RET Signaling Is Required for Survival and Normal Function of Nonpeptidergic Nociceptors

Abstract

Small unmyelinated sensory neurons classified as nociceptors are divided into two subpopulations based on phenotypic differences, including expression of neurotrophic factor receptors. Approximately half of unmyelinated nociceptors express the NGF receptor TrkA, and half express the GDNF family ligand (GFL) receptor Ret. The function of NGF/TrkA signaling in the TrkA population of nociceptors has been extensively studied, and NGF/TrkA signaling is a well established mediator of pain. The GFLs are analgesic in models of neuropathic pain emphasizing the importance of understanding the physiological function of GFL/Ret signaling in nociceptors. However, perinatal lethality ofRet-null mice has precluded the study of the physiological role of GFL/Ret signaling in the survival, maintenance, and function of nociceptors in viable mice. We deletedRetexclusively in nociceptors by crossing nociceptor-specificNa_v1.8Cre andRetconditional mice to produceRet-Na_v1.8conditional knock-out (CKO) mice. Loss of Ret exclusively in nociceptors results in a reduction in nociceptor number and size, indicating that Ret signaling is important for the survival and trophic support of these cells.Ret-Na_v1.8CKO mice exhibit reduced epidermal innervation but normal central projections. In addition,Ret-Na_v1.8CKO mice have increased sensitivity to cold and increased formalin-induced pain, demonstrating that Ret signaling modulates the function of nociceptorsin vivo. Enhanced inflammation-induced pain may be mediated by decreased prostatic acid phosphatase (PAP), as PAP levels are markedly reduced inRet-Na_v1.8CKO mice. The results of this study identify the physiological role of endogenous Ret signaling in the survival and function of nociceptors.