Nielsen Carsten K, Ross Fraser B, Lotfipour Shahrdad, Saini Kamal S, Edwards Stephen R, Smith Maree T
School of Pharmacy, The University of Queensland, St. Lucia Campus, St. Lucia, Brisbane, Qld 4072, Australia.
Pain. 2007 Dec 5;132(3):289-300. doi: 10.1016/j.pain.2007.03.022. Epub 2007 Apr 30.
Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-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 approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) 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 [(3)H]bremazocine 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 mu-opioid receptors.
此前，我们报道基于以下研究，羟考酮是一种假定的κ-阿片受体激动剂：用κ-选择性阿片受体拮抗剂诺-纳洛酮啡（nor-BNI）对大鼠进行脑室内（i.c.v.）预处理，可消除i.c.v. 羟考酮的作用，但不能消除吗啡的镇痛作用，而用i.c.v. 纳洛嗪（μ-选择性拮抗剂）预处理则产生相反的效果。在本研究中，我们在机械性和生化性神经损伤的大鼠模型中进行行为实验，并结合放射性配体结合实验，以进一步研究羟考酮的药理学特性。在大鼠坐骨神经慢性压迫损伤（CCI）后，鞘内（i.t.）注射诺-纳洛酮啡可消除i.t. 羟考酮的镇痛作用，但不能消除i.t. 吗啡的镇痛作用。在链脲佐菌素（STZ）诱导的糖尿病大鼠中，发现羟考酮和吗啡的镇痛特性存在显著差异。虽然在STZ给药后12周和24周时吗啡的镇痛效果消失，但皮下注射羟考酮的镇痛效果在24周内得以维持，尽管效价降低了约3至4倍。在不可逆地耗尽μ-和δ-阿片受体结合位点的大鼠脑膜中，羟考酮以相对高的亲和力取代[(3)H]布托啡诺（在耗尽的膜中为κ(2)-选择性）的结合，而选择性μ-和δ-阿片受体配体，即CTOP（D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-鸟氨酸-苏氨酸-苯丙氨酸-苏氨酸-NH(2)）和DPDPE（[D-青霉胺(2,5)]-脑啡肽），则不能。在耗尽的脑膜中，κ(2b)-配体亮氨酸脑啡肽可阻止羟考酮对高亲和力[(3)H]布托啡诺结合的取代，这表明羟考酮是一种κ(2b)-阿片受体配体。总体而言，本研究结果进一步支持了以下观点：羟考酮和吗啡通过截然不同的阿片受体群体产生镇痛作用。羟考酮似乎作为一种κ(2b)-阿片受体激动剂，对μ-阿片受体的亲和力相对较低。
