Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates
Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates
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DOI：
10.1124/jpet.104.068411
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发表时间：
2004-10-01
影响因子：
3.5
通讯作者：
Kreek, MJ
中科院分区：
文献类型：
--
作者：
Butelman, ER;Harris, TJ;Kreek, MJ
辣椒素通过作为香草素受体亚型1 [VR 1;也称为瞬时受体电位香草素1型（TRPV 1）]的激动剂在动物和人类中产生热异常性疼痛。VR 1受体广泛分布于外周（例如，在初级传入神经元上）。这些研究检查了洛哌丁胺（0.1-1 mg/kg s.c.;一种μ-阿片激动剂，在全身给药后具有外周选择性），在尾部撤回试验（n=4; 38 ℃和42 ℃;通常为无害的热刺激）中，在恒河猴中预防和逆转由局部辣椒素（0.004M）引起的热异常性疼痛。洛哌丁胺的作用与中枢渗透性μ受体激动剂芬太尼（0.0032-0.032 mg/kg s.c.）的作用进行了比较。我们还表征了内源性VR 1激动剂（“类香草醛”）N-油酰多巴胺（OLDA; 0.0013-0.004 M）的异常性疼痛效应。在该模型中，洛哌丁胺和芬太尼产生辣椒素诱导的异常性疼痛的剂量依赖性预防，而只有芬太尼产生持续异常性疼痛的强烈逆转。用纳洛酮（0.1 mg/kg s.c.）或其类似物甲基纳洛酮（0.32 mg/kg s.c.），其不容易穿过血脑屏障，表明洛哌丁胺和芬太尼的抗异常性疼痛作用主要分别由位于外周和中心的μ受体介导。洛哌丁胺和芬太尼（分别为1 mg/kg和0.032 mg/kg）也可预防OLDA（0.004 M）诱导的异常性疼痛。直到研究的最大剂量，洛哌丁胺在48 ℃没有热抗伤害感受作用（在没有辣椒素的情况下，是一种有害的热刺激）。相比之下，芬太尼（0.01-0.032 mg/kg）在该敏感的热抗伤害感受试验中引起剂量依赖性抗伤害感受（推测的中枢介导效应）。这些研究表明，洛哌丁胺，作为外周选择性μ受体激动剂后，全身给药，可以防止辣椒素诱导的热异常性疼痛在灵长类动物体内，在没有热抗伤害效应。
Capsaicin produces thermal allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1-1 mg/kg s.c.; a mu-opioid agonist that is peripherally selective after systemic administration), in preventing and reversing thermal allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay (n=4; 38degreesC and 42degreesC; normally non-noxious thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating mu-agonist, fentanyl (0.0032-0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist ("endovanilloid"), N-oleoyldopamine (OLDA; 0.0013-0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced allodynia, whereas only fentanyl produced robust reversal of ongoing allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located mu-receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced allodynia. Up to the largest dose studied, loperamide was devoid of thermal antinociceptive effects at 48 C (a noxious thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01-0.032 mg/kg) caused dose-dependent antinociception in this sensitive thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective mu-agonist after systemic administration, can prevent capsaicin-induced thermal allodynia in primates in vivo, in the absence of thermal antinociceptive effects.