Mechanisms of Peripheral Analgesia: Group II mGluRs

周围镇痛机制：II 组 mGluR

• 批准号: 6772750
• 负责人: Susan M Carlton
• 金额: $ 31.43万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772750
• 关键词: afferent nerve; capsaicin; electron microscopy; evoked potentials; glutamate receptor; hyperalgesia; inflammation; laboratory rat; microdialysis; neuropharmacology; neurotrophic factors; pain threshold; peripheral nervous system; receptor binding; receptor expression; sensory mechanism; spinal ganglion

DESCRIPTION (provided by applicant): Our long-term objectives are to elucidate peripheral receptors on nociceptors that can be targeted to control pain. We are focusing on metabotropic glutamate receptors (mGluRs), Group II mGluRs in particular, because they produce inhibition and long term neuronal depression in the CNS. If Group I1activation produces the same inhibitory modulation in the periphery, selective activation of Group II mGluRs on nociceptors may provide powerful and long lasting depression of noxious input. Our central hypothesis is that Group II mGluRs are integral components of peripheral sensory integration. Specifically, we hypothesize that the anti-hyperalgesic effect of Group II mGluR activation is achieved by inhibition of capsaicin (VR1) and ATP (P2X3) receptors and by a reduction in excitatory glutamate-induced activation and glutamate release from primary afferent fibers and a decrease in neurogenic inflammation. We will co-localize VR1 and P2X3 receptors with Group II mGluRs in dorsal root ganglion (DRG) cells, demonstrating that these receptor populations are present and can interact within the same DRG cell (specific aim 1). Physiological studies using an in vitro skin-nerve preparation and behavioral studies will confirm the presence of Group II mGluRs on nociceptors and demonstrate that their activation does not effect normal nociception but reduces nociceptor sensitization and nociceptive behaviors induced by capsaicin, ATP or glutamate (specific aims 2,3). Microdialysis studies in the hindpaw will show that Group II mGluR activation can reduce glutamate release (specific aim 4). Activation of peripheral Group II mGluRs will reduce signs of neurogenic inflammation (specific aim 5). Finally, in Specific aim 6 will we show that Group I! mGluRs and VR1 receptors are functionally linked through a cAMPIPKA pathway. The data suggest that inhibitory Group II mGluRs play a major role in the modulation of inflammatory pain and so are likely targets for the development of peripherally acting therapeutics for pain control. There is obvious value for human health if our hypotheses are borne out. Targeting a peripheral receptor population selectively to produce multiple antihyperalgesic effects is highly desirable for an analgesic compound. Enhancing activity of peripheral inhibitory Group II mGluRs could provide a non-opioid therapy for pain, avoiding CNS and PNS side effects inherent in opioid treatment.

描述(由申请人提供)：我们的长期目标是阐明伤害性感受器上的外周受体，这些受体可以靶向控制疼痛。我们正在关注代谢性谷氨酸受体(MGluRs)，特别是第二类mGluRs，因为它们在中枢神经系统产生抑制和长期的神经元抑制。如果I1组的激活在外周产生相同的抑制性调制，那么II组mGluRs在伤害性感受器上的选择性激活可能会对伤害性输入提供强大而持久的抑制。我们的中心假设是，第二组mGluRs是外周感觉整合的组成部分。具体地说，我们假设激活II组mGluR的抗痛敏作用是通过抑制辣椒素(VR1)和ATP(P2X3)受体、减少兴奋性谷氨酸诱导的激活和初级传入纤维的谷氨酸释放以及神经源性炎症来实现的。我们将VR1和P2X3受体与第二组mGluRs共同定位于背根神经节(DRG)细胞，证明这些受体群体存在，并可以在同一DRG细胞内相互作用(特定目标1)。使用体外皮肤神经制剂的生理学研究和行为学研究将证实伤害性感受器上存在第二组mGluR，并证明它们的激活不会影响正常的伤害性感受，但会减少伤害性感受器的敏化和辣椒素、三磷酸腺苷或谷氨酸诱导的伤害性行为(特定目标2，3)。在后爪进行的微透析研究将显示，第二组mGluR的激活可以减少谷氨酸的释放(特定目标4)。外周II组mGluRs的激活将减少神经源性炎症的迹象(特定目标5)。最后，在特定的目标6中，我们将展示第一组！MGluRs和VR1受体通过cAMPIPKA途径在功能上相连。这些数据表明，抑制II组mGluRs在炎症性疼痛的调节中发挥着重要作用，因此可能是开发外周作用的疼痛控制疗法的靶点。如果我们的假设得到证实，对人类健康有明显的价值。对于止痛化合物来说，选择性地以外周受体群体为靶点以产生多种抗痛觉过敏效果是非常理想的。增强外周抑制II组mGluRs的活性可以为疼痛提供一种非阿片类药物治疗，避免阿片类药物治疗中固有的CNS和PNS副作用。