Solomon R E, Gebhart G F
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City.
J Pharmacol Exp Ther. 1988 May;245(2):444-54.
The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. Chronic treatment with morphine (32.0 micrograms/day for 7 days) produced tolerance to the antinociceptive effects of morphine in conscious rats, and chronic morphine or chronic clonidine (32.0 micrograms/day for 7 days) reduced the antinociceptive potency of morphine in lightly anesthetized rats. The pressor effects of morphine were attenuated by chronic morphine and were converted to marked, dose-dependent depressor effects by chronic clonidine. Clonidine dose dependently inhibited the tail-flick reflex in lightly anesthetized rats (ED50 = 1.7 micrograms) and produced biphasic effects on blood pressure; lesser doses (0.1-3.2 micrograms) produced depressor effects whereas a greater dose (10.0 micrograms) produced a pressor response. Yohimbine, but not naloxone, antagonized the antinociceptive effects of clonidine, whereas both yohimbine and naloxone altered the dose-response function for the effects of clonidine on blood pressure. Tolerance developed to the antinociceptive effects of clonidine in the hot-plate, but not in the tail-flick, test in conscious rats. In lightly anesthetized rats, the antinociceptive potency of clonidine was reduced by chronic clonidine or chronic morphine, whereas chronic clonidine, but not chronic morphine, shifted the dose-response function for effects of clonidine on blood pressure to the right. These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.
研究了鞘内（i.t.）急性和慢性给予阿片受体激动剂吗啡或α-2肾上腺素能受体激动剂可乐定对大鼠痛觉和血压的影响。在用戊巴比妥轻度麻醉的大鼠中，吗啡产生剂量依赖性的伤害性甩尾反射抑制作用（ED50 = 10.0微克）和小的、与剂量无关的升压作用。这些作用被阿片受体拮抗剂纳洛酮（30.0微克i.t.）预处理所拮抗，而α-2肾上腺素能受体拮抗剂育亨宾（30.0微克i.t.）增强了升压作用，且未改变吗啡的抗伤害感受作用。吗啡慢性治疗（32.0微克/天，共7天）使清醒大鼠对吗啡的抗伤害感受作用产生耐受性，慢性给予吗啡或可乐定（32.0微克/天，共7天）降低了轻度麻醉大鼠中吗啡的抗伤害感受效能。吗啡的升压作用被慢性吗啡减弱，并被慢性可乐定转变为明显的、剂量依赖性的降压作用。可乐定在轻度麻醉大鼠中剂量依赖性地抑制甩尾反射（ED50 = 1.7微克），并对血压产生双相作用；较小剂量（0.1 - 3.2微克）产生降压作用，而较大剂量（10.0微克）产生升压反应。育亨宾而非纳洛酮拮抗了可乐定的抗伤害感受作用，而育亨宾和纳洛酮均改变了可乐定对血压作用的剂量 - 反应函数。在清醒大鼠的热板试验中对可乐定的抗伤害感受作用产生了耐受性，但在甩尾试验中未产生。在轻度麻醉大鼠中，慢性给予可乐定或慢性给予吗啡降低了可乐定的抗伤害感受效能，而慢性给予可乐定而非慢性给予吗啡使可乐定对血压作用的剂量 - 反应函数右移。这些结果表明，急性鞘内给予吗啡和可乐定的抗伤害感受作用分别由脊髓阿片受体和α-2肾上腺素能受体介导。然而，鞘内给予吗啡和鞘内给予可乐定之间的耐受性和交叉耐受性表明，脊髓阿片系统和α-2肾上腺素能系统在产生抗伤害感受方面相互作用。这些系统似乎也以复杂的方式相互作用以对血压产生影响。
