The mixed kappa and delta opioid receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain.
The mixed kappa and delta opioid receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain.
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混合阿片受体激动剂MP1104可减轻化疗引起的神经性疼痛。
DOI：
10.1016/j.neuropharm.2020.108445
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发表时间：
2021-03-01
影响因子：
4.7
通讯作者：
Kivell BM
中科院分区：
文献类型：
--
作者：
Atigari DV;Paton KF;Uprety R;Váradi A;Alder AF;Scouller B;Miller JH;Majumdar S;Kivell BM
迫切需要有效的治疗慢性疼痛而不滥用责任。五分之一的成年人患有慢性疼痛，其中一半的患者报告治疗无效。Mu阿片受体激动剂（MOP），包括羟考酮、曲马多和吗啡，通常用于治疗慢性疼痛，然而，使用靶向MOP的药物可导致药物依赖、耐受和过量死亡。κ阿片受体（KOP）激动剂具有抗伤害作用，无滥用潜力;然而，由于烦躁和镇静，它们尚未在临床上使用。我们假设靶向KOP和δ阿片受体（DOP）的混合阿片受体激动剂将具有更广泛的治疗指数，DOP的奖励作用抵消了KOP的负面作用。MP1104是一种新型的混合型阿片受体激动剂，其镇痛作用主要通过KOP和DOP介导，无奖赏或厌恶效应。在这项研究中，我们表明MP1104在雄性和雌性小鼠和大鼠的温水尾部戒断试验中具有强效，长效的抗伤害作用;并且比吗啡作用更长。在紫杉醇诱导的小鼠神经性疼痛模型中，MP1104降低了机械性和冷异常性疼痛，并且与吗啡不同，当每天给药23天时，不产生耐受性。此外，MP1104在旷场自发活动试验中没有诱导镇静作用，使用全身体积描记法在小鼠中没有诱导呼吸抑制，或者与吗啡具有交叉耐受性。该数据支持混合阿片受体激动剂，特别是混合KOP/DOP激动剂作为耐受性降低的非成瘾性止痛药的治疗开发。
Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance.
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影响因子：
4.7
作者：
Atigari, Diana V.;Uprety, Rajendra;Kivell, Bronwyn M.
通讯作者：
Kivell, Bronwyn M.
影响因子：
7.3
作者：
Balboni, G;Guerrini, R;Lazarus, LH
通讯作者：
Lazarus, LH
DOI：
10.1124/jpet.108.146969
发表时间：
2009-04-01
影响因子：
3.5
作者：
Codd, Ellen E.;Carson, John R.;Flores, Christopher M.
通讯作者：
Flores, Christopher M.
影响因子：
64.8
作者：
Bohn, LM;Gainetdinov, RR;Caron, MG
通讯作者：
Caron, MG
影响因子：
3.6
作者：
Coffeen, U.;Canseco-Alba, A.;Pellicer, F.
通讯作者：
Pellicer, F.