Taylor D A, Leedham J A, Bennett L E, Fleming W W
Department of Pharmacology and Toxicology, West Virginia University Health Sciences Center, Morgantown.
J Pharmacol Exp Ther. 1991 Dec;259(3):1094-101.
The effect of chronic treatment with morphine via pellet implantation on the sensitivity of the longitudinal smooth muscle-myenteric plexus of the guinea pig ileum to the contractile effects of gamma-aminobutyric acid (GABAA)-receptor agonists was assessed. GABA and muscimol elicited concentration-dependent contractions of the longitudinal smooth muscle which were due to the release of acetylcholine because the contractile effects were markedly attenuated by atropine (10 nM). The contractile action of GABA agonists does not involve an intermediate step mediated by nicotinic receptors because the concentration-response curves for GABA were unaffected by hexamethonium (1 mM). Bicuculline (10 microM) produced nearly equivalent rightward shifts of the concentration-response curves for both GABA and muscimol, indicating mediation of the contractile effects of these agents by GABAA receptors. Chronic exposure to morphine via pellet implantation did not alter the sensitivity of this preparation to either GABA or muscimol. This is in contrast to the development of supersensitivity of the longitudinal smooth muscle-myenteric plexus to other excitatory agonists (nicotine, 5-hydroxytryptamine and potassium), which accompanies the development of tolerance to opioids. GABA induces depolarization of myenteric neurons that is observed most prominently in AH neurons and rarely in S neurons. The stimulatory effects of nicotine and of GABA were inhibited by morphine (a predominantly mu opioid agonist) and by U50,488H (a predominantly kappa opioid agonist). The results are discussed within the context that supersensitivity to neuronal stimulants of the myenteric plexus in morphine-tolerant preparations is limited to substances which depolarize S neurons.
通过植入微丸长期给予吗啡对豚鼠回肠纵行平滑肌 - 肌间神经丛对γ-氨基丁酸（GABAA）受体激动剂收缩作用的敏感性进行了评估。GABA和蝇蕈醇可引起纵行平滑肌浓度依赖性收缩，这是由于乙酰胆碱释放所致，因为阿托品（10 nM）可显著减弱收缩作用。GABA激动剂的收缩作用不涉及由烟碱受体介导的中间步骤，因为GABA的浓度 - 反应曲线不受六甲铵（1 mM）的影响。荷包牡丹碱（10 μM）使GABA和蝇蕈醇的浓度 - 反应曲线几乎同等程度地右移，表明这些药物的收缩作用是由GABAA受体介导的。通过植入微丸长期暴露于吗啡并未改变该制剂对GABA或蝇蕈醇的敏感性。这与纵行平滑肌 - 肌间神经丛对其他兴奋性激动剂（尼古丁、5 - 羟色胺和钾）的超敏反应形成对比，后者伴随对阿片类药物耐受性的发展而出现。GABA可诱导肌间神经原去极化，这在AH神经元中最为明显，而在S神经元中很少见。尼古丁和GABA的刺激作用被吗啡（一种主要的μ阿片受体激动剂）和U50,488H（一种主要的κ阿片受体激动剂）抑制。在对吗啡耐受的制剂中，肌间神经丛对神经元兴奋剂的超敏反应仅限于使S神经元去极化的物质这一背景下对结果进行了讨论。
