Endogenous and exogenous melanocortin antagonists induce anti-allodynic effects in a model of rat neuropathic pain
Endogenous and exogenous melanocortin antagonists induce anti-allodynic effects in a model of rat neuropathic pain
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DOI：
10.1016/j.bbr.2004.06.008
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发表时间：
2005-02-10
影响因子：
2.7
通讯作者：
Reggiani, A
中科院分区：
文献类型：
--
作者：
Bertorelli, R;Fredduzzi, S;Reggiani, A
许多研究表明黑素皮质素(MC)系统参与了伤害性感受的调制。尽管这种情况发生的机制尚不清楚，但实验证据表明，MC4受体起着主要作用。为了进一步探讨这种MC受体亚型在慢性疼痛中的意义，我们研究了几种MC拮抗剂对脊神经结扎诱导的大鼠伤害性行为的影响。鞘内注射对MC4受体具有不同选择性的合成拮抗剂和内源性拮抗剂A-RP可减少神经病理性大鼠的机械性痛觉异常。用冯·弗雷毛发试验测量。1.5nmoL剂量的治疗产生了抗痛觉异常的效果(最大可能效果的25-30%，MPE，P<；0.0-5)。为了进一步探讨A-RP在痛觉调制中可能的生理作用，我们用实时定量聚合酶链式反应和免疫组织化学方法研究了A-RP在假手术组和神经病理性大鼠脊髓和背根节中的表达。AgRP在脊髓和背根节均有表达，并有表达。在有神经病的动物身上没有变化。结论：MC4受体拮抗剂具有不同的选择性，可在最相关的神经病理性疼痛模型中诱导抗痛觉超敏作用。此外，AgRP在脊髓和DRG中的表达提示了内源性离子抑制对照油MC系统的活性。在病理条件下，这种稳定的控制可能不足以应对过度激活的MC系统，从而导致伤害性感受的增加。这些数据表明，用合成拮抗剂靶向M4可以恢复平衡，从而减少伤害性感受。(C)2004爱思唯尔B.V.保留所有权利。
A number of studies suggest melanocortin (MC) system involvement in nociceptive modulation. Although the mechanism through which this occurs is still unknown, experimental evidence would Suggest a primary role of MC4 receptors. To further investigate the implication of this MC receptor subtype in chronic pain, we have studied the effects of several MC antagonists on spinal nerve ligation-induced nociceptive behavior in rats. The intrathecal injection of synthetic antagonists with different selectivity to MC4 receptor and of an endogenous antagonist (Agouti related protein: A-RP) reduced mechanical allodynia in neuropathic rats. as measured by von Frey hair test. Treatments produced an anti-allodynic effect at the dose of 1.5 nmol (25-30% maximum possible effect, MPE, P < 0.0-5). To further investigate, the possible physiological role of A-RP in pain modulation we studied its expression in both sham and neuropathic rat spinal cord and dorsal root-ganglia (DRG) by quantitative real time PCR and immunohistochemistry. AgRP was present in both spinal cord and DRG, and its expression. Was unchanged in neuropathic animals. In conclusion MC4 receptor antagonists with different selectivity profile, induce anti-allodynic effects in one of the most relevant neuropathic pain model. In addition the expression of AgRP in spinal cord and DRG suggests an endogenous ionic inhibitory control oil MC system activity. In pathological conditions this steady control could be, insufficient to cope with an over activated MC system leading to increase in nociception. These data Suggest that targeting M4 with synthetic antagonists could restore the balance and hence reduce nociception. (C) 2004 Elsevier B.V. All rights reserved.