Schools of Physiology and Pharmacology, University of Bristol, UK.
Mol Pain. 2011 Apr 16;7:26. doi: 10.1186/1744-8069-7-26.
Galanin is expressed at low levels in the intact sensory neurons of the dorsal root ganglia with a dramatic increase after peripheral nerve injury. The neuropeptide is also expressed in primary afferent terminals in the dorsal horn, spinal inter-neurons and in a number of brain regions known to modulate nociception. Intrathecal administration of galanin modulates sensory responses in a dose-dependent manner with inhibition at high doses. To date it is unclear which of the galanin receptors mediates the anti-nociceptive effects of the neuropeptide and whether their actions are peripherally and/or centrally mediated. In the present study we investigated the effects of direct administration into the receptive field of galanin and the galanin receptor-2/3-agonist Gal2-11 on nociceptive primary afferent mechanical responses in intact rats and mice and in the partial saphenous nerve injury (PSNI) model of neuropathic pain.
Exogenous galanin altered the responses of mechano-nociceptive C-fibre afferents in a dose-dependent manner in both naive and nerve injured animals, with low concentrations facilitating and high concentrations markedly inhibiting mechano-nociceptor activity. Further, use of the galanin fragment Gal2-11 confirmed that the effects of galanin were mediated by activation of galanin receptor-2 (GalR2). The inhibitory effects of peripheral GalR2 activation were further supported by our demonstration that after PSNI, mechano-sensitive nociceptors in galanin over-expressing transgenic mice had significantly higher thresholds than in wild type animals, associated with a marked reduction in spontaneous neuronal firing and C-fibre barrage into the spinal cord.
These findings are consistent with the hypothesis that the high level of endogenous galanin in injured primary afferents activates peripheral GalR2, which leads to an increase in C-fibre mechanical activation thresholds and a marked reduction in evoked and ongoing nociceptive responses.
Galanin 在背根神经节感觉神经元中低水平表达，在外周神经损伤后显著增加。该神经肽也在背角初级传入末梢、脊髓中间神经元和许多已知调节痛觉的脑区表达。鞘内给予 galanin 以剂量依赖的方式调节感觉反应，高剂量时抑制。迄今为止，尚不清楚哪种 galanin 受体介导神经肽的抗伤害感受作用，以及它们的作用是外周和/或中枢介导的。在本研究中，我们研究了 galanin 和 galanin 受体-2/3-激动剂 Gal2-11 直接给药到感受野对完整大鼠和小鼠以及部分隐鼠神经损伤（PSNI）模型中伤害感受初级传入机械反应的影响。
外源性 galanin 以剂量依赖的方式改变机械伤害性 C 纤维传入的反应，在未损伤和神经损伤动物中，低浓度促进，高浓度明显抑制机械伤害感受器活性。此外，使用 galanin 片段 Gal2-11 证实 galanin 的作用是通过激活 galanin 受体-2（GalR2）介导的。外周 GalR2 激活的抑制作用进一步得到证实，我们的研究表明，在 PSNI 后，galanin 过表达转基因小鼠的机械敏感伤害感受器的阈值明显高于野生型动物，与自发神经元放电和 C 纤维爆发到脊髓明显减少有关。
这些发现与假说一致，即损伤初级传入中的内源性 galanin 水平升高激活外周 GalR2，导致 C 纤维机械激活阈值增加，并显著减少诱发和持续的伤害感受反应。
