The tao of IGF-1: insulin-like growth factor receptor activation increases pain by enhancing T-type calcium channel activity

Abstract

T-type calcium channels are important players in the transmission of pain signals in the primary afferent pathway. Indeed, inhibiting or depleting T-type calcium channels in dorsal root ganglion (DRG) neurons mediates analgesia. Conversely, nerve injury or peripheral inflammation have been shown to induce T-type calcium channel activity in DRG neurons, and this in turn has been linked to the development of chronic pain states. The mechanisms that underlie this enhancement of T-type channels remain incompletely understood and may include changes in channel stability in the plasma membrane or alterations in channel function. In this issue of Science Signaling, Zhang and colleagues identify a cell signaling pathway that potently regulates T-type calcium channel activity in afferent neurons and link this process to pain hypersensitivity. Specifically, they show that insulin-like growth factor-1 receptors in DRG neurons mediate a protein kinase C α (PKCα)-dependent enhancement of T-type calcium currents and that interfering with this pathway reduces both mechanical and thermal pain hypersensitivity in rodents. Targeting this process offers a new avenue for developing pain therapeutics.