Molecular and cellular mechanisms that initiate pain and itch

Abstract

Somatosensory neurons mediate our sense of touch. They are critically involved in transducing pain and itch sensations under physiological and pathological conditions, along with other skin resident cells. Tissue damage and inflammation can produce a localized or systemic sensitization of our senses of pain and itch, which can facilitate our detection of threats in the environment. Although acute pain and itch protect us from further damage, persistent pain and itch are debilitating. Recent exciting discoveries have significantly advanced our knowledge of the roles of membrane-bound G protein-coupled receptors and ion channels in the encoding of information leading to pain and itch sensations. This review focuses on molecular and cellular events that are important in early stages of the biological processing that culminates in our senses of pain and itch.

Eact, a small molecule activator of TMEM16A, activates TRPV1 and elicits pain‐ and itch‐related behaviours

“…Eact elicits both itch-and pain-related behaviours in a TRPV1-dependent manner TMEM16A is activated by increased intracellular free Ca 2+ ([Ca 2+ ] i ) evoked by activation of many GPCRs including the histamine H 1 receptor and endothelin ETA receptor, which are important itch mediators (Cho et al, 2012;Luo et al, 2015;Yang et al, 2008). Furthermore, TMEM16A is also reported to mediate the bradykinin-induced nocifensive response and is required for generating nociceptive behaviours in mouse models of thermal pain (Jin et al, 2013;Liu et al, 2010).…”

Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis

“…Median heat response thresholds did not differ between C-fibers from HbSS-BERK sickle mice (40[38,43]°C) and those from HbAA-BERK control mice (42[40,42]°C; Mann-Whitney U = 37.0, n 1 = 9, n 2 = 11, n.s.). In C-fibers exposed to the entire range of heat stimuli, those from HbSS-BERK mice exhibited higher cumulative responses (118.9±16.2 impulses vs. 65.7±18.2 impulses; t 18 = 2.1, p <.05), but responses to individual temperatures did not differ between the groups ( F 1,18 = 0.5, n.s., Figure 3A).…”

“…Interestingly, the CB2 receptor agonist JWH-133 reduced deep tissue hyperalgesia and attenuated mast cell degranulation [60]. Degranulation of mast cells releases inflammatory mediators that sensitize nociceptors (see reviews [2,3,26,40]).…”

The antimicrobial peptide human beta-defensin 2 promotes itch through Toll-like receptor 4 signaling in mice

“…Previous studies have demonstrated that sensory transient receptor potential cation channel subfamily V member 1 (TRPV1) and subfamily A member 1 (TRPA1) channels are selectively expressed by a subpopulation of primary afferent nociceptors and serve as molecular integrators for numerous endogenous pruritogens released by skin-resident cells to provoke both histaminergic and non-histaminergic itch 7 . Furthermore, the TRPV1-expressing sensory fibers mediate skin inflammation through facilitating the function of dermal immune cells in a mouse model of psoriasis 8 .…”