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

•Female and male mice display comparable behavioral patterns of pain hypersensitivity, and both show increases in glutamatergic receptor expression in the cingulate cortex. Female mice however show glutamatergic changes rapidly upon injury, whereas changes in male mice take 7 days.•Male, but not female mice, show sustained increases in lactate levels in the cingulate cortex, and show sustained enhanced expression of proteins involved in astrocyte-neuronal lactate shuttling.•Targeted disruption of astrocyte-neuronal lactate shuttling in the ACC through antisense-mediated knockdown reduces pain hypersensitivity in a chronic inflammatory pain model in female and male mice.•Targeted disruption of astrocyte-neuronal lactate shuttling in the ACC through antisense-mediated knockdown reduces pain sensation in a temporary inflammatory pain model in male but not female mice.•Using a transgenic mouse model (itga1-null mice) of spontaneous osteoarthritis (OA), we show that astrocyte-neuronal lactate shuttling is sex-dependently enhanced in the cingulate cortex, indicating that astrocyte-neuronal lactate shuttling is involved in a naturally occurring, painful inflammatory pain condition in male, but not female, mice. 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 expr