Song Z H, Takemori A E
Department of Pharmacology, Medical School, University of Minnesota, Minneapolis.
J Pharmacol Exp Ther. 1991 Mar;256(3):909-12.
Intrathecally (i.t.) administered corticotropin-releasing factor (CRF) has been shown to produce antinociception in the mouse abdominal stretching (writhing) assay. It also has been demonstrated that spinal kappa opioid receptors as well as CRF receptors are involved in the antinociception induced by CRF. In the present study, the role of CRF i.t. in modulating nociception was assessed further using the mouse tail-flick test. In addition, the modulatory effect of i.t. administered CRF on the antinociceptive activity of morphine was studied. Despite its potent and long-lasting antinociceptive effect in the writhing assay, CRF injected i.t. produced no consistent antinociception in the tail-flick test at doses up to 20 times the antinociceptive ED50 of CRF in the writhing test. In contrast, i.t. injection of CRF significantly attenuated the antinociceptive action of s.c. administered morphine. CRF at doses of 0.1 and 0.2 nmol/mouse i.t. increased the antinociceptive ED50 of s.c. morphine by 2- and 4-fold, respectively. The antagonistic action of CRF peaked between 15 min and 1 hr after i.t. injection and was still observable 4 hr after injection, demonstrating a time course similar to that of the antinociceptive effect of CRF in the writhing test. Intrathecal injection of alpha-helical CRF(9-41), a competitive CRF receptor antagonist, was able to inhibit, in a dose-dependent manner, the antagonistic activity of CRF. The antagonistic action of CRF also was attenuated dose-dependently by i.t. injection of nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist. However, intrathecal injection of (+)-1-nor-BNI, an inactive enantiomer of nor-BNI, did not affect the antagonistic action of CRF. These data suggest that spinal kappa opioid receptors as well as CRF receptors are involved in the antagonistic effect of CRF against morphine antinociception.
鞘内注射促肾上腺皮质激素释放因子（CRF）已被证明在小鼠腹部伸展（扭体）试验中可产生抗伤害感受作用。研究还表明，脊髓κ阿片受体以及CRF受体均参与CRF诱导的抗伤害感受。在本研究中，利用小鼠甩尾试验进一步评估了鞘内注射CRF在调节伤害感受中的作用。此外，还研究了鞘内注射CRF对吗啡抗伤害感受活性的调节作用。尽管CRF在扭体试验中具有强效且持久的抗伤害感受作用，但在甩尾试验中，鞘内注射高达扭体试验中抗伤害感受ED50的20倍剂量的CRF，并未产生一致的抗伤害感受作用。相反，鞘内注射CRF显著减弱了皮下注射吗啡的抗伤害感受作用。鞘内注射剂量为0.1和0.2 nmol/小鼠的CRF，分别使皮下注射吗啡的抗伤害感受ED50增加了2倍和4倍。CRF的拮抗作用在鞘内注射后15分钟至1小时达到峰值，注射后4小时仍可观察到，这表明其时间进程与CRF在扭体试验中的抗伤害感受作用相似。鞘内注射竞争性CRF受体拮抗剂α-螺旋CRF（9-41）能够以剂量依赖的方式抑制CRF的拮抗活性。CRF的拮抗作用也因鞘内注射高度选择性κ阿片受体拮抗剂诺-纳曲酮（nor-BNI）而呈剂量依赖性减弱。然而，鞘内注射诺-纳曲酮的无活性对映体（+）-1-诺-纳曲酮对CRF的拮抗作用没有影响。这些数据表明，脊髓κ阿片受体以及CRF受体均参与CRF对吗啡抗伤害感受的拮抗作用。
