Johnson Emma E, Chieng Billy, Napier Ian, Connor Mark
Pain Management Research Institute, E25, Kolling Institute, University of Sydney at Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales 2065, Australia.
Br J Pharmacol. 2006 Aug;148(7):947-55. doi: 10.1038/sj.bjp.0706820. Epub 2006 Jun 19.
Sensory neurons are a major site of opioid analgesic action, but the effect of chronic morphine treatment (CMT) on mu-opioid receptor function in these cells is unknown. We examined mu-opioid receptor modulation of calcium channel currents (I(Ca)) in small trigeminal ganglion (TG) neurons from mice chronically treated with morphine and measured changes in mu-opioid receptor mRNA levels in whole TG. Mice were injected subcutaneously with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). CMT mice had a significantly reduced response to the acute antinociceptive effects of 30 mg kg(-1) morphine compared with controls (P=0.035).Morphine inhibited I(Ca) in neurons from CMT (EC(50) 300 nM) and vehicle (EC(50) 320 nM) mice with similar potency, but morphine's maximum effect was reduced from 36% inhibition in vehicle to 17% in CMT (P<0.05). Similar results were observed for the selective mu-opioid agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO). Inhibition of I(Ca) by the GABA(B) agonist baclofen was unaffected by CMT. In neurons from CMT mice, there were significant reductions in P/Q-type (P=0.007) and L-type (P=0.002) I(Ca) density.mu-Opioid receptor mRNA levels were not altered by CMT. These data demonstrate that CMT produces a significant reduction of the effectiveness of mu-opioid agonists to inhibit I(Ca) in TG sensory neurons, accompanied by a reduction in I(Ca) density. Thus, adaptations in sensory neurons may mediate some of the tolerance to the antinociceptive effects of morphine that develop during systemic administration.
感觉神经元是阿片类镇痛药作用的主要部位，但慢性吗啡治疗（CMT）对这些细胞中μ-阿片受体功能的影响尚不清楚。我们研究了慢性吗啡处理的小鼠三叉神经节（TG）小神经元中μ-阿片受体对钙通道电流（I(Ca)）的调节作用，并测量了整个TG中μ-阿片受体mRNA水平的变化。小鼠在5天内分三次皮下注射300 mg kg(-1)的吗啡碱缓释乳剂，或仅注射乳剂（对照）。与对照组相比，CMT小鼠对30 mg kg(-1)吗啡的急性镇痛作用反应显著降低（P = 0.035）。吗啡以相似的效力抑制CMT小鼠（半数有效浓度[EC(50)] 300 nM）和对照小鼠（EC(50) 320 nM）神经元中的I(Ca)，但吗啡的最大效应从对照小鼠的36%抑制降低至CMT小鼠的17%（P < 0.05）。选择性μ-阿片激动剂酪氨酸-D-丙氨酸-甘氨酸-N-甲基苯丙氨酸-甘醇脑啡肽（DAMGO）也观察到类似结果。γ-氨基丁酸B（GABA(B)）激动剂巴氯芬对I(Ca)的抑制作用不受CMT影响。在CMT小鼠的神经元中，P/Q型（P = 0.007）和L型（P = 0.002）I(Ca)密度显著降低。μ-阿片受体mRNA水平不受CMT影响。这些数据表明，CMT使μ-阿片激动剂抑制TG感觉神经元中I(Ca)的有效性显著降低，并伴有I(Ca)密度降低。因此，感觉神经元的适应性变化可能介导了全身给药期间对吗啡镇痛作用产生的部分耐受性。
