摘要
目的:探讨吗啡耐受后大鼠脊髓水平降钙素基因相关肽抑制剂CGRP8-37镇痛效应的变化及对降钙素基因相关肽表达的影响。方法:在大鼠脊髓蛛网膜下腔内埋管,应用热板法和Randall Selitto Test测量大鼠对伤害性热刺激和机械刺激引起的后爪缩爪反应潜伏期(hindpaw withdrawl lantency,HWL)作为痛觉反应指标,应用免疫组织化学法观察吗啡耐受前、后及耐受恢复后大鼠脊髓背角和背根神经节中降钙素基因相关肽免疫活性物质的变化。结果:在脊髓蛛网膜下腔注射10 nmol的CGRP8-37后,大鼠对伤害性热刺激和机械刺激的缩爪反应潜伏期显著增加,表明在正常大鼠脊髓水平CGRP8-37具明确的镇痛作用。在吗啡耐受大鼠蛛网膜下腔注射10 nmol CGRP8-37后,大鼠对伤害性热刺激和机械刺激的缩爪反应潜伏期显著增加,表明吗啡耐受大鼠脊髓水平CGRP8-37具有明确的镇痛作用。在吗啡耐受恢复后,脊髓水平CGRP8-37具有镇痛作用。与正常大鼠相比,在吗啡耐受大鼠蛛网膜下腔注射同样剂量的CGRP8-37所产生的镇痛作用有显著性下降,而在耐受恢复后,其作用基本恢复到正常水平。应用免疫组化方法 ,证实在L3~L5段脊髓背角第Ⅰ、Ⅱ层中存在大量CGRP免疫活性纤维,在脊髓L3~L5段背根神经节中存在大量的小到中等大小的CGRP免疫阳性的神经元。在吗啡耐受后,L3~L5段脊髓背角和L3~L5段背根神经节中的CGRP免疫活性物质的含量明显升高。耐受恢复后,背根神经节中CGRP免疫活性物质的含量基本恢复到正常水平,脊髓背角浅层中CGRP免疫活性物质的含量虽然有所下降,但仍稍高于正常水平。结论:在吗啡耐受后,大鼠脊髓水平CGRP8-37的镇痛作用及CGRP的含量都发生了可塑性变化,提示CGRP在吗啡耐受中具有重要作用。
Objective:It is known that intrathecal administration of calcitonin generelated peptide 8-37(CGRP_(8-37)) an antagonist to CGRP1 receptor,induced antinociception.The present study was performed to investigate the changes in nociceptive modulation of CGRP_(8-37) and CGRP-immunoreactivity at spinal levels after morphine tolerance.Methods:The hindpaw withdrawal latencies(HWLs) to both thermal and mechanical stimulation were assessed by hot plate and Randall Selitto Test.The CGRP-like immunoreactivity at spinal levels was tested by immunohistochemistry.Results:HWLs to both thermal and mechanical stimulation increased significantly after intrathecal injection of 10 nmol of CGRP_(8-37).There were also significant increases in HWLs to both thermal and mechanical stimulation after intrathecal administration of CGRP_(8-37) in morphine tolerant rats and rats recovered from morphine tolerance.It is interesting that the CGRP_(8-37)-induced antinociceptive effects were lower in morphine tolerant rats than those in morphine naive rats and rats recovered from morphine tolerance.Furthermore,there were increases in CGRP-like immunoreactivity in dorsal horn of the spinal cord and the dorsal root ganglia(DRG) of L3~L5 in morphine tolerant rats.Conclusions:The results of the present study demonstrated the downregulations in CGRP_(8-37)-induced antinociception after morphine tolerance,which is possibly resulted from the changes in both the opioid and the CGRP systems.The latter was implicated partly in the present study,that there were plastic changes in CGRP-like immunoreactivity in dorsal horn and DRG after morphine tolerance.All results suggested that CGRP might play an important role in morphine tolerance at the spinal levels.
出处
《神经药理学报》
2013年第2期1-12,共12页
Acta Neuropharmacologica
基金
国家自然科学基金项目(No.30470542,No.30870802,No.8117043)
君政基金项目(No.20040001057)
国家重点基础研究发展计划(973)项目(No.2009CB522002)
