Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China; Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
Neurochem Int. 2024 Oct;179:105840. doi: 10.1016/j.neuint.2024.105840. Epub 2024 Aug 22.
Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than β-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1β in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1β, these effects were reversed by EGLU instead of β-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1β in normal rats, while intrarubral injection of EGLU rather than β-NAAG significantly boosted the expressions of TNF-α and IL-1β. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain.
我们之前的研究已经证实，红核（RN）中Ⅰ型代谢型谷氨酸受体（mGluRⅠ）的激活有助于病理性疼痛的发展。在这里，我们进一步探讨了红核 mGluRⅡ（mGluR2 和 mGluR3）在 spared nerve injury（SNI）诱导的病理性疼痛发展中的作用和可能的分子机制。我们的结果表明，mGluR2 和 mGluR3 在正常大鼠的 RN 中均有组成性表达。在 SNI 后 2 周，与神经损伤侧相对的 RN 中 mGluR2 的蛋白表达而非 mGluR3 的蛋白表达明显减少。在 SNI 后 2 周，将 mGluR2/3 激动剂 LY379268 注射到神经损伤对侧的 RN 中，显著减轻了 SNI 诱导的病理性疼痛，而 mGluR2/3 拮抗剂 EGLU 而非选择性 mGluR3 拮抗剂β-NAAG 逆转了这种作用。LY379268 皮内注射在正常大鼠中不会改变对侧后爪的 PWT，而 EGLU 皮内注射而不是β-NAAG 会引起明显的机械性痛觉过敏。进一步的研究表明，在 SNI 后 2 周，RN 中痛觉因子 TNF-α 和 IL-1β 的表达增强。在 SNI 后 2 周，LY379268 皮内注射显著抑制了 TNF-α 和 IL-1β 的过度表达，而 EGLU 而非β-NAAG 逆转了这种作用。LY379268 皮内注射在正常大鼠中不影响 TNF-α 和 IL-1β 的蛋白表达，而 EGLU 皮内注射而不是β-NAAG 显著增强了 TNF-α 和 IL-1β 的表达。这些发现表明，红核 mGluR2 而非 mGluR3 通过抑制 TNF-α 和 IL-1β 的表达来介导 SNI 诱导的病理性疼痛发展中的抑制作用。mGluR Ⅱ可能是病理性疼痛药物开发和临床治疗的潜在靶点。
