Kappa opioid receptor blockade in the nucleus accumbens shell prevents sex-dependent alcohol deprivation effect induced by inflammatory pain.

ABSTRACT: Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUDs). Indeed, clinical data suggest pain as a risk factor to suffer AUDs, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptor (KOR) activation in mediating these pain-induced effects because KORs play an important role in pain-driven negative affect and AUD. Female and male Sprague-Dawley rats underwent 2 alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant model of inflammatory pain was introduced during abstinence, and alcohol intake before and after alcohol reintroduction was assessed. In addition, we used behavioural approaches to measure stress and memory impairment and biochemical assays to measure KOR expression in abstinence and reintroduction periods. Only female CFA-treated rats increased alcohol intake during the reintroduction period. Concomitantly, this group showed enhanced anxiety-like behaviour and increased KOR expression in the nucleus accumbens shell that was developed during abstinence and remained during the reintroduction period. Finally, KOR antagonist norbinaltorphimine was administered in the nucleus accumbens shell during abstinence to prevent a pain-induced alcohol deprivation effect, a phenomenon observed in CFA-female rats. The administration of norbinaltorphimine effectively blocked a pain-induced alcohol deprivation effect in female rats. Our data evidenced that inflammatory pain constitutes a risk factor to increase alcohol consumption during a reintroduction phase only in female rats by the rise and maintenance of stress probably mediated by KOR signalling in the nucleus accumbens.

Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference.

Learned associations between environmental cues and morphine use play an important role in the maintenance and/or relapse of opioid addiction. Although previous studies suggest that context-dependent morphine treatment alters glutamatergic transmission and synaptic plasticity in the hippocampus, their role in morphine conditioned place preference (CPP) and reinstatement remains unknown. We investigated changes in synaptic plasticity and NMDAR expression in the hippocampus after the expression, extinction, and reinstatement of morphine CPP. Here we report that morphine CPP is associated with increased basal synaptic transmission, impaired hippocampal long-term potentiation (LTP), and increased synaptic expression of the NR1 and NR2b NMDAR subunits. Changes in synaptic plasticity, synaptic NR1 and NR2b expression, and morphine CPP were absent when morphine was not paired with a specific context. Furthermore, hippocampal LTP was impaired and synaptic NR2b expression was increased after extinction of morphine CPP, indicating that these alterations in plasticity may be involved in the mechanisms underlying the learning of drug-environment associations. After extinction of morphine CPP, a priming dose of morphine was sufficient to reinstate morphine CPP and was associated with LTP that was indistinguishable from saline control groups. In contrast, morphine CPP extinguished mice that received a saline priming dose did not show CPP and had disrupted hippocampal LTP. Finally, we found that reinstatement of morphine CPP was prevented by the selective blockade of the NR2b subunit in the hippocampus. Together, these data suggest that alterations in synaptic plasticity and glutamatergic transmission play an important role in the reinstatement of morphine CPP.