Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain

被引:155
作者
Nielsen, Carsten K. [1 ]
Ross, Fraser B. [1 ]
Lotfipour, Shahrdad [1 ]
Saini, Kamal S. [1 ]
Edwards, Stephen R. [1 ]
Smith, Maree T. [1 ]
机构
[1] Univ Queensland, Sch Pharm, Brisbane, Qld 4072, Australia
关键词
oxycodone; morphine; kappa(2)-opioid receptors; chronic constriction injury (CCI); streptozolocin (STZ); painful diabetic neuropathy; radioligand binding;
D O I
10.1016/j.pain.2007.03.022
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Previously, we reported that oxycodone is a putative K-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the K-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine ([L-Selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an similar to 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of alpha- and delta-opioid binding sites, oxycodone displaced [H-3]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Plie-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thi-NH2) and DPDPE [D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [H-3]breinazocine binding, suggesting the notion that oxycodone is a kappa(2b)-Opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for p-opioid receptors. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:289 / 300
页数:12
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