Title

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

RIS ID

60992

Publication Details

Linley, J. E., Ooi, L., Pettinger, L., Kirton, H., Boyle, J. P., Peers, C. & Gamper, N. (2012). Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons. Proceedings of the National Academy of Sciences of USA, 109 (N/A), E1578-E1586.

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 Gi/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 Ca2+ 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 Ca2+ 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.

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Link to publisher version (DOI)

http://dx.doi.org/10.1073/pnas.1201544109