RESUMEN
Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LCspinal) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LCspinal neurons or genetic ablation of Panx1 in microglia blunted CSF NE release, reduced LC neuron hyperexcitability, and concomitantly decreased opioid withdrawal behaviours in mice. Using probenecid as an initial lead compound, we designed a compound (EG-2184) with greater potency in blocking Panx1. Treatment with EG-2184 significantly reduced both the physical signs and conditioned place aversion caused by opioid withdrawal in mice, as well as suppressed cue-induced reinstatement of opioid seeking in rats. Together, these findings demonstrate that microglial Panx1 channels modulate LC noradrenergic circuitry during opioid withdrawal and reinstatement. Blocking Panx1 to dampen LC hyperexcitability may therefore provide a therapeutic strategy for alleviating the physical and aversive components of opioid withdrawal.
Asunto(s)
Conexinas , Locus Coeruleus , Proteínas del Tejido Nervioso , Probenecid , Médula Espinal , Síndrome de Abstinencia a Sustancias , Animales , Locus Coeruleus/metabolismo , Locus Coeruleus/efectos de los fármacos , Conexinas/metabolismo , Conexinas/genética , Conexinas/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Ratones , Masculino , Ratas , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Probenecid/farmacología , Morfina/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismo , Analgésicos Opioides/farmacología , Norepinefrina/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismo , Ratones NoqueadosRESUMEN
Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.
RESUMEN
Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.
Asunto(s)
Señales (Psicología) , Comportamiento de Búsqueda de Drogas , Hipocampo , Locus Coeruleus , Autoadministración , Animales , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/metabolismo , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratas , Femenino , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Morfina/farmacología , Morfina/administración & dosificación , Ratas Sprague-Dawley , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Analgésicos Opioides/farmacología , Analgésicos Opioides/administración & dosificación , Trastornos Relacionados con Opioides/fisiopatología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiologíaRESUMEN
The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPCâNAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity's role in reward-seeking behaviors.
Asunto(s)
Dinorfinas , Núcleo Accumbens , Éteres Fosfolípidos , Núcleo Accumbens/fisiología , Hipocampo/fisiología , Recompensa , Neuronas/fisiologíaRESUMEN
Introduction: Epidemiological studies have shown that there is a relation between pain and alcohol use disorder (AUD). Persistent pain is directly correlated with an increment in alcohol consumption and an increased risk of developing an AUD. Greater levels of pain intensity and unpleasantness are associated with higher levels of relapse, an increase in alcohol consumption, rates of hazardous drinking, and delay to seek for treatment. However, this interaction has not been deeply studied in the preclinical setting. Methods: Here, we aim to evaluate how inflammatory pain affects levels of alcohol drinking in male and female rats with a history of alcohol. For that, we used an intermittent access 2-bottle choice paradigm combined with the complete Freund Adjuvant (CFA) model of inflammatory pain. Results: Our results show that CFA-induced inflammatory pain does not alter total intake of 20% alcohol in male or female rats. Interestingly, in males, the presence of CFA-induced inflammatory pain blunts the decrease of alcohol intake when higher concentrations of alcohol are available, whereas it does not have an effect on intake at any concentration in female rats. Conclusion: Altogether, this study provides relevant data and constitutes an important contribution to the study of pain and AUD and it highlights the necessity to design better behavioral paradigms in animal models that are more translational and reflect current epidemiological findings.
RESUMEN
LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
Asunto(s)
Analgésicos Opioides , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Epidemia de OpioidesRESUMEN
In females, the hippocampus, a critical brain region for coordination of learning, memory, and behavior, displays altered physiology and behavioral output across the estrous or menstrual cycle. However, the molecular effectors and cell types underlying these observed cyclic changes have only been partially characterized to date. Recently, profiling of mice null for the AMPA receptor trafficking gene Cnih3 have demonstrated estrous-dependent phenotypes in dorsal hippocampal synaptic plasticity, composition, and learning/memory. We therefore profiled dorsal hippocampal transcriptomes from female mice in each estrous cycle stage, and contrasted it with that of males, across wild-type (WT) and Cnih3 mutants. In wild types, we identified only subtle differences in gene expression between the sexes, while comparing estrous stages to one another revealed up to >1000 differentially expressed genes (DEGs). These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Surprisingly, Cnih3 knock-outs (KOs) showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knock-out drove subtle but extensive expression changes accentuating sex differential expression at diestrus and estrus. Altogether, our profiling highlights cell types and molecular systems potentially impacted by estrous-specific gene expression patterns in the adult dorsal hippocampus, enabling mechanistic hypothesis generation for future studies of sex-differential neuropsychiatric function and dysfunction. Moreover, these findings suggest an unrecognized role of Cnih3 in buffering against transcriptional effects of estrous, providing a candidate molecular mechanism to explain estrous-dependent phenotypes observed with Cnih3 loss.
Asunto(s)
Ciclo Estral , Hipocampo , Animales , Femenino , Masculino , Ratones , Ciclo Estral/genética , Hipocampo/metabolismo , Aprendizaje , Plasticidad Neuronal , TranscriptomaRESUMEN
Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the µ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides ß-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids-primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies.
RESUMEN
ABSTRACT: Many analgesics inadequately address the psychiatric comorbidities of chronic and persistent pain, but there is no standard preclinical model of pain-altered behavior to support the development of new therapies. To explore this conflicting and inconclusive literature, we conducted a focused systematic review and meta-analysis on the effect of complete Freund adjuvant-induced (CFA) rodent hind paw inflammation on multiple classical indicators of exploratory behavior, stress coping, and naturalistic behavior. Our primary objective was to define CFA's effect on assays including, but not limited to, the elevated plus maze and forced swim test. Our secondary objective was to discover how variables such as species and strain may influence outcomes in such assays. We searched Ovid MEDLINE, Embase, Scopus, and Web of Science in April and October 2020 for studies with adult rodents injected with CFA into the hind paw and subsequently tested for aspects of "anxiety-like" or "depressive-like" behaviors. Forty-four studies evaluated performance in the elevated plus or zero maze, open field test, light-dark box, place escape and avoidance paradigm, forced swim test, tail suspension test, sucrose preference test, wheel running, and burrowing assay. Complete Freund adjuvant modestly but significantly decreased exploratory behavior, significantly increased passive stress coping in the tail suspension test but not the forced swim test, and significantly decreased preference for sucrose and naturally rewarding activity. Subgroup analyses revealed significant differences between species and animal sourcing. Based on the evidence provided here, we conclude future studies should focus on CFA's effect on natural rewards and naturalistic behaviors.
Asunto(s)
Actividad Motora , Roedores , Animales , Conducta Animal , Modelos Animales de Enfermedad , Adyuvante de Freund/toxicidad , Dolor/inducido químicamente , Dolor/psicología , Sacarosa/farmacologíaRESUMEN
µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose1-3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.
Asunto(s)
Analgésicos Opioides/farmacología , Núcleo Accumbens/fisiología , Receptores Opioides mu/fisiología , Recompensa , Animales , Encefalinas , Femenino , Masculino , Ratones , Ratones NoqueadosRESUMEN
The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression-major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.
Asunto(s)
Adaptación Fisiológica/fisiología , Anhedonia/fisiología , Neuronas Dopaminérgicas/metabolismo , Dolor/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Condicionamiento Operante/fisiología , Neuronas Dopaminérgicas/química , Femenino , Masculino , Optogenética/métodos , Dolor/genética , Ratas , Ratas Long-Evans , Ratas Transgénicas , Área Tegmental Ventral/químicaRESUMEN
BACKGROUND: CNIH3 is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, the effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. METHODS: We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3-/- C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN (Synaptic Evaluation and Quantification by Imaging of Nanostructure), for analysis of nanoscale synaptic connectivity in the dHPC. RESULTS: Overexpression of Cnih3 in the dHPC improved short-term spatial memory in female mice but not in male mice. Cnih3-/- female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated long-term potentiation maintenance compared with Cnih3+/+ control mice; Cnih3-/- males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3-/- mice. CONCLUSIONS: This study identified a novel effect of sex and estrous on CNIH3's role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function.
Asunto(s)
Caracteres Sexuales , Memoria Espacial , Animales , Femenino , Hipocampo/metabolismo , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal , Receptores AMPA/genética , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Transmisión SinápticaRESUMEN
INTRODUCTION: The periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals. Few studies have reported on the role of CB1 receptors in the PAG during conditions which would prompt the administration of analgesics, namely, during pain states. OBJECTIVES: To examine inflammatory pain-induced changes in CB1 receptor expression and function in the midbrain periaqueductal gray. METHODS: In this study, we used the Complete Freund Adjuvant model to characterize CB1 receptor expression and G-protein coupling during persistent inflammatory pain. RESULTS: Inflammatory pain induced an upregulation in the expression of synaptic CB1 receptors in the PAG. Despite this pain-induced change in CB1 expression, there was no corresponding upregulation of CB1 mRNA after the induction of inflammatory pain, suggesting a pain-induced recruitment of CB1 receptors to the synaptic sites within PAG neurons or increased coupling efficiency between the receptor and effector systems. Inflammatory pain also enhanced ventrolateral PAG CB1 receptor activity, as there was an increase in CP55,940-stimulated G-protein activation compared with pain-naïve control animals. CONCLUSION: These findings complement a growing body of evidence which demonstrate pain-induced changes in brain regions that are responsible for both the analgesic and rewarding properties of analgesic pharmacotherapies. Because much of our understanding of the pharmacology of cannabinoids is based on studies which use largely pain-naïve male animals, this work fills in important gaps in the knowledge base by incorporating pain-induced adaptations and cannabinoid pharmacology in females.
RESUMEN
Across centuries and civilizations opioids have been used to relieve pain. In our modern societies, opioid-based analgesics remain one of the most efficient treatments for acute pain. However, the long-term use of opioids can lead to the development of analgesic tolerance, opioid-induced hyperalgesia, opioid use disorders, and overdose, which can ultimately produce respiratory depressant effects with fatal consequences. In addition to the nociceptive sensory component of pain, negative affective states arising from persistent pain represent a risk factor for developing an opioid use disorder. Several studies have indicated that the increase in prescribed opioid analgesics since the 1990s represents the root of our current opioid epidemic. In this review, we will present our current knowledge on the endogenous opioid system within the pain neuroaxis and the plastic changes occurring in this system that may underlie the occurrence of pain-induced negative affect leading to misuse and abuse of opioid medications. Dissecting the allostatic neuronal changes occurring during pain is the most promising avenue to uncover novel targets for the development of safer pain medications. We will discuss this along with current and potential approaches to treat pain-induced negative affective states that lead to drug misuse. Moreover, this chapter will provide a discussion on potential avenues to reduce the abuse potential of new analgesic drugs and highlight a basis for future research and drug development based on recent advances in this field.
Asunto(s)
Dolor Agudo , Analgésicos Opioides , Manejo del Dolor , Dolor Agudo/tratamiento farmacológico , Afecto , Analgésicos Opioides/efectos adversos , Humanos , Trastornos Relacionados con Opioides/prevención & control , Manejo del Dolor/efectos adversos , Trastornos Relacionados con Sustancias/prevención & controlRESUMEN
ABSTRACT: Pain puts patients at risk for developing psychiatric conditions such as anxiety and depression. Preclinical mouse models of pain-induced affective behavior vary widely in methodology and results, impairing progress towards improved therapeutics. To systematically investigate the effect of long-term inflammatory pain on exploratory behavior and stress coping strategy, we assessed male C57BL/6J mice in the forced swim test (FST), elevated zero maze, and open field test at 4 and 6 weeks postinjection of Complete Freund's Adjuvant, while controlling for testing order and combination. Inflammatory pain did not induce a passive stress coping strategy in the FST and did not reduce exploratory behavior in the elevated zero maze or the open field test. Using systematic correlational analysis and composite behavioral scores, we found no consistent association among measures for mice with or without inflammatory pain. A meta-analysis of similar studies indicated a modest, significant effect of Complete Freund's Adjuvant on exploratory behavior, but not immobility in the FST, and high heterogeneity among effect sizes in all 3 paradigms. Given the urgency for understanding the mechanisms of pain comorbidities and identifying novel therapies, these findings support the reallocation of our limited resources away from such unreliable assays and toward motivated and naturalistic behaviors. Future studies in pain and psychiatric translational research may benefit by considering outcomes beyond binary categorization, quantifying the associations between multiple measured behaviors, and agnostically identifying subtle yet meaningful patterns in behaviors.
Asunto(s)
Conducta Exploratoria , Dolor , Adaptación Psicológica , Animales , Ansiedad , Conducta Animal , Depresión/etiología , Modelos Animales de Enfermedad , Humanos , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Dolor/etiologíaRESUMEN
In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (µOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at µ-δ heteromers compared to the homomeric δOR or µOR and low ß-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting µ-δ heteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.
Asunto(s)
Fentanilo/análogos & derivados , Receptores Opioides delta/agonistas , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Línea Celular , Fentanilo/síntesis química , Fentanilo/farmacología , Humanos , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Ratas Long-Evans , Receptores Opioides delta/metabolismoRESUMEN
The neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-d-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRNA levels of GluN1 and GluN2A subunits in designated brain areas. The expression of CPP or CPA was characterized following intra-VTA ethanol administration and we showed that either reinforcing (CPP) or aversive (CPA) properties are dependent on the dose administered (ranging here from 35 to 300 nmol). Furthermore, the critical contribution of local MORs in the acquisition of CPP was revealed by a selective antagonist, namely ß-Funaltrexamine. Finally, modifications of the expression of NMDA receptor subunits in the Nucleus Accumbens (NAc) and Hippocampus after ethanol-induced CPP were analyzed at the proteomic and transcriptomic levels by western blot and In Situ Hybridation RNAscope techniques, respectively. Results showed that the mRNA levels of GluN2A but not GluN1 in NAc are higher after ethanol CPP. These novel results pave the way for further characterisation of the mechanisms by which ethanol motivational properties are associated with learned environmental cues.
Asunto(s)
Reacción de Prevención/fisiología , Condicionamiento Psicológico/fisiología , Etanol/administración & dosificación , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides mu/fisiología , Área Tegmental Ventral/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Infusiones Intraventriculares , Masculino , Microinyecciones/métodos , Ratas , Ratas Wistar , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Two major questions about addictive behaviors need to be explained by any worthwhile neurobiological theory. First, why do people seek drugs in the first place? Second, why do some people who use drugs seem to eventually become unable to resist drug temptation and so become "addicted"? We will review the theories of addiction that address negative-reinforcement views of drug use (i.e., taking opioids to alleviate distress or withdrawal), positive-reinforcement views (i.e., taking drugs for euphoria), habit views (i.e., growth of automatic drug-use routines), incentive-sensitization views (i.e., growth of excessive "wanting" to take drugs as a result of dopamine-related sensitization), and cognitive-dysfunction views (i.e., impaired prefrontal top-down control), including those involving competing neurobehavioral decision systems (CNDS), and the role of the insula in modulating addictive drug craving. In the special case of opioids, particular attention is paid to whether their analgesic effects overlap with their reinforcing effects and whether the perceived low risk of taking legal medicinal opioids, which are often prescribed by a health professional, could play a role in the decision to use. Specifically, we will address the issue of predisposition or vulnerability to becoming addicted to drugs (i.e., the question of why some people who experiment with drugs develop an addiction, while others do not). Finally, we review attempts to develop novel therapeutic strategies and policy ideas that could help prevent opioid and other substance abuse.
Asunto(s)
Conducta Adictiva/psicología , Epidemia de Opioides , Trastornos Relacionados con Opioides/psicología , Ansia , Toma de Decisiones , HumanosRESUMEN
Pain has a useful protective role; through avoidance learning, it helps to decrease the probability of engaging in tissue-damaging, or otherwise dangerous experiences. In our modern society, the experience of acute post-surgical pain and the development of chronic pain states represent an unnecessary negative outcome. This has become an important health issue as more than 30% of the US population reports experiencing "unnecessary" pain at any given time. Opioid therapies are often efficacious treatments for severe and acute pain; however, in addition to their powerful analgesic properties, opioids produce potent reinforcing properties and their inappropriate use has led to the current opioid overdose epidemic in North America. Dissecting the allostatic changes occurring in nociceptors and neuronal pathways in response to pain are the first and most important steps in understanding the physiologic changes underlying the opioid epidemic. Full characterization of these adaptations will provide novel targets for the development of safer pharmacotherapies. In this review, we highlight the current efforts toward safer opioid treatments and describe our current knowledge of the interaction between pain and opioid systems.
RESUMEN
Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders. VIDEO ABSTRACT.