Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine
Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine
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DOI：
10.1038/sj.bjp.0706315
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发表时间：
2005-09-01
影响因子：
7.3
通讯作者：
Connor, M
中科院分区：
文献类型：
--
作者：
Bagley, EE;Chieng, BCH;Connor, M
1 中脑导水管周围灰质 (PAG) 是阿片类药物镇痛作用的主要部位，也是细胞适应慢性吗啡治疗 (CMT) 的重要部位。 We examined m-opioid receptor ( MOP) regulation of voltage-gated calcium channel currents (I-Ca) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice.2 Mice were injected s.c. 300 mg kg(-1) 吗啡碱缓释乳剂，5 天内 3 次，或单独乳剂（载体）。该方案在热伤害感受测试中对吗啡的镇痛作用产生了显着的耐受性。3 电压钳记录由急性分离的 PAG 神经元中的 I-Ca 和 PAG 切片中的 GIRK 进行。 MOP 激动剂 DAMGO（Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol 脑啡肽）抑制 CMT 小鼠神经元中的 I-Ca (230 nM)，其效力与载体 (150 nM) 相似，但最大有效性降低（载体神经元中抑制 37%，CMT 神经元中抑制 27%）。 CMT 不会改变 GABA(B) 激动剂巴氯芬对 ICa 的抑制作用。4 PAG 切片中记录的蛋氨酸脑啡肽激活的 GIRK 电流在 CMT 小鼠的神经元中显着小于载体，而巴氯芬激活的 GIRK 电流没有改变。5 这些数据表明，CMT 诱导的镇痛耐受伴随着 MOP 激动剂抑制 I-Ca 和激活 GIRK 的有效性同源降低。因此，MOP 数量和/或与 G 蛋白功能耦合的减少伴随着先前在 PAG 神经元中描述的对 CMT 的特征性细胞适应。
1 The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined m-opioid receptor ( MOP) regulation of voltage-gated calcium channel currents (I-Ca) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice.2 Mice were injected s.c. with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). This protocol produced significant tolerance to the antinociceptive effects of morphine in a test of thermal nociception.3 Voltage clamp recordings were made of I-Ca in acutely isolated PAG neurons and GIRK in PAG slices. The MOP agonist DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin) inhibited I-Ca in neurons from CMT mice (230 nM) with a similar potency to vehicle (150 nM), but with a reduced maximal effectiveness (37% inhibition in vehicle neurons, 27% in CMT neurons). Inhibition of ICa by the GABA(B) agonist baclofen was not altered by CMT.4 Met-enkephalin-activated GIRK currents recorded in PAG slices were significantly smaller in neurons from CMT mice than vehicles, while GIRK currents activated by baclofen were unaltered.5 These data demonstrate that CMT-induced antinociceptive tolerance is accompanied by homologous reduction in the effectiveness of MOP agonists to inhibit I-Ca and activate GIRK. Thus, a reduction in MOP number and/or functional coupling to G proteins accompanies the characteristic cellular adaptations to CMT previously described in PAG neurons.