Type III Neuregulin1 Signaling in Peripheral Sensory Neurons Affects Thermal Pain Sensation and Hyperalgesia

Abstract

Type III Neuregulin1 (Nrg1), a member of the Nrg1 family of signaling proteins, is highly expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with members of the ErbB family of receptor tyrosine kinases (Bao, Wolpowitz et al. 2003; Falls 2003). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors (α7* nAChRs), along sensory axons (Hancock, Canetta et al. 2008). Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hyperalgesia under inflammatory conditions (Caterina, Leffler et al. 2000). Levels of functional TRPV1 can be enhanced by activation of PtdIns3K (Bonnington and McNaughton 2003; Zhang, Huang et al. 2005; Stein, Ufret-Vincenty et al. 2006; Zhu and Oxford 2007), making it a potential target for regulation by Type III Nrg1. I now show that Type III Nrg1 signaling along sensory axons enhances levels of functional α7* nAChRs and TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hyperalgesia. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function