期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 24, 页码 E1578-E1586出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201544109
关键词
G protein coupled receptors; inflammatory pain; intracellular signaling; KCNQ; M current
资金
- Wellcome Trust [080593/Z06/Z, 080833/Z/06/Z]
- Medical Research Council [G0700966, G1002183]
- Wellcome Trust [080833/Z/06/Z] Funding Source: Wellcome Trust
- Medical Research Council [G1002183, G0700966] Funding Source: researchfish
- MRC [G1002183, G0700966] Funding Source: UKRI
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 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 Ca(2+)d 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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