The Antinociceptive Effects of Nicotinic Receptors α7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models
The Antinociceptive Effects of Nicotinic Receptors α7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models
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DOI：
10.1124/jpet.112.197871
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Damaj, M. Imad
中科院分区：
文献类型：
--
作者：
Freitas, Kelen;Carroll, F. Ivy;Damaj, M. Imad
α7 烟碱乙酰胆碱受体 (nAChR) 亚型在中枢神经系统和外周神经系统中大量表达。最近的证据表明，α 7 nAChR 亚型可被内源性胆碱能张力（包括乙酰胆碱和 α 7 nAChR 激动剂胆碱）激活，在亚慢性疼痛和炎症中发挥重要作用。本研究的目的是测试 α7 nAChR 阳性变构调节剂 (PAM) 是否在急性和持续性疼痛的体内小鼠模型中产生镇痛作用。测试类型 I [N-(5-氯-2-羟基苯基)-N'-[2-氯-5-(三氟甲基)苯基] (NS1738)] 和类型 II [1-(5-氯-2,4-二甲氧基-苯基)-3-(5-甲基-异恶唑-3-基) (PNU-120596)] alpha 7 nAChR PAM 在急性和持续性疼痛中的作用，我们发现，尽管两者都没有减轻急性热痛，但在福尔马林测试中，只有 PNU-120596 剂量依赖性地减弱了舔爪行为。该测试中 PNU-120596 的长效作用与其在小鼠中的药代动力学特征不一致，这表明涉及受体后信号传导机制。我们对选择性丝裂原激活蛋白激酶激酶抑制剂 1,4-二氨基-2,3-二氰基-1,4-双(邻氨基苯硫基)丁二烯单乙醇酯 (U0126) 的研究结果表明，细胞外信号调节激酶 1/2 通路激活在 PNU-120596 的抗伤害作用中发挥着重要作用。鞘内给药的 α 7 拮抗剂 MLA 可逆转 PNU-120596 的作用，部分证实了 PNU-120596 通过中枢 α 7 nAChR 的作用。重要的是，在药物亚慢性治疗后并未产生对 PNU-120596 的耐受性。令人惊讶的是，PNU-120596 的抗伤害作用被 NS1738 阻断。我们的结果表明，II 型 α 7 nAChR PAM PNU-120596，而不是 I 型 α 7 nAChR PAM NS1738，在小鼠持续性疼痛模型中显示出显着的镇痛作用。
The alpha 7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that alpha 7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the alpha 7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether alpha 7 nAChR positive allosteric modulators (PAMs) produce antinociception in in vivo mouse models of acute and persistent pain. Testing type I [N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl) phenyl] (NS1738)] and type II [1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) (PNU-120596)] alpha 7 nAChR PAMs in acute and persistent pain, we found that, although neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggests the involvement of postreceptor signaling mechanisms. Our results with selective mitogen-activated protein kinase kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate (U0126) argues for an important role of extracellular signal-regulated kinase-1/2 pathways activation in PNU-120596's antinociceptive effects. The alpha 7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central alpha 7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after subchronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS1738. Our results indicate that type II alpha 7 nAChR PAM PNU-120596, but not type I alpha 7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice.