Paul Alok K, Woolley Krystel L, Rahmatullah Mohammed, Wilairatana Polrat, Smith Jason A, Gueven Nuri, Dietis Nikolas
School of Pharmacy and Pharmacology, University of Tasmania, Hobart, TAS 7001, Australia.
School of Natural Sciences, University of Tasmania, Hobart, TAS 7001, Australia.
Pharmaceuticals (Basel). 2022 Jun 24;15(7):789. doi: 10.3390/ph15070789.
Analgesic tolerance is a major problem in the clinic for the maintenance of opioid-induced long-term pain relief. Opioids with mixed activity on multiple opioid receptors promise reduced antinociceptive tolerance in preclinical studies, but these compounds typically show poor bioavailability upon oral, subcutaneous, intraperitoneal, or intravenous administration. We designed UTA1003 as a novel opioid that acts as a mu (MOP) and kappa (KOP) opioid receptor agonist and a partial agonist for delta (DOP) opioid receptor. In the present study, its antinociceptive effects, as well as its effects on antinociceptive tolerance and motor behaviour, were investigated in male rats. Acute antinociception was measured before (basal) and at different time points after subcutaneous injection of UTA1003 or morphine using the tail flick and hot plate assays. Various motor behavioural activities, including horizontal locomotion, rearing, and turning, were automatically measured in an open-field arena. The antinociceptive and behavioural effects of repeated administration of UTA1003 and morphine were determined over eight days. UTA1003 induced mild antinociceptive effects after acute administration but induced no tolerance after repeated treatment. Importantly, UTA1003 co-treatment with morphine prevented antinociceptive tolerance compared to morphine alone. UTA1003 showed less motor suppression than morphine in both acute and sub-chronic treatment regimens, while it did not affect morphine-induced motor suppression or hyper-excitation. Based on these activities, we speculate that UTA1003 crosses the blood-brain barrier after subcutaneous administration and, therefore, could be developed as a lead molecule to avoid opioid-induced antinociceptive tolerance and motor suppression. Further structural modifications to improve its antinociceptive effects, toxicity profile, and ADME parameters are nevertheless required.
镇痛耐受性是临床中维持阿片类药物诱导的长期疼痛缓解的一个主要问题。在临床前研究中，对多种阿片受体具有混合活性的阿片类药物有望降低抗伤害感受耐受性，但这些化合物在口服、皮下、腹腔内或静脉给药后通常表现出较差的生物利用度。我们设计了UTA1003作为一种新型阿片类药物，它作为μ（MOP）和κ（KOP）阿片受体激动剂以及δ（DOP）阿片受体的部分激动剂。在本研究中，在雄性大鼠中研究了其抗伤害感受作用以及对抗伤害感受耐受性和运动行为的影响。使用甩尾和热板试验在皮下注射UTA1003或吗啡之前（基础值）和之后的不同时间点测量急性抗伤害感受。在旷场实验中自动测量各种运动行为活动，包括水平运动、竖毛和转身。在八天内确定重复给予UTA1003和吗啡的抗伤害感受和行为影响。UTA1003在急性给药后诱导轻度抗伤害感受作用，但在重复治疗后未诱导耐受性。重要的是，与单独使用吗啡相比，UTA1003与吗啡联合治疗可预防抗伤害感受耐受性。在急性和亚慢性治疗方案中，UTA1003的运动抑制作用均比吗啡小，同时它不影响吗啡诱导的运动抑制或过度兴奋。基于这些活性，我们推测UTA1003在皮下给药后可穿过血脑屏障，因此可开发为一种先导分子以避免阿片类药物诱导的抗伤害感受耐受性和运动抑制。然而，仍需要进一步的结构修饰以改善其抗伤害感受作用、毒性特征和药代动力学参数。
