Molecular and cellular influences of permethrin on mammalian nociceptors at physiological temperatures

- Permethrin interacted differently with skin, muscle and vascular nociceptors.
- Permethrin altered the voltage dependent activation and deactivation of Nav1.8.
- Permethrin activated and increased the excitability of muscle nociceptors only.
- Permethrin had no influence on Kv7 amplitude or voltage dependence.
- Increasing the temperature to 35 °C reduced but did not eliminate permethrin effects.

The influence of pyrethroid insecticides is thought to be abrogated at mammalian physiological temperatures. Yet there are many reports of transient pain and paresthesia following accidental exposures. Using whole cell patch clamp techniques, we examined the interaction of the pyrethroid insecticide permethrin on skin, muscle and putative vascular nociceptors of the rat DRG (dorsal root ganglion). Following permethrin (10 μM) application, action potential (AP) duration was increased in all nociceptor populations, but only muscle nociceptors developed spontaneous activity or increased excitability (tests at 21 °C). TTX (tetrodotoxin) did not prevent the development of spontaneous activity or reduce excitability. We examined the influence of permethrin on TTX resistant channel proteins that control excitability and spontaneous activity (Nav1.8, voltage-gated sodium channel 1.8; Kv7, voltage gated potassium channel 7). In all nociceptor populations, permethrin increased the tau of deactivation (taudeact), in a voltage dependent manner, and hyperpolarized the V1/2 for activation over 10 mV. There were no permethrin dependent influences on Kv7, or on the voltage dependence of inactivation of Nav1.8. The influence of permethrin on AP duration, after hyperpolarization, spontaneous activity, half-activation potential (V1/2) and taudeact were reduced, but not fully reversed, when tests were conducted at 35 °C. In conclusion, permethrin greatly modifies the voltage dependent activation and deactivation of Nav1.8 expressed in skin, muscle and vascular nociceptors. These influences remain significant at 35 °C. One population of muscle nociceptors exhibited a unique vulnerability to the acute administration of permethrin manifested as increased excitability and spontaneous activity.