Grup de Recerca en Neurobiologia del Comportament (GRNC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Dr Aiguader, 88, 08003 Barcelona, Spain.
Neuropharmacology. 2011 Jul-Aug;61(1-2):43-50. doi: 10.1016/j.neuropharm.2011.02.014. Epub 2011 Feb 23.
GPR3 is an orphan G-protein coupled receptor broadly expressed in brain structures controlling emotional-like behaviors and pain. GPR3 receptor up-regulates cAMP and promotes neurite outgrowth in mammalian neurons, being a good candidate to participate in the pathophysiology of neurodegenerative diseases as well as brain and spinal cord injuries. In this study, we evaluated the role of GPR3 receptor in the development and expression of neuropathic pain after sciatic nerve ligature, and the inflammatory reaction in the dorsal horn of the spinal cord in both Gpr3-/- and Gpr3+/+ mice. Hyperalgesia to noxious thermal stimulus and allodynia to cold and mechanical stimuli were evaluated using the plantar test, the cold-plate test and the Von Frey filament model, respectively. Additionally, we evaluated the involvement of GPR3 receptors in morphine-induced antinociception using the tail immersion test. After nerve injury, Gpr3-/- mice showed a higher sensitivity to thermal non-noxious and noxious stimuli than Gpr3+/+ mice, whereas no differences were observed between genotypes in mechanical allodynia. In addition, no differences in microglia and astrocytes activation were found when compared the ipsilateral dorsal horn of Gpr3-/- and Gpr3+/+ mice exposed to nerve ligature. On the other hand, the genetic deletion of GPR3 receptors reduced morphine antinociception in the tail immersion test in mice without any changes in basal thermal threshold. Taken together, our results demonstrate, for the first time, the involvement of the orphan GPR3 receptor in the expression and development of neuropathic pain and in the analgesia induced by morphine. The lack of GPR3 receptors produced hypersensitivity to thermal non-noxious and noxious stimuli without affecting the spinal inflammatory response associated to sciatic nerve injury and reduced morphine antinociception in the tail immersion test. Our findings propose GPR3 receptors as a new molecular target in neuropathic pain therapy as well as a new component of a pro-opioid receptor system.
GPR3 是一种孤儿 G 蛋白偶联受体，广泛表达于控制情绪样行为和疼痛的脑结构中。GPR3 受体上调 cAMP 并促进哺乳动物神经元的神经突生长，是参与神经退行性疾病以及脑和脊髓损伤的病理生理学的良好候选物。在这项研究中，我们评估了 GPR3 受体在坐骨神经结扎后神经性疼痛的发展和表达中的作用，以及在 Gpr3-/-和 Gpr3+/+小鼠脊髓背角中的炎症反应。使用足底测试、冷板测试和 Von Frey 丝模型分别评估对有害热刺激的痛觉过敏和对冷和机械刺激的感觉异常。此外，我们使用尾部浸入试验评估了 GPR3 受体在吗啡诱导的镇痛作用中的参与。在神经损伤后，与 Gpr3+/+小鼠相比，Gpr3-/-小鼠对热非伤害性和伤害性刺激的敏感性更高，而在机械感觉异常方面，两种基因型之间没有差异。此外，与 Gpr3+/+小鼠相比，在暴露于神经结扎的同侧背角中，未发现小胶质细胞和星形胶质细胞激活的差异。另一方面，GPR3 受体的基因缺失减少了小鼠尾部浸入试验中的吗啡镇痛作用，而对基础热阈值没有任何改变。总之，我们的研究结果首次表明孤儿 GPR3 受体参与神经性疼痛的表达和发展，以及吗啡诱导的镇痛作用。缺乏 GPR3 受体导致对热非伤害性和伤害性刺激的敏感性增加，而不影响与坐骨神经损伤相关的脊髓炎症反应，并减少尾部浸入试验中的吗啡镇痛作用。我们的发现提出 GPR3 受体作为神经性疼痛治疗的新分子靶点，以及阿片前体受体系统的新组成部分。
