The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.
The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.
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DOI：
10.1007/s00213-021-05965-x
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发表时间：
2021-12
影响因子：
3.4
通讯作者：
Freeman KB
中科院分区：
文献类型：
--
作者：
Zamarripa CA;Pareek T;Schrock HM;Prisinzano TE;Blough BE;Sufka KJ;Freeman KB
三氮唑1.1是一种新型的kappa-阿片受体(KOR)激动剂，据报道可以产生抗伤害效应，而没有KOR典型的不良反应。当与MU阿片受体(MOR)激动剂羟考酮联合使用时，三氮唑1.1可阻断羟考酮引起的瘙痒，而不会在非人类灵长类动物中产生镇静样作用。然而，目前尚不清楚三氮唑1.1是否能像其他KOR激动剂一样减少羟考酮的滥用相关效应或增强其抗伤害效应。本研究的目的是定量比较三氮唑1.1与KOR激动剂U50,488h和呋喃呋喃对羟考酮自身给药和羟考酮诱导的热抗伤害作用的影响。在自我给药研究中，雄性SD大鼠(n=6)静脉注射。羟考酮(0.056 mg/kg/inj)或与U50,488h(0.032-0.32 mg/kg/inj)、呋喃呋喃(0.00032-0.0032 mg/kg/inj)或三唑1.1(0.32-1.8 mg/kg/inj)联合应用。在热板法中，雄性SD大鼠(n=6)接受静脉注射。注射羟考酮(1.0-5.6 mg/kg)、U50、488h(1.0-18.0 mg/kg)、呋喃西林(0.01-1.0 mg/kg)或三氮唑1.1(3.2-32.0 mg/kg)，或根据单一药物的相对效力，与羟考酮按固定比例联合注射。每项研究都以给予KOR拮抗剂NOR-BNI和对先前条件进行一定程度的重新测试来验证行为效应是由KOR激活所介导的。所有KOR激动剂均以剂量依赖的方式减少羟考酮自身给药。此外，所有单一药物和药物组合都产生剂量依赖的、完全有效的热抗伤害效应。所有KOR激动剂：羟考酮组合可产生添加或超添加的热抗伤害性作用。最后，在两种行为测量中，每种KOR激动剂都被Nor-BNI阻断。这项研究表明，三氮唑1.1降低了羟考酮的增强效应，并增强了羟考酮诱导的抗伤害作用，其程度与典型的KOR激动剂相当。鉴于三氮唑1.1‘S的轻微不良反应，从三氮唑1.1系列开发MOR-KOR激动剂组合可能会使新的止痛药减少滥用倾向。
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 U50,488h (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.
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影响因子：
5
作者：
Bolanos, CA;Garmsen, GM;McDougall, SA
通讯作者：
McDougall, SA
影响因子：
3.4
作者：
Lazenka ML;Moerke MJ;Townsend EA;Freeman KB;Carroll FI;Negus SS
通讯作者：
Negus SS
影响因子：
5.6
作者：
Bedini, Andrea;Mannelli, Lorenzo Di Cesare;Spampinato, Santi
通讯作者：
Spampinato, Santi
DOI：
10.1124/jpet.108.143925
发表时间：
2009-01-01
影响因子：
3.5
作者：
Ko, Mei-Chuan;Husbands, Stephen M.
通讯作者：
Husbands, Stephen M.
影响因子：
--
作者：
Bruijnzeel AW
通讯作者：
Bruijnzeel AW