Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1069, USA.
Neuroscience. 2012 Aug 16;217:130-9. doi: 10.1016/j.neuroscience.2012.05.014. Epub 2012 May 17.
Several lines of evidence indicate group III metabotropic glutamate receptors (mGluRs) have systemic anti-hyperalgesic effects. We hypothesized this could occur through modulation of transient receptor potential vanilloid 1 (TRPV1) receptors on nociceptors. To address this question we performed anatomical studies to determine if group III mGluRs were expressed on cutaneous axons and if they co-localized with TRPV1. Immunostaining at the electron microscopic level demonstrated that 22% of unmyelinated axons labeled for mGluR8. Immunostaining at the light microscopic level in lumbar dorsal root ganglia (DRG) demonstrated that 80% and 28% of neurons labeled for mGluR8 or TRPV1, respectively. Of those neurons labeled for mGluR8, 25% labeled for TRPV1; of those labeled for TRPV1, 71% labeled for mGluR8. In behavior studies intraplantar injection of the group III mGluR agonist, L-(+)-2-amino-4-phosphonobutyric acid (L-AP-4: 0.1, 1.0, and 10.0 μM) had no effect on paw withdrawal latency (PWL) to heat in naïve rats but administration of 10 μM L-AP-4 prior to 0.05% capsaicin (CAP), significantly attenuated CAP-induced lifting/licking and reduced flinching behavior. The L-AP-4 effect was specific since administration of a group III antagonist α-methyl-3-methyl-4-phosphonophenylglycine (UBP1112) (100μM) blocked the L-AP-4 effect on CAP, resulting in behaviors similar to CAP alone. Intraplantar injection of UBP1112 alone did not result in nociceptive behaviors, indicating group III mGluRs are not tonically active. Finally, the anti-hyperalgesic effect of group III in this paradigm was local and not systemic since intraplantar administration of L-AP-4 in one hind paw did not attenuate nociceptive behaviors following CAP injection in the contralateral hind paw. Adenyl cyclase/cyclic AMP/PKA may be the second messenger pathway linking these two receptor families because intraplantar injection of forskolin (FSK, 10 μM) reduced PWL to heat and L-AP-4 reversed this FSK effect. Taken together, these results suggest group III mGluRs can negatively modulate TRPV1 through inhibition of adenyl cyclase and downstream intracellular activity, blocking TRPV1-induced activation of nociceptors.
有几条证据表明，III 型代谢型谷氨酸受体 (mGluRs) 具有全身抗痛觉过敏的作用。我们假设这可能是通过调制伤害感受器上的瞬时受体电位香草酸 1 型 (TRPV1) 受体而发生的。为了解决这个问题，我们进行了解剖学研究，以确定 III 型 mGluRs 是否在皮肤轴突上表达，以及它们是否与 TRPV1 共定位。在电子显微镜水平的免疫染色显示，22%的无髓轴突标记为 mGluR8。在腰椎背根神经节 (DRG) 的光镜水平的免疫染色显示，分别有 80%和 28%的神经元标记为 mGluR8 或 TRPV1。在标记为 mGluR8 的神经元中，有 25%标记为 TRPV1；在标记为 TRPV1 的神经元中，有 71%标记为 mGluR8。在行为研究中，足底内注射 III 型 mGluR 激动剂 L-(+)-2-氨基-4-磷酸基丁酸 (L-AP-4：0.1、1.0 和 10.0 μM) 对热诱导的足底撤回潜伏期 (PWL) 没有影响，但在 0.05%辣椒素 (CAP) 之前给予 10 μM L-AP-4 ，显著减弱了 CAP 诱导的抬起/舔舐和退缩行为。L-AP-4 的作用是特异性的，因为给予 III 型拮抗剂 α-甲基-3-甲基-4-膦苯甘氨酸 (UBP1112)(100μM) 阻断了 L-AP-4 对 CAP 的作用，导致与 CAP 单独给药相似的行为。单独足底内注射 UBP1112 不会导致伤害性行为，表明 III 型 mGluRs 不是持续活跃的。最后，在这种范式中，III 型的抗痛觉过敏作用是局部的，而不是全身的，因为在一只后爪内注射 L-AP-4 不会减弱对侧后爪注射 CAP 后的伤害性行为。环腺苷酸/环 AMP/PKA 可能是连接这两个受体家族的第二信使途径，因为足底内注射 forskolin (FSK，10 μM) 降低了热诱导的 PWL，而 L-AP-4 逆转了 FSK 的这种作用。综上所述，这些结果表明，III 型 mGluRs 可以通过抑制腺苷酸环化酶和下游细胞内活性来负性调节 TRPV1，阻断 TRPV1 诱导的伤害感受器激活。
