Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
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DOI：
10.1111/j.1476-5381.2012.02139.x
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Kato, Akira
中科院分区：
文献类型：
--
作者：
Nakamura, Atsushi;Hasegawa, Minoru;Kato, Akira
背景和结论：骨癌疼痛是慢性的，通常难以用阿片类药物控制。然而，最近的研究表明，几种阿片类药物在慢性疼痛中具有不同的镇痛作用。实验方法为了阐明这些不同镇痛作用的机制，使用小鼠股骨骨癌（FBC）模型检测了m-阿片受体的功能变化。关键词在FBC模型中，[H-3]-DAMGO结合的B-max在导水管周围灰质（PAG）中降低了15-45%，PAG腹侧区（vPAG）、背内侧丘脑（mTH）、腹侧丘脑和脊髓。羟考酮（10（8）-10（5）M）和吗啡（10（-8）-10（5）M）可激活[S-35]-GTP γ S结合，但在FBC模型中PAG、vPAG、mTH和脊髓中的激活作用显著减弱。有趣的是，在PAG、vPAG和mTH中，羟考酮诱导的[35 S]-GTPgS结合的衰减（9-26%）与吗啡（46-65%）相比是相当有限的，但在脊髓中不是。此外，每只小鼠0.02-1.0 μ g剂量的i. c. v.羟考酮明显抑制FBC模型小鼠中的疼痛相关行为，例如防卫、肢体使用异常和异常性疼痛样行为，而静脉注射吗啡（每只小鼠0.05-2.0 μ g）对肢体使用异常和异常性疼痛仅有部分或很少的镇痛作用，结论和启示这些结果表明，μ阿片受体功能减弱，在几个疼痛相关的地区在骨癌中的激动剂依赖性的方式，并建议，μ阿片受体的修饰是负责羟考酮和吗啡的不同的镇痛效果。
BACKGROUND AND PURPOSEBone cancer pain is chronic and often difficult to control with opioids. However, recent studies have shown that several opioids have distinct analgesic profiles in chronic pain.EXPERIMENTAL APPROACHTo clarify the mechanisms underlying these distinct analgesic profiles, functional changes in the m-opioid receptor were examined using a mouse femur bone cancer (FBC) model.KEY RESULTSIn the FBC model, the B-max of [H-3]-DAMGO binding was reduced by 15-45% in the periaqueductal grey matter (PAG), region ventral to the PAG (vPAG), mediodorsal thalamus (mTH), ventral thalamus and spinal cord. Oxycodone (10 (8)-10 (5) M) and morphine (10(-8)-10(-5) M) activated [S-35]-GTP gamma S binding, but the activation was significantly attenuated in the PAG, vPAG, mTH and spinal cord in the FBC model. Interestingly, the attenuation of oxycodone-induced [35S]-GTPgS binding was quite limited (9-26%) in comparison with that of morphine (46-65%) in the PAG, vPAG and mTH, but not in the spinal cord. Furthermore, i.c.v. oxycodone at doses of 0.02-1.0 mu g per mouse clearly inhibited pain-related behaviours, such as guarding, limb-use abnormalities and allodynia-like behaviour in the FBC model mice, while i.c.v. morphine (0.05-2.0 mu g per mouse) had only partial or little analgesic effect on limb-use abnormalities and allodynia-like behaviour.CONCLUSION AND IMPLICATIONSThese results show that mu-opioid receptor functions are attenuated in several pain-related regions in bone cancer in an agonist-dependent manner, and suggest that modification of the mu-opioid receptor is responsible for the distinct analgesic effect of oxycodone and morphine.