Spinal nitric oxide contributes to the analgesic effect of inntrathecal [D-Pen2, D-Pen5]-enkepahlin in normal and diabetic rats
Spinal nitric oxide contributes to the analgesic effect of inntrathecal [D-Pen2, D-Pen5]-enkepahlin in normal and diabetic rats
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DOI：
10.1097/00000542-200301000-00033
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发表时间：
2003-01-01
期刊：
影响因子：
8.8
通讯作者：
Pan, HL
中科院分区：
文献类型：
--
作者：
Chen, SR;Pan, HL
背景：脊髓一氧化氮（NO）在吗啡和胆碱能药物的镇痛作用中起重要作用。其在δ-阿片受体激动剂的镇痛作用中的作用尚不清楚。在正常大鼠和糖尿病神经病理性疼痛大鼠模型上，作者研究了脊髓内源性NO在鞘内注射δ阿片受体激动剂[D-Pen（2），D-Pen（5）]-脑啡肽（DPDPE）抗伤害效应中的作用。在年龄匹配的正常和糖尿病大鼠中植入鞘内导管。通过对后爪施加伤害性压力刺激来确定伤害性阈值。首先确定鞘内注射DPDPE的剂量依赖性效应。脊髓NO在鞘内注射DPDPE镇痛效应中的作用通过鞘内注射NO合成酶抑制剂（NMMA和TRIM）和特异性NO清除剂（carboxy-PTIO）来检测。鞘内注射2 - 20 μ g DPDPE可剂量依赖性地增加正常大鼠和糖尿病大鼠对伤害性压力的反应阈值。糖尿病大鼠DPDPE的ED_（50）约为正常大鼠的2倍。NMMA、TRIM或羧基PTIO鞘内预处理可减弱DPDPE对正常和糖尿病大鼠的镇痛作用。鞘内注射L-精氨酸可逆转NMMA对鞘内注射DPDPE的抑制作用，但对DPDPE的抑制作用无明显影响。鞘内注射DPDPE在正常大鼠和糖尿病神经病理性疼痛大鼠模型中产生抗伤害感受作用。脊髓内源性NO对正常和糖尿病神经性疼痛条件下鞘内注射DPDPE的镇痛作用有重要贡献。
Background: Spinal nitric oxide (NO) is important for the analgesic actions of morphine and cholinergic agents. Its role in the analgesic effect of delta-opioid receptor agonists is not known. in the present study, the authors determined the role of spinal endogenous NO in the antinociceptive effect of intrathecal [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE), a delta-opioid receptor agonist, in normal rats and a rat model of diabetic neuropathic pain.Methods: Rats were rendered diabetic with streptozotocin (50 mg/kg, intraperitoneal). Intrathecal catheters were implanted in age-matched normal and diabetic rats. Nociceptive thresholds were determined by application of a noxious pressure stimulus to the hind paw. The dose-dependent effect of intrathecal DPDPE was first determined. The role of spinal NO in the analgesic effect of intrathecal DPDPE was then examined through intrathecal treatments with NO synthase inhibitors (NMMA and TRIM) and a specific NO scavenger (carboxy-PTIO).Results: The diabetic rats developed a sustained mechanical hyperalgesia within 3 weeks after streptozotocin injection. Intrathecal DPDPE, 2-20 mug, dose-dependently increased the withdrawal threshold in response to the noxious pressure in normal and diabetic rats. However, the ED50 of DPDPE in diabetic rats was about twofold higher than that in normal rats. Intrathecal pretreatment with NMMA, TRIM, or carboxy PTIO diminished die analgesic effect of DPDPE in both normal and diabetic rats. Furthermore, the inhibitory effect of NMMA on the action of intrathecal DPDPE was reversed by intrathecal L-arginine but not D-arginine.Conclusions. Intrathecal DPDPE produces an antinociceptive effect in normal rats and a rat model of diabetic neuropathic pain. Spinal endogenous NO contributes importantly to the analgesic action of Intrathecal DPDPE in both normal and diabetic neuropathic pain conditions.