Cellular Mechanisms Underlying Central Sensitization in a Mouse Model of Chronic Muscle Pain

Chronic pain disorders are often associated with psychiatric symptoms. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during the development of central pain. Although the exact cause for this process remains unknown, prior adverse injuries are precipitating factors and thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent pain chronification remains unknown. Here, we investigated cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or selective inactivation of somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented pain chronification. Further, electrophysiological recording revealed that CeA-SST neurons received increased excitatory transmission and showed enhanced excitability in chronic pain states. In line with the possible role of CeA-SST neurons in central sensitization, chemogenetic inactivation of CeA-SST neurons or pharmacological suppression of nociceptive afferents from the brainstem to CeA-SST neurons by pregabalin after the development of chronic muscle pain alleviated pain and negative emotions.