Su X, Joshi S K, Kardos S, Gebhart G F
Department of Pharmacology, College of Medicine, The University of Iowa, Bowen Science Building, Iowa City, IA 52242, USA.
J Neurophysiol. 2002 Mar;87(3):1271-9. doi: 10.1152/jn.00624.2001.
The goal of the present study was to determine whether the kappa-opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic kappa-ORA (+/-)-trans U50,488, its enantiomers (-)-trans (1S,2S)-U50,488 and non kappa-ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer (-)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 > U50,488 angle quotation mark, right (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6-10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the kappa-ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions.
本研究的目的是确定κ-阿片受体激动剂（ORA）U50,488是否通过钠通道阻滞来减弱对有害性结直肠扩张（CRD）的行为和初级传入神经反应。我们测试了镇痛性κ-ORA（±）-反式U50,488、其对映体（-）-反式（1S,2S）-U50,488和非κ-ORA（+）-反式（1R,2R）-U50,488，以及/或者其非对映体（-）-顺式（1S,2R）-U50,488在体内减弱对有害性CRD的内脏运动和盆腔神经传入纤维反应以及在体外减弱结肠感觉神经元中电压激活钠电流的能力。在未麻醉的大鼠中，皮下给予U50,488、（1S,2S）-U50,488和（1R,2R）-U50,488减弱了对有害性CRD的行为内脏运动反应；效价顺序为：（1S,2S）-U50,488＞U50,488＞（1R,2R）-U50,488。U50,488及其立体异构体也以剂量依赖性方式抑制了去传入盆腔神经传入纤维对有害性CRD的反应。累积剂量为16mg/kg的（1S,2S）-U50,488、（1S,2R）-U50,488和（1R,2R）-U50,488分别将反应降低至对照的平均29%、30%和47%。这些药物的平均抑制剂量无差异（范围：6.6 - 10.8mg/kg）。钠通道阻滞剂美西律和卡马西平模拟了U50,488的作用。相反，κ-ORA强啡肽（1 - 13）和ICI 204,488在减弱盆腔神经活动方面无效。在体外对结肠感觉神经元灌注（1S,2S）-U50,488、（1S,2R）-U50,488或（1R,2R）-U50,488可降低电压激活钠电流。U50,488及其立体异构体的这种抑制作用不是由阿片受体介导的，因为它不能被阿片受体拮抗剂纳洛酮逆转，也不是G蛋白介导的效应。此处报道的结果表明，U50,488及其立体异构体的内脏抗伤害感受作用是由其外周钠通道阻滞作用所致。
