Cannabinoid-Induced Desensitization of TRPV1 Receptors

描述（由申请人提供）：大麻素包括一类内源性和外源性化合物，在许多伤害性系统中已证明具有镇痛特性。最近的研究发现，内源性大麻素anandamide是CB1/CB2受体和香草样TRPV1受体的激动剂，它可以使离子通道活性增敏和脱敏。大麻素介导TRPV1受体的机制在很大程度上尚未表征，因此研究这一现象很重要。在本课题中，我们将通过药理学、生化和分子技术研究大麻素对TRPV1受体的脱敏作用，弥合基础研究和临床研究之间的差距。我们将描述大麻素治疗后TRPV1脱敏的受体去磷酸化，确定磷酸酶钙调磷酸酶在大麻素信号通路中负责TRPV1脱敏的作用，并研究大麻素在炎症性牙髓坏死患者中降低致敏TRPV1活性的作用。这些研究的结果将提供证据，支持使用大麻素作为局部炎症性疼痛患者的可能治疗方法。

DESCRIPTION (provided by applicant): Cannabinoids encompass a class of endogenous and exogenous compounds that have demonstrated analgesic properties in a number of nociceptive systems. Recent work has identified the endocannabinoid anandamide as an agonist at CB1/CB2 receptors, and at the vanilloid TRPV1 receptor where it can sensitize and desensitize ion channel activity. The mechanism(s) by which cannabinoids mediate TRPV1 receptors have been largely uncharacterized, thus it is important to investigate this phenomenon. In this proposal we will study the desensitization of TRPV1 receptors by cannabinoids through pharmacological, biochemical, and molecular techniques, bridging the gap between basic and clinical research. We will characterize receptor dephosphorylation on TRPV1 desensitization following cannabinoid treatments, determine the role of the phosphatase calcineurin in the cannabinoid signaling pathway responsible for TRPV1 desensitization, and investigate the use of cannabinoids in reducing sensitized TRPV1 activity in patients diagnosed with inflammatory pulpal necrosis. Results from these studies will provide evidence supporting the use of cannabinoids as a possible treatment for patients suffering from local inflammatory pain.