The Role of Astrocyte Neuronal Metabolic Coupling in the Anterior Cingulate Cortex in the Perception and Behavioural Response to Continuous Inflammatory Pain in Mice
Chronic pain is a complex, debilitating, and unfortunately common disease that has been shown to correspond with significant changes in neuronal structure and function in emotion-related brain regions. While mounting evidence indicates that astrocyte-neuronal lactate shuttling (ANLS) is necessary for learning-induced neuroplasticity, the role of this mechanisms in pain-induced neuroplasticity remained unknown. To determine the involvement of ANLS in pain this thesis investigated if astrocyte-neuronal metabolic coupling in the anterior cingulate cortex (ACC) is necessary for the perception and behavioural response to continuous inflammatory pain. To study this, adult male C57BL/6 mice received hind paw injections of formalin or Complete Freund’s Adjuvant to induce continuous or chronic inflammatory pain, respectively. It was found that the expression of MCT4, a lactate transporter located on astrocytes, was significantly elevated in the ACC in both continuous and chronic inflammatory pain states. Accordingly, antisense-oligodeoxynucleotide mediated knockdown of MCT4 in the ACC was able to significantly reduce continuous inflammatory pain, without affecting acute pain or general motor abilities. Administration of lactate into the ACC following MCT4 knockdown was able to rescue continuous pain perception and behaviours. Together these results provide substantial evidence supporting the necessary role of lactate release from astrocytes in the ACC in the perception and behavioural response to continuous inflammatory pain, and identifies ANLS as a potential target for novel chronic pain treatments.