Astrocyte neuronal metabolic coupling in the anterior cingulate cortex of mice with inflammatory pain.

Chronic pain is a major global concern, with at least 1 in 5 people suffering from chronic pain worldwide. Mounting evidence indicates that neuroplasticity of the anterior cingulate cortex (ACC) is a critical step in the development of chronic pain. Previously, we found that chronic pain and fear learning are both associated with enhanced neuronal excitability and cause similar neuroplasticity-related gene expression changes in the ACC of male mice. However, neuroplasticity, imposes large metabolic demands. In the brain, neurons have the highest energy needs and interact with astrocytes, which extract glucose from blood, mobilize glycogen, and release lactate in response to neuronal activity. Here, we use chronic and continuous inflammatory pain models in female and male mice to investigate the involvement of astrocyte-neuronal lactate shuttling (ANLS) in the ACC of female and male mice experiencing inflammatory pain. We found that ANLS in the mouse ACC promotes the development of chronic inflammatory pain, and expresses sex specific patterns of activation. Specifically, whereas both male and female mice show similar levels of chronic pain hypersensitivity, only male mice show sustained increases in lactate levels. Accordingly, chronic pain alters the expression levels of proteins involved in lactate metabolism and shuttling in a sexually dimorphic manner. We found that disrupting astrocyte-neuronal lactate shuttling in the ACC prior to inflammatory injury prevents the development of pain hypersensitivity in female and male mice, but only reduces temporary pain in male mice. Furthermore, using a transgenic mouse model (itga1-null mice) that displays a naturally occurring form of spontaneous osteoarthritis (OA), a painful inflammatory pain condition, we found that whereas both female and male mice develop OA, only male mice show increases in mechanisms involved in astrocyte-neuronal lactate shuttling. Our findings thus indicate that there are sex differences in astrocyte-neuronal metabolic coupling in the mouse ACC during chronic pain development.