Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
J Neurosci. 2011 Sep 7;31(36):12727-37. doi: 10.1523/JNEUROSCI.6558-10.2011.
There is pharmacological evidence that group II and III metabotropic glutamate receptors (mGluRs) function as activity-dependent autoreceptors, inhibiting transmission in supraspinal sites. These receptors are expressed by peripheral nociceptors. We investigated whether mGluRs function as activity-dependent autoreceptors inhibiting pain transmission to the rat CNS, particularly transient receptor potential vanilloid 1 (TRPV1)-induced activity. Blocking peripheral mGluR activity by intraplantar injection of antagonists LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] (LY) (20, 100 μm, group II/III), APICA [(RS)-1-amino-5-phosphonoindan-1-carboxylic acid] (100 μm, group II), or UBP1112 (α-methyl-3-methyl-4-phosphonophenylglycine) (30 μm, group III) increased capsaicin (CAP)-induced nociceptive behaviors and nociceptor activity. In contrast, group II agonist APDC [(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate] (0.1 μm) or group III agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP-4) (10 μm) blocked the LY-induced increase. Ca(2+) imaging in dorsal root ganglion (DRG) cells confirmed LY enhanced CAP-induced Ca(2+) mobilization, which was blocked by APDC and l-AP-4. We hypothesized that excess glutamate (GLU) released by high intensity and/or prolonged stimulation endogenously activated group II/III, dampening nociceptor activation. In support of this, intraplantar GLU + LY produced heat hyperalgesia, and exogenous GLU + LY applied to nociceptors produced enhanced nociceptor activity and thermal sensitization. Intraplantar Formalin, known to elevate extracellular GLU, enhanced pain behaviors in the presence of LY. LY alone produced no pain behaviors, no change in nociceptor discharge rate or heat-evoked responses, and no change in cytosolic Ca(2+) in DRG cells, demonstrating a lack of tonic inhibitory control. Group II/III mGluRs maintain an activity-dependent autoinhibition, capable of significantly reducing TRPV1-induced activity. They are endogenously activated after high-frequency and/or prolonged nociceptor stimulation, acting as built-in negative modulators of TRPV1 and nociceptor function, reducing pain transmission to the CNS.
有药理学证据表明，第二组和第三组代谢型谷氨酸受体（mGluR）作为活性依赖性自受体发挥作用，抑制脊髓以上部位的传递。这些受体由周围伤害感受器表达。我们研究了 mGluR 是否作为活性依赖性自受体发挥作用，抑制疼痛向大鼠中枢神经系统的传递，特别是瞬时受体电位香草酸 1（TRPV1）诱导的活动。通过向足底注射拮抗剂 LY341495[（2S）-2-氨基-2-[[1S，2S）-2-羧基环丙烷-1-基]-3-（黄嘌呤-9-基）丙氨酸]（LY）（20、100μm，II/III 组）、APICA[（RS）-1-氨基-5-磷酸吲哚烷-1-羧酸]（100μm，II 组）或 UBP1112（α-甲基-3-甲基-4-膦基苯甘氨酸）（30μm，III 组）来阻断外周 mGluR 活性，增加辣椒素（CAP）诱导的伤害性行为和伤害感受器活性。相比之下，II 组激动剂 APDC[（2R，4R）-4-氨基吡咯烷-2,4-二羧酸]（0.1μm）或 III 组激动剂 l-（+）-2-氨基-4-膦丁酸（l-AP-4）（10μm）阻断了 LY 引起的增加。背根神经节（DRG）细胞中的钙成像证实，LY 增强了 CAP 诱导的钙动员，这被 APDC 和 l-AP-4 阻断。我们假设高强度和/或长时间刺激释放的谷氨酸（GLU）内源性激活 II/III 组，抑制伤害感受器的激活。支持这一观点的是，足底注射 GLU+LY 会产生热痛觉过敏，而应用于伤害感受器的外源性 GLU+LY 会产生增强的伤害感受器活性和热敏化。已知足底福尔马林会升高细胞外 GLU，在 LY 存在的情况下会增强疼痛行为。LY 单独使用不会产生疼痛行为、伤害感受器放电率或热诱发反应没有变化，DRG 细胞中的细胞溶质钙（Ca2+）也没有变化，表明缺乏紧张性抑制控制。II/III 组 mGluR 保持活性依赖性自动抑制，能够显著降低 TRPV1 诱导的活性。它们在高频和/或长时间伤害感受器刺激后被内源性激活，作为 TRPV1 和伤害感受器功能的内置负调节剂，减少疼痛向中枢神经系统的传递。
