Dickenson Anthony H, Sullivan Ann F
Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT U.K.
Pain. 1987 Sep;30(3):349-360. doi: 10.1016/0304-3959(87)90023-6.
Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.
许多关于疼痛和伤害感受的研究使用的是短暂的急性刺激，而这些刺激与持续或慢性疼痛状态的关联可能有限。本研究利用大鼠腰脊髓背角的细胞外单单位记录技术，检测神经元对持久伤害性刺激的反应，即向同侧后爪相应感受野注射50微升5%的福尔马林，并研究阿片类药物对该反应的调节作用。福尔马林在所有受试的会聚神经元中产生了明显的双相兴奋性反应；注射后0 - 10分钟出现立即的急性或相位性放电峰值（平均最大22个脉冲/秒），福尔马林注射后20 - 65分钟出现第二个更持久的紧张性兴奋性反应（平均最大12个脉冲/秒）。仅由无害刺激激活的细胞对福尔马林无反应，这表明C纤维传入神经参与了会聚神经元对福尔马林的兴奋性反应。神经元反应的双相性质和时间进程与行为学研究中观察到的相似。鞘内注射DAGO（酪氨酰-D-丙氨酰-甘氨酰-甲基苯丙氨酰-甘氨醇），一种强效且选择性的μ阿片受体激动剂，在福尔马林注射前20分钟应用，可完全抑制两个兴奋峰值。鞘内注射纳洛酮与激动剂共同给药可恢复双相反应。相比之下，当纳洛酮给药延迟至福尔马林注射后2分钟，使得DAGO预处理对第一个峰值的抑制已经发生时，尽管会发生阿片类药物的拮抗作用，但随后没有第二个活动峰值出现。当福尔马林注射后2分钟应用DAGO，使得初始急性反应已经发生时，激动剂对第二个峰值的抑制作用要小得多。因此，DAGO调节细胞对福尔马林双相兴奋性反应的相对能力取决于激动剂是在福尔马林之前还是之后给药，并且第二个峰值的出现可能取决于第一个峰值的存在。根据这些神经元在伤害感受、阿片类药物作用以及外周刺激后神经系统变化中的作用，对这些结果进行了讨论。
