Bogulavsky Johanna J, Gregus Ann M, Kim Paul T-H, Costa Alberto C S, Rajadhyaksha Anjali M, Inturrisi Charles E
Department of Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
J Pharmacol Exp Ther. 2009 Feb;328(2):579-87. doi: 10.1124/jpet.108.144121. Epub 2008 Oct 28.
Previous reports utilizing pharmacological antagonists implicate kainate receptor (KAR) activation in the development of morphine tolerance, dependence, conditioned place preference (CPP), and locomotor sensitization, but the role of glutamate receptor (GluR) 5-containing KAR in these effects remains unclear because of limited selectivity of the inhibitors employed. Therefore, we examined responses to systemic morphine treatment in mice expressing a constitutive deletion of GluR5 [GluR5 knockout (KO)]. Unlike wild-type (WT) littermates, GluR5 KO mice do not develop tolerance after repeated morphine administration by subcutaneous injection or via subcutaneous pellet implantation. In contrast, GluR5 KO mice do not differ from WT with respect to thermal or mechanical nociceptive thresholds, acute morphine antinociception, morphine disposition in the central nervous system (CNS), morphine physical dependence as revealed by naloxone-precipitated withdrawal or development of place preference and locomotor hyperresponsiveness after chronic morphine administration. It is surprising that continuous subcutaneous infusion of the GluR2/GluR5-preferring antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] decreased the number of naloxone-precipitated jumps to a similar extent in WT and GluR5 KO mice. We observed opioid-induced hypersensitivity in both groups during morphine withdrawal as demonstrated by equivalent reductions in thermal and mechanical thresholds; however, this hypersensitivity was not evident during continuous systemic morphine infusion. These data collectively indicate that KARs containing the GluR5 subunit contribute to the development of morphine tolerance without affecting nociceptive thresholds, morphine analgesia, or disposition in CNS of morphine and its metabolite morphine-3-glucuronide. In addition, constitutive deletion of GluR5 does not alter the morphine-induced increase in locomotor activity or the acquisition of morphine reward as measured by a CPP paradigm.
以往利用药理学拮抗剂的报告表明，海人酸受体（KAR）激活与吗啡耐受性、依赖性、条件性位置偏爱（CPP）和运动敏化的发展有关，但由于所用抑制剂的选择性有限，含谷氨酸受体（GluR）5的KAR在这些效应中的作用仍不清楚。因此，我们研究了表达GluR5组成性缺失的小鼠[GluR5基因敲除（KO）]对全身吗啡治疗的反应。与野生型（WT）同窝小鼠不同，GluR5基因敲除小鼠经皮下注射或皮下植入药丸反复给予吗啡后不会产生耐受性。相比之下，在热或机械伤害性感受阈值、急性吗啡镇痛作用、吗啡在中枢神经系统（CNS）中的分布、纳洛酮诱发的戒断所揭示的吗啡身体依赖性或慢性吗啡给药后位置偏爱和运动高反应性的发展方面，GluR5基因敲除小鼠与野生型小鼠没有差异。令人惊讶的是，持续皮下输注优先作用于GluR2/GluR5的拮抗剂LY293558[（3S，4aR，6R，8aR）-6-[2-（1（2）H-四氮唑-5-基）乙基]十氢异喹啉-3-羧酸]在野生型和GluR5基因敲除小鼠中使纳洛酮诱发的跳跃次数减少的程度相似。我们观察到两组在吗啡戒断期间均出现阿片类药物诱发的超敏反应，热和机械阈值同等程度降低证明了这一点；然而，在持续全身输注吗啡期间，这种超敏反应并不明显。这些数据共同表明，含GluR5亚基的KAR有助于吗啡耐受性的发展，而不影响伤害性感受阈值、吗啡镇痛作用或吗啡及其代谢产物吗啡-3-葡萄糖醛酸在中枢神经系统中的分布。此外，GluR5的组成性缺失不会改变吗啡诱导的运动活动增加或通过CPP范式测量的吗啡奖赏获得。
