The Plant-Derived Alkylamide, Hydroxy-Alpha-Sanshool, Induces Analgesia through Inhibition of Voltage-Gated Sodium Channels

Abstract

Many native cultures use extracts from Xanthozylum plants to topically treat toothache and joint pain. One active component of these extracts is the alkylamide, hydroxy-α-sanshool, which induces tingling and numbing paresthesia when applied to the skin or tongue. To understand the physiological mechanisms underlying paresthesias, we sought to identify the molecular targets of sanshool in the somatosensory system. We first measured the analgesic properties of sanshool using mouse models of somatosensory behavior. Topical application of sanshool on the hind paw of naive mice did not alter their sensitivity to noxious thermal or mechanical stimuli. However, in a model of neurogenic inflammation, sanshool acutely suppressed inflammatory hypersensitivity to mechanical force whereas it did not suppress hypersensitivity to heat. These data suggest that sanshool inhibits activity of a subset of sensory neurons that transduce mechanical, but not thermal, stimuli. In cultured dorsal root ganglion (DRG) neurons from mice, sanshool inhibited action potential (AP) firing in a subset of medium-to-large diameter neurons, which are thought to mediate mechanotransduction. In contrast, sanshool did not inhibit AP firing in small-diameter sensory neurons, which predominantly transduce noxious heat. In addition to size, sensory neurons are distinct in their expression of sensory neuron-specific voltage-gated sodium channels. Thus the differential effect of sanshool on sensory neurons may be due to selective activity of sanshool on different sodium channels. To test this idea, we compared the effects of sanshool on two sodium channel subtypes that are expressed in sensory neurons, Nav1.7 and 1.8. Sanshool reduced the magnitude of Nav1.7 and Nav1.8 currents but caused a hyperpolarizing shift in the steady-state inactivation curve of Nav1.7 only. Thus intrinsic molecular differences between sensory neurons, such as expression of different sodium channel subtypes, may underlie specificity of sanshool action.