Opioid-reward

Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu-opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR-mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction...

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared to the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared to BALB/cByJ mice...

Understanding the pharmacokinetic profile of an opioid drug is vital to therapeutic success, and mutations in human PK genes can drastically alter therapeutic efficacy of opioids. We observed that at 30 min post-oxycodone administration (1.25 mg/kg, i.p.) BALB/cJ mice showed a higher whole brain concentration of oxycodone, and female specific increase in noroxycodone, and oxymorphone compared to BALB/cByJ. This observation could explain the sex-specific increase in oxycodone state-dependent conditioned place preference in BALB/cJ female mice...

Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects' times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects...

Social motivation and reward are dynamic and flexible, shifting adaptively across contexts to meet changing social demands. This is exceptionally apparent when seasonal contexts are considered in seasonally breeding songbirds as they cycle from periods of sexual motivation and reward during the breeding season to periods of extreme gregariousness outside the breeding season when non-sexual social interactions gain reward value, motivating birds to form flocks. Here we review evidence demonstrating a key integrative role for the medial preoptic area (mPOA) in the seasonally-appropriate adjustment of behaviors, with seasonal changes in dopamine activity in mPOA adjusting social motivation and changes in opioid activity modifying social reward...

Opioid-induced microglia reactivity affects opioid reward and analgesic processes in ways that may contribute to the neurocognitive impairment observed in opioid addicted individuals. Opioids elicit microglia reactivity through the actions of opioid metabolites at TLR4 receptors, that are located primarily on microglia but are also present on astrocytes. Specifically, the M3G metabolite, which has no affinity for opioid receptors, exerts off-target effects on TLR4 receptors that can trigger downstream immunologic consequences...

Concomitant use of tobacco and opioids represents a growing public health concern. In fact, the mortality rate due to smoking-related illness approaches 50% among SUD patients. Cumulative evidence demonstrates that the vulnerability to drugs of abuse is influenced by behavioral, environmental, and genetic factors. This review explores the contribution of genetics and neural mechanisms influencing nicotine and opioid reward, respiration, and antinociception, emphasizing the interaction of cholinergic and opioid receptor systems...

Background and Purpose: This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. Experimental Approach: To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials...

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse...

Plasticity of neurons in the ventral tegmental area (VTA) is critical for establishment of drug dependence. However, the remodeling of the circuits mediating the transition between positive and negative effect remains unclear. Here, we used neuronal activity-dependent labeling technique to characterize and temporarily control the VTA neuronal ensembles recruited by the initial morphine exposure (morphine-positive ensembles, Mor-Ens). Mor-Ens preferentially projected to NAc, and induced dopamine-dependent positive reinforcement...

Naltrexone (NTX) is a well-tolerated drug with a wide safety margin and mechanism of action that affords use across a wide variety of indications in adults and children. By antagonizing the opioid reward system, NTX can modulate behaviors that involve compulsivity or impulsivity, such as substance use, obesity, and eating disorders. Evidence regarding the disposition and efficacy of NTX is mainly derived from adult studies of substance use disorders and considerable variability exists. Developmental changes, plausible disease-specific alterations and genetic polymorphisms in NTX disposition, and pharmacodynamic pathways should be taken into consideration when optimizing the use of NTX in the pediatric population...

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Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0...

Early life surgery produces peripheral nociceptive activation, inflammation, and stress. Early life nociceptive input and inflammation have been shown to produce long-term processing changes that are not restricted to the dermatome of injury. Additionally stress has shown long-term effects on anxiety, depression, learning, and maladaptive behaviors including substance abuse disorder and we hypothesized that early life surgery would have long-term effects on theses complex behaviors in later life. In this study surgery in the rat hindpaw was performed to determine if there are long-term effects on anxiety, depression, audiovisual attention, and opioid reward behaviors...

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry...

Opioid analgesics remain a gold standard for the treatment of moderate to severe pain. However, their clinical utility is seriously limited by a range of adverse effects. Among them, their high-addictive potential appears as very important, especially in the context of the opioid epidemic. Therefore, the development of safer opioid analgesics with low abuse potential appears as a challenging problem for opioid research. Among the last few decades, different approaches to the discovery of novel opioid drugs have been assessed...

Opioid use disorder (OUD) rarely presents as a unitary psychiatric condition, and the comorbid symptoms likely depend upon the diverse risk factors and mechanisms by which OUD can arise. These factors are heterogeneous and include genetic predisposition, exposure to prescription opioids, and environmental risks. Crucially, one key environmental risk factor for OUD is early life adversity (ELA). OUD and other substance use disorders are widely considered to derive in part from abnormal reward circuit function, which is likely also implicated in comorbid mental illnesses such as depression, bipolar disorder, and schizophrenia...

BACKGROUND: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP)...

Purpose of review: This review aims to discuss sex differences observed in preclinical rodent models of opioid reward. Recent findings: Utilizing a variety of methodological approaches and drug regimens, no clear consensus has emerged regarding the effects of opiates between males and females. This is quite dissimilar to work examining psychostimulants, where female animals reliably exhibit stronger behavioral responses. Summary: With opioid research quickly expanding to determine the neural underpinnings of opioid addiction, further research is essential to determine the conditions wherein sex differences may occur and how they may relate to the human condition...

Pain is a complex experience with far-reaching organismal influences ranging from biological factors to those that are psychological and social. Such influences can serve as pain-related risk factors that represent susceptibilities to opioid use disorder. This review evaluates various pain-related risk factors to form a consensus on those that facilitate opioid abuse. Epidemiological findings represent a high degree of co-occurrence between chronic pain and opioid use disorder that is, in part, driven by an increase in the availability of opioid analgesics and the diversion of their use in a non-medical context...