Novel anesthetic mechanisms that desensitize nociceptors

疼痛是一个重大的临床问题，任何方法缓解疼痛对患者和社会都是有益的。痛感通常由被称为痛觉感受器的外周感觉神经元的激活而开始。化学刺激可以使伤害性感受器变得敏感，导致痛觉过敏和/或痛觉过敏，而化学刺激的减敏则会导致痛觉减退或疼痛减轻。辣椒素是辣椒中的一种辛辣化合物，临床上用于减轻关节炎、口腔面部疼痛，甚至慢性疼痛。促炎介质可以敏化伤害性感受器的机制是相对众所周知的。目前尚不清楚的是，辣椒素及其非刺激性类似物奥凡尼等辛辣的香草素受体激动剂如何选择性地脱敏(或麻醉)哺乳动物三叉神经细胞中的伤害性感受器，这也是这项提议的主要主题。香草素受体和导致伤害性感受器脱敏的电压门控离子通道之间的相互作用尚不清楚。奥伐尼能在不引起兴奋的情况下使伤害性感受器去极化的机制也是未知的，显然对开发新型麻醉药很重要。Olvanil还激活大麻素CB1受体，因此，通过研究它们对电压门控钠(VGSC)和钾(VGPC)通道的影响，将确定通过香草素和CB1受体双重激活导致伤害性感受器脱敏的内源性途径。这些实验将确定是否只有具有香草素和/或CB1受体的神经元才会被辣椒素或奥香尼脱敏，以及调节VGSC的细胞内通路(TTX-S，TTX-r)和VGPC(Ik和IA)。量化辣椒素和奥伐尼抑制VGSC和VGPC有效性的电生理测量将与VGSC和VGPC不同亚基的单细胞RT-PCR、IB4标记和酶免疫分析测量相结合。这些信息将导致新的麻醉机制，包括可逆的伤害性感受器脱敏。

Pain is a major clinical problem and its alleviation by any method is beneficial to patients and society. The sensation of pain is usually initiated by the activation of peripheral sensory neurons, called nociceptors. Chemical stimuli may sensitize nociceptors resulting in allodynia and/or hyperalgesia whereas their desensitization will result in hypoalgesia or a diminution of pain. Topical applications of capsaicin, the pungent compound in hot pepper, is used clinically to reduce pain arising from arthritis, oral facial pain, and even chronic pain. The mechanism by which pro-inflammatory mediators can sensitize nociceptors is relatively well known. What is not known, and which is the primary topic of this proposal, is how pungent vanilloid receptor activators like capsaicin and its non-pungent analogue, olvanil, can selectively desensitize (or anesthetize) nociceptors in mammalian trigeminal neurons. The interactions between vanilloid receptors and voltage-gated ion channels that cause desensitization in nociceptors are not understood. The mechanisms by which olvanil can depolarize nociceptors without causing excitation is also unknown and is obviously important in developing novel types of anesthetics. Olvanil also activates cannabinoid CB1 receptors, so the endogenous pathways that lead nociceptor desensitization via the dual activation of vanilloid and CB1 receptors will be determined by investigating their effects on voltage-gated sodium (VGSC) and potassium (VGPC) channels. These experiments will determine whether only neurons having vanilloid and or CB1 receptors will be desensitized by capsaicin or olvanil and the intracellular pathways that modulate VGSCs (TTX-s, TTX-r) and VGPCs (IK and IA). Electrophysiological measurements quantifying the efficacy of capsaicin and olvanil to inhibit VGSC and VGPCs will be combined with single cell RT-PCR of the various subunits of VGSC and VGPCs, with IB4 labeling, and with enzyme immunoassay measurements. This information will lead to novel anesthetic mechanisms that involve the reversible desensitization of nociceptors.