A medial prefrontal cortex-nucleus acumens corticotropin-releasing factor circuitry for neuropathic pain-increased susceptibility to opioid reward

Yuanzhong Kai,Weiwei Yin,Yu Mao,Zhi Zhang,Wenjuan Tao,Tingting Sun,Shi Chen,Juan Li,Yanhua Li,Wen Xie,Jie Li,Likui Wang

doi:10.1038/s41398-018-0152-4

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.

Highlights

Non-medical abuse of prescription opioids has risen rapidly in recent years[1,2,3,4], and how pain affects the likelihood of prescription opioid abuse has long been a topic of research and clinical interest[5,6,7,8]
The morphine conditioned place preference (CPP) paradigm was used to determine the response to morphine reward, and we compared the rate of CPP induction by morphine conditioning sessions in constriction injury (CCI) and sham mice from 21 days after surgery (Fig. 1b)
Increased medial prefrontal cortex (mPFC) corticotropin-releasing factor (CRF) neuronal activity contributes to morphine rewarding facilitation Given the role of mPFC CRF signaling in drug addiction[24], we wondered whether mPFC CRF neuronal plasticity participates in neuropathic pain-induced hypersensitivity to morphine reward

Summary

Introduction

Non-medical abuse of prescription opioids has risen rapidly in recent years[1,2,3,4], and how pain affects the likelihood of prescription opioid abuse has long been a topic of research and clinical interest[5,6,7,8]. An important link between opioid reward and chronic pain is emotional processing, as drug reward induces a positive euphoric emotion, whereas pain is associated with a negative affective state[9,10,11,12]. Several brain regions, such as the amygdala, thalamus, medial prefrontal cortex (mPFC), and nucleus acumens (NAc), have been implicated in both chronic pain and emotional processing[11,13,14]. Addictive substances can alter synaptic plasticity in both the mPFC and the NAc15–18.

Methods

Results

Conclusion