术后疼痛的新机制：脊髓背角GIP/GIP受体信号的作用

手术后疼痛是临床最常见疼痛，其机制尚不清楚。我们前期基因芯片研究发现，术后疼痛可诱发脊髓背根神经节葡萄糖依赖性促胰岛素多肽（GIP）基因表达上调。形态学研究证实，GIP可作为一种神经递质表达于初级感觉神经元，而其受体在脊髓背角神经元有表达。预实验发现鞘内给予GIP受体拮抗剂可抑制大鼠术后保护性疼痛行为。据此，我们推测脊髓背角GIP/GIP 受体可能是参与术后疼痛发生发展的新信号分子。为验证此假说，我们将采用免疫组化、免疫印迹、脊髓微透析、基因沉默、激动剂拮抗剂、基因敲除小鼠和在体电生理等方法，研究①术后GIP/GIP受体在脊髓背角表达的时空规律；②鞘内GIP受体激动剂、拮抗剂或siRNA对术后痛敏的影响；③GIP受体激活及其下游胞内PKCγ激活、AMPA受体GluR1亚基Serine-831磷酸化和突触靶向在脊髓中枢敏化中的作用。该项目将揭示术后疼痛的新机制，为新型镇痛药研发提供理论依据。

The mechanisms underlying postoperative pain are unclear. Using gene chips microarray, we found that glucose-dependent insulinotropic peptide (GIP) mRNA was upregulated in dorsal root ganglion during postoperative pain. Previous histological study has shown that GIP may act as a neurotransmitter in primary sensory neurons and its receptor may be expressed in spinal cord dorsal horn. Our preliminary experiments found that intrathecal GIP antagonist may inhibit the guarding pain behaviors after incison. Therefore, we assume that GIP/GIP receptor in spinal dorsal horn may be new molecules involving postoperative pain. To test the hypothesis, we will investigate ① the expression profile of spinal GIP/GIP receptor during postoperative pain; ②the effects of intrathecal agonist, antagonist or siRNA on pain hyperalgesia and ③the roles of GIP receptor and its downstream signaling cascades such as PKC γ, phosphorylation of AMPA receptor GluR1 at Serine 831 and synaptic target. Our proposal will reveal a new mechanism underlying postoperative pain, and provide theoretical basis for developing new analgesics.