Mu opioid receptor-positive neurons in the dorsal raphe nucleus are impaired by morphine abstinence
Résumé
Background: Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, we test the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence, using both molecular and behavioral approaches.
Methods: MOR-Cre mice were exposed to chronic morphine then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence (ABS). We studied DRN-MOR neurons of ABS mice using (i) viral translating ribosome affinity for transcriptome profiling, (ii) fiber photometry to measure neuronal activity and (iii) opto-intracranial self-stimulation (oICSS) paradigm applied to DRN-MOR neurons to assess responses related to addiction vulnerability: persistence to respond, motivation to obtain the stimulation, self-stimulation despite punishment and cue-induced reinstatement.
Results: DRN-MOR neurons of ABS animals showed a down-regulation of genes involved in ion conductance and MOR-mediated signaling, as well as altered responding to acute morphine. Opto-ICSS data showed that abstinent animals execute more impulsive-like and persistent responses during acquisition, and score higher for addiction-like criteria.
Conclusion: Our data suggest that protracted abstinence to chronic morphine leads to reduced MOR function in DRN-MOR neurons, and abnormal self-stimulation of these neurons. We propose that DRN-MOR neurons have partially lost their reward-facilitating properties, which in turn may lead to increased propensity to perform addiction-related behaviors.