Inner ear AVP-V2R-AQP2 signaling pathway is involved in the induction of motion sickness.

It has been identified that arginine vasopressin (AVP), AVP receptor 2 (V2R) and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R down-regulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training or a V2R antagonist mozavaptan or a PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reduced rotatory stimulus- or ddAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness and thus, mozavaptan targeting AVP V2 receptors in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people travelling or working. In the present study our results showed that activation of the inner ear AVP-V2R-AQP2 signaling pathway was potentially involved in the development of motion sickness and blocking V2R with mozavaptan, therefore we demonstrated a new mechanism to underlie motion sickness and a new candidate drug for preventing motion sickness. The American Society for Pharmacology and Experimental Therapeutics.