Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain.
Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain.
复制标题
DOI：
10.1111/ejn.12829
复制
发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Morón JA
中科院分区：
文献类型：
--
作者：
Beaudry H;Gendron L;Morón JA
阿片类药物以其强大的镇痛作用而闻名。然而，mu阿片受体（MOPs）的慢性激活伴随着各种不良影响，如镇痛耐受性。在其他机制中，MOP和δ阿片受体（DOP）之间的相互作用被认为在吗啡诱导的行为适应中起重要作用。有趣的是，某些情况，如炎症，通过依赖于mop的机制增强DOP的功能。在此，我们在慢性炎症性疼痛动物模型中研究了DOP在吗啡耐受性发展中的作用。通过行为学方法，我们首次确定了反复全身吗啡治疗可诱导慢性炎症性疼痛大鼠的吗啡镇痛耐受。然后我们观察到，选择性DOP拮抗剂皮下纳曲多（NTI）阻断DOP，以剂量依赖的方式显著减弱吗啡耐受的发展。通过在naïve动物中显示急性注射NTI对吗啡诱导的镇痛没有影响，我们证实了这种作用是dopp介导的。先前的药理学特征显示DOP1和DOP2亚型的存在。与NTI相反，7-苄基烯醛曲酮（BNTX）和硝三苯（NTB）分别是选择性DOP1和DOP2拮抗剂。有趣的是，NTB而不是BNTX能够减弱炎症大鼠吗啡镇痛耐受性的发展。总之，我们的研究结果表明，拮抗剂靶向DOP2提供了一种有价值的策略，可以减轻慢性炎症性疼痛中反复使用吗啡后产生的镇痛耐受性。
Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is however accompanied by various unwanted effects such as analgesic tolerance. Among other mechanisms, interactions between MOP and delta opioid receptor (DOP) are thought to play an important role in morphine-induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP-dependent mechanism. Here, we investigated the role of DOP during the development of morphine-tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches we first established that repeated systemic morphine treatment induces morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOP with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuates the development of morphine tolerance in a dose-dependent manner. We confirmed that this effect was DOP-mediated by showing that an acute injection of NTI had no effect on morphine-induced analgesia in naïve animals. Previous pharmacological characterizations revealed the existence of DOP1 and DOP2 subtypes. As opposed to NTI, 7-benzylidenenaltrexone (BNTX) and naltriben (NTB) were reported to be selective DOP1 and DOP2 antagonists, respectively. Interestingly, NTB but not BNTX was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.
登录
查看更多内容
影响因子：
3.8
作者：
Kest, B;Lee, CE;Inturrisi, CE
通讯作者：
Inturrisi, CE
影响因子：
4.4
作者：
Maslov, Leonid N.;Oeltgen, Peter R.;Pei, Jian-Ming
通讯作者：
Pei, Jian-Ming
影响因子：
5
作者：
HYLDEN, JLK;THOMAS, DA;DUBNER, R
通讯作者：
DUBNER, R
影响因子：
5
作者：
Lenard, Natalie R.;Daniels, David J.;Roerig, Sandra C.
通讯作者：
Roerig, Sandra C.
影响因子：
5.3
作者：
Gendron, L;Lucido, AL;Beaudet, A
通讯作者：
Beaudet, A