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Peripheral pain is enhanced by insulin-like growth factor 1 through a G protein–mediated stimulation of T-type calcium channels

Blocking insulin-like growth factor–induced stimulation of a calcium channel in sensory neurons may be a therapeutic target in pain disorders. Enhancing Pain with a Growth Factor Muscle injury is associated with inflammation and pain and requires muscle growth to restore damaged tissue. The sensation of pain in the periphery is transmitted to the brain through sensory neurons, which are activated by an influx of calcium. Insulin-like growth factor 1 (IGF-1) stimulates muscle growth. Zhang et al. report that IGF-1 increases the sensitivity of sensory neurons to painful stimuli. Mouse sensory neurons had increased activity of a specific type of voltage-gated calcium channel (CaV3.2) when exposed to IGF-1. Although most growth factor signals are relayed through receptor tyrosine kinases, this enhanced channel activity involved IGF-1–mediated signaling through G proteins. Blocking this pathway or the CaV3.2 channel genetically or pharmacologically in sensory neurons prevented increased sensitivity to touch or heat in mice experiencing chronic inflammation. Thus, targeting this pathway may be a therapeutic option for patients suffering from chronic pain. Insulin-like growth factor 1 (IGF-1) is implicated in the nociceptive (pain) sensitivity of primary afferent neurons. We found that the IGF-1 receptor (IGF-1R) functionally stimulated voltage-gated T-type Ca2+ (CaV3) channels in mouse dorsal root ganglia (DRG) neurons through a mechanism dependent on heterotrimeric G protein (heterotrimeric guanine nucleotide–binding protein) signaling. IGF-1 increased T-type channel currents in small-diameter DRG neurons in a manner dependent on IGF-1 concentration and IGF-1R but independent of phosphatidylinositol 3-kinase (PI3K). The intracellular subunit of IGF-1R coimmunoprecipitated with Gαo. Blocking G protein signaling by the intracellular application of guanosine diphosphate (GDP)-β-S or with pertussis toxin abolished the stimulatory effects of IGF-1. Antagonists of protein kinase Cα (PKCα), but not of PKCβ, abolished the IGF-1–induced T-type channel current increase. Application of IGF-1 increased membrane abundance of PKCα, and PKCα inhibition (either pharmacologically or genetically) abolished the increase in T-type channel currents stimulated by IGF-1. IGF-1 increased action potential firing in DRG neurons and increased the sensitivity of mice to both thermal and mechanical stimuli applied to the hindpaw, both of which were attenuated by intraplantar injection of a T-type channel inhibitor. Furthermore, inhibiting IGF-1R signaling or knocking down CaV3.2 or PKCα in DRG neurons abolished the increased mechanical and thermal sensitivity that mice exhibited under conditions modeling chronic hindpaw inflammation. Together, our results showed that IGF-1 enhances T-type channel currents through the activation of IGF-1R that is coupled to a G protein–dependent PKCα pathway, thereby increasing the excitability of DRG neurons and the sensitivity to pain.