Vrinten D H, Gispen W H, Groen G J, Adan R A
Departments of Medical Pharmacology and Anesthesiology, Rudolf Magnus Institute for Neurosciences, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands.
J Neurosci. 2000 Nov 1;20(21):8131-7. doi: 10.1523/JNEUROSCI.20-21-08131.2000.
The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic constriction injury (CCI) to the rat sciatic nerve, a lesion that produces neuropathic pain, results in changes in the spinal cord MC system, as shown by an increased binding of (125)I-NDP-MSH to the dorsal horn. Furthermore, we investigated whether intrathecal administration (in the cisterna magna) of selective MC receptor ligands can affect the mechanical and cold allodynia associated with the CCI. Mechanical and cold allodynia were assessed by measuring withdrawal responses of the affected limb to von Frey filaments and withdrawal latencies upon immersion in a 4.5 degrees C water bath, respectively. We show that treatment with the MC receptor antagonist SHU9119 has a profound anti-allodynic effect, suggesting that the endogenous MC system has a tonic effect on nociception. In contrast, administration of the MC4 receptor agonists MTII and d-Tyr-MTII primarily increases the sensitivity to mechanical and cold stimulation. No antinociceptive action was observed after administration of the selective MC3 receptor agonist Nle-gamma-MSH. Together, our data suggest that the spinal cord MC system is involved in neuropathic pain and that the effects of MC receptor ligands on the responses to painful stimuli are exerted through the MC4 receptor. In conclusion, antagonism of the spinal melanocortin system might provide a new approach in the treatment of neuropathic pain.
脊髓中伤害性感受相关区域同时存在阿片促黑皮质素原衍生肽和黑皮质素（MC）受体，这表明在脊髓水平，MC系统可能参与伤害性信息传递。在本研究中，我们证明对大鼠坐骨神经进行慢性压迫损伤（CCI）（一种产生神经性疼痛的损伤）会导致脊髓MC系统发生变化，如（125）I-NDP-MSH与背角的结合增加所示。此外，我们研究了鞘内注射（在大脑延髓池）选择性MC受体配体是否会影响与CCI相关的机械性和冷觉异常性疼痛。分别通过测量患侧肢体对von Frey细丝的退缩反应和浸入4.5℃水浴后的退缩潜伏期来评估机械性和冷觉异常性疼痛。我们发现用MC受体拮抗剂SHU9119治疗具有显著的抗异常性疼痛作用，这表明内源性MC系统对伤害性感受具有紧张性作用。相反，给予MC4受体激动剂MTII和d-Tyr-MTII主要会增加对机械性和冷刺激的敏感性。给予选择性MC3受体激动剂Nle-γ-MSH后未观察到抗伤害性作用。总之，我们的数据表明脊髓MC系统参与神经性疼痛，并且MC受体配体对疼痛刺激反应的影响是通过MC4受体发挥的。总之，脊髓黑皮质素系统的拮抗作用可能为神经性疼痛的治疗提供一种新方法。
