Connexin-36-positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.

Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance can become negatively reinforcing. Put differently, drug use can transform from a form of pleasure-seeking to a form of relief-seeking. Ventral tegmental area (VTA) GABA neurons form an anatomical point of divergence between two double dissociable pathways that have been shown to be functionally implicated and necessary for these respective motivations to seek drugs. The tegmental pedunculopontine nucleus (TPP) is necessary for opiate conditioned place preferences (CPP) in previously drug-naïve rats and mice, whereas dopaminergic (DA) transmission in the nucleus accumbens (NAc) is necessary for opiate CPP in opiate-dependent and withdrawn (ODW) rats and mice. Here, we show that this switch in functional anatomy is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve-like state wherein the TPP was necessary for opiate CPP and where opiate withdrawal aversions were lost. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36 fl(CFP)/fl(CFP)) exhibited a perpetual drug-naïve-like state wherein opiate CPP was always DA independent, and opiate withdrawal aversions were absent even in mice subjected to an opiate dependence and withdrawal induction protocol. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to an ODW state wherein opiate CPP was DA dependent. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction.

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence.

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, a phenomenon termed incubation of oxycodone craving. We previously demonstrated a causal role of orbitofrontal cortex (OFC) in this incubation. Here, we studied the interaction between glutamatergic projections from OFC and dopamine 1-family receptor (D1R) signaling in dorsal striatum (DS) in this incubation in male rats. We first examined the causal role of D1R signalling in DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos (a neuronal activity marker) to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a pharmacological asymmetrical disconnection procedure to examine the role of the interaction between projections from OFC and D1R signalling in DS in incubated oxycodone seeking. We also tested the effect of unilateral pharmacological inactivation of OFC or unilateral D1R blockade of DS on incubated oxycodone seeking. Finally, we assessed whether contralateral disconnection of OFC→DS projections impacted non-incubated oxycodone seeking on abstinence day 1. We found that D1R blockade in DS decreased incubated oxycodone seeking and OFC→DS projections were activated during incubated oxycodone seeking. Moreover, anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or unilateral D1R blockade in DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving.

Processing abnormalities in monetary outcome evaluations among male individuals with opioid use disorder: evidence from feedback-related negativity.

Background: Numerous studies have highlighted the pivotal role of alterations in the monetary reward system in the development and maintenance of substance use disorder (SUD). Although these alterations have been well documented in various forms of SUD, the electrophysiological mechanisms specific to opioid use disorder (OUD) remain underexplored. Understanding these mechanisms is critical for developing targeted interventions and advancing theories of addiction specific to opioid use.Objectives: To explore abnormalities in monetary reward outcome processing in males with OUD. We hypothesized that control individuals would show higher feedback-related negativity (FRN) to losses, unlike those in the OUD group, where FRN to losses and gains would not differ significantly.Methods: Fifty-seven participants (29 male individuals with OUD [heroin] and 28 male controls) were evaluated. A combination of the monetary incentive delay task (MIDT) and event-related potential (ERP) technology was used to investigate electrophysiological differences in monetary reward feedback processing between the OUD and healthy control groups.Results: We observed a significant interaction between group (control vs. OUD) and monetary outcome (loss vs. gain), indicated by p < .05 and η2p = 0.116. Specifically, control participants showed stronger negative FRN to losses than gains (p < .05), unlike the OUD group (p > .05).Conclusion: This study's FRN data indicate that males with OUD show altered processing of monetary rewards, marked by reduced sensitivity to loss. These findings offer electrophysiological insights into why males with OUD may pursue drugs despite potential economic downsides.

Sleep Health Among Adults in Outpatient Opioid Use Disorder Treatment: A Systematic Review.

The current systematic review synthesized available original research on objective and self-reported sleep health dimensions among adults aged 18 to 50 years in outpatient treatment for opioid use disorder (OUD). A comprehensive search was conducted using multiple electronic databases followed by screening 2,738 records published in English from the inception of each database to September 14, 2021. Quality was assessed with the Mixed Methods Appraisal Tool (version 2001). Fifty nine studies-50 descriptive (21 longitudinal, 18 cross-sectional, and 11 case control), seven interventional (five non-randomized), and two mixed/multi method designs-were included, comprising 18,195 adults with mean ages ranging from 23 to 49 years (mean age = 37.5 [SD = 5.9] years; 54.4% female) with OUD and 604 comparison participants without OUD. Studies were predominantly observational with various designs with self-report and objective measures with participants at various points in treatment. More work is needed to understand the multidimensional depth of sleep health in adults with OUD. Optimizing sleep health in adults with OUD may improve their addiction trajectory and should be a priority in practice and research. [Journal of Psychosocial Nursing and Mental Health Services, 62(1), 19-26.].

The changing opioid crisis: development, challenges and opportunities.

The current opioid epidemic is one of the most severe public health crisis in US history. Responding to it has been difficult due to its rapidly changing nature and the severity of its associated outcomes. This review examines the origin and evolution of the crisis, the pharmacological properties of opioids, the neurobiology of opioid use and opioid use disorder (OUD), medications for opioid use disorder (MOUD), and existing and promising approaches to prevention. The results of the review indicate that the opioid epidemic is a complex, evolving phenomenon that involves neurobiological vulnerabilities and social determinants of health. Successfully addressing the epidemic will require advances in basic science, development of more acceptable and effective treatments, and implementation of public health approaches, including prevention. The advances achieved in addressing the current crisis should also serve to advance the science and treatment of other substance use disorders.

A thalamic input to the nucleus accumbens mediates opiate dependence.

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

A Meta-Analysis of Breastfeeding Effects for Infants With Neonatal Abstinence Syndrome.

BACKGROUND: Neonatal abstinence syndrome (NAS) rates have dramatically increased. Breastfeeding is a nonpharmacological intervention that may be beneficial, reducing NAS symptom severity and thus the need for and duration of pharmacological treatment and length of hospital stay. OBJECTIVES: Conduct meta-analysis to determine whether breastfeeding results in better outcomes for NAS infants. Variables included symptom severity, need for and duration of pharmacological treatment, and length of hospital stay. METHODS: PubMed, Scopus, Embase, and Cochrane Library were searched from 2000 to 2020, and comparative studies examining breastfeeding for NAS infants were extracted. Randomized trials and cohort studies were included. Data were extracted and evaluated with Review Manager Version 5.3. A random-effects model was used to pool discontinuous outcomes using risk ratio and 95% confidence intervals. Continuous outcomes were evaluated by mean differences and 95% confidence intervals. RESULTS: Across 11 studies, 6,375 neonates were included in the meta-analysis. Using a random-effects analysis, breastfeeding reduced initiation of pharmacological treatment, reduced duration of pharmacological treatment, and reduced length of stay. No differences were detected for severity of NAS symptoms. Most studies only reported one to two variables of interest. For most studies, these variables were not the primary study outcomes. All studies were found to be of low risk and good quality based on the Cochrane Risk Assessment Tools. Varying breastfeeding definitions limit generalizability. DISCUSSION: Breastfeeding is associated with decreased initiation and duration of pharmacological treatment and length of stay.

Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence.

We recently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here, we used this model to study the role of the orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed relapse to fentanyl seeking after 13-14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl infusions and palatable food (20 trials/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) decreased relapse to fentanyl seeking. We then determined projection-specific activation of OFC afferents during the relapse test by using Fos plus the retrograde tracer cholera toxin B (injected into the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the OFC in the contralateral, but not ipsilateral, hemisphere decreased relapse. Our results identify Pir-OFC projections as a new motivation-related pathway critical to relapse to opioid seeking after voluntary abstinence.SIGNIFICANCE STATEMENT There are few preclinical studies of fentanyl relapse, and these studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of nondrug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here, we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to opioid seeking after voluntary abstinence.

Increase of Cry 1 expression is a common phenomenon of the disturbed circadian clock in ischemic stroke and opioid addiction.

Increasing evidences suggest the involvement of disrupted circadian clock in various pathologies including stroke and substance abuse. Here we took an attempt to do a comparative study on the regulation of circadian clock gene expression under two pathological circumstances - Opioid addiction and Ischemic stroke in the same cell line model (human neuroblastoma SH-SY5Y cells). To mimic in vivo ischemic stroke condition cells were placed in a hypoxia chamber and incubated for 10 h in balanced salt solution lacking glucose, aerated with an anaerobic gas mixture (95% N2 and 5% C02). For opioid addiction cells were treated with morphine sulphate at 10 µM dose for 48 h. We found that although circadian clock gets disturbed in both states, pattern of alteration of clock gene expressions were different and change was more severe in ischemic stroke than addiction. Interestingly, increase in expression of Cry1 showed as a common factor to both the diseases. This paper also emphasizes the interconnection between the severities of neuronal injury induced by ischemic stroke or opioid abuse to circadian system. Finally, this study will further enrich our knowledge towards the pattern of circadian rhythm disturbances under different pathological states.

Identifying the Neurodevelopmental Differences of Opioid Withdrawal.

Stopping opioid medications can result in a debilitating withdrawal syndrome in chronic users. Opioid withdrawal can occur at all ages, but mechanistic understanding of this condition is predominantly derived from adult studies. Here, we examined whether there are age-dependent differences in the behavioural phenotype and cellular indices of opioid withdrawal. We tested this by assessing the behavioural and cFos response (a surrogate marker for neuronal activation) to morphine withdrawal in C57BL/6J mice across key developmental stages-neonatal, adolescent, and adulthood. Mice in all age groups received escalating doses of morphine (10-50 mg/kg) over 5 days and withdrawal was precipitated by a single injection of the opioid receptor antagonist naloxone (2 mg/kg) two hours after the last morphine dose. In adult and adolescent mice, withdrawal behaviours were robust, with age-related differences in autonomic and somatic signs. In both groups, cFos expression was increased in spinally projecting neurons within the Periaqueductal Grey (PAG), Rostro-ventromedial Medulla (RVM), and Locus Coeruleus. Neonatal animals displayed both a distinct behavioural withdrawal and cFos expression profile. Notably, in young animals cFos expression was increased within the PAG and LC, but decreased in the RVM. In summary, naloxone challenge precipitated robust opioid withdrawal behaviours across all developmental stages with neonatal animals displaying differences in withdrawal behaviours and unique neuronal activation patterns within key brainstem regions.

Association of Testosterone Levels and Steroid 5-Alpha-Reductase 2 Polymorphisms with Opioid Craving.

BACKGROUND/AIMS: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. METHODS: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). RESULTS: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. CONCLUSION: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.

Substance use disorders and chronic itch.

Chronic pruritus is one dermatologic manifestation of an underlying substance use disorder. Recent literature has uncovered similarities between the general neurologic mechanisms of addiction and chronic itch, largely involving activation of the dopaminergic reward circuits within the brain and imbalances between mu and kappa opioid receptor activation. It is likely that the use of specific drugs, like central nervous system stimulants and opioids, results in further activation and imbalances within these pathways, perpetuating both addiction and pruritus simultaneously. Opioid users often present to dermatology clinics with a generalized pruritus, whereas individuals using central nervous system stimulants like cocaine and methylenedioxymethamphetamine (MDMA), as well as legally prescribed drugs like treatments for attention deficit hyperactivity disorder, frequently complain of crawling, delusional infestation-like sensations underneath the skin. Because of these overlapping mechanisms and similar clinical presentations to many other chronically itchy conditions, it is necessary for dermatologists to consider and investigate an underlying substance use disorder to effectively treat these patients.

Impaired working memory performance in opioid-dependent patients is related to reduced insula gray matter volume: a voxel-based morphometric study.

Opioid-dependent patients frequently show deficits in multiple cognitive domains that might impact on their everyday life performance and interfere with therapeutic efforts. To date, the neurobiological underpinnings of those deficits remain to be determined. We investigated working memory performance and gray matter volume (GMV) differences in 17 patients on opioid maintenance treatment (OMT) and 17 healthy individuals using magnetic resonance imaging and voxel-based morphometry. In addition, we explored associations between substance intake, gray matter volume, and working memory task performance. Patients on OMT committed more errors during the working memory task than healthy individuals and showed smaller insula and putamen GMV. The duration of heroin use prior to OMT was associated with working memory performance and insula GMV in patients. Neither the substitution agent (methadone and buprenorphine) nor concurrent abuse of illegal substances during the 3 months prior to the experiment was significantly associated with GMV. Results indicate that impaired working memory performance and structural deficits in the insula of opioid-dependent patients are related to the duration of heroin use. This suggests that early inclusion into OMT or abstinence-oriented therapies that shorten the period of heroin abuse may limit the impairments to GMV and cognitive performance of opioid-dependent individuals.

Chronic Opioid Use and Central Sleep Apnea, Where Are We Now and Where To Go? A State of the Art Review.

Opioids are commonly used for pain management, perioperative procedures, and addiction treatment. There is a current opioid epidemic in North America that is paralleled by a marked increase in related deaths. Since 2000, chronic opioid users have been recognized to have significant central sleep apnea (CSA). After heart failure-related Cheyne-Stokes breathing (CSB), opioid-induced CSA is now the second most commonly seen CSA. It occurs in around 24% of chronic opioid users, typically after opioids have been used for more than 2 months, and usually corresponds in magnitude to opioid dose/plasma concentration. Opioid-induced CSA events often mix with episodes of ataxic breathing. The pathophysiology of opioid-induced CSA is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes. Opioids have a paradoxical effect on different brain regions, which result in irregular respiratory rhythm. Regarding ventilatory chemoreflexes, chronic opioid use induces hypoxia that appears to stimulate an augmented hypoxic ventilatory response (high loop gain) and cause a narrow CO2 reserve, a combination that promotes respiratory instability. To date, no direct evidence has shown any major clinical consequence from CSA in chronic opioid users. A line of evidence suggested increased morbidity and mortality in overall chronic opioid users. CSA in chronic opioid users is likely to be a compensatory mechanism to avoid opioid injury and is potentially beneficial. The current treatments of CSA in chronic opioid users mainly focus on continuous positive airway pressure (CPAP) and adaptive servo-ventilation (ASV) or adding oxygen. ASV is more effective in reducing CSA events than CPAP. However, a recent ASV trial suggested an increased all-cause and cardiovascular mortality with the removal of CSA/CSB in cardiac failure patients. A major reason could be counteracting of a compensatory mechanism. No similar trial has been conducted for chronic opioid-related CSA. Future studies should focus on (1) investigating the phenotypes and genotypes of opioid-induced CSA that may have different clinical outcomes; (2) determining if CSA in chronic opioid users is beneficial or detrimental; and (3) assessing clinical consequences on different treatment options on opioid-induced CSA.

The role of withdrawal in mesocorticolimbic drug cue reactivity in opioid use disorder.

Opioid use disorder (OUD) is characterized by heightened cognitive, physiological, and neural responses to opioid-related cues that are mediated by mesocorticolimbic brain pathways. Craving and withdrawal are key symptoms of addiction that persist during physiological abstinence. The present study evaluated the relationship between the brain response to drug cues in OUD and baseline levels of craving and withdrawal. We used functional magnetic resonance imaging (fMRI) to examine brain responses to opioid-related pictures and control pictures in 29 OUD patients. Baseline measures of drug use severity, opioid craving, and withdrawal symptoms were assessed prior to cue exposure and correlated with subsequent brain responses to drug cues. Mediation analysis was conducted to test the indirect effect of drug use severity on brain cue reactivity through craving and withdrawal symptoms. We found that baseline drug use severity and opioid withdrawal symptoms, but not craving, were positively associated with the neural response to drug cues in the nucleus accumbens, orbitofrontal cortex, and amygdala. Withdrawal, but not craving, mediated the effect of drug use severity on the nucleus accumbens' response to drug cues. We did not find similar effects for the neural responses to stimuli unrelated to drugs. Our findings emphasize the central role of withdrawal symptoms as the mediator between the clinical severity of OUD and the brain correlates of sensitization to opioid-related cues. They suggest that in OUD, baseline withdrawal symptoms signal a high vulnerability to drug cues.

The impact of adherence to a guideline for minimizing opioid use for treatment of pain in an urban emergency department.

INTRODUCTION: The opioid epidemic has significantly evolved over the last three decades. The initiation and continuation of prescription opioids for pain control were one of the primary contributors, across different medical settings. The emergency department (ED) is typically the first place patients go to for management of acute pain, and often where opioid naïve patients first become exposed to opioids. In 2018, the ED of University Hospital located in Newark, NJ implemented a pain guideline to ensure that patients are not unnecessarily exposed to opioids. The goal of our study was to determine whether provider adherence was successful in reducing opioid administration. METHODS: We conducted a retrospective review of pharmacy records of patients treated for pain in the ED within the time frame January 1, 2017 and December 31, 2019. We analyzed the change in our practice by comparing the amount of opioid and non-opioid medications administered and the number of patients administered each type, as well as the change in our utilization of specific medications. The t-test or the χ2 test were used as applicable. RESULTS: There were decreases in the mean number of opioid doses administered in 2017 (1273) compared to 2019 (498; p = 0.027). There was an increase in non-opioid analgesics administered, (mean 2017: 1817, mean 2019: 2432.5, p = 0.018). There was also an increase in the proportion of patients given non-opioid analgesics (mean 2017: 22%, mean 2019: 28%, p < 0.0001). There were increases in administrations of acetaminophen (40% to 52%) and ibuprofen (30% to 35.1%), and decreases in administrations of hydromorphone (2.5% to 0.03%), morphine (11.5% to 5.6%), oxycodone (10.6% to 5.3%), and tramadol (5.7% to 1.9%) (all p < 0.0001). DISCUSSION: A guideline that emphasizes the use of non-opioid analgesics first line treatment for acute pain can be effective for reducing opioid administration in the ED. Through the use of our guideline, we reduced the number of patients who have received opioid analgesics and, at the same time, increased non-opioid analgesic administration. Future studies should explore readmission rates, duration of pain relief in patients managed with non-opioid versus opioid analgesics, and perception of relief through the use of satisfaction scores.

Neural responses to negative events and subsequent persistence behavior differ in individuals recovering from opioid use disorder compared to controls.

Background: Negative emotion is associated with substance craving and use in individuals recovering from substance use disorders, including prescription opioid use disorder (POUD). Decisions to abandon or persist towards a goal after negative emotion-eliciting events, and neural responses that shape such decisions, may be important in maintaining recovery from POUD.Objectives: We examined differences in neural responses to negative events and subsequent persistence decisions in individuals recovering from POUD without a history of a substance use disorder. Methods: 20 individuals with POUD (POUD group: 4 females, abstinent 2-3 weeks after admission to an inpatient treatment facility post-detoxification, no other substance use disorder), and 20 individuals with no substance use history (control group: 6 females) completed a persistence-after-setbacks task during functional magnetic resonance imaging. Participants advanced along a path toward a reward; after encountering each negative event (i.e., progress-erasing setback), participants made decisions to persist or abandon the path. Persistence decision rates were compared between groups and blood-oxygen-level-dependent signal to negative events was analyzed within a striatum region of interest (ROI) as well as whole-brain.Results: The POUD group persisted less (t(38) = 2.293, p = .028, d = .725) and showed lower striatum (left ventral putamen) signal to negative events compared to the control group (p < .05, corrected for striatum ROI).Conclusions: In POUD, neural and behavioral responses to negative events differ from controls. These differences are a target for research to address whether POUD treatment increases persistence and striatum responses to negative events and improves recovery outcomes.

Biomarkers to predict staging and treatment response in opioid dependence: A narrative review.

Opioid use disorder is a devastating disorder with a high burden in terms of overdose mortality, with an urgent need for more personalized prevention or therapeutic interventions. For this purpose, the description and validation of biological measures of staging or treatment response is a highly active research field. We conducted a narrative review on the pathophysiology of opioid use disorder to propose staging of the disease and search for research studies proposing or demonstrating the predictive value of biomarkers. We propose a IV stage description of opioid use disorder, from (I) vulnerability stage to (II) disease progression, (III) constituted opioid dependence and were several type of treatments can be applied, to the reach a (IV) modified health state. We classified biomarkers studies according to the stage of the disorder they were intended to predict, and to the three categories of methods they used: anatomical and functional aspects of the brain, genetic/transcriptomic/epigenetic studies, and lastly biomarkers of systemic modifications associated with opioid use disorder, especially regarding the immune system. Most studies predicting Stage III that we reviewed collected data from small samples sizes and were cross-sectional association studies comparing opioid dependent patients and control groups. Pharmacogenetic biomarkers are proposed to predict treatment response. Future research should now emphasize prospective studies, replication in independent samples, and predictive value calculation of each biomarker. The most promising results are multimodal evaluations to be able to measure the state of the brain reward system in living individuals.

Recent Progress in Opioid Research from an Electrophysiological Perspective.

Electrophysiological approaches provide powerful tools to further our understanding of how different opioids affect signaling through opioid receptors; how opioid receptors modulate circuitry involved in processes such as pain, respiration, addiction, and feeding; and how receptor signaling and circuits are altered by physiologic challenges, such as injury, stress, and chronic opioid treatment. The use of genetic manipulations to alter or remove µ-opioid receptors (MORs) with anatomic and cell type specificity and the ability to activate or inhibit specific circuits through opto- or chemogenetic approaches are being used in combination with electrophysiological, pharmacological, and systems-level physiology experiments to expand our understanding of the beneficial and maladaptive roles of opioids and opioid receptor signaling. New approaches for studying endogenous opioid peptide signaling and release and the dynamics of these systems in response to chronic opioid use, pain, and stress will add another layer to our understanding of the intricacies of opioid modulation of brain circuits. This understanding may lead to new targets or approaches for drug development or treatment regimens that may affect both acute and long-term effects of manipulating the activity of circuits involved in opioid-mediated physiology and behaviors. This review will discuss recent advancements in our understanding of the role of phosphorylation in regulating MOR signaling, as well as our understanding of circuits and signaling pathways mediating physiologic behaviors such as respiratory control, and discuss how electrophysiological tools combined with new technologies have and will continue to advance the field of opioid research. SIGNIFICANCE STATEMENT: This review discusses recent advancements in our understanding of µ-opioid receptor (MOR) function and regulation and the role of electrophysiological approaches combined with new technologies in pushing the field of opioid research forward. This covers regulation of MOR at the receptor level, adaptations induced by chronic opioid treatment, sites of action of MOR modulation of specific brain circuits, and the role of the endogenous opioid system in driving physiology and behavior through modulation of these brain circuits.