Mechanisms of Peripheral Analgesia: Group II mGluRs

描述（由申请人提供）：我们的长期目标是阐明可以靶向控制疼痛的伤害感受器上的外周受体。我们专注于代谢型谷氨酸受体（mGluRs），特别是II组mGluRs，因为它们在CNS中产生抑制和长期神经元抑制。如果组I1激活在外周产生相同的抑制性调节，则组II mGluRs对伤害感受器的选择性激活可能提供对伤害性输入的强大且持久的抑制。我们的中心假设是，第二组mGluRs是外周感觉整合的组成部分。具体而言，我们假设，第二组mGluR激活的抗痛觉过敏作用是通过抑制辣椒素（VR 1）和ATP（P2 X3）受体，减少兴奋性谷氨酸诱导的激活和谷氨酸释放初级传入纤维和减少神经源性炎症。我们将在背根神经节（DRG）细胞中共定位VR 1和P2 X3受体与II组mGluRs，证明这些受体群体存在并可在同一DRG细胞内相互作用（具体目标1）。使用体外皮肤-神经制备物的生理学研究和行为研究将证实伤害感受器上存在II组mGluR，并证明它们的激活不影响正常的伤害感受，但减少了由辣椒素、ATP或谷氨酸诱导的伤害感受器敏化和伤害感受行为（具体目的2、3）。后爪中的微透析研究将表明，组II mGluR活化可减少谷氨酸释放（具体目的4）。外周II组mGluR的激活将减少神经源性炎症的体征（具体目的5）。最后，在具体目标6中，我们将展示第一组！mGluR和VR 1受体通过cAMPIPKA途径功能性连接。这些数据表明，抑制性II组mGluRs在炎症性疼痛的调节中起主要作用，因此可能是开发用于疼痛控制的外周作用疗法的靶点。如果我们的假设得到证实，对人类健康有明显的价值。选择性地靶向外周受体群体以产生多种抗痛觉过敏作用对于镇痛化合物是高度期望的。增强外周抑制性II组mGluRs的活性可以提供用于疼痛的非阿片类药物疗法，避免阿片类药物治疗中固有的CNS和PNS副作用。

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.