Novel anesthetic mechanisms that desensitize nociceptors

疼痛是一个主要的临床问题，通过任何方法缓解疼痛对患者和社会都是有益的。 疼痛的感觉通常是由外周感觉神经元（称为伤害感受器）的激活引发的。 化学刺激可使伤害感受器敏感，导致异常性疼痛和/或痛觉过敏，而它们的脱敏将导致痛觉减退或疼痛减轻。 辣椒素的局部应用，辣椒中的辛辣化合物，临床上用于减轻关节炎引起的疼痛，口腔面部疼痛，甚至慢性疼痛。促炎介质可使伤害感受器敏感的机制是相对公知的。 目前尚不清楚的是，辛辣的香草素受体激活剂如辣椒素及其非辛辣类似物奥瓦尼尔如何选择性地使哺乳动物三叉神经元中的伤害感受器脱敏（或麻醉），这也是本提案的主要主题。 香草酸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的脱敏还不清楚。 奥瓦尼在不引起兴奋的情况下抑制伤害感受器的机制也是未知的，这在开发新型麻醉剂中显然是重要的。 Olvanil还激活大麻素CB 1受体，因此将通过研究它们对电压门控钠（VGSC）和钾（VGPC）通道的影响来确定通过香草素和CB 1受体的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CB 1受体的神经元才会被辣椒素或奥瓦尼尔以及调节VGSC（TTX-s，TTX-r）和VGPCs（IK和IA）的细胞内途径脱敏。 将量化辣椒素和奥瓦尼抑制VGSC和VGPCs的功效的电生理学测量与VGSC和VGPCs的各种亚基的单细胞RT-PCR、IB 4标记和酶免疫测定测量组合。 这一信息将导致新的麻醉机制，涉及可逆脱敏的伤害感受器。

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.