Drug developmental strategies based on functional analysis of pain-regulating molecules in astrocytes under chronic pain

Spinal cord astrocytes are activated in chronic pain models, especially under conditions of prolonged pain. Hence, targeting spinal cord astrocytes for the development of useful analgesics has attracted much attention. In the CNS, connexin43 (Cx43), a membrane protein expressed and functioning exclusively in astrocytes, is well known to be involved in intercellular signaling as a component of gap junction, but also interacts with intracellular molecules via its characteristically long C-terminal region, thereby affecting cellular function. Previously, we found that Cx43 expression was markedly reduced in spinal dorsal horn astrocytes from a mouse model of neuropathic pain. In order to investigate the relationship between reduced Cx43 expression in spinal astrocytes and the onset of pain, we showed that reduced Cx43 expression altered the expression of pain-related molecules such as the glutamate transporter GLT-1 and the pro-inflammatory cytokine interleukin-6 (IL-6). In particular, we focused on the regulation of IL-6 expression by reduced Cx43 expression in both in vivo and in vitro analyses, and found that IL-6 expression is increased through the Akt- glycogen synthase kinase-3β (GSK-3β) signaling system driven by reduced Cx43 expression during neuropathic pain, which in turn triggers pain. These findings suggest that astrocyte Cx43 is involved in pain prolongation by regulating gene expression of nociceptive factors through interactions with intracellular signaling molecules, which is different from its previously known function, and thus raises expectations for its potential as a new drug target for chronic pain.