Neural and molecular investigation into the paraventricular thalamic-nucleus accumbens circuit for pain sensation and non-opioid analgesia

Guangchao Zhang; Mengqiao Cui; Ran Ji; Shiya Zou; Lingzhen Song; Bingqian Fan; Li Yang; Di Wang; Suwan Hu; Xiao Zhang; Tantan Fang; Xiaolu Yu; Jun-Xia Yang; Dipesh Chaudhury; He Liu; Ankang Hu; Hai-Lei Ding; Jun-Li Cao; Hongxing Zhang

doi:10.1016/j.phrs.2023.106776

Neural and molecular investigation into the paraventricular thalamic-nucleus accumbens circuit for pain sensation and non-opioid analgesia

Pharmacol Res. 2023 May:191:106776. doi: 10.1016/j.phrs.2023.106776. Epub 2023 Apr 19.

Authors

Guangchao Zhang¹, Mengqiao Cui², Ran Ji², Shiya Zou², Lingzhen Song², Bingqian Fan², Li Yang², Di Wang², Suwan Hu², Xiao Zhang³, Tantan Fang², Xiaolu Yu², Jun-Xia Yang², Dipesh Chaudhury⁴, He Liu⁵, Ankang Hu⁶, Hai-Lei Ding⁷, Jun-Li Cao⁸, Hongxing Zhang⁹

Affiliations

¹ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Anesthesiology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China.
² Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
³ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Anesthesiology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, China.
⁴ Division of Science, New York University Abu Dhabi (NYUAD), Saadiyat Island, Abu Dhabi 129188, United Arab Emirates.
⁵ Department of Anesthesiology, Huzhou Central Hospital, Huzhou, Zhejiang 313000, China.
⁶ The Animal Facility of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
⁷ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: haileimdar@yahoo.com.
⁸ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Anesthesiology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: caojl0310@aliyun.com.
⁹ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: hongxing.zhang@xzhmu.edu.cn.

PMID: 37084858
DOI: 10.1016/j.phrs.2023.106776

Abstract

The paucity of medications with novel mechanisms for pain treatment combined with the severe adverse effects of opioid analgesics has led to an imperative pursuit of non-opioid analgesia and a better understanding of pain mechanisms. Here, we identify the putative glutamatergic inputs from the paraventricular thalamic nucleus to the nucleus accumbens (PVT^Glut→NAc) as a novel neural circuit for pain sensation and non-opioid analgesia. Our in vivo fiber photometry and in vitro electrophysiology experiments found that PVT^Glut→NAc neuronal activity increased in response to acute thermal/mechanical stimuli and persistent inflammatory pain. Direct optogenetic activation of these neurons in the PVT or their terminals in the NAc induced pain-like behaviors. Conversely, inhibition of PVT^Glut→NAc neurons or their NAc terminals exhibited a potent analgesic effect in both naïve and pathological pain mice, which could not be prevented by pretreatment of naloxone, an opioid receptor antagonist. Anterograde trans-synaptic optogenetic experiments consistently demonstrated that the PVT^Glut→NAc circuit bi-directionally modulates pain behaviors. Furthermore, circuit-specific molecular profiling and pharmacological studies revealed dopamine receptor 3 as a candidate target for pain modulation and non-opioid analgesic development. Taken together, these findings provide a previously unknown neural circuit for pain sensation and non-opioid analgesia and a valuable molecular target for developing future safer medication.

Keywords: Acetamide (PubChem CID:178); CGS21680 (PubChem CID: 3086599); L-371257 (PubChem CID: 6918320); LIT-001 (PubChem CID: 145711713); Luzindole (PubChem CID: 122162); NGB2904 (PubChem CID: 19366304); Non-opioid analgesia; Nucleus accumbens; Pain; Paraventricular thalamic nucleus; Pramipexole (PubChem CID: 119570); SCH58261 (PubChem CID: 176408).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesia*
Analgesics, Non-Narcotic*
Animals
Mice
Midline Thalamic Nuclei
Nucleus Accumbens / physiology
Pain / drug therapy

Substances

Analgesics, Non-Narcotic