Functional and Molecular Characterization of Mechanoinsensitive “Silent” Nociceptors

Abstract

Mechanical and thermal hyperalgesia (pain hypersensitivity) are cardinal signs of inflammation. Although the mechanism underlying thermal hyperalgesia is well understood, the cellular and molecular basis of mechanical hyperalgesia is poorly described. Here, we have identified a subset of peptidergic C-fiber nociceptors that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli when exposed to the inflammatory mediator nerve growth factor (NGF). Strikingly, NGF did not affect mechanosensitivity of other nociceptors. We show that these mechanoinsensitive "silent" nociceptors are characterized by the expression of the nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) and that the mechanically gated ion channel PIEZO2 mediates NGF-induced mechanosensitivity in these neurons. Retrograde tracing revealed that CHRNA3 nociceptors account for ∼50% of all peptidergic nociceptive afferents innervating visceral organs and deep somatic tissues. Hence, our data suggest that NGF-induced "un-silencing" of CHRNA3 nociceptors significantly contributes to the development of mechanical hyperalgesia during inflammation.

The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli

“…In agreement with Prato and colleagues 21 , we provide evidence that silent nociceptors are present in deep tissues. In our model of CIBP they are activated to potently increase nociceptive input to the CNS.…”

“…NGF-mediated sensitization is thought to occur via Piezo2 channels 21 . We observed the 'un-silencing' of dormant nociceptors in CIBP.…”

“…This venom peptide potently inhibits cationic mechanosensitive channels, including Trpc1, Trpc6 and Piezo2 22,23 . Previously, GsMTx4 effectively blocked Piezo2 currents in vitro, resulting in the 're-silencing' of silent nociceptors previously unmasked by NGF 21 . Here, we show that the toxin has a similar effect in vivo: GsMTx4 (10 µg in 50 µl saline) delivered to cancer rats significantly reduced the number of responding cells to knee…”

Ameliorating effects of optimized gastric electrical stimulation and mechanisms involving nerve growth factor and opioids in a rodent model of gastric hypersensitivity

“…In this study, we focused on two mechanisms, nerve growth factor (NGF) and opioids. Extensive evidence suggests that NGF is an important pain mediator . NGF was reported to play an important role in visceral hypersensitivity in both patients with irritable bowel syndrome (IBS) and rodent model of IBS .…”

“…Extensive evidence suggests that NGF is an important pain mediator. [41][42][43][44] NGF was reported to play an important role in visceral hypersensitivity in both patients with irritable bowel syndrome (IBS) and rodent model of IBS. [45][46][47][48] NGF was also reported to be associated with gastric hypersensitivity in rats treated for colon inflammation.…”