Reversal of pain by group II metabotropic glutamate receptors

描述（由申请人提供）：炎症或损伤可使伤害感受神经元敏感，并且认为由此产生的过度兴奋性介导痛觉增加。虽然疼痛通常会随着时间的推移而消退，但人们对促使G博士回归的机制知之甚少。这种机制的功能障碍可能导致慢性疼痛的持续，而激活可以缓解疼痛。这个建议的中心假设是，外周II组代谢型谷氨酸受体（mGluRs）调节伤害感受器敏化和痛觉过敏的逆转。将结合解剖学、神经生理学和行为学方法对这一假设进行检验。存在II组mGluR的两种亚型，mGluR2和mGluR3。将表征背根神经节（DRG）内每种亚型的特异性表达。然后，我们将使用mGluR2和mGluR3敲除小鼠确定mGluR2或mGluR3是否是从炎性和神经性疼痛正常恢复所必需的。我们建议，第二组mGluRs可以逆转伤害感受器敏化。为了测试这一点，将使用膜片钳技术来测量致敏背根神经节神经元的神经元兴奋性。II组mGluRs的药理学操作后，将重新评估兴奋性。膜兴奋性由通过离子通道的电流通量决定，但尚不清楚II组mGluRs是否调节涉及敏化的电流。将测试两种候选电流，河豚毒素抗性Na+和T型Ca2+电流，以确定其在致敏DRG神经元中被II组mGluR调节的能力。我们推测，第二组mGluRs参与内源性恢复从痛觉过敏。为了验证这一点，我们将确定是否积极的变构调节剂组II mGluRs加速炎症性痛觉过敏的恢复。最后，我们将确定II组mGluRs是否能够使用操作性条件反射范式缓解持续的神经性疼痛。

DESCRIPTION (provided by applicant): Inflammation or injury can sensitize nociceptive neurons and the resulting hyperexcitability is thought to mediate increased pain sensation. Although pain typically resolves with time, the mechanisms that promote the return to Dr. g are poorly understood. Dysfunction of such a mechanism could contribute to the persistence of chronic pain, while activation could provide relief from pain. The central hypothesis of this proposal is that peripheral group II metabotropic glutamate receptors (mGluRs) regulate the reversal of nociceptor sensitization and hyperalgesia. This hypothesis will be tested with a combination of anatomical, neurophysiological, and behavioral methods. Two subtypes of group II mGluRs exist, mGluR2 and mGluR3. The specific expression of each subtype within dorsal root ganglia (DRG) will be characterized. We will then determine whether mGluR2 or mGluR3 is necessary for the normal recovery from inflammatory and neuropathic pain using mGluR2 and mGluR3 knockout mice. We propose that group II mGluRs can reverse nociceptor sensitization. To test this, patch-clamp techniques will be used to measure neuronal excitability in sensitized DRG neurons. After pharmacological manipulation of group II mGluRs excitability will be reassessed. Membrane excitability is determined by current flux through ion channels, but it is not clear whether group II mGluRs regulate currents involved in sensitization. Two candidate currents, the tetrodotoxin- resistant Na+ and T-type Ca2+ current will be tested for their ability to be modulated by group II mGluRs in sensitized DRG neurons. We hypothesize that group II mGluRs are involved in the endogenous recovery from hyperalgesia. To test this, we will determine whether positive allosteric modulators of group II mGluRs accelerate the recovery from inflammatory hyperalgesia. Finally, we will determine whether group II mGluRs are capable of relieving ongoing neuropathic pain using an operant conditioning paradigm.