The industrial solvent 1,4-Dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1

Background: The synthetic chemical 1,4-dioxane is used as industrial solvent, food and care product additive. 1,4-Dioxane has been noted to influence the nervous system in long-term animal experiments and in humans, but the molecular mechanisms underlying its effects on animals were not previously known.

Results: Here, we report that 1,4-dioxane potentiates the capsaicin-sensitive transient receptor potential (TRP) channel TRPV1, thereby causing hyperalgesia in mouse model. This effect was abolished by CRISPR/Cas9-mediated genetic deletion of TRPV1 in sensory neurons, but enhanced under inflammatory conditions. 1,4-Dioxane lowered the temperature threshold for TRPV1 thermal activation and potentiated the channel sensitivity to agonistic stimuli. 1,3-dioxane and tetrahydrofuran which are structurally related to 1,4-dioxane also potentiated TRPV1 activation. The residue M572 in the S4-S5 linker region of TRPV1 was found to be crucial for direct activation of the channel by 1,4-dioxane and its analogues. A single residue mutation M572V abrogated the 1,4-dioxane-evoked currents while largely preserving the capsaicin responses. Our results further demonstrate that this residue exerts a gating effect through hydrophobic interactions and support the existence of discrete domains for multimodal gating of TRPV1 channel.

Conclusions: Our results suggest TRPV1 is a co-receptor for 1,4-dioxane, and that this accounts for its ability to dysregulate body nociceptive sensation.

Methods
Electrophysiological data were mainly collected from traditional patch-clamp recordings and Ca2+ imaging. All behavioral experiments with mice were conducted in a double-blind manner. Paw-withdrawal latency of thermal or mechanical hyperalgesia was determined by a temperature-controlled Plantar Test Instrument and von Frey apparatus, respectively.