健康与遗传心理学研究室知识库

虽然脊髓节段的P物质在伤害性信息传递通路的初级加工中的易化作用已经得到了比较充分的研究，而且也有证据表明P物质在中枢神经系统内参与到内源性生物钟系统的调节，但是，至今仍无证据显示其是否具有调节疼痛行为日节律波动的功能。
在本研究中，疼痛行为学实验证据表明，福尔马林足底注射引起的炎性伤害行为反应具有日节律波动的性质，且这一节律性可以被脊髓鞘内给予的P物质特异性受体拮抗剂所抑制。在体和离体的实验证据进一步解释了P物质与脊髓的外周生物钟的关系:脊髓背根节的细胞内存在节律基因构成的反馈环路;节律基因BMAL 1和CLOCK蛋白复合物对P物质的编码基因Tacl有转录调控作用，这种转录调控作用直接导致P物质在脊髓背角浅层的伤害性信息传入神经纤维中的表达具有了节律性。但是，通过具体分析福尔马林伤害性刺激诱导的炎性伤害性行为的节律特性与P物质节律特性之间的关系我们发现:伤害性刺激诱导P物质在脊髓背角浅层神经纤维内增加量的节律性波动有可能是影响节律性炎性伤害行为反应的关键。最后，我们使用了一种节律基因缺陷型小鼠Per2Brdm，对P物质参与炎性伤害行为的日节律波动的调节的功能进行了进一步验证。
通过本研究提供的一系列实验证据我们认为可以得到以下主要结论:
1.脊髓背根节神经元内存在的外周生物钟信号对脊髓背角浅层的P物质的功能具有调节作用;
2.福尔马林伤害性刺激引起P物质在脊髓背角浅层内的突触间隙的节律性释放以及在脊髓背根节神经元内的节律性生成、运输是产生炎性伤害行为反应节律振荡的关键因素。

Although the nociceptive facilitating functions of substance P (SP) in primary afferent terminals of the spinal dorsal horn have been studied extensively, the role of SP in circadian variations of pain sensitivity is still unknown. This study investigated the circadian fluctuation in nociceptive behavioral reactions to subcutaneous formalin injection in hind-paw of mice. Blockade of SP pathway’s nociceptive transmission blocks the oscillation in nociceptive behavior. It was further demonstrated that under transcriptional regulation of BMAL1:CLOCK heterodimers, expression of Tac1, the SP-encoding gene, oscillates in the mouse dorsal root ganglion, which houses the nociceptive primary sensory neurons to synthesize SP. SP cycled in primary afferent terminals in the superficial laminae of the spinal dorsal horn. This rhythmicity was determined by circadian expression of Tac1 in dorsal root ganglia. There is a circadian fluctuation in the magnitude of the increase in SP production induced by subcutaneous formalin injection that closely tracks the nociceptive-behaviors elicited by formalin injections.

Therefore, the present study indicated that spinal SP plays a pivotal role in modulating circadian inflammatory pain and suggest that peripheral circadian-regulated signaling is an essential pathway for circadian pain response.