title: Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons.
abstract: Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G(i/o) proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca(2+) stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca(2+) stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.
authors.affiliation: Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Linley
authors.forename: Lezanne
authors.initials: L
authors.lastname: Ooi
authors.forename: Louisa
authors.initials: L
authors.lastname: Pettinger
authors.forename: Hannah
authors.initials: H
authors.lastname: Kirton
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.forename: Nikita
authors.initials: N
authors.lastname: Gamper
mesh_terms: D000818:Animals; D016466:CHO Cells; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015290:Second Messenger Systems; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide