Opioid Peptides Research Articles

The opioid peptide dynorphin interferes with testicular activity in Mozambique tilapia

The opioid peptide dynorphin interferes with testicular activity in Mozambique tilapia

The opioid peptide leucine enkephalin modulates hypothalamic-hypophysial axis in the cichlid fish Oreochromis mossambicus

In vertebrates, opioid peptides are thought to be involved in the regulation of reproduction; however, the significance of enkephalins in testicular function remains unclear. We examined the influence of δ-opioid receptor agonist leucine enkephalin (L-ENK) on the hypophysial-testicular axis of the cichlid fish Oreochromis mossambicus. Treatment with a low dose of L-ENK (60 µg) caused a significant increase in the numbers of primary and secondary spermatocytes and early and late spermatids, concomitant with intense immunolabelling of testicular androgen receptors, but did not significantly alter serum luteinizing hormone (LH) and 11-ketotestosterone (11-KT) levels compared to those of controls. Nevertheless, treatment with a high dose of L-ENK (200 µg) caused a significant reduction in the numbers of secondary spermatocytes as well as late spermatids associated with marginal immunolabelling of androgen receptors and significantly lower concentrations of serum 11-KT and LH compared to controls. In addition, the serum cortisol level was not affected in low-dose L-ENK-treated fish, but its level was significantly increased in the high-dose L-ENK-treated group. Together, these findings indicate that a low dose of L-ENK stimulates the germ cells at the meiosis stage and promotes further stages of spermatogenesis, whereas a high concentration of L-ENK inhibits spermatogenesis at the advanced stages. This effect appears to be mediated through the suppression of testicular steroidogenesis and the reduction of LH release in the pituitary gland of tilapia. The findings also suggest that elevated L-ENK levels in teleosts may exert their inhibitory influence on the hypophysial-testicular axis via glucocorticoids.

Sensitivity to the initial rewarding effects of alcohol: Influence of age, sex, and β-endorphin.

Alcohol use disorders (AUDs) are widespread, devastating and complex. About 20% of people who consume alcohol develop problem use, accounting for over 5% of worldwide deaths. While numerous animal models have facilitated understanding of the consequences of excessive drinking, translational models allow for experimental manipulation of factors thought to contribute to AUD liability. We employ a single-exposure conditioned place preference assay (SE-CPP) to investigate the influence of age, sex and the opioid peptide β-endorphin (bE) on the initial rewarding effects of ethanol, a strong predictor of AUDs. Adolescent (PND28-35) and adult (PND70-90) male and female, control C57BL/6J and bE-deficient mice were tested following a single injection of 1.5 g/kg of ethanol. Following the SE-CPP test, animals were deeply anesthetized, sacrificed, and perfused, and the brains were subsequently sectioned at 40 microns and processed for immunohistochemical localization of c-fos. One-sample, two-tailed t-tests were used to assess drug preference or aversion and the locomotor effects of alcohol. In general, adults were more sensitive to the effects of alcohol than adolescents, and outcomes depended on sex and bE. For example, among females, adolescents were stimulated by the drug, but insensitive to locomotor effects as adults, while among males, adolescents were insensitive and adults sedated. Wild-type adolescents of both sexes failed to evince initial subjective reward from the drug, but bE-deficient adolescents, and all adult subjects, preferred a context once associated with ethanol over one that had been paired with saline. c-fos immunoreactivity in multiple brain regions was attenuated in bE-deficient animals, though influences of both sex and bE grew stronger with age. This study demonstrates the utility of the SE-CPP paradigm for elucidating factors that contribute to the liability for AUDs, and supports the growing body of research that shows that sensitivity to the rewarding effects of alcohol changes during the course of development. Our results also suggest that developmental contributions are sex-dependent, and may also depend on the influence of endogenous opioid signaling.

µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice

Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ−opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ−opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ−opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ−opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ−opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress.

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.

Adeno-associated virus-mediated gene transfer of arginine decarboxylase to the central nervous system prevents opioid analgesic tolerance.

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for site-specific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAV-hADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pre-treatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of anti-agmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance.

An examination of the effects of nucleus accumbens core nociceptin on appetitive and consummatory motivation for food

The nucleus accumbens (NAc) is a critical region for regulating the appetitive and consummatory aspects of motivated behavior. Previous work has shown differential effects of NAc µ-, δ-, and κ- receptor stimulation on food intake and for shifting motivation within an effort-based choice (EBC) task. However, the motivational role of the nociceptin opioid peptide (NOP) receptor, a fourth member of the opioid receptor family, is less well understood. These experiments therefore characterized the effect of NAc injections of nociceptin, the endogenous ligand for the NOP receptor, on consummatory and appetitive motivation. Three groups of male Sprague-Dawley rats received nociceptin injections into the NAc core prior to testing in a progressive ratio lever pressing task, an EBC task, or a palatable feeding assay. In the feeding experiment, 10 nmol of nociceptin increased consumption in the first 30 min, but this increase was not sustained through the end of the 2-hr session. Additionally, nociceptin injections did not alter breakpoint in the progressive ratio task. However, in the EBC task, nociceptin significantly decreased breakpoint for sugar pellets without affecting consumption of rat chow. These data suggest that NAc NOP receptor stimulation transiently increases consummatory motivation toward palatable diets and inhibits appetitive motivation when alternate food options are freely available. This pattern of effects contrasts with those obtained following NAc stimulation of other opioid receptors, suggesting that the four opioid receptor classes each serve unique roles in modulating food-directed motivation within the NAc core.

Ex vivo degradation of β-Casomorphin-7 by human plasma peptidases: Potential implications for peptide systemic effects

Susceptibility to proteolytic activity is a critical limitation for food-derived peptides possibly influencing human physiological processes. This study explores the ex vivo stability and degradation kinetics of the milk-derived opioid peptide β-casomorphin-7 (BCM7) in human blood. Blood specimens collected from three healthy volunteers were individually spiked with synthetic BCM7 and sampled at seven time points over 2 h. Liquid chromatography-electrospray-high resolution tandem mass spectrometry was used to monitor the stability of BCM7 and the formation of its hydrolytic fragments. Human plasma peptidases rapidly hydrolyzed BCM7 generating inactive peptides with similar sharp degradation kinetics across the blood of different individuals. The estimated plasma half-life (t1/2) value of BCM7 ranged from 35 to 40 min. The peptide degradation pattern pointed to prolyl oligopeptidase, prolidase, and dipeptidyl peptidase as the primary enzyme candidates responsible for BCM7 hydrolysis. Overall, the findings of this study suggest that BCM7 cannot exert systemic effects in humans.

Role of neuropeptides in orofacial pain: A literature review.

Neuropeptides play a critical role in regulating pain and inflammation. Despite accumulating evidence has further uncovered the novel functions and mechanisms of different neuropeptides in orofacial pain sensation and transmission, there is deficient systematic description of neuropeptides' pain modulation in the orofacial region, especially in the trigeminal system. The present review aims to summarise several key neuropeptides and gain a better understanding of their major regulatory roles in orofacial inflammation and pain. We review and summarise current studies related to calcitonin gene-related peptide (CGRP), substance P (SP), opioid peptide (OP), galanin (GAL) and other neuropeptides' functions and mechanisms as well as promising targets for orofacial pain control. A number of neuropeptides are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain. The functions, possible cellular and molecular mechanisms have been introduced and discussed. Neuropeptides and their agonists or antagonists which are widely studied to be potential treatment options of orofacial pain has been evaluated. Various neuropeptides play important but distinct (pro-nociceptive or analgesic) roles in orofacial pain with different mechanisms. In summary, CGRP, SP, NPY, NKA, HK-1, VIP mainly play proinflammatory and pro-nociceptive effects while OP, GAL, OXT, OrxA mainly have inhibitory effects on orofacial pain.

Opioid peptides in the regulation of eating behavior and appetite. (A Narrative Review)

Opioid peptides in the regulation of eating behavior and appetite. (A Narrative Review)

Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach.

This work focuses on the δ receptor (DOR), a G protein-coupled receptor (GPCR) belonging to the opioid receptor group. DOR is expressed in numerous tissues, particularly within the nervous system. Our study explores computationally the receptor's interactions with various ligands, including opiates and opioid peptides. It elucidates how these interactions influence the δ receptor response, relevant in a wide range of health and pathological processes. Thus, our investigation aims to explore the significance of DOR as an incoming drug target for pain relief and neurodegenerative diseases and as a source for novel opioid non-narcotic analgesic alternatives. We analyze the receptor's structural properties and interactions using Molecular Dynamics (MD) simulations and Gaussian-accelerated MD across different functional states. To thoroughly assess the primary differences in the structural and conformational ensembles across our different simulated systems, we initiated our study with 1 μs of conventional Molecular Dynamics. The strategy was chosen to encompass the full activation cycle of GPCRs, as activation processes typically occur within this microsecond range. Following the cMD, we extended our study with an additional 100 ns of Gaussian accelerated Molecular Dynamics (GaMD) to enhance the sampling of conformational states. This simulation approach allowed us to capture a comprehensive range of dynamic interactions and conformational changes that are crucial for GPCR activation as influenced by different ligands. Our study includes comparing agonist and antagonist complexes to uncover the collective patterns of their functional states, regarding activation, blocking, and inactivation of DOR, starting from experimental data. In addition, we also explored interactions between agonist and antagonist molecules from opiate and opioid classifications to establish robust structure-activity relationships. These interactions have been systematically quantified using a Quantitative Structure-Activity Relationships (QSAR) model. This research significantly contributes to our understanding of this significant pharmacological target, which is emerging as an attractive subject for drug development.

The Role of Endogenous Opioids in Cardioprotection.

The opioid system involves opioid receptors (OPRs) and endogenous opioid peptides.This chapter will focus on the distribution of OPRs in the cardiovascular system, the expression pattern in the heart, the activation by opioid peptides, and the effects of OPRs activation with potential relevance in cardiovascular performance. In the heart, OPRs are co-expressed with beta adrenergic receptors (β-ARs) in the G-protein-coupled receptor (GPCR) superfamily, functionally cross-talk with β-Ars and modify catecholamine-induced effects. They are involved in cardiac contractility, energy metabolism, myocyte survival or death, vascular resistance. The effects of the opioid system in the regulation of systemic circulation at both the central and peripheral level are presented. The pathways are discussed under physiological (i.e., aging) and pathological conditions (atherosclerosis, heart failure, essential hypertension, ischemic stress). Stimulation of OPRs not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury. An enhanced sensitivity to opioids of endocrine organs and neuronal systems is operative in hypertensive patients. The opioid system can be pharmacologically engaged to selectively mimic these responses via cardiac and nervous signaling. The clinical opportunities for the use of cardioprotective effects of opioids require future investigations to provide more specific details of the impact on cardiac performance and electrophysiological properties.

Enkephalin Rescues Temporomandibular Joint Pain-Related Behavior in Rats.

Temporomandibular joint disorders include a variety of clinical syndromes that are difficult to manage if associated with debilitating severe jaw pain. Thus, seeking additional experimental therapies for temporomandibular joint pain reduction is warranted. Targeted enkephalin gene therapy approaches provide clear promise for pain control. The studies detailed here indicate significant analgesia and protection of joint tissue are provided after injection of an overexpression viral vector gene therapy near the joint. The viral vector gene therapy described provides overexpression of naturally occurring opioid peptides after its uptake by trigeminal nerve endings. The viral vectors act as independent "minipump" sources for the opioid peptide synthesis in the neuronal cytoplasm producing the intended biological function, reduction of pain, and tissue repair. The antinociceptive effects provided with this delivery method of opioid expression persist for over 4weeks. This is coincident with the expected time frame for the duration of the transgene overproduction of the endogenous opioid peptide before its diminution due to dormancy of the virus. These experimental studies establish a basis for the use of replication-defective herpes simplex type 1-based gene therapy for severe chronic inflammatory temporomandibular joint destruction and pain. As innovative means of significantly reducing joint inflammation and preserving tissue architecture, gene therapies may extend their clinical usefulness for patients with temporomandibular joint disorders.

Low-frequency electroacupuncture exerts antinociceptive effects through activation of POMC neural circuit induced endorphinergic input to the periaqueductal gray from the arcuate nucleus.

It has been widely recognized that electroacupuncture (EA) inducing the release of β-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of β-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2Hz EA at the Zusanli (ST36) increased the level of β-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the β-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2Hz EA promoted the neural projection from ARC to PAG compared to 100Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of β-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of β-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of β-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.

Deletion of arrestin-3 does not reduce drug-seeking behavior in a longitudinal paradigm of oral morphine self-administration.

Opioid drugs are potent analgesics that mimic the endogenous opioid peptides, endorphins and enkephalins, by activating the µ-opioid receptor. Opioid use is limited by side effects, including significant risk of opioid use disorder. Improvement of the effect/side effect profile of opioid medications is a key pursuit of opioid research, yet there is no consensus on how to achieve this goal. One hypothesis is that the degree of arrestin-3 recruitment to the µ-opioid receptor impacts therapeutic utility. However, it is not clear whether increased or decreased interaction of the µ-opioid receptor with arrestin-3 would reduce compulsive drug-seeking. We utilized three genotypes of mice with varying abilities to recruit arrestin-3 to the µ-opioid receptor in response to morphine in a novel longitudinal operant self-administration model. We also created a quantitative method to define compulsivity in drug-seeking based on a multi-variate analysis of several operant response variables. We demonstrate that arrestin-3 knockout and wild type mice have highly variable drug-seeking behavior with few genotype differences. In contrast, in mice where the µ-opioid receptor strongly recruits arrestin-3, drug-seeking behavior is much less varied. We found that mice lacking arrestin-3 were more likely to meet the criteria for compulsivity whereas mice with enhanced arrestin-3 recruitment did not develop a compulsive phenotype. These experiments show that a lack of arrestin-3 is not protective against the abuse liability of morphine in an operant self-administration context. Our data also suggest that opioids that engage both G protein and arrestin-3, recapitulating the endogenous signaling pattern, will reduce abuse liability.

Interactions Between Endogenous Opioids and the Immune System.

The endogenous opioid system, which consists of opioid receptors and their ligands, is widely expressed in the nervous system and also found in the immune system. As a part of the body's defense machinery, the immune system is heavily regulated by endogenous opioid peptides. Many types of immune cells, including macrophages, dendritic cells, neutrophils, and lymphocytes are influenced by endogenous opioids, which affect cell activation, differentiation, proliferation, apoptosis, phagocytosis, and cytokine production. Additionally,immune cells also synthesize and secrete endogenous opioid peptides and participate peripheral analgesia. This chapter is structured into two sections. Part one focuses on immunoregulatory functions of central endogenous opioids; and part two describes how opioid peptide-containing immune cells participate in local analgesia.

Effects of hexarelin and isolation stress on the Met-enkephalin system in young lambs

Koziec K., S canes C.G., Z ubel-Łojek J., Gajewska A. 2023. Effects of hexarelin and isolation stress on the Met-enkephalin system in young lambs. Folia Biologica (Kraków) 71: 195-206.Stress stands out as the primary instigator of numerous diseases – ranging from cardiovascular and gastro- intestinal to diabetes and nervous disturbances – in most developed nations. Endogenous opioid peptides (EOP), particularly Met-enkephalin, play a crucial role in mitigating the up-regulation of the hypothalamo- pituitary-adrenal axis during stress responses, consequently reducing the risk of serious diseases. Hexarelin, a synthetic analog of Met-enkephalin, has been predominantly investigated for its impact on growth hormone (GH) release in both human subjects and rodent models. This study was undertaken to evaluate the influence of isolation stress and/or hexarelin administration on various Met-enkephalin-related parameters in a novel animal model – 3-month-old lambs. Four distinct groups were established: a control group, a group intravenously injected with hexarelin, a group subjected to 60 min of isolation stress from the herd, and a group treated with both hexarelin and stress. Blood and hypothalamus samples were collected to analyze cortisol and Met-enkephalin profiles, proenkephalin (PENK) gene expression, Met-enkephalin concentration, in vitro Met-enkephalin secretion, and opioid receptor binding. The findings revealed a significant impact of stress on all assessed parameters. Hexarelin alone led to a decrease in cortisol levels and Met-enkephalin synthesis, release, and receptor binding in the hypothalamus. When administered prior to stress, hexarelin potentiated the responses of opioid parameters to isolation. These results, for the first time, demonstrate that hexarelin interacts with Met-enkephalin, modulating the stress response at both central and peripheral levels in growing lambs. It is suggested that hexarelin plays a crucial role during stress responses; however, further research on its effects should be conducted concurrently with the examination of opioid profiles.

Novel Opioids in the Setting of Acute Postoperative Pain: A Narrative Review.

Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as alternatives that provide potent pain relief while minimizing adverse effects. In this review, we discuss the mechanisms of action, findings from preclinical studies and clinical trials, and potential advantages of several novel opioids. The more established include oliceridine (biased ligand activity to activate analgesia and downregulate opioid-related adverse events), tapentadol (mu-opioid agonist and norepinephrine reuptake inhibitor), and cebranopadol (mu-opioid agonist with nociceptin opioid peptide activity)-all of which have demonstrated success in the clinical setting when compared to traditional opioids. On the other hand, dinalbuphine sebacate (DNS; semi-synthetic mu partial antagonist and kappa agonist), dual enkephalinase inhibitors (STR-324, PL37, and PL265), and endomorphin-1 analog (CYT-1010) have shown good efficacy in preclinical studies with future plans for clinical trials. Rather than relying solely on mu-opioid receptor agonism to relieve pain and risk opioid-related adverse events (ORAEs), novel opioids make use of alternative mechanisms of action to treat pain while maintaining a safer side-effect profile, such as lower incidence of nausea, vomiting, sedation, and respiratory depression as well as reduced abuse potential.

Hemorphins—a Family of Atypical Opioid Peptides

Hemorphins—a Family of Atypical Opioid Peptides

Estradiol and Mu opioid-mediated reward: The role of estrogen receptors in opioid use

Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu within and across individuals. This review focuses on the role of ovarian hormones, and particularly estradiol, on the endogenous mu opioid receptor system. There is an abundance of data indicating that estradiol influences the activity of endogenous mu opioid peptides, the activation of mu opioid receptors, and the internalization and desensitization of mu opioid receptors. These effects have functional consequences on behaviors mediated by endogenous mu opioid receptor activity and on sensitivity to mu opioid agonists and antagonists. Recent behavioral data suggest these consequences extend to mu opioid reward, and preclinical studies report that estradiol decreases self-administration of mu opioid receptor agonists across a range of experimental conditions. Data collected in human laboratory studies suggest that estradiol may have functionally similar effects in clinical populations, and thus estrogen receptors may be a potential target in the development of novel therapeutics. This review summarizes data from cellular assays to clinical trials to explore how estradiol influences mu opioid receptor activity, as well as potential ways in which estrogen receptors may be targeted to address the problems of opioid use.