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首页> 外文期刊>Anesthesia and Analgesia: Journal of the International Anesthesia Research Society >Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain.
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Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain.

机译：鞘内可乐定抑制神经性疼痛大鼠脊髓背角神经元中N-甲基-D-天冬氨酸受体NR1亚基的磷酸化。

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BACKGROUND: Intrathecal (IT) administration of the alpha-2 adrenoceptor agonist, clonidine, produces significant analgesic effects. Although several mechanisms underlying clonidine-induced analgesia have been proposed, the possible interaction with N-methyl-D-aspartate (NMDA) receptors as a major antinociceptive mechanism has not been addressed. We designed the present study to determine whether clonidine or other analgesics can affect spinal NMDA receptor activation in rats with chronic constriction injury (CCI)-induced neuropathy. METHODS: Rats underwent unilateral CCI, and received IT clonidine (1, 5, 20 microg/rat), [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO, mu opioid receptor agonist, 1 microg/rat), gabapentin (anticonvulsant, 100 microg/rat) or vehicle 2 wks later. After drug injection, we measured the pain response to thermal or mechanical stimuli and used immunohistochemistry to evaluate spinal cord phosphorylated NMDA-receptor subunit 1 (pNR1) expression. RESULTS: Two weeks after CCI surgery, rats displayed significant mechanical allodynia and thermal hyperalgesia, and the spinal cord dorsal horn showed a significant increase in the number of pNR1 immunoreactive neurons. IT injection of clonidine (20 microg/rat), DAMGO and gabapentin potently reduced mechanical allodynia and thermal hyperalgesia. Importantly, IT clonidine, but not IT DAMGO or gabapentin, dose-dependently reduced CCI-induced pNR1 expression in all lamina of the spinal cord dorsal horn by 30 min after injection. In addition, IT injection of the alpha-2 adrenoceptor antagonist, idazoxan (40 microg/rat) 10 min before clonidine injection completely reversed clonidine's antihyperalgesic and antiallodynic effects, as well as clonidine's suppressive effect on CCI-induced NR1 phosphorylation in the spinal cord dorsal horn. CONCLUSIONS: Our data indicate that IT clonidine's antihyperalgesic/antiallodynic effect on neuropathic pain is associated with a significant reduction in spinal NMDA receptor phosphorylation and suggests a potentially novel mechanism of clonidine's action.
机译：背景：α-2肾上腺素受体激动剂可乐定的鞘内（IT）给药产生明显的镇痛作用。尽管已提出了可乐定诱导镇痛的几种机制，但尚未解决与N-甲基-D-天冬氨酸（NMDA）受体相互作用的可能，这是一种主要的抗伤害感受性机制。我们设计了本研究，以确定可乐定或其他镇痛药是否可以影响慢性收缩损伤（CCI）诱发的神经病大鼠的脊髓NMDA受体活化。方法：大鼠接受单侧CCI，并接受IT可乐定（1、5、20微克/大鼠），[D-Ala2，NMe-Phe4，Gly-ol5]-脑啡肽（DAMGO，阿片类阿片受体激动剂，1微克/大鼠） ，加巴喷丁（抗惊厥药，100微克/大鼠）或载剂2周后。注射药物后，我们测量了对热刺激或机械刺激的疼痛反应，并使用免疫组织化学评估了脊髓磷酸化的NMDA受体亚基1（pNR1）的表达。结果：CCI手术后两周，大鼠表现出明显的机械性异常性疼痛和热痛觉过敏，脊髓背角显示pNR1免疫反应性神经元数量显着增加。 IT注射可乐定（20微克/大鼠），DAMGO和加巴喷丁可有效减少机械性异常性疼痛和热痛觉过敏。重要的是，注射后30分钟，IT可乐定（而非IT DAMGO或加巴喷丁）可剂量依赖性地降低CCI诱导的脊髓背角所有层中cCI诱导的pNR1表达。此外，在可乐定注射前10分钟，IT注射α-2肾上腺素受体拮抗剂伊达唑烷（40微克/大鼠）可完全逆转可乐定的抗痛觉过敏和抗痛觉过敏作用，以及可乐定对脊髓背侧CCI诱导的NR1磷酸化的抑制作用喇叭。结论：我们的数据表明，可乐定对神经性疼痛的抗痛觉过敏/抗痛觉过敏作用与脊髓NMDA受体磷酸化的显着降低有关，并暗示了可乐定作用的潜在新机制。

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