Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2009 Nov-Dec;61(6):1086-95. doi: 10.1016/s1734-1140(09)70171-9.
Recent studies have suggested that melanocortins contribute to the generation and/or maintenance of pathological pain. Experimental evidence indicates a primary role for melanocortin 4 (MC4) receptors in pathological pain. In a previous study, we described the presence of MC4 receptor transcripts in the dorsal root ganglia (DRG). This finding prompted us to investigate the peripheral antinociceptive effects of MC4 receptor antagonists. In addition, we assess the expression of MC4 receptors in the spinal cord and the DRG of rats subjected to neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Injection of the MC4 receptor antagonists Asp3-Lys8- Ac-Nle-Asp-His-D-Nal(2')-Arg-Trp-Lys-NH(2) (SHU9119) and Mpr1-Cys8-Mpr-Glu-His-(D-Nal)-Arg-Trp-Gly-Cys-Pro-Pro-Lys-Asp-NH(2) (JKC-363) into the ipsilateral paw resulted in a significant and dose-dependent alleviation of mechanical allodynia (assayed by the von Frey test) and thermal hyperalgesia (assayed by the Hargreaves test). Compared to naive control animals, immunohistochemistry revealed a 40% and 22% increase in MC4 receptor-immunoreactivity (IR) in the dorsal horn of the spinal cord ipsilateral to the injury at 3 and 14 days after CCI, respectively. Similarly, in the ipsilateral L4-L5 DRG, a 21.1% enhancement in MC4 receptor-IR was seen 3 days after CCI, as well as a 40.5% increase 14 days after CCI. Together, painful neuropathy resulted in the up-regulation of MC4 receptors in the spinal and peripheral nociceptive pathways. This up-regulation of MC4 receptors promotes the pronociceptive action of their endogenous ligands. Therefore, a block of the MC4 receptors results in the antagonism of neuropathic pain and such treatment could be beneficial therapeutically for individuals with chronic neuropathic pain.
最近的研究表明，黑色素皮质素有助于病理性疼痛的产生和/或维持。实验证据表明，黑色素皮质素 4 (MC4) 受体在病理性疼痛中起主要作用。在之前的一项研究中，我们描述了背根神经节 (DRG) 中存在 MC4 受体转录本。这一发现促使我们研究 MC4 受体拮抗剂的外周抗伤害作用。此外，我们评估了 MC4 受体在坐骨神经慢性缩窄性损伤 (CCI) 引起的神经病理性疼痛大鼠脊髓和 DRG 中的表达。将 MC4 受体拮抗剂 Asp3-Lys8- Ac-Nle-Asp-His-D-Nal(2')-Arg-Trp-Lys-NH(2) (SHU9119) 和 Mpr1-Cys8-Mpr-Glu-His-(D-Nal)-Arg-Trp-Gly-Cys-Pro-Pro-Lys-Asp-NH(2) (JKC-363) 注射到同侧爪中，可显著缓解机械性痛觉过敏（通过 von Frey 试验测定）和热痛觉过敏（通过 Hargreaves 试验测定），且呈剂量依赖性。与未受伤的对照组动物相比，CCI 后 3 天和 14 天，受伤侧脊髓背角的 MC4 受体免疫反应性 (IR) 分别增加了 40%和 22%。同样，在同侧 L4-L5 DRG 中，CCI 后 3 天 MC4 受体-IR 增强了 21.1%，CCI 后 14 天增加了 40.5%。总之，疼痛性神经病变导致脊髓和外周伤害性通路中 MC4 受体的上调。MC4 受体的这种上调促进了其内源性配体的促伤害作用。因此，阻断 MC4 受体可拮抗神经病理性疼痛，这种治疗方法对患有慢性神经病理性疼痛的个体可能具有治疗益处。
