Kotlinska Jolanta, Bochenski Marcin, Lagowska-Lenard Monika, Gibula-Bruzda Ewa, Witkowska Ewa, Izdebski Jan
Department of Pharmacology and Pharmacodynamics, Medical University School, Staszica 4, 20-081 Lublin, Poland.
Neuropeptides. 2009 Jun;43(3):221-8. doi: 10.1016/j.npep.2009.03.003. Epub 2009 Apr 18.
The aim of the study was to evaluate whether the newly synthesized analog of enkephalin, cyclo[N(epsilon),N(beta)-carbonyl-D-Lys(2), Dap(5)] enkephalinamide (cUENK6), a highly potent mu- (guinea pig ileum assay) and delta-receptors (mouse vas deferens assay) ligand, induces an antinociceptive effect in the hot-plate test and tail-immersion test after intracerebroventricular administration. Our study indicated that this peptide at the dose of 0.25 nmol produced comparable but at the dose of 0.5 nmol stronger than morphine (13 nmol), antinociceptive effect in both tests. Furthermore, rats with developed tolerance to morphine indicated cross-tolerance to antinociceptive effects of cUENK6. The antinociceptive effects of cUENK6 and morphine were inhibited by non-selective opioid receptor antagonist--naloxone. More detailed study indicated that the delta-opioid receptor antagonist - naltrindole very strongly and, to the lower extent, mu-opioid antagonist - beta-funaltrexamine (beta-FNA), inhibited antinociceptive effect of cUENK6 in the tail-immersion test. Nor-binaltorphimine (nor-BNI), a kappa-opioid receptor antagonist, did not influence this effect. These data suggest the dominant role of delta-opioid receptors as compared with mu-receptors in mediation antinociceptive effect of cUENK6. Furthermore, we found that cUENK6 is much more effective in inhibiting pain in the hot-plate (ED(50)=0.0792 nmol) than in the tail-immersion (ED(50)=0.3526 nmol) test. However, cUENK6 at the antinociceptive doses induced hypolocomotion, and although this effect is observed after administration of opioid agonists in rats as a one phase of their biphasic action (inhibition followed by activation), in our study it was not naloxone-reversible. Therefore, our study suggests that not only opioid receptors may be involved in behavioral effects of cUENK6.
本研究的目的是评估新合成的脑啡肽类似物环[ N(ε),N(β)-羰基-D-赖氨酸(2), 二氨基丙酸(5)]脑啡肽酰胺（cUENK6），一种高效的μ-（豚鼠回肠试验）和δ-受体（小鼠输精管试验）配体，在脑室内给药后，在热板试验和尾浸试验中是否能诱导抗伤害感受作用。我们的研究表明，该肽在剂量为0.25 nmol时产生的抗伤害感受作用与吗啡（13 nmol）相当，但在剂量为0.5 nmol时比吗啡更强，在两种试验中均如此。此外，对吗啡产生耐受性的大鼠对cUENK6的抗伤害感受作用表现出交叉耐受性。cUENK6和吗啡的抗伤害感受作用均被非选择性阿片受体拮抗剂——纳洛酮所抑制。更详细的研究表明，δ-阿片受体拮抗剂——纳曲吲哚非常强烈地，且在较低程度上，μ-阿片拮抗剂——β-氟纳曲胺（β-FNA），在尾浸试验中抑制了cUENK6的抗伤害感受作用。κ-阿片受体拮抗剂诺宾那托啡（nor-BNI）对此作用没有影响。这些数据表明，与μ-受体相比，δ-阿片受体在介导cUENK6的抗伤害感受作用中起主导作用。此外，我们发现cUENK6在抑制热板试验中的疼痛（ED50 = 0.0792 nmol）比在尾浸试验（ED50 = 0.3526 nmol）中更有效。然而，cUENK6在产生抗伤害感受的剂量下会诱导运动减少，尽管这种作用在大鼠中给予阿片类激动剂后作为其双相作用的一个阶段（抑制后激活）会被观察到，但在我们的研究中它不是纳洛酮可逆的。因此，我们的研究表明，不仅阿片受体可能参与cUENK6的行为效应。
