MECHANISMS OF PERIPHERALLY-MEDIATED NICOTINIC ANALGESIA

提出的研究将测试假设，神经元烟碱受体激动剂产生抗感觉外周部位的行动。这些研究的具体目的是评估神经元烟碱受体激活在完全弗氏佐剂（CFA）和慢性收缩性损伤（CCI）实验性疼痛模型中的抗伤害性作用。此外，分子生物学技术将被用来确定沿起源于三叉神经节的外周感觉神经元过程的神经元烟碱受体的表达和分布。在炎症性和神经性实验性疼痛条件下对神经元烟碱受体表达的影响以及这些改变在多大程度上依赖于神经生长因子也将被评估。因此，目前的研究将检查周围神经元尼古丁受体在尼古丁激动剂引起的抗伤害感受作用中的作用。由于阿片类药物或非甾体类抗炎药（NSAIDS）的不良副作用以及它们对某些类型的神经性疼痛无效，因此开发具有不同机制的镇痛药物非常重要。建立尼古丁镇痛药的外周作用部位具有消除中枢作用尼古丁镇痛药对中枢神经系统潜在副作用的优势。

The proposed studies will test the hypothesis that neuronal nicotinic receptor agonists produce antinociception at peripheral sites of action. The specific aims of these studies will be to assess the antinociceptive effects of neuronal nicotinic receptor activation in the complete Freund's adjuvant (CFA) and chronic constriction injury (CCI) models of experimental pain. In addition, molecular biological techniques will be utilized to determine the expression and distribution of neuronal nicotinic receptors along peripheral sensory neuronal processes originating in the trigeminal ganglion. The effects on neuronal nicotinic receptor expression under conditions of inflammatory and neuropathic experimental pain and the extent to which these alterations are dependent upon nerve growth factor will also be assessed. Thus, the present studies will examine the role that peripheral neuronal nicotinic receptors play in the antinociceptive effects seen due to nicotinic agonists. The development of analgesic drugs with distinct mechanisms than those of opioids or non-steroidal anti inflammatory drugs (NSAIDS) is important due to the undesirable side effects of these drugs and their ineffectiveness in certain types of neuropathic pain. Establishing a peripheral site of action for nicotinic analgesic drugs holds out the advantage of eliminating any potential central nervous system side effects of centrally acting nicotinic analgesics.