Antinociceptive Effects of Spinal Cholinesterase Inhibition and Isobolographic Analysis of the Interaction with μ and α2 Receptor Systems
Antinociceptive Effects of Spinal Cholinesterase Inhibition and Isobolographic Analysis of the Interaction with μ and α2 Receptor Systems
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脊髓胆碱酯酶抑制的镇痛作用以及与μ和α2受体系统相互作用的等辐射分析
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发表时间：
1994
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通讯作者：
T. Yaksh
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作者：
M. Naguib;T. Yaksh
脊髓胆碱能受体已被证明具有有效的抗感知作用，这种作用可以被脊髓胆碱酯酶抑制剂所模仿。我们(1)研究了胆碱能受体系统，胆碱酯酶抑制剂通过该系统产生抗伤害效应；(2)研究了它们与脊髓μ阿片和α2肾上腺素能受体的相互作用。方法用慢性鞘内置管制备大鼠，用辐射热诱发后爪退缩法测定痛觉阈值。结果脊髓给药新司格明、伊曲芬铵、卡巴考、可乐定和吗啡可使热诱发的后爪戒断潜伏期呈剂量依赖性增加。效价（产生50%效果的剂量，以纳米摩尔为单位）的顺序为吗啡(1.1)=新斯特明（1.2），可乐定（4.4），恰巴醇（15），埃洛芬铵（112）。脊髓前处理阿托品（35 nmol）可减弱鞘内卡巴醇（55 nmol）、新斯的明（15 nmol）和伊曲芬铵（500 nmol）的抗伤性作用，但不影响鞘内吗啡（15 nmol）或克拉定（435 nmol）的效力。此外，鞘内预处理纳洛酮（31 nmol）和育亨宾（28 nmol）分别减弱了鞘内给药吗啡和克拉定的作用，但没有显著影响卡巴考、新斯的明或埃洛芬铵的效力。烟碱受体拮抗剂甲美胺（60 nmol）不影响热痛觉。等密度分析显示，新斯特姆林-可乐定（P < 0.001）、埃洛芬-可乐定（P < 0.0001）和埃洛芬卢顿-吗啡（P < 0.01）混合物共给药后存在同能相互作用。新斯特明-吗啡表现出简单的可加性。结论脊髓胆碱酯酶抑制后的镇痛是通过毒蕈碱介导的，而不是通过胆碱能、阿片或α2-肾上腺素能受体系统介导的，这些脊髓胆碱酯酶抑制作用与鞘内μ和α2激动剂的抗疼痛作用协同作用。
BackgroundSpinal chollnergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which in-trathecally applied cholinesterase inhibitors produce their antinociceptive effect and (2) examined their interaction with spinal μ opioid and α2-adrenergic receptors. MethodsRats were prepared with chronic intrathecal catheters and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. ResultsSpinal administration of neostlgmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1) = neostlgmine (1.2) > clonidine (4.4) > carbachol (15) > edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neo-stigmine (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a syn-ergistlc interaction after the coadminlstratlon of neostlgmlne-clonidine (P > < 0.001), edrophonium-clonldine (P < 0.0001), and edrophonlutn-morphine (P < 0.01) mixtures. Neostlgmine-morphine exhibited simple additivity. ConclusionsThese data indicate that analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nlcotlnic cholinerglc, opioid, or α2-adrenergic receptor systems, and that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal μ and α2 agonists.