Randich A, Thurston C L, Ludwig P S, Timmerman M R, Gebhart G F
Department of Psychology, University of Iowa, Iowa City 52242.
Brain Res. 1991 Mar 15;543(2):256-70. doi: 10.1016/0006-8993(91)90036-u.
The mechanisms of the antinociceptive, depressor and bradycardic responses produced by intravenous (i.v.) administration of morphine were examined in rats lightly anesthetized with pentobarbital sodium. Intravenous administration of 0.1, 0.25, 0.5, 1.0 or 2.5 mg/kg of morphine produced dose-dependent inhibition of the nociceptive tail flick (TF) reflex, hypotension, and bradycardia. Bilateral cervical vagotomy (CVAG) significantly attenuated the antinociception produced by i.v. morphine and the degree of attenuation was inversely related to drug dose. CVAG had no effect on the depressor response produced by lesser doses of morphine (0.1 or 0.5 mg/kg), but at greater doses converted the depressor response into either a pressor response (1.0 mg/kg) or an initial pressor response followed by a depressor response (2.5 mg/kg). Morphine-induced bradycardia was blocked by CVAG at all drug doses tested (0.1, 0.5, 1.0 and 2.5 mg/kg). In selective tests of either 0.5 or 2.5 mg/kg of i.v. morphine, prior administration of the peripherally acting opioid receptor antagonist naloxone methobromide (NMB) attenuated the antinociception to the same degree as CVAG. NMB also completely blocked the depressor and bradycardic responses of these doses of morphine. Bilateral subdiaphragmatic vagotomy (SDVAG) resulted in a marginal attenuation of antinociception at 0.5 mg/kg but not 2.5 mg/kg of morphine, and the attenuation produced by SDVAG was delayed in onset following morphine administration relative to that produced by CVAG. Bilateral sino-aortic deafferentation (SAD) had no significant effect on the antinociception in tests with 0.5 mg/kg of morphine. SDVAG and SAD had little effect on cardiovascular responses produced by these doses of morphine. The spinal antinociceptive systems activated by vagal afferents following i.v. morphine administration were characterized with the 0.5 mg/kg dose. Spinal cold block significantly antagonized the antinociception, hypotension and bradycardia produced by this dose of morphine. Intrathecal administration of naloxone (1.5, 15 or 30 micrograms) significantly antagonized the antinociception compared to saline controls, whereas intrathecal administration of methysergide (30 micrograms), phentolamine (30 micrograms), or the combination of methysergide with phentolamine (30 micrograms each) had no significant effect on the antinociception. These intrathecal doses of naloxone also antagonized the depressor and bradycardic responses produced by morphine. However, the antagonism produced by 1.5 micrograms of intrathecal naloxone was not due to spread to the systemic circulation, since i.v. administration of 1.5 micrograms of naloxone did not significantly affect either the antinociceptive or cardiovascular responses produced by morphine. These findings indicate that vagal afferents play a significant role in the antinociception produced by i.v. administration of morphine.(ABSTRACT TRUNCATED AT 400 WORDS)
在戊巴比妥钠轻度麻醉的大鼠中，研究了静脉注射吗啡产生的抗伤害感受、降压和心动过缓反应的机制。静脉注射0.1、0.25、0.5、1.0或2.5mg/kg吗啡可产生剂量依赖性的伤害感受性甩尾（TF）反射抑制、低血压和心动过缓。双侧颈迷走神经切断术（CVAG）显著减弱了静脉注射吗啡产生的抗伤害感受作用，且减弱程度与药物剂量呈负相关。CVAG对较小剂量吗啡（0.1或0.5mg/kg）产生的降压反应无影响，但在较大剂量时，将降压反应转变为升压反应（1.0mg/kg）或先升压后降压反应（2.5mg/kg）。在所有测试的药物剂量（0.1、0.5、1.0和2.5mg/kg）下，CVAG均阻断了吗啡诱导的心动过缓。在选择性测试静脉注射0.5或2.5mg/kg吗啡时，预先给予外周作用的阿片受体拮抗剂甲溴化纳洛酮（NMB），其对抗伤害感受作用的程度与CVAG相同。NMB也完全阻断了这些剂量吗啡的降压和心动过缓反应。双侧膈下迷走神经切断术（SDVAG）在0.5mg/kg吗啡剂量时对抗伤害感受作用有轻微减弱，但在2.5mg/kg吗啡剂量时无此作用，且SDVAG产生的减弱作用在吗啡给药后相对于CVAG产生的作用延迟出现。双侧窦主动脉去传入神经术（SAD）在0.5mg/kg吗啡测试中对抗伤害感受作用无显著影响。SDVAG和SAD对这些剂量吗啡产生的心血管反应影响很小。静脉注射吗啡后由迷走神经传入激活的脊髓抗伤害感受系统以0.5mg/kg剂量进行了表征。脊髓冷阻滞显著对抗了该剂量吗啡产生的抗伤害感受、低血压和心动过缓。与生理盐水对照相比，鞘内注射纳洛酮（1.5、15或30微克）显著对抗了抗伤害感受作用，而鞘内注射麦角新碱（30微克）、酚妥拉明（30微克）或麦角新碱与酚妥拉明联合使用（各30微克）对抗伤害感受作用无显著影响。这些鞘内剂量的纳洛酮也对抗了吗啡产生的降压和心动过缓反应。然而，鞘内注射1.5微克纳洛酮产生的拮抗作用并非由于扩散至全身循环，因为静脉注射1.5微克纳洛酮对吗啡产生的抗伤害感受或心血管反应均无显著影响。这些发现表明迷走神经传入在静脉注射吗啡产生的抗伤害感受中起重要作用。（摘要截短至400字）
