A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats

Abstract

Szechuan peppers contain hydroxy-α-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-α-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal.

Hairy Sensation

“…Singlefiber recordings have shown that, among identified cutaneous afferents, D-hair receptors are very strongly activated by hydroxy-␣-sanshool (42). However, this substance activates C-fiber nociceptors directly as well as RAMs; therefore, the behavioral effects of this substance will be the result of the ensemble activation of both mechanoreceptors and C fibers (32). Selective ways of activating Dhair receptors could be useful tools in the future to probe their precise functional role in sensation from the hairy skin.…”

Food vibrations: Asian spice sets lips trembling

“…It is known from the unique somatosensory sensations of tingling and numbing it induces [5,6]. Previous neurophysiological studies using animal models (mice and rats) have demonstrated that the bioactive component of Szechuan pepper, hydroxyl-a-sanshool (hereafter sanshool), induces bursts of neuronal firing in specific cutaneous afferents through chemical events within the receptor membrane [7][8][9][10]. However, these studies focused on molecular receptor mechanisms and did not directly assess how chemical receptor events could relate to the tingling somatosensory experience.…”

Thermosensitive Transient Receptor Potential (TRP) Channel Agonists and Their Role in Mechanical, Thermal and Nociceptive Sensations as Assessed Using Animal Models

“…Capsaicin, piperine, and zingerone all elicited irritant sensations of burning quality when applied to the lingual surface in humans (Green, 1993; Dessirier et al, 1999). Intraplantar administration of capsaicin evoked hindpaw licking and biting in rats and mice (Klein et al, 2011; Sakurada et al, 1992). Capsaicin, olvanil and piperine all evoked ocular wiping after corneal exposure in mice (Ursu et al, 2010; Karai et al, 2004).…”