Novel anesthetic mechanisms that desensitize nociceptors

疼痛是一个重要的临床问题，任何缓解疼痛的方法都有利于患者和社会。疼痛的感觉通常是由被称为伤害感受器的外周感觉神经元的激活引起的。化学刺激可能使痛觉感受器致敏，导致异常痛觉和/或痛觉过敏，而它们的脱敏将导致痛觉减退或疼痛减轻。辣椒素是辣椒中的刺激性化合物，临床上用于减轻关节炎、口腔面部疼痛甚至慢性疼痛引起的疼痛。促炎介质使伤害感受器致敏的机制是相对已知的。目前尚不清楚的是，辛辣的香草受体激活剂，如辣椒素及其非辛辣的类似物，榄香素，是如何选择性地使哺乳动物三叉神经中的伤害受体脱敏（或麻醉）的，这也是本提案的主要主题。香草受体和电压门控离子通道之间的相互作用导致伤害感受器脱敏尚不清楚。榄香素在不引起兴奋的情况下使伤害感受器去极化的机制也是未知的，这在开发新型麻醉剂中显然是重要的。香草素还能激活大麻素CB1受体，因此，通过香草素和CB1受体的双重激活导致伤害感受器脱敏的内源性途径将通过研究它们对电压门控钠（VGSC）和钾（VGPC）通道的影响来确定。这些实验将确定是否只有具有香草素和CB1受体的神经元会被辣椒素或香草素脱敏，以及调节VGSCs （TTX-s, TTX-r）和VGPCs （IK和IA）的细胞内通路。定量辣椒素和橄榄香素抑制VGSC和VGPCs功效的电生理测量将与VGSC和VGPCs各亚基的单细胞RT-PCR、IB4标记和酶免疫测定相结合。这一信息将导致涉及伤害感受器可逆脱敏的新的麻醉机制。

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.