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.
Highlights
Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing neurons; these neurons express SP receptors
We focused our study on the small-diameter dorsal root ganglia (DRG) neurons (20–30 μM), which we characterized in detail in our previous study [12]; 60–70% of these neurons express TRPV1 [12]
We show that (i) nociceptive DRG neurons express functional NKR1–3, but NK1 predominates, and neurons expressing NK2 and NK3 most likely express NK1; all three receptor types are capable of potentiating CAP responses. (ii) When overexpressed in CHO cells or sensory neurons, neurokinin receptors (NKR) couple to the Gq/11 cascade, but native NKR in DRG neurons signal predominantly through a Pertussis toxin (PTX)-sensitive protein
Summary
Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons express SP receptors. 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. 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. Common downstream steps of Gq/11 signaling include IP3-mediated release of Ca2+ from intracellular stores and DAG-mediated activation of PKC It was hitherto unknown whether NKR in peripheral sensory neurons couple fully to this signaling cascade, because a lack of coupling between NKR and Ca2+ release in dorsal root ganglia (DRG) neurons has been noted Our data identify the existence of distinct molecular mechanisms for spontaneous pain and hyperalgesia, which can coexist in a single nociceptive neuron
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