Activation of lumbar spinal wide-dynamic range neurons by a sanshool derivative

The enigmatic sensation of tingle involves the activation of primary sensory neurons by hydroxy-alpha-sanshool, a tingly agent in Szechuan peppers, by inhibiting two-pore potassium channels. Central mechanisms mediating tingle sensation are unknown. We investigated whether a stable derivative of sanshool-isobutylalkenyl amide (IBA)-excites wide-dynamic range (WDR) spinal neurons that participate in transmission of chemesthetic information from the skin. In anesthetized rats, the majority of WDR and low-threshold units responded to intradermal injection of IBA in a dose-related manner over a >5-min time course and exhibited tachyphylaxis at higher concentrations (1 and 10%). Almost all WDR and low-threshold units additionally responded to the pungent agents mustard oil (allyl isothiocyanate) and/or capsaicin, prompting reclassification of the low-threshold cells as WDR. The results are discussed in terms of the functional role of WDR neurons in mediating tingle sensation.