Distinct Amygdala Neuronal Populations Control Opioid Use and Withdrawal in Mice

Opioid use disorder (OUD) is a chronic and recurring psychiatric disorder that is associated with high morbidity and mortality. The central nucleus of the amygdala (CeA) undergoes neuroadaptations in both humans with OUD and opioid-dependent rodents. As part of a heterogeneous microcircuit, the CeA integrates internal and external sensory inputs that drive innate and adaptive behaviors. Key CeA neuronal populations, including protein kinase C-δ (PKC-δ), corticotropin-releasing factor (CRF), and somatostatin (SST) neurons, regulate behaviors that are disrupted in addiction, such as pain, stress, reward function, and anxiety/arousal. We hypothesized that these CeA neuronal populations differentially regulate opioid-related behaviors.

We used in situ hybridization to characterize the expression of μ opioid receptor (MOR) (Oprm1), and we used behavioral and molecular approaches to assess the functional role of these CeA neuronal populations in opioid-dependent mice.

We identified a decrease in Oprm1 messenger RNA (mRNA) expression in the CeA in opioid-dependent mice that were undergoing withdrawal compared with nondependent mice. In contrast, the expression of PKC-δ (Prkcd), CRF (Crh), and SST (Sst) mRNA levels remained unchanged. The chemogenetic inhibition of CeA^PKC-δ neurons decreased fentanyl vapor self-administration and alleviated fentanyl withdrawal-induced hyperalgesia. The inhibition of CeA^CRF neurons reduced irritability and somatic withdrawal signs. The activation of CeA^SST neurons reduced somatic withdrawal signs.

These findings suggest that distinct CeA neuronal populations uniquely regulate different aspects of opioid use and withdrawal, highlighting cell type-specific targets for potential therapeutic interventions.