The Role of Cholecystokinin Expressing Neurons in Socially Enhanced Pain

Abstract

Mice that interact with social partners expressing pain behaviors, such as paw licking and guarding, exhibit more pain behavior than mice interacting with social partners exhibiting no pain. When mice are pre-treated with proglumide, an antagonist of cholecystokinin receptors, the elevated pain behavior after interaction with a partner in pain is decreased, indicating involvement of cholecystokinin expressing neurons. The purpose of this study was to uncover the functional role of cholecystokinin expressing neurons in elevated pain responses of mice that interact with social partners expressing pain behaviors. We used immunohistochemistry for c-fos, an early immediate gene that indicates neural activity, to compare activation during behavior between groups, and we used chemogenetics in a CCK-Cre mouse line to explore the necessity of cholecystokinin expressing neurons in socially enhanced pain. We found that c-fos is more highly expressed in the prefrontal cortex and dorsal region of the periaqueductal grey in mice that interaction with partners in pain compared to saline, and that proglumide lowers c-fos expression. Additionally, we show that silencing CCK-expressing neurons during social interaction lowers pain behavior. Our data indicate involvement of prefrontal and midbrain regions in the social enhancement of pain and lend evidence toward the need for cholecystokinin neuronal activity in the social enhancement of pain. Our work aims to build a better understanding neural circuitry underlying social aspects of the biopsychosocial model of pain. Grant support from Canadian Foundation for Innovation 36548 NSERC RGPIN-2016-06284 Ontario Ministry of Innovation ER16-12-060.