Search Results (114)

Background: The endogenous opioid system plays a pivotal role in numerous physiological processes and is implicated in a range of diseases, including atherosclerosis, a condition contributing to nearly 50% of deaths in Western societies. Objectives: This study investigates the effects of opioid receptor blockade, using naloxone, on the plasma lipid profile and atherosclerosis progression. Methods: ApoE^−/− mice with advanced atherosclerosis were treated with naloxone for seven days, and the effects on atherosclerotic plaque development and liver steatosis were evaluated. Results: A proteomic analysis of liver samples post-treatment identified 38 proteins with altered abundance. The results revealed that naloxone treatment led to an increase in HDL cholesterol, a lipid fraction associated with protective cardiovascular effects. Furthermore, naloxone did not influence the progression of atherosclerotic plaques or the development of liver steatosis. Conclusions: In conclusion, while short-term naloxone treatment in mice with advanced atherosclerosis does not alter overall atherosclerotic plaque progression or liver steatosis, the observed elevation in HDL cholesterol and the extensive changes in liver protein abundance underscore the complex and multifaceted role of the opioid system in lipid metabolism and cardiovascular health. These findings provide a foundation for further exploration of opioid receptor antagonists as modulators of lipid profiles and potential contributors to cardiovascular therapy. Full article

Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC. Full article

Physical exercise may affect drug use by balancing neurohormonal system mechanisms. Cortisol and β-endorphin, associated with stress, mood, and pleasure feelings, can be affected by exercise and act as regulators of withdrawal symptoms associated with drug use during short-term abstinence. The present study investigated the effect of a supervised, two-month moderate-intensity aerobic exercise program on salivary cortisol and β-endorphin levels in patients with an opioid use disorder (OUD) and on a substitution treatment during a short-term, 24–36 h withdrawal phase from methadone/buprenorphine medication. Ninety opioid users (41 females) in methadone and buprenorphine substitution treatment were randomly divided into four groups: (a) buprenorphine exercise (BEX) (n = 26; age (mean ± SD): 41.9 ± 6.1 yrs), (b) buprenorphine control (BCON) (n = 25; age: 41.9 ± 5.6 yrs), (c) methadone exercise (MEX) (n = 20; age: 46.7 ± 6.6 yrs), and (d) methadone control (MCON) (n = 19; age: 46.1 ± 7.5 yrs). The exercise intervention groups (BEX and MEX) followed a training program on a treadmill for 20 min at 70% HRmax, 3 days/week for 8 weeks. The responses of cortisol and β-endorphin were measured before (t0) and immediately after an exercise session (t20) on different days (i.e., the 1st, 12th, and 24th session) corresponding to the beginning, middle, and end of the training program. A significant increase in β-endorphin levels was observed after the completion of the training intervention (24th exercise session) in both exercise groups (BEX before: 63.8 ± 33; BEX after: 185.6 ± 182.8 pg/mL; MEX before: 115 ± 211; MEX after: 262.3 ± 505.7 pg/mL), whereas β-endorphin was decreased in the control groups (BCON before: 34.7 ± 20.1; BCON after: 24.2 ± 8.8 pg/mL; MCON before: 129.7 ± 185.7; MCON after: 84.9 ± 104.3 pg/mL) (p < 0.05). Inversely, cortisol decreased in both exercise groups post-intervention (BEX before: 9.5 ± 5.9; BEX after: 2.8 ± 1.5 ng/mL; MEX before: 9.3 ± 6.6; MEX after: 3.1 ± 1.5 ng/mL) and increased in control groups (BCON before: 6.3 ± 2.5; BCON after: 10.1 ± 5.4 ng/mL; MCON before: 7.5 ± 3.2; MCON after: 12.5 ± 4.3 ng/mL) (p < 0.05). Moderate-intensity aerobic exercise can beneficially influence β-endorphin and cortisol levels in individuals undergoing treatment for OUD. By increasing endogenous opioid levels and reducing stress hormones, exercise emerges as a promising adjunctive strategy for alleviating withdrawal symptoms, enhancing emotional regulation, and potentially reducing the risk of relapse. The inverse relationship between β-endorphin and cortisol highlights the role of physical activity as a long-term modulator of neuroendocrine function in the context of substance use recovery. Future research should prioritize longitudinal studies extending beyond two months and involving larger, more diverse populations. Additionally, investigating the integration of exercise with non-pharmacological interventions—and its effects on relapse rates, mental health outcomes, and overall quality of life—would provide further insight into its therapeutic value in addiction recovery. Full article

The presence and function of the opioidergic system in sensory dorsal root ganglia (DRG) was demonstrated in various animal models of pain. To endorse recent functional and transcriptional evidence of opioid receptors in human DRG, this study compared morphological and transcriptional evidence in human and rat DRG using immunofluorescence confocal microscopy and mRNA transcript analysis. Specifically, it examined the neuronal expression of mu (MOR), delta (DOR), and kappa (KOR) opioid receptors, opioid peptide precursors (POMC, PENK, and PDYN), and key pain-signaling molecules. The results demonstrate abundant immunoreactivity in human DRG for key pain transduction receptors, including the thermosensitive ion channels TRPV1, TRPV4 and TRPA1, mechanosensitive PIEZO1 and PIEZO2, and the nociceptive-specific Nav1.8. They colocalized with calcitonin gene-related peptide (CGRP), a marker for peptidergic sensory neurons. Within this same subpopulation, we identified MOR, DOR, and KOR, while their ligand precursors were less abundant. Notably, the mRNA transcripts of MOR and PENK in human DRG were highest among the opioid-related genes; however, they were considerably lower than those of key pain-signaling molecules. These findings were corroborated by functional evidence in demonstrating the fentanyl-induced inhibition of voltage-gated calcium currents in rat DRG, which was antagonized by naloxone. The immunohistochemical and transcriptional demonstration of opioid receptors and their endogenous ligands in both human and rat DRG support recent electrophysiologic and in situ hybridization evidence in human DRG and confirms their potential as analgesic targets. This peripherally targeted approach has the advantage of mitigating central opioid-related side effects, endorsing the potential of future translational pain research from rodent models to humans. Full article

As the number of cancer patients and survivors increases, we face a rising challenge: the long-term impact of the adverse effects of cancer treatment. One of the known adverse effects is chemotherapy-induced peripheral neuropathy (CIPN), which courses with pain complaints. The treatments of CIPN have reduced efficacy. The neurobiological causes of CIPN have been mainly ascribed to peripheral nerve damage, but recent studies show effects in the brain, namely in the descending pain modulatory systems. Physical exercise seems to be associated with better outcomes in CIPN patients, but the mechanisms underlying the effects have not been discussed, namely considering the recent results of the effects of CIPN in brain structures involved in pain modulation. In this critical review, we propose that the beneficial effects of exercise in CIPN also have central mechanisms, namely neuroinflammation and oxidative stress, as well as changes in the actions of neurotransmitters and neurotrophic factors, with a direct effect on optimizing the endogenous pain modulation, namely opioids, monoamines, and endocannabinoids. The effects are multifactorial, as mood improvement and the other psychological benefits of exercise should be considered. The emerging role of the microbiome, which is affected during CIPN, also needs to be considered. This review critically synthesizes the available literature to highlight how the neurobiological effects of physical exercise make it a promising strategy for managing CIPN, both from preventive and treatment perspectives. Full article

Heart failure (HF) is a challenging clinical syndrome with high morbidity and mortality rates. Along the spectrum of cardiovascular diseases, HF constitutes an ever-expanding area of research aiming at combating the associated mortality and improving the prognosis of patients with HF. Although natriuretic peptides have an established role among biomarkers in HF diagnosis and prognosis, several novel biomarkers reflecting the complex pathophysiology of HF are under investigation for their ability to predict adverse clinical outcomes in HF. Proenkephalin 119–159 (PENK_119–159) is a non-functional peptide belonging to the enkephalin family of the endogenous opioid system and is considered a surrogate biomarker of the biologically active enkephalin peptides. PENK_119–159 has demonstrated promising results in predicting short- and long-term mortality, readmission rates, and worsening renal function in patients with HF. Indeed, in the setting of HF, the levels of both active enkephalins and their surrogate PENK_119–159 are elevated and are associated with a dismal prognosis. However, the biological effects of PENK_119–159 remain largely unknown. Thus, it is crucial to gain a deeper insight into both the physiology of the enkephalin peptide family and the enkephalin-mediated cardiovascular regulation. In order to elucidate the complex pathophysiological mechanisms that lead to the upregulation of enkephalins in patients with HF, as well as the potential clinical implications of elevated enkephalins and PENK_119–159 levels in this patient population, the present review will describe the physiology and distribution of the endogenous opioid peptides and their corresponding opioid receptors, with a particular focus on the action of enkephalins. The effects of the enkephalin peptides will be analyzed in both healthy subjects and patients with HF, especially with regard to their role in the regulation of cardiovascular and renal function. The review will also discuss the findings of recent studies that have explored the prognostic value of PENK_119–159 in patients with HF. Full article

Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms. Full article

The placebo effect has been widely documented across various medical conditions, demonstrating its ability to influence both subjective and objective outcomes. Placebo responses can significantly improve symptoms in these different conditions, such as pain, Parkinson’s disease, depression, anxiety, and addiction. Psychological mechanisms, particularly the power of patient expectations, appear to play a central role, with neurobiological evidence supporting the activation of dopamine, endogenous opioids, and endocannabinoids in response to placebo interventions. Studies have demonstrated that placebo injections and more complex procedures, including sham surgeries, can produce therapeutic effects comparable to real treatments, particularly in pain management and neurological disorders. Moreover, placebo responses could be amplified when patients are aware of receiving treatment, as shown by research on open-label placebos and open versus hidden medical treatments. The effectiveness of 0.9% sodium chloride solution as a placebo in clinical trials is debated, with some studies indicating its potential to induce clinical improvements, though it may not be an ideal control in inflammatory pain conditions. Advances in neuroimaging have revealed that placebo treatments trigger tangible biological processes in the brain and body and are supported by psychological and physiological mechanisms that interact, suggesting real biological processes are involved in the observed effects. Overall, the growing understanding of placebo mechanisms suggests that incorporating placebo-based strategies, with patient awareness and appropriate ethical considerations, may offer significant potential for improving patient outcomes, particularly in chronic pain, mental health, and neurological conditions. Full article

Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases. Full article

Background: Fibromyalgia syndrome (FMS), a chronic pain syndrome affecting 0.2–6.6% of the general population, is known for its challenging diagnosis and treatment. The known dysregulation in the Endogenous Pain Modulatory System (EPMS) characteristic of the pathology contributes to enhanced pain sensitivity. Fibromyalgia patients, who are often overmedicated, may experience, in addition to the drug-related known adverse effects, effects on fibromyalgia sensory-related outcomes. Therefore, the focus of this analysis is to explore the bidirectional drug–sensory outcome interactions, indexed by the conditioned pain modulation (CPM), an important assessment element in regard to an EPMS’s efficacy. Methods: Baseline data from a randomized, double-blind, single-center (Boston-based tertiary hospital) clinical trial (NCT03371225) were analyzed. Participants aged 18–65 with an FMS diagnosis and resistance to common analgesics were included. Demographic, clinical, and sensory variables, including CPM, temporal summation, and Pain-60 outcomes, were collected alongside a pain medication diary. Multivariable regression models adjusted for confounders were applied to explore associations between medication classes and quantitative sensory outcomes. Results: Out of 101 recruited FMS patients, we categorized the use of the following medications: antidepressants with 50% use (n = 50), muscle relaxants with 26% use (n = 26), and gabapentin with 25% use (n = 25). The results showed that antidepressant use correlated with worsened CPM, Odds Ratio = 0.39 (95% CI = 0.17–0.91), while muscle relaxants were linked to increased TSPS, β coefficient = 0.72 (95% CI = 0.0021–1.4431). On the other hand, gabapentin use was associated with elevated Pain-60, OR = 2.68 (95% CI = 0.98–7.31). Interestingly, the use of low doses of opioids was not associated with altered sensory measures. Conclusion: This cross-sectional analysis suggests that common pain medications may affect quantitative sensory outcomes in FMS patients. We provided important insights into bidirectional drug–sensory outcome interactions and their influence on pain medicine. Full article

Background: There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol, by causing the release of opioid peptides, may sensitize the system to the action of exogenous opioids such as morphine. Objectives: In this study, using the place conditioning paradigm, a model of reward, we determined whether a morphine challenge would alter the pre-established preference induced by ethanol conditioning in mice, and whether this response was mediated by the mu opioid receptor (MOP). Given that ethanol exposure stimulates the release of opioid peptides, we also assessed the role of beta-endorphin (β-END) and enkephalins (ENKs) in this response. Methods: Mice lacking MOPs, β-END, and/or ENKs, and their respective wild-type controls were tested for preconditioning place preference on day 1. Mice were then conditioned with ethanol (2 g/kg) versus saline on days 2 to 4 and then tested under a drug-free state for postconditioning place preference on day 5. On day 8, mice received a single injection of morphine (5 mg/kg) and were tested for place preference. On the test days, mice were placed in the central chamber and allowed to explore the chambers. The amount of time that mice spent in the drug-paired chamber was recorded. Results: We found that a challenge dose of morphine given on day 8 enhanced the conditioned place preference (CPP) response in mice previously conditioned with ethanol. This response was abolished in MOP-null mice, confirming the role of MOPs in this response. Although this enhanced response was not altered in mice lacking either β-END or ENKs compared to their wild-type littermates/controls, it was completely blunted in mice lacking both β-END and enkephalins. Conclusions: Together, these results suggest that these opioid peptides jointly mediate the crosstalk between the rewarding actions of morphine and ethanol. Full article

Fibromyalgia represents a chronic pain disorder characterized by musculoskeletal pain, fatigue, and cognitive impairments. The exact mechanisms underlying fibromyalgia remain undefined; as a result, diagnosis and treatment present considerable challenges. On the other hand, the endogenous opioid system is believed to regulate pain intensity and emotional responses; hence, it might be expected to play a key role in the enhanced sensitivity experienced by fibromyalgia patients. One explanation for the emergence of disrupted pain modulation in individuals with fibromyalgia is a significant reduction in opioid receptor activity or an imbalance in the levels of endogenous opioid peptides. Further research is essential to clarify the complex details of the mechanisms underlying this abnormality. This complexity arises from the notion that an improved understanding could contribute to the development of innovative therapeutic strategies aimed at targeting the endogenous opioid system in the context of fibromyalgia. Although progress is being made, a complete understanding of these complexities remains a significant challenge. This paradigm has the potential to revolutionize the complex management of fibromyalgia, although its implementation may experience challenges. The effectiveness of this approach depends on multiple factors, but the implications could be profound. Despite the challenges involved in this transformation, the potential for improving patient care is considerable, as this condition has long been inadequately treated. Full article

Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT’s role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. Full article

In this review, we aim to draw a connection between drug addiction and overconsumption of highly palatable food (OHPF) by discussing common behaviors and neurochemical pathways shared by these two states. OHPF can stimulate reward pathways in the brain that parallel those triggered by drug use, increasing the risk of dependency. Behavioral similarities between food and drug addiction can be addressed by tracking their stages: loss of control when eating (bingeing), withdrawal, craving, sensitization, and cross-sensitization. The brain adapts to addiction by way of the mesolimbic dopamine system, endogenous opioids and receptors, acetylcholine and dopamine balance, and adaptations of serotonin in neuroanatomy. Studies from the current literature are reviewed to determine how various neurological chemicals contribute to the reinforcement of drug addiction and OHPF. Finally, protocols for treating food addiction are discussed, including both clinical and pharmacological modalities. There is consistent evidence that OHPF changes brain chemistry and leads to addiction in similar ways to drugs. However, more long-term research is needed on food addiction, binge eating, and their neurobiological effects. Full article

Enkephalins, a subclass of endogenous opioid peptides, play a pivotal role in pain modulation. Enkephalins primarily exert their effects through opioid receptors located widely throughout both the central and peripheral nervous systems. This review will explore the mechanisms by which enkephalins produce analgesia, emotional regulation, neuroprotection, and other physiological effects. Furthermore, this review will analyze the involvement of enkephalins in the modulation of different pathologies characterized by severe pain. Understanding the complex role of enkephalins in pain processing provides valuable insight into potential therapeutic strategies for managing pain disorders. Full article