A medial prefrontal cortex-nucleus acumens corticotropin-rele

AAV-hM3D(Gq) and AAV- hM4D(Gi) were used for chemogenetic manipulations to excite or inhibit mPFC CRF neurons. AAV- hChR2 (H134R) and AAV-eNpHR3.0 were used for optogenetic manipulations to activate or inhibit the mPFC→NAc pathway. (All viruses were packaged by BrainVTA)

The viruses used in this article from BrainVTA are in the table below

Optogenetic	PT-0002 rAAV-Ef1α-DIO-hChR2 (H134R)-mCherry-WPRE-pA PT-0003 rAAV-Ef1α-DIO-eNpHR3.0-EYFP-WPRE-pA
Chemogenetics	PT-0042 rAAV-Ef1α- DIO-hM3D(Gq)-mCherry-WPRE-pA PT-0043 rAAV-Ef1α-DIO- hM4D(Gi)-mCherry-WPRE-pA
Control	PT-0013 rAAV-Ef1α-DIO-mCherry-WPRE-pA PT-0012 rAAV-DIO-EYFP-WPRE-pA

Yuanzhong Kai, Yanhua Li, Tingting Sun, WeiweiYin,YuMao, JieLi, Wen Xie, Shi Chen, LikuiWang, JuanLi, Zhi Zhang and Wenjuan Tao
Pub Date: 2018-05-21, DOI: 10.1038/s41398-018-0152-4, Email: sales@brainvta.com
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.

Figure. 1 Neuropathic pain increases mPFC CRF neuronal activity, contributing to morphine reward facilitation.

To test the hypothesis that the CRF/CRFR system may bridge the mPFC-NAc functional circuit in chronic pain-promoted susceptibility of opioid reward, the authors investigated the CRFergic mPFC-NAc circuitry and molecular mechanisms underlying opioid reward facilitation under chronic neuropathic pain conditions in mice. The results 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.

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