Differential modulation of voltage-gated sodium channels by nervegrowth factor in three major subsets of TrkA-expressingnociceptors

摘要

Nerve growth factor is an inflammatory mediator that induces long-lastinghyperalgesia, which can partially be attributed to nerve growth factor-inducedsensitization of primary afferent nociceptors. It was shown that nerve growthfactor increases the excitability of polymodal C-fibre nociceptors by modulatingtetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium channels,but hitherto only little is known about the effects of nerve growth factor onsodium currents in other nociceptor subtypes that express the nerve growthfactor receptor TrkA. We previously characterized two reporter mouse lines thatallow the unequivocal identification of two important subclasses ofTrkA-expressing nociceptors – i.e. neuropeptide Y receptor type 2(NPY2R ) Aδ-fibre nociceptors that mediate pinprick pain andnicotinic acetylcholine receptor alpha-3 subunit (CHRNA3 ) silentnociceptors, which are the most abundant TrkA nociceptors invisceral organs and deep somatic tissues. Here, we utilized these mouse lines toinvestigate the expression patterns and the possible nerve growthfactor-dependent modulation of sodium channels in these neurons using whole-cellpatch-clamp recordings and quantitative real-time polymerase chain reaction. Wedemonstrate that NPY2R nociceptors, CHRNA3 ‘silent’nociceptors and polymodal C-fibre nociceptors express different combinations ofsodium channel α- and β-subunits and accordingly exhibit functionally differentsodium currents. Moreover, we demonstrate that nerve growth factor producesrobust hyperpolarizing shifts in the half-activation voltage oftetrodotoxin-resistant currents in NPY2R nociceptors and polymodalC-fibre nociceptors and also shifts the half-activation oftetrodotoxin-sensitive currents in polymodal C-fibre nociceptors. In silentnociceptors, however, nerve growth factor solely increases the current densityof the tetrodotoxin-resistant current but does not alter other sodium channelproperties. Considering the different peripheral target tissues and thepreviously reported roles in different forms of pain of the nociceptorsubpopulations that were examined here, our results suggest that nerve growthfactor differentially contributes to the development visceral and cutaneous painhypersensitivity and highlights the importance of developing differenttherapeutic strategies for different forms of pain.