Chen S R, Eisenach J C, Pan H L
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Neuroscience. 2000;101(3):759-65. doi: 10.1016/s0306-4522(00)00415-2.
Spinal norepinephrine release and activation of spinal alpha(2)-adrenergic receptors represent important components of descending control of nociception. Recent studies have shown that nitric oxide is capable of stimulating neuronal norepinephrine release in the presence of thiol-containing compounds such as L-cysteine. In the present study, we tested a hypothesis in a rodent model of neuropathic pain that intrathecal injection of the nitric oxide donor S-nitroso-N-acetylpenicillamine and L-cysteine produces an antiallodynic action mediated by the spinal alpha(2)-adrenergic receptors. Allodynia was induced in rats by ligation of the left lumbar L5/L6 spinal nerves. Mechanical allodynia was quantified by application of von Frey filaments to the left hindpaw. Intrathecal injection of 20-100microg of S-nitroso-N-acetylpenicillamine in the presence of 200microg of L-cysteine, but not D-cysteine, dose-dependently attenuated the allodynia. Intrathecal injection of a combination of 100microg of S-nitroso-N-acetylpenicillamine and 50-200microg of L-cysteine also inhibited the allodynia in a dose-dependent manner. Pretreatment with a nitric oxide scavenger, carboxy-PTIO, or depletion of norepinephrine with a specific neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, prevented the antiallodynic action of intrathecal S-nitroso-N-acetylpenicillamine and L-cysteine. Furthermore, the antiallodynic effect produced by intrathecal injection of a combination of S-nitroso-N-acetylpenicillamine and L-cysteine was abolished by pretreatment with intrathecal injection of a non-specific alpha-adrenergic receptor antagonist, phentolamine, or an alpha(2) receptor antagonist, idazoxan. This study provides the first functional evidence that spinal nitric oxide interacts with the thiol-containing compounds to produce an antiallodynic effect in neuropathic pain. We propose that such an action is mediated by endogenous norepinephrine and spinal alpha(2)-adrenergic receptors.
脊髓去甲肾上腺素的释放以及脊髓α₂-肾上腺素能受体的激活是伤害性感受下行控制的重要组成部分。最近的研究表明，在含硫醇化合物（如L-半胱氨酸）存在的情况下，一氧化氮能够刺激神经元去甲肾上腺素的释放。在本研究中，我们在神经性疼痛的啮齿动物模型中检验了一个假设，即鞘内注射一氧化氮供体S-亚硝基-N-乙酰青霉胺和L-半胱氨酸会产生由脊髓α₂-肾上腺素能受体介导的抗痛觉过敏作用。通过结扎大鼠左侧腰5/腰6脊神经诱导痛觉过敏。通过将von Frey细丝施加到左后爪来量化机械性痛觉过敏。在存在200μg L-半胱氨酸而非D-半胱氨酸的情况下，鞘内注射20 - 100μg S-亚硝基-N-乙酰青霉胺可剂量依赖性地减轻痛觉过敏。鞘内注射100μg S-亚硝基-N-乙酰青霉胺与50 - 200μg L-半胱氨酸的组合也以剂量依赖性方式抑制痛觉过敏。用一氧化氮清除剂羧基-PTIO预处理，或用特异性神经毒素N-(2-氯乙基)-N-乙基-2-溴苄胺使去甲肾上腺素耗竭，可阻止鞘内注射S-亚硝基-N-乙酰青霉胺和L-半胱氨酸的抗痛觉过敏作用。此外，鞘内注射非特异性α-肾上腺素能受体拮抗剂酚妥拉明或α₂受体拮抗剂咪唑克生预处理可消除鞘内注射S-亚硝基-N-乙酰青霉胺和L-半胱氨酸组合所产生的抗痛觉过敏效应。本研究提供了首个功能性证据，即脊髓一氧化氮与含硫醇化合物相互作用，在神经性疼痛中产生抗痛觉过敏作用。我们提出这种作用是由内源性去甲肾上腺素和脊髓α₂-肾上腺素能受体介导的。
