Psychophysical and Physiological Evidence for Parallel Afferent Pathways Mediating the Sensation of Itch

Abstract

The neuronal pathways for itch have been characterized mainly based on responses to histamine. Intracutaneous application of histamine produces intense itch and a large area of axon-reflexive vasodilation ("flare") around the application site. Both phenomena are thought to be mediated through neuronal activity in itch-specific, mechanoinsensitive C-fiber afferents (CMi). However, mechanical and electrical stimuli that do not activate CMi fibers can cause the sensation of itch, and itch may occur without flare, suggesting that other neuronal itch pathways exist. Because cutaneous application of spicules from the plant Mucuna pruriens (cowhage) has been anecdotally reported to produce itch without flare, we performed psychophysical experiments to investigate whether the mechanisms underlying cowhage-and histamine-induced itch differ. Although histamine and cowhage produced itch of similar magnitude, the itch to cowhage was not correlated with the itch to histamine; some subjects had intense itch to cowhage and little itch to histamine and visa versa. Laser Doppler measurements of blood flow revealed that histamine led to a large area of vasodilation, whereas cowhage produced vasodilation restricted to the application site. Pretreatment of the skin with an antihistamine blocked the itch produced by histamine but did not prevent cowhage-induced itch. Desensitization of the skin with topical capsaicin abolished cowhage-induced itch but did not significantly alter histamine-induced itch. These findings indicate that cowhage itch is signaled through a population of capsaicin-sensitive afferent nerve fibers that is distinct from CMi fibers mediating histamine-induced itch. Cowhage may be useful to investigate the neural pathway mediating nonhistaminergic itch.

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

“…The existence of multiple subsets of neurons responding to itch-provoking stimuli is supported by recent reports that histamine-and cowhage-induced itch involve different sensory circuits (26)(27)(28)(29). Histamine-induced calcium responses were observed in 23% of IB ϩ and 7% of the IB4 Ϫ neurons (9).…”

Cowhage-Evoked Itch Is Mediated by a Novel Cysteine Protease: A Ligand of Protease-Activated Receptors

“…Shelley and Arthur (1955) suggested that the active component, although not isolated, was a protease, which they named mucunain. Cowhage has been used recently to investigate sensory modalities and distinguish between histamine and nonhistamine pathways in humans and monkeys (Johanek et al, 2005(Johanek et al, , 2007Davidson et al, 2007).…”

“…1a) into the superficial skin produces itching. This itching may be accompanied by localized erythema and edema of a few millimeters but a flare or wheal does not occur (Johanek et al, 2007). The response to the active component is not considered allergic, because pruritus is noted after first exposure.…”

Wound pruritus: pathophysiology and management

“…Johanek et al 31 compared skin reaction to histamine, with skin reaction to cowhage spicules. 5,13 The cowhage spicules produced less vasodilation.…”

“…Additionally, topical capsaicin eliminated cowhage-induced itch but not histamine-induced itch, implicating a separate group of itch-sensitive neurons. 5,13,31 Andrew and Craig 32 used histamine on the lumbosacral spinal cords of 33 anesthetized cats to categorize neurons into functional categories. They were able to demonstrate a functionally unique subset of histamine-selective lamina I SST neurons in the cats, which match the response of human neurons to the itch sensation.…”