Functional compartmentalization of opioid desensitization in primary sensory neurons.
Functional compartmentalization of opioid desensitization in primary sensory neurons.
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发表时间：
2000-08
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通讯作者：
G. Samoriski;R. Gross
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作者：
G. Samoriski;R. Gross
脱敏或耐受的细胞相关性知之甚少。为了解决这个问题，我们研究了急性和长期μ阿片脱敏，相对于Ca（2+）电流，在培养的大鼠背根神经节（DRG）神经元。DRG神经元暴露于mu-激动剂[D-Ala（2），N-MePhe（4），Gly-ol（5）]-脑啡肽（DAMGO; 3 μ M）使全细胞电流降低约35%，但在持续应用激动剂的情况下，52%的反应在10至12分钟内丧失。DRG神经元暴露于DAMGO 24小时导致在洗涤和再暴露于DAMGO后几乎完全丧失Ca（2+）通道调节。对γ-氨基丁酸（B）激动剂巴氯芬的反应在这些神经元中没有受到影响。急性脱敏优先影响μ-阿片和γ-氨基丁酸（B）反应的电压敏感成分。在急性脱敏神经元中，强去极化前脉冲对DAMGO和Bactin抑制电流的促进作用显著减弱。由于G（β-γ）亚基介导神经递质诱导的通道电压依赖性变化，这些数据表明G（β-γ）亚基与Ca（2+）通道的相互作用发生了改变。用ω-芋螺毒素GVIA阻断N-型Ca（2+）通道揭示了阿片类反应的一个组成部分，在10分钟内不脱敏。我们得出结论，DRG神经元中的急性和长期μ-阿片类脱敏是通过不同的机制发生的。急性脱敏是异源的和功能区室化的：靶向非N型通道的途径对连续激动剂暴露的早期效应具有相对抗性;以主要电压不敏感方式靶向N型通道的途径部分脱敏;以主要电压敏感方式靶向N型通道的途径完全脱敏。
The cellular correlates of desensitization or tolerance are poorly understood. To address this, we studied acute and long-term mu-opioid desensitization, with respect to Ca(2+) currents, in cultured rat dorsal root ganglion (DRG) neurons. Exposure of DRG neurons to the mu-agonist [D-Ala(2),N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO; 3 microM) reduced whole-cell currents approximately 35%, but with continued agonist application, 52% of the response was lost over 10 to 12 min. In contrast, exposure of DRG neurons to DAMGO for 24 h resulted in a nearly complete loss of Ca(2+) channel regulation after washing and re-exposure to DAMGO. Responses to the gamma-aminobutyric acid(B) agonist baclofen were not affected in these neurons. Acute desensitization preferentially affected the voltage-sensitive component of mu-opioid and gamma-aminobutyric acid(B) responses. Facilitation of both the DAMGO- and baclofen-inhibited current by a strong depolarizing prepulse was significantly attenuated in acutely desensitized neurons. Because G(betagamma)-subunits mediate neurotransmitter-induced changes in channel voltage-dependent properties, these data suggest an altered interaction of the G(betagamma)-subunit with the Ca(2+) channel. Block of N-type Ca(2+) channels with omega-conotoxin GVIA revealed a component of the opioid response that did not desensitize over 10 min. We conclude that acute and long-term mu-opioid desensitization in DRG neurons occurs by different mechanisms. Acute desensitization is heterologous and functionally compartmentalized: the pathway targeting non-N-type channels is relatively resistant to the early effects of continuous agonist exposure; the pathway targeting N-type channels in a largely voltage-insensitive manner is partially desensitized; and the pathway targeting N-type channels in a largely voltage-sensitive manner is completely desensitized.