Targeting the neuropeptide Y system in the locus coeruleus

Neuropeptide Y (NPY), a neurochemical mediator of stress resilience, may possess therapeutic efficacy in stress-induced opioid abuse and relapse. The locus coeruleus (LC)-noradrenergic system is an important target for therapeutic development for opioid abuse, as it modulates arousal and stress and is significantly regulated by opioids. Hyperactivity of the LC-norepinephrine (NE) system during opioid withdrawal contributes to many of the somatic and affective symptoms of opioid withdrawal. Alpha2-adrenergic receptor (AR) agonists, because of their auto-inhibitory function, restrain LC-NE hyperactivity and are FDA-approved to mitigate opioid withdrawal symptoms; however, they carry significant negative side-effects, including hypotension. We investigated adaptations in the anti-stress NPY system in the LC, following chronic morphine exposure and naltrexone-induced withdrawal in male and female rats. NPY exerts an inhibitory influence on the LC-NE system and its dysregulation would contribute to enhanced LC-NE activity. Results showed that there were no baseline differences in NPY levels in the LC across sexes. Chronic morphine significantly decreased NPY levels in both sexes. Naltrexone-induced withdrawal also decreased NPY from baseline in both sexes; however, NPY levels in males were further decreased when compared to morphine-only male counterparts. NPY in naltrexone-only groups was unchanged compared to controls, irrespective of sex. Relative RNA expression analysis in the LC showed that naltrexone-precipitated withdrawal decreased NPY compared to baseline and chronic morphine levels in both sexes. To determine the anatomical basis for functional interactions between NPY and LC neurons, we defined the synaptic relationship between the anti-stress NPY system and the pro-stress corticotropin-releasing factor (CRF) system in the LC that provides an excitatory influence on noradrenergic neurons. Results showed that NPY and CRF were co-localized in the same LC axon terminals, and revealed a complex organization with NPY receptors. Taken together, the results demonstrate that opioid-induced decreases in NPY transmission contribute to dysregulation of LC activity by promoting enhanced neuronal excitation via removal of an endogenous inhibitory drive impacting noradrenergic neurons. Decreasing the NPY inhibitory influence in axon terminals that co-localize excitatory neuromodulators, such as CRF, creates an imbalance in homeostatic regulation of LC neurons, leading to hyper-arousal and increased anxiety. Targeting the NPY system may, therefore, be a novel therapeutic target for stress-induced opioid abuse by restoring homeostasis to a dysregulated noradrenergic system.