperfusion, mitigates apoptosis, and stimulates autophagy in animals with coronary artery occlusion and reperfusion. Endogenous opioid peptides and adenosine could be involved in RPost. It was found that kinases and NO-synthase participate in RPost. KATP channels, MPT pore, and STAT3 could be hypothetical end-effectors of RPost. Metabolic syndrome and old age abolish the cardioprotective effect of RPost in rats. The data on the efficacy of RPost in clinical practice are inconsistent. These data are discussed in the review. [ABSTRACT FROM AUTHOR]

Introduction: An Anterior Cruciate Ligament (ACL) injury produces a 5-40% reduction in quadriceps strength over time. Neuromuscular electrical stimulation is used to help the quadriceps muscle weaken after ACL surgery. The ACL is the primary stabiliser for anterior tibial displacement and the secondary stabiliser for tibial rotation; an ACL-deficient knee can result in devastating consequences like articular cartilage injuries, meniscus tears, functional instability, and the risk of early-onset osteoarthritis. Following an ACL injury, the goal of ACL restoration is to restore functional knee stability. Journals have indicated an increased interest in combining ACL restoration with extraarticular augmentation in recent years. Several studies have demonstrated that the extra reconstruction not only protects the graft from high loads, but also enhances lateral rotational control. In patients with sore joints after ACL reconstruction, cryotherapy can help by releasing endogenous opiates and decreasing nerve conduction velocity. Exercise performance for the physical qualities of strength and power, like many other sports activities, has a short time element for successful performance. As a result, these workouts are performed at the highest possible speed in the least amount of time. Need for the study: There are many evidences that theraband exercises are essential for the patients with ACL reconstruction. Even in athletes, there are literature that proves ballistic training is essential for the patients with ACL reconstruction, but there is no literature for the ballistic training in normal population undergoing ACL reconstruction surgery. There is a strong need to perform a study and evaluate them. Aim: To find out effectiveness of ballistic training in phase II rehabilitation on the patients with ACL reconstruction. Materials and Methods: This randomised control trial will be conducted from May 2022 to May 2023 in the Outpatient and the Inpatient Department of Physiotherapy, Acharya Vinoba Bhave Rural Hospital, Sawangi (Meghe), Wardha, India, during which 100 patients with ACL reconstruction will be divided into two groups, one group will receive conventional therapy along with theraband exercises and another group will receive conventional therapy exercises along with ballistic training. Treatment will be given for eight weeks, five days in a week. The assessment will be done on day one of the treatment and at the end of treatment that is 8th week. Student's t-test and Chi-square tests will be applied for statistical comparison. [ABSTRACT FROM AUTHOR]

The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol‐preferring and alcohol‐avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge‐like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, in vitro evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources in vitro. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors. [ABSTRACT FROM AUTHOR]

Microglia are glial cells centrally related to pathophysiology and neuroimmunological regulation of pain through microglia–neuron crosstalk mechanisms. In contrast, anti-inflammatory mechanisms guided by immunological effectors such as IL-10 trigger the secretion of analgesic substances, culminating in the differential expression of genes encoding endogenous opioid peptides, especially β-endorphin. Thus, when β-endorphin binds to the µ-opioid receptor, it generates neuronal hyperpolarization, inhibiting nociceptive stimuli. This review aimed to summarize the recent advances in understanding the mechanism by which IL-10/β-endorphin can reduce pain. For this, databases were searched for articles from their inception up until November 2022. Two independent reviewers extracted the data and assessed the methodological quality of the included studies, and seventeen studies were considered eligible for this review. Several studies have demonstrated the impact of IL-10/β-endorphin in reducing pain, where IL-10 can stimulate GLP-1R, GRP40, and α7nAChR receptors, as well as intracellular signaling pathways, such as STAT3, resulting in increased β-endorphin expression and secretion. In addition, molecules such as gabapentinoids, thalidomide, cynandione A, morroniside, lemairamin, and cinobufagin, as well as non-pharmacological treatments such as electroacupuncture, reduce pain through IL-10 mediated mechanisms, reflecting a microglia-dependent β-endorphin differential increase. This process represents a cornerstone in pain neuroimmunology knowledge, and the results obtained by different studies about the theme are presented in this review. [ABSTRACT FROM AUTHOR]

Background : Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. Methods: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. Discussion: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. Trial registration: EudraCT no. 2021–000069-34. ClinicalTrials.gov NCT04966559. Registered on July 8, 2021. [ABSTRACT FROM AUTHOR]

Ion channels of the degenerin (DEG)/epithelial Na+ channel (ENaC) family serve diverse functions ranging from mechanosensation over Na+ reabsorption to H+ sensing and neurotransmission. However, several diverse DEG/ENaCs interact with neuropeptides; some are directly activated, whereas others are modulated by neuropeptides. Two questions arise: does this interaction have a common structural basis and does it have an ancient origin? Current evidence suggests that RFamide neuropeptides activate the FMRFamide‐activated Na+ channels (FaNaCs) of invertebrates via binding to a pocket at the external face of their large extracellular domain. It is likely that RFamides might activate DEG/ENaCs from the freshwater polyp Hydra (the HyNaCs) via binding to a similar pocket, although there is not yet any experimental evidence. In contrast, RFamide neuropeptides modulate acid‐sensing ion channels (ASICs) from vertebrates via binding to a central cavity enclosed by β‐sheets of the extracellular domain. Dynorphin opioid peptides, for their part, bind to the acidic pocket of ASICs, which might be evolutionarily related to the peptide binding pocket of FaNaCs, but instead of opening the channels they work as antagonists to stabilize its closed state. Moreover, peptides interacting with DEG/ENaCs from animals of different phyla, although having similar sequences, are evolutionarily unrelated to each other. Collectively, it appears that despite a seemingly similar interaction with similar peptides, the interaction of DEG/ENaCs with neuropeptides has diverse structural bases and many origins. [ABSTRACT FROM AUTHOR]

Acupuncture is a traditional Chinese therapeutic method that uses a sterile thin needle technique to puncture the skin at specific strategic points on the body. World Health Organisation has acknowledged acupuncture as a complementary treatment method for over 300 diseases. Nowadays, many available studies conducted in China, the United States, and Europe confirm the efficacy of acupuncture, its analgesic effect, while providing direct health benefits without or with minimal side-effects. There are many scientific evidence mechanisms of acupuncture’s analgesic effects. One of the mechanisms is described in the oldest and best-known Gate Control Theory which explains how pain pathways are modulated through normal anti-nociceptive pathways in the spinal cord. The second mechanism of analgesia shows that there are changes in descendent inhibition of pain pathway and secretion of neurotransmitters when the acupuncture needle is placed at the specific acupuncture point. In addition, it has been proved that there is an increased secretion of endogenous opioids during acupuncture procedures, which help reduce the pain sensations. Analgesic effects of acupuncture on cerebral function have been confirmed with use of functional magnetic resonance imaging and positron emission tomography scans. Although there is an increased number of relevant studies that confirm the effects and benefits of acupuncture therapy in the perioperative period, some important factors are still missing: the standardization process of acupuncture technique, the determination of types of surgery where the acupuncture method shows the best therapeutic effect, the determination of the best technique and time interval for the most effective analgesia. [ABSTRACT FROM AUTHOR]

1. By understanding the opioidergic etiology of pruritus and the theoretical rationale for treating pruritus with buprenorphine, learners will self-report the ability to propose future studies to investigate this potential therapeutic option for refractory pruiritus. 2. Using a case-based approach to explore the psychosocial impact of chronic pruritus, learners will self-report the ability to apply a psychosocial lens to the treatment of this symptom, and to advocate for urgent and effective treatment options in their clinical practice. Pruritus is a bothersome symptom that can worsen anxiety, stress, and overall quality of life for patients with serious illness. Improved treatment algorithms and new therapeutics are needed. We present a case of treating lymphoma-associated pruritus with transdermal buprenorphine. Pruritus is a symptom that is incompletely understood, difficult to treat, and bothersome to patients (4). Pruritus may occur in patients with cancer (via immunologic or paraneoplastic mechanisms), uremia, cholestasis, and those receiving opioid medications. Multiple mechanisms have been implicated, including histaminergic, immunologic, and neuropathic. Chronic pruritus worsens quality of life and is associated with anxiety, stress, and other psychological symptoms (3). Anxiety has also been demonstrated to worsen pruritus, leading to an "itch-anxiety cycle." Activation of the mu-opioid receptor worsens pruritus, whereas activation of the kappa-opioid receptor suppresses itch (1,5). Based on this mechanism, transdermal buprenorphine, a partial mu agonist, has been trialed in patients with cholestatic pruritus, which is mediated by endogenous opioids (2). Case: A 22-year-old woman with refractory primary mediastinal large B-cell lymphoma with CNS involvement, anxiety, depression, and healthcare-associated PTSD was admitted to the neuro ICU with increased intracranial pressure from her CNS disease. She had profound altered mental status, with delirium worsened by her chronic severe pruritus. The pruritus was attributed to her lymphoma, and she previously tried many medications without effect. She had trialed transdermal buprenorphine for pain, and found her pruritus had improved. During this hospitalization, the palliative care team trialed multiple medications to treat pruritus without effect. Transdermal buprenorphine was trialed, and symptoms improved. Her altered mental status and anxiety also improved. There is tremendous need for more effective treatment for pruritus in patients with serious illness. We will outline the mechanisms of pruritus and identify evidence-based treatments. We will focus on the potential role of transdermal buprenorphine in treatment of opioidergic pruritus, and propose studies to further investigate its potential. Chronic pruritus contributes to anxiety, stress, and other psychosocial symptoms for patients receiving palliative care. Treating the pruritus effectively is a key step in supporting quality of life. Managing Suffering and Distress / Emergencies / Refractory Symptom Management [ABSTRACT FROM AUTHOR]

Loss of function of sodium channel Na V 1.7 produces pain insensitivity. In this issue, Deng et al. 1 show that analgesia after Na V 1.7 removal or pharmacological blockade is not driven by enkephalin overexpression. These results underscore the essential role, independent of endogenous opioids, of Na V 1.7 for nociceptor firing and pain. Loss of function of sodium channel Na V 1.7 produces pain insensitivity. In this issue, Deng et al.1 show that analgesia after Na V 1.7 removal or pharmacological blockade is not driven by enkephalin overexpression. These results underscore the essential role, independent of endogenous opioids, of Na V 1.7 for nociceptor firing and pain. [ABSTRACT FROM AUTHOR]

Background and Purpose: Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C‐nociceptors (TRPV1+), glial cell line‐derived neurotrophic factor (GDNF) sensitizes non‐peptidergic C‐neurons (IB4+). The sigma‐1 receptor (sigma‐1R) is a Ca2+‐sensing chaperone known to modulate opoid analgesia. This receptor binds both to TRPV1 and the μ opioid receptor, although the functional repercussions of these physical interactions in peripheral sensitization are unknown. Experimental Approach: We tested the effects of sigma‐1 antagonism on PGE2‐, NGF‐, and GDNF‐induced mechanical and heat hyperalgesia in mice. We used immunohistochemistry to determine the presence of endomorphin‐2, an endogenous μ receptor agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between sigma‐1R, μ‐ receptor, and TRPV1. We used calcium imaging to study the effects of sigma‐1 antagonism on PGE2‐induced sensitization of TRPV1+ nociceptors. Key Results: Sigma1 antagonists reversed PGE2‐ and NGF‐induced hyperalgesia but not GDNF‐induced hyperalgesia. Endomorphin‐2 was detected on TRPV1+ but not on IB4+ neurons. Peripheral opioid receptor antagonism by naloxone methiodide or administration of an anti‐endomorphin‐2 antibody to a sensitized paw reversed the antihyperalgesia induced by sigma‐1 antagonists. Sigma‐1 antagonism transfers sigma‐1R from TRPV1 to μ receptors, suggesting that sigma‐1R participate in TRPV1‐μ receptor crosstalk. Moreover, sigma‐1 antagonism reversed, in a naloxone‐sensitive manner, PGE2‐induced sensitization of DRG neurons to the calcium flux elicited by capsaicin, the prototypic TRPV1 agonist. Conclusion and Implications: Sigma‐1 antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing μ receptor activity. [ABSTRACT FROM AUTHOR]

Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney disease-associated pruritus (CKD-aP) most often affects people with end-stage renal disease. The etiology of this condition is still not fully understood, but researchers are currently focusing on a thorough analysis of the association between disturbed opioid balance and increased neuronal signaling leading to pruritus. The aim of this study is to assess the concentration of endogenous opioids in dialysis patients with and without pruritus and in the control group, and to determine the correlation between the concentration of these substances and the occurrence and severity of itching. The study involved 126 dialysis patients and 50 healthy controls. Patients were divided into groups with pruritus (n = 62) and without pruritus (n = 64). The severity of pruritus was assessed using the NRS scale. The concentration of endogenous opioids was determined using the ELISA. The concentration of met-enkephalin was higher in the group of patients with pruritus compared to the control group. Moreover, significantly lower levels of β-endorphin and dynorphin A were observed in the group of dialysis patients compared to the control group. In addition, a statistically significant difference was seen between the β-endorphin concentration in the group of dialysis patients with pruritus compared to the group without pruritus. The ratio of β-endorphin/dynorphin A concentrations was significantly lower in the group of patients with pruritus compared to patients without pruritus and the control group. No correlations were found between serum level of studied opioids and the severity of pruritus. The concentrations of the studied opioids did not correlate with the severity of pruritus. Observed opioid imbalance may affect the occurrence of CKD-aP in dialysis patients, but a thorough understanding of the mechanism of action of these substances in the sensation of pruritus is necessary to assess the possibility of finding a new therapeutic target. [ABSTRACT FROM AUTHOR]

Endogenous opioid peptides were reported to be involved in the regulation of reproductive physiology and their precursors and receptors were described in many of the male and female reproductive tissues. Mu opioid receptor (MOR) was described in human endometrial cells and its expression and localization changed during the menstrual cycle. However, there is no data from the distribution of the other opioid receptors: Delta (DOR) and Kappa (KOR). The objective of the present work was to analyze the dynamics of expression and localization of DOR and KOR in human endometrium throughout the menstrual cycle. Human endometrial samples from different menstrual cycle phases were analyzed by immunohistochemistry. DOR and KOR were present in all samples analyzed and the protein expression and localization changed throughout the menstrual cycle. Both receptor expression increased during the late proliferative phase and decreased during the late secretory-one, especially in the luminal epithelium. DOR expression was generally higher than KOR expression in all cell compartments. The presence of DOR and KOR in human endometrium and their dynamic changes during the menstrual cycle join the results previously obtained in MOR suggesting a possible role of opioids in reproduction events related to the human endometrium. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Pain-processing anterior cingulate and primary somatosensory cortical areas display distinct MOR expression profiles with prominent differences between output layers and sexes. The anterior cingulate cortex (ACC) processes the affective component of pain, whereas the primary somatosensory cortex (S1) is involved in its sensory-discriminative component. Injection of morphine in the ACC has been reported to be analgesic, and endogenous opioids in this area are required for pain relief. Mu opioid receptors (MORs) are expressed in both ACC and S1; however, the identity of MOR-expressing cortical neurons remains unknown. Using the Oprm1-mCherry mouse line, we performed selective patch clamp recordings of MOR+ neurons, as well as immunohistochemistry with validated neuronal markers, to determine the identity and laminar distribution of MOR+ neurons in ACC and S1. We found that the electrophysiological signatures of MOR+ neurons differ significantly between these 2 areas, with interneuron-like firing patterns more frequent in ACC. While MOR+ somatostatin interneurons are more prominent in ACC, MOR+ excitatory neurons and MOR+ parvalbumin interneurons are more prominent in S1. Our results suggest a differential contribution of MOR-mediated modulation to ACC and S1 outputs. We also found that females had a greater density of MOR+ neurons compared with males in both areas. In summary, we conclude that MOR-dependent opioidergic signaling in the cortex displays sexual dimorphisms and likely evolved to meet the distinct function of pain-processing circuits in limbic and sensory cortical areas. [ABSTRACT FROM AUTHOR]

Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid‐like side effects. Dual enkephalinase inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins and increasing their half‐lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well‐demonstrated safety, suggests that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the major limitations of exogenous opioids, representing a novel approach to overcome the problem of opioid use disorders. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

It is now evident that the M1 family of aminopeptidases play important roles in many pathophysiological processes. Among them, the enzymatic properties of arginyl aminopeptidase-like 1 (RNPEPL1) are characterized only by its truncated form. No peptide substrate has been identified. To characterize the enzymatic properties of RNPEPL1 in more detail, the full-length protein was expressed in Escherichia coli and purified to homogeneity. The full-length RNPEPL1 showed rather restricted substrate specificity and basic amino acid preference towards synthetic substrates, which was different from the previously reported specificity characterized by the truncated form. Searching for peptide substrates, we found that several peptides, such as Met-enkephalin and kallidin, were cleaved. RNPEPL1 cleaved bradykinin to de-[Arg]-bradykinin despite the presence of proline at the P2'-position. The enzyme cleaved Met-enkephalin but not dynorphin A1–17. Similar to aminopeptidase B, the full-length RNPEPL1 showed basic amino acid preference towards both synthetic and peptide substrates. In addition to the unusual cleavage of bradykinin, this enzyme shows chain length-dependent cleavage of peptide substrates sharing N-terminal amino acid sequence. This is the first study to report the enzymatic properties of the full-length human RNPEPL1 as an aminopeptidase enzyme. [ABSTRACT FROM AUTHOR]

The method allows the screening of numerous peptides for their anti-cancer potential, avoiding the time-consuming and expensive classical approach for bioactive peptides discovery. Bioactive peptides are defined as short amino acid sequences that may have specific physiological functions, ultimately affecting human health and protecting against the development of several diseases. Despite the original peptide antamanide not showing any inhibitory activity, the derived cyclic peptides were able to inhibit tyrosinase activity. Several exogenous bioactive peptides share structural features with endogenous bioactive peptides and may act through similar mechanisms or in synergy with endogenous bioactive peptides. [Extracted from the article]

While the physical signs of opioid withdrawal are most readily observable, withdrawal insidiously drives relapse and contributes to compulsive drug use, by disrupting emotional learning circuits. How these circuits become disrupted during withdrawal is poorly understood. Because amygdala neurons mediate relapse, and are highly opioid sensitive, we hypothesized that opioid withdrawal would induce adaptations in these neurons, opening a window of disrupted emotional learning circuit function. Under normal physiological conditions, synaptic transmission between the basolateral amygdala (BLA) and the neighboring main island (Im) of GABAergic intercalated cells (ITCs) is strongly inhibited by endogenous opioids. Using patch-clamp electrophysiology in brain slices prepared from male rats, we reveal that opioid withdrawal abruptly reduces the ability of these peptides to inhibit neurotransmission, a direct consequence of a protein kinase A (PKA)-driven increase in the synaptic activity of peptidases. Reduced peptide control of neurotransmission in the amygdala shifts the excitatory/inhibitory balance of inputs onto accumbens-projecting amygdala cells involved in relapse. These findings provide novel insights into how peptidases control synaptic activity within the amygdala and presents restoration of endogenous peptide activity during withdrawal as a viable option to mitigate withdrawal-induced disruptions in emotional learning circuits and rescue the relapse behaviors exhibited during opioid withdrawal and beyond into abstinence. [ABSTRACT FROM AUTHOR]

Opioid peptides are well‐known modulators of the central control of reproduction. Among them, dynorphin coexpressed in kisspeptin (KP) neurons of the arcuate nucleus (ARC) has been thoroughly studied for its autocrine effect on KP release through κ opioid receptors. Other studies have suggested a role for β‐endorphin (BEND), a peptide cleaved from the pro‐opiomelanocortin precursor, on food intake and central control of reproduction. Similar to KP, BEND content in the ARC of sheep is modulated by day length and BEND modulates food intake in a dose‐dependent manner. Because KP levels in the ARC vary with photoperiodic and metabolic status, a photoperiod‐driven influence of BEND neurons on neighboring KP neurons is plausible. The present study aimed to investigate a possible modulatory action of BEND on KP neurons located in the ovine ARC. Using confocal microscopy, numerous KP appositions on BEND neurons were found but there was no photoperiodic variation of the number of these interactions in ovariectomized, estradiol‐replaced ewes. By contrast, BEND terminals on KP neurons were twice as numerous under short days, in ewes having an activated gonadotropic axis, compared to anestrus ewes under long days. Injection of 5 μg BEND into the third ventricle of short‐day ewes induced a significant and specific increase of activated KP neurons (16% vs. 9% in controls), whereas the percentage of overall activated (c‐Fos positive) neurons, was similar between both groups. These data suggest a photoperiod‐dependent influence of BEND on KP neurons of the ARC, which may influence gonadotropin‐releasing hormone pulsatile secretion and inform KP neurons about metabolic status. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase III (DPP III), a zinc exopeptidase, is involved in the final steps of intercellular protein degradation and has a marked affinity for opioid peptides such as enkephalins and endomorphins. Recently, we characterized a number of neuropeptides as potential substrates and inhibitors of human DPP III and provided an explanation for their differential behavior. These studies prompted us to investigate the influence of the conserved R399 and R669 on neuropeptides binding to DPP III. Measuring kinetic parameters in inhibitory assays, we found that mutation of R669 to Ala or Met significantly reduced the inhibitory properties of the slow substrates tynorphin and valorphin, whereas the effects on binding of the good substrates Arg2-2NA and Leu-enkephalin were small. Molecular dynamics simulations of wild-type (WT) and mutant DPP III complexes with Leu-enkephalin, tynorphin, valorphin, and Arg2-2NA in conjunction with calculations of binding free energies revealed that the lower inhibitory potency of slow substrates in the R669A mutant can be explained by the lower binding affinity of tynorphin and the higher propensity of valorphin to hydrolyze in the mutant than in WT. The R399A mutation was shown to affect the binding and/or hydrolysis of both good and slow substrates, with the effects on Leu-enkephalin being the most pronounced. [ABSTRACT FROM AUTHOR]

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2. [ABSTRACT FROM AUTHOR]

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked. [ABSTRACT FROM AUTHOR]

Behavioral disorders, such as anxiety and depression, are prevalent globally and touch children and adults on a regular basis. Therefore, it is critical to comprehend how these disorders are affected. It has been demonstrated that neuropeptides can influence behavior, emotional reactions, and behavioral disorders. This review highlights the majority of the findings demonstrating neuropeptides' behavioral role and functional engineering in depression and anxiety. Gut–brain peptides, hypothalamic releasing hormone peptides, opioid peptides, and pituitary hormone peptides are the four major groups of neuropeptides discussed. Some neuropeptides appear to promote depression and anxiety-like symptoms, whereas others seem to reduce it, all depending on the receptors they are acting on and on the brain region they are localized in. The data supplied here are an excellent starting point for future therapy interventions aimed at treating anxiety and depression. [ABSTRACT FROM AUTHOR]

Electrochemical transformations provide enticing opportunities for programmable, residue‐specific peptide modifications. Herein, we harness the potential of amidic side‐chains as underutilized handles for late‐stage modification through the development of an electroauxiliary‐assisted oxidation of glutamine residues within unprotected peptides. Glutamine building blocks bearing electroactive side‐chain N,S‐acetals are incorporated into peptides using standard Fmoc‐SPPS. Anodic oxidation of the electroauxiliary in the presence of diverse alcohol nucleophiles enables the installation of high‐value N,O‐acetal functionalities. Proof‐of‐principle for an electrochemical peptide stapling protocol, as well as the functionalization of dynorphin B, an endogenous opioid peptide, demonstrates the applicability of the method to intricate peptide systems. Finally, the site‐selective and tunable electrochemical modification of a peptide bearing two discretely oxidizable sites is achieved. [ABSTRACT FROM AUTHOR]

Electrochemical transformations provide enticing opportunities for programmable, residue‐specific peptide modifications. Herein, we harness the potential of amidic side‐chains as underutilized handles for late‐stage modification through the development of an electroauxiliary‐assisted oxidation of glutamine residues within unprotected peptides. Glutamine building blocks bearing electroactive side‐chain N,S‐acetals are incorporated into peptides using standard Fmoc‐SPPS. Anodic oxidation of the electroauxiliary in the presence of diverse alcohol nucleophiles enables the installation of high‐value N,O‐acetal functionalities. Proof‐of‐principle for an electrochemical peptide stapling protocol, as well as the functionalization of dynorphin B, an endogenous opioid peptide, demonstrates the applicability of the method to intricate peptide systems. Finally, the site‐selective and tunable electrochemical modification of a peptide bearing two discretely oxidizable sites is achieved. [ABSTRACT FROM AUTHOR]

Opioid analgesics are mu-opioid agonists used in practice for pain management which pose significant health risks including, but not limited to, abuse, dependence, respiratory depression, overdose, and death. Medical devices such as spinal cord stimulators (SCS) - which fall under the category of neurostimulators - may offer an alternative method for pain management. Four searches were conducted on PubMed and the Cochrane Trials database to assess the effects neurostimulation has on opioid consumption. Sixty-two (62) unique results originally populated, and six studies out of the 62 results met inclusion criteria. One result was a neurophysiological study which found transcranial magnetic stimulation (TMS) decreased mu-opioid receptor availability (P < 0.001), thereby suggesting TMS may activate the release of endogenous opioids. Five results were clinical studies utilizing SCS for chronic pain. These five studies cumulatively enrolled 330 participants, 57 of which were withdrawn and 139 of which were using opioids at the time of enrollment. Following neurostimulation, 41% of participants discontinued opioid use altogether, 26.6% of participants decreased opioid use, 26.6% of participants remained on the same opioid dose, and 5.8% of participants increased opioid use. Overall opioid use decreased by an estimated 45.6% ± 13 following SCS. The median trial duration was 1 year, and the median sample size was 23 participants. Although the results unanimously showed effectiveness for pain control and opioid dose reductions, the studies in this review were small, and none were placebo-controlled. The statistical fallbacks of the five SCS studies make it difficult to draw concrete conclusions. More research is needed to ascertain the risk-benefit profiles of neurostimulators in chronic pain patients. [ABSTRACT FROM AUTHOR]

Background: Hypnoanesthesia is a state of anesthesia achieved through hypnosis techniques. Meanwhile, hypnosis is a condition in which the mind receives information without analyzing it. Hypnoanesthesia has been empirically utilized in surgery since the 18th century, but the mechanism remains unclear. Objective: This study aims to prove nociceptive pain relief due to hypnoanesthesia in minor surgery, with indications of changes in the serum levels of several excitatory and inhibitory neurotransmitters in the physiological mechanism of pain. Methods: The study subjects included patients with benign soft tissue tumors consisting of 40 people who were divided into 2 groups (treatment and control). The treatment group underwent minor surgery using hypnoanesthesia, while the control group underwent minor surgery using 2% lidocaine local anesthesia. Pain in both groups was measured by FPS (Face Pain Scale) and monitored by a vital sign monitor. Changes in the serum levels of glutamic acid, substance P, beta-endorphin and enkephalin neurotransmitters in both groups before and after the intervention were analyzed using ELISA. Results: There were no significant changes in serum levels of neurotransmitters, pre and post intervention in both groups, both excitatory neurotransmitters Glutamic Acid and Substance P and inhibitory neurotransmitters Beta Endorphins and Enkephalin (p > 0.05). Conclusion: Based on the results of the data analysis, it can be concluded that the empirical nociceptive pain relief occurred in patients who underwent minor surgery with hypnoanesthesia and there was no significant change in betaendorphin, enkephalin, glutamate acid, and substance P serum levels before and after hypnoanesthesia. Key words: Hypnoanesthesia, Beta-Endorphin, Enkephalin, Glutamic Acid, Substance P. [ABSTRACT FROM AUTHOR]

Chronic pain represents one of the most serious worldwide medical problems, in terms of both social and economic costs, often causing severe and intractable physical and psychological suffering. The lack of biological markers for pain, which could assist in forming clearer diagnoses and prognoses, makes chronic pain therapy particularly arduous and sometimes harmful. Opioids are used worldwide to treat chronic pain conditions, but there is still an ambiguous and inadequate understanding about their therapeutic use, mostly because of their dual effect in acutely reducing pain and inducing, at the same time, tolerance, dependence, and a risk for opioid use disorder. In addition, clinical studies suggest that opioid treatment can be associated with a high risk of immune suppression and the development of inflammatory events, worsening the chronic pain status itself. While opioid peptides and receptors are expressed in both central and peripheral nervous cells, immune cells, and tissues, the role of opioids and their receptors, when and why they are activated endogenously and what their exact role is in chronic pain pathways is still poorly understood. Thus, in this review we aim to highlight the interplay between pain and immune system, focusing on opioids and their receptors. [ABSTRACT FROM AUTHOR]

The effect of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 (Taphalgin), a synthetic derivative of dermorphine, was evaluated in the tail-flick test in mice after a single subcutaneous (s.c.) injection. Taphalgin significantly prolongs the tail-flick latency when administered in the dose range 0.01 – 5 mg/kg. The analgesic effect of a single s.c. injection of Taphalgin at 1 mg/kg exceeds the effect of morphine hydrochloride at the same dose. The effect of Taphalgin at 0.5 mg/kg is comparable to that of morphine hydrochloride at 1 mg/kg. The magnitude and duration of the analgesic effect grow as the dose of Taphalgin increases from 0.5 to 1.5 and 4.5 mg/kg. The maximum 4-h duration of the analgesic effect is observed at doses of 1.5 and 4.5 mg/kg. [ABSTRACT FROM AUTHOR]

Objectives: We have previously shown that the combined consumption of fat and a sucrose solution induces overeating, and there is evidence indicating that sucrose drinking directly stimulates fat intake. One neurochemical pathway by which sucrose may enhance fat intake is through the release of endogenous opioids in the nucleus accumbens (NAC). Methods: To test this hypothesis, we provided rats with a free-choice high-fat diet for two weeks. During the second week, rats had access to an additional bottle of water or a 30% sucrose solution for five minutes per day. After these two weeks, we infused vehicle or the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAC 30 min after their daily access to the additional bottle of water or the sucrose solution. Results: Sucrose drinking had two effects, (1) it stimulated fat intake in the absence of DAMGO infusion, (2) it diminished sensitivity to DAMGO, as it prevented the rapid increase in fat intake typically seen upon DAMGO infusion in the nucleus accumbens. In a second experiment, we confirmed that these results are not due to the ingested calories of the sucrose solution. Lastly, we investigated which brain areas are involved in the observed effects on fat intake by assessing c-Fos-expression in brain areas previously linked to DAMGO's effects on food intake. Both intra-NAC DAMGO infusion and sucrose consumption in the absence of DAMGO infusion had no effect on c-Fos-expression in orexin neurons and the central amygdala but increased c-Fos-expression in the NAC as well as the basolateral amygdala. Discussion: In conclusion, we confirm that sucrose drinking stimulates fat intake, likely through the release of endogenous opioids. [ABSTRACT FROM AUTHOR]

Each cerebral hemisphere is functionally connected to the contralateral side of the body through the decussating neural tracts. The crossed neural pathways set a basis for contralateral effects of brain injury such hemiparesis and hemiplegia as it has been already noted by Hippocrates. Recent studies demonstrated that, in addition to neural mechanisms, the contralateral effects of brain lesions are mediated through the humoral pathway by neurohormones that produce either the left or right side-specific effects. The side-specific humoral signaling defines whether the left or right limbs are affected after a unilateral brain injury. The hormonal signals are released by the pituitary gland and may operate through their receptors that are lateralized in the spinal cord and involved in the side-specific control of symmetric neurocircuits innervating the left and right limbs. Identification of features and a proportion of neurological deficits transmitted by neurohormonal signals vs. those mediated by neural pathways is essential for better understanding of mechanisms of brain trauma and stroke and development of new therapies. In a biological context, the left–right side-specific neuroendocrine signaling may be fundamental for the control of the left- and right-sided processes in bilaterally symmetric animals. [ABSTRACT FROM AUTHOR]

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer. [ABSTRACT FROM AUTHOR]

Positive social contact predicts better health, but the mechanisms for this association remain debated. One way to explore this link is through the social regulation of emotion, particularly anticipatory anxiety. Previous research finds less neural threat response during partner handholding than when people are alone or stranger handholding. Various mechanistic accounts have been forwarded, including the hypothesis that this effect is mediated by endogenous opioid activity. This experiment critically tested the opioid hypothesis in 60 married participants and their partners. The study used a naltrexone opioid blockade in a double‐blind placebo control with functional magnetic resonance imaging to determine whether endogenous opioids were necessary for handholding effects. Regulatory effects of supportive handholding manifested in threat network regions during opioid blockade, but not with placebo. Despite a surprising lack of effect in the placebo group, the overall study findings provide initial evidence that endogenous opioids may not be necessary for the social regulation of neural threat responding. Our findings suggest compelling evidence against a major outstanding hypothesis that the stimulation of endogenous opioid release during social touch mediates neural threat response. This has major implications for understanding the salubrious effects of close relationships. Ultimately, we believe these findings provide critical clues as to the processes by which stress and relationships are linked. [ABSTRACT FROM AUTHOR]