The Roles of Periaqueductal Gray and Dorsal Raphe Nucleus Dopaminergic Systems in the Mechanisms of Thermal Hypersensitivity and Depression in Mice

Depression and thermal hypersensitivity share pathogenic features and symptomol-ogy, but their pathophysiologic interactions have not been fully elucidated. Dopaminergic sys-tems in the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus have been implicated in these conditions due to their antinociception and antidepression effects, although their specific roles and underlying mechanisms remain obscure. In this study, chronic unpredict-able mild stress (CMS) was used to induce depression-like behaviors and thermal hypersensitivity in C57BL/6J (wild-type) or dopamine transporter promoter mice to establish a mouse model of pain and depression comorbidity. Microinjections of quinpirole, a dopamine D2 receptor agonist, up-regulated D2 receptor expression in dorsal raphe nucleus and reduced depressive behaviors and thermal hypersensitivity with CMS, while dorsal raphe nucleus injections of JNJ-37822681, an antagonist of D2 receptors, had the reciprocal effect on dopamine D2 receptor expression and behaviors. Moreover, using a chemical genetics approach to activate or inhibit dopaminergic neu-rons in vlPAG ameliorated or exacerbated depression-like behaviors and thermal hypersensitivity, respectively, in dopamine transporter promoter-Cre CMS mice. Collectively these results demon-strated the specific role of vlPAG and dorsal raphe nucleus dopaminergic systems in the regula-tion of pain and depression comorbidity in mice.Perspective: The current study provides insights into the complex mechanisms underlying thermal hypersensitivity induced by depression, and the findings suggest that pharmacological and chemoge-netic modulation of dopaminergic systems in the vlPAG and dorsal raphe nucleus may be a promising therapeutic strategy to simultaneously mitigate pain and depression.& COPY; 2023 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

This study reveals some common features and pathophysiological interactions between depression and thermal hypersensitivity, and suggests that modulation of the dopaminergic systems in the brain may be a promising therapeutic strategy for alleviating both pain and depression.