Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome

Sex differences in the nervous system have gained recent academic interest. While the prominent differences are observed in mood and anxiety disorders, growing number of evidences also suggest sex difference in pain perception. This review focuses on estrogen as the key molecule underlying such difference, because estrogen plays many functions in the nervous system, including modulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3), two important nociceptive receptors. Estrogen was shown in various studies to up-regulate TRPV1 expression through two distinct pathways, resulting in pro-nociceptive effect. However, estrogen alleviated pain in other studies, by down-regulating nerve growth factor (NGF)–activated pathways and TRPV1. Estrogen may also attenuate nociception by inhibiting P2X3 receptors and ATP-signaling. Understanding the mechanism underlying the pro- and anti-nociceptive effect of estrogen might be crucial to understand pathophysiology of the burning mouth syndrome (BMS), a common chronic orofacial pain disorder in menopausal women. The involvement of TRPV1 is strongly suspected because of burning sensation. Reduced estrogen level of the BMS patient might have caused increased activity of P2X3 receptors. Interestingly, the increased expression of TRPV1 and P2X3 in oral mucosa of BMS patients was reported. The combinational impact of differential modulation of TRPV1/P2X3 during menopause might be an important contributing factor of etiology of BMS. Understanding the estrogen-dependent regulation of nociceptive receptors may provide a valuable insight toward the peripheral mechanism of sex-difference in pain perception.