Cannabinoid-Induced Desensitization of TRPV1 Receptors

描述(申请人提供)：大麻素包括一类内源性和外源性化合物，在许多伤害感受系统中显示出止痛特性。最近的工作发现内源性大麻酰胺是CB1/CB2受体的激动剂，也是香草素TRPV1受体的激动剂，在那里它可以敏化和脱敏离子通道的活动。大麻素介导TRPV1受体的机制(S)在很大程度上还不清楚，因此研究这一现象很重要。在这项建议中，我们将通过药理学、生化和分子技术来研究大麻类药物对TRPV1受体的脱敏作用，从而弥合基础研究和临床研究之间的差距。我们将对大麻素治疗后TRPV1脱敏的受体去磷酸化进行表征，确定磷酸酶钙调神经磷酸酶在导致TRPV1脱敏的大麻素信号通路中的作用，并研究大麻素在炎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，支持使用大麻类药物作为治疗局部炎症性疼痛的可能方法。

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.