Abstract
Recent studies have shown that persistent pain facilitates the response to morphine reward. However, the circuit mechanism underlying this process remains ambiguous. In this study, using chronic constriction injury (CCI) of the sciatic nerve in mice, we found that persistent neuropathic pain reduced the minimum number of morphine conditioning sessions required to induce conditioned place preference (CPP) behavior. This dose of morphine had no effect on the pain threshold. In the medial prefrontal cortex (mPFC), which is involved in both pain and emotion processing, corticotropin-releasing factor (CRF) expressing neuronal activity was increased in CCI mice. Chemogenetic inhibition of mPFC CRF neurons reversed CCI-induced morphine CPP facilitation. Furthermore, the nucleus acumens (NAc) received mPFC CRF functional projections that exerted excitatory effects on NAc neurons. Optogenetic inhibition of mPCF neuronal terminals or local infusion of the CRF receptor 1 (CRFR1) antagonist in the NAc restored the effects of neuropathic pain on morphine-induced CPP behavior, but not in normal mice. On a molecular level, in CCI mice, CRFR1 protein expression was increased in the NAc by a histone dimethyltransferase G9a-mediated epigenetic mechanism. Local G9a knockdown increased the expression of CRFR1 and mimicked CCI-induced hypersensitivity to acquiring morphine CPP. Taken together, these findings demonstrate a previously unknown and specific mPFC CRF engagement of NAc neuronal circuits, the sensitization of which facilitates behavioral responses to morphine reward in neuropathic pain states via CRFR1s.