Differential roles of galanin on mechanical and cooling responses at the primary afferent nociceptor.
Differential roles of galanin on mechanical and cooling responses at the primary afferent nociceptor.
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DOI：
10.1186/1744-8069-8-41
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发表时间：
2012-06-06
期刊：
影响因子：
3.3
通讯作者：
Wynick D
中科院分区：
文献类型：
--
作者：
Hulse RP;Donaldson LF;Wynick D
甘丙素在背根神经节的少量完整小直径感觉神经元和脊髓背角浅层的传入终末表达。神经肽调节伤害性感受，在幼稚的动物中表现出剂量依赖性的促痛和抗伤害性作用。甘丙素在慢性疼痛中也发挥着重要作用，在啮齿动物神经病理性疼痛模型中，其抗伤害性作用增强。在这项研究中，我们通过识别单个大鼠C纤维伤害性感受器并描述它们对机械刺激或丙酮刺激的反应，比较了甘丙肽及其受体在机械性和冷冷性痛觉过敏中所起的作用。在动脉内注入甘丙素或Gal2-11(甘丙素受体-2/3激动剂)后，幼鼠C纤维伤害性感受器的机械诱发反应变得敏感，这证实了先前的数据，甘丙素通过激活GalR2来调节伤害性感受。相反，相同剂量和途径的甘丙肽，而不是Gal2-11，抑制了丙酮和薄荷醇冷却引起的反应，表明这种抑制机制不是通过激活GalR2介导的。然后，我们使用神经病理性疼痛的部分隐神经结扎损伤模型(PSNI)和完全弗氏佐剂炎症模型，证明动脉内紧密注入Galanin(而不是Gal2-11)可以降低这两种模式下的伤害性感受器活动和降冷性痛觉过敏，而Galanin和Gal2-11都降低了机械激活阈值。之前描述的在神经损伤后可诱导Galanin(Gal-OE)过度表达的转基因小鼠，随后被用来研究控制内源性Galanin水平是否也调节了PSNI后冷却诱发的伤害性行为。幼稚小鼠的丙酮戒断行为在Gal-OE和野生型(WT)小鼠之间没有差异。PSNI后7天，Gal-OE小鼠与WT小鼠相比，丙酮诱导的伤害行为持续时间显著缩短。这些数据确定了一种新的Galanine能机制，该机制通过推测的GalR1作用模式来抑制冷却引起的神经元活动和伤害性行为，这也与Trp通道依赖的机制一致。
Galanin is expressed in a small percentage of intact small diameter sensory neurons of the dorsal root ganglia and in the afferent terminals of the superficial lamina of the dorsal horn of the spinal cord. The neuropeptide modulates nociception demonstrating dose-dependent pro- and anti-nociceptive actions in the naïve animal. Galanin also plays an important role in chronic pain, with the anti-nociceptive actions enhanced in rodent neuropathic pain models. In this study we compared the role played by galanin and its receptors in mechanical and cold allodynia by identifying individual rat C-fibre nociceptors and characterising their responses to mechanical or acetone stimulation. Mechanically evoked responses in C-fibre nociceptors from naive rats were sensitised after close intra-arterial infusion of galanin or Gal2-11 (a galanin receptor-2/3 agonist) confirming previous data that galanin modulates nociception via activation of GalR2. In contrast, the same dose and route of administration of galanin, but not Gal2-11, inhibited acetone and menthol cooling evoked responses, demonstrating that this inhibitory mechanism is not mediated by activation of GalR2. We then used the partial saphenous nerve ligation injury model of neuropathic pain (PSNI) and the complete Freund’s adjuvant model of inflammation in the rat and demonstrated that close intra-arterial infusion of galanin, but not Gal2-11, reduced cooling evoked nociceptor activity and cooling allodynia in both paradigms, whilst galanin and Gal2-11 both decreased mechanical activation thresholds. A previously described transgenic mouse line which inducibly over-expresses galanin (Gal-OE) after nerve injury was then used to investigate whether manipulating the levels of endogenous galanin also modulates cooling evoked nociceptive behaviours after PSNI. Acetone withdrawal behaviours in naive mice showed no differences between Gal-OE and wildtype (WT) mice. 7-days after PSNI Gal-OE mice demonstrated a significant reduction in the duration of acetone-induced nociceptive behaviours compared to WT mice. These data identify a novel galaninergic mechanism that inhibits cooling evoked neuronal activity and nociceptive behaviours via a putative GalR1 mode of action that would also be consistent with a TRP channel-dependent mechanism.
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