Zamarripa C Austin, Pareek Tanya, Schrock Hayley M, Prisinzano Thomas E, Blough Bruce E, Sufka Kenneth J, Freeman Kevin B
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
School of Pharmacy, University of Kentucky, Lexington, KY, USA.
Psychopharmacology (Berl). 2021 Dec;238(12):3463-3476. doi: 10.1007/s00213-021-05965-x. Epub 2021 Aug 25.
Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists.
The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone.
In the self-administration study, male Sprague-Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488 h (0.032-0.32 mg/kg/inj), nalfurafine (0.00032-0.0032 mg/kg/inj), or triazole 1.1 (0.32-1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6 mg/kg), U50,488h (1.0-18.0 mg/kg), nalfurafine (0.01-1.0 mg/kg), or triazole 1.1 (3.2-32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation.
All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures.
This study demonstrates that triazole 1.1 reduces oxycodone's reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1's mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.
三唑1.1是一种新型κ-阿片受体（KOR）激动剂，据报道可产生镇痛作用且无KOR典型的不良反应。与μ-阿片受体（MOR）激动剂羟考酮联合使用时，三唑1.1可阻断羟考酮引起的瘙痒，且在非人类灵长类动物中不会产生类似镇静的作用。然而，三唑1.1是否能像其他KOR激动剂一样降低与滥用相关的作用或增强羟考酮的镇痛作用尚不清楚。
本研究的目的是定量比较三唑1.1与KOR激动剂U50,488h和纳曲酮在与羟考酮混合给药时对羟考酮自我给药和羟考酮诱导的热镇痛的行为学影响。
在自我给药研究中，雄性Sprague-Dawley（SD）大鼠（n = 6）单独静脉注射（i.v.）羟考酮（0.056 mg/kg/注射）或与U50,488h（0.032 - 0.32 mg/kg/注射）、纳曲酮（0.00032 - 0.0032 mg/kg/注射）或三唑1.1（0.32 - 1.8 mg/kg/注射）联合使用，采用累进比率强化程序。在热板试验中，雄性SD大鼠（n = 6）静脉注射羟考酮（1.0 - 5.6 mg/kg）、U50,488h（1.0 - 18.0 mg/kg）、纳曲酮（0.01 - 1.0 mg/kg）或三唑1.1（3.2 - 32.0 mg/kg），单独或根据单一药物的相对效价与羟考酮按固定比例联合使用。每项研究最后给予KOR拮抗剂nor-BNI，并在一定程度上重新测试先前的条件，以验证行为学效应是由KOR激活介导的。
所有KOR激动剂均以剂量依赖性方式降低羟考酮的自我给药。此外，所有单一药物和药物组合均产生剂量依赖性、完全有效的热镇痛作用。所有KOR激动剂与羟考酮的组合均产生相加或超相加的热镇痛作用。最后，在两种行为学测量中，每种KOR激动剂的作用均被nor-BNI阻断。
本研究表明，三唑1.1可降低羟考酮的强化作用，并增强羟考酮诱导的镇痛作用，其程度与典型的KOR激动剂相当。鉴于三唑1.1的不良反应较轻，开发三唑1.1系列的MOR-KOR激动剂组合可能会产生滥用可能性降低的新型疼痛治疗药物。
