Garaulet J V, Laorden M L, Milanés M V
Department of Physiology and Pharmacology, University School of Medicine, Murcia, Spain.
Regul Pept. 1996 May 7;63(1):1-8. doi: 10.1016/0167-0115(96)00006-7.
The present investigation was aimed at elucidating if the entry of Ca2+ plays a role in the development of tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus. For this purpose, the influence of the L-type Ca2+ channel modulators nimodipine (Ca2+ blocker) and Bay K 8644 (Ca2+ activator) on the expression of tolerance to the inhibitory effects of mu- and kappa-opioid agonists in the ileum of guinea pigs rendered tolerant to sufentanil was investigated. Chronic perfusion of guinea pigs with nimodipine (2 micrograms/microliter/h for 7 days) or Bay K 8644 (0.5 microgram/microliter/h for 7 days) did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) strip from naive animals. Tolerance to sufentanil (a selective mu-agonist) was induced by s.c. implantation of osmotic minipumps for 7 days, which deliver at 2 micrograms/microliter/h. Control groups received saline. Tolerance to sufentanil as well as to U-50,488H (selective kappa-agonist) was observed following chronic treatment with sufentanil and was revealed as a rightward shift of the concentration-response curves. Chronic perfusion of guinea pigs with the Ca2+ antagonist nimodipine concurrently with chronic sufentanil, markedly blocked the expression of tolerance to sufentanil, as well as the cross-tolerance between sufentanil and U-50,488H. On the contrary, when guinea pigs were perfused with the Ca2+ agonist Bay K 8644 concurrently with sufentanil, it enhanced the magnitude of tolerance to both sufentanil and U-50,488H. These results suggest that, in guinea pig ileum, chronic exposure to opioids may involve the activation of L-type Ca2+ channel, which would indicate that intracellular Ca2+ may be one of the final pathways through which myenteric neurons adapt to the chronic opioid exposure.
本研究旨在阐明Ca2+的内流是否在豚鼠回肠肌间神经丛对μ和κ阿片样激动剂耐受性的形成中发挥作用。为此，研究了L型Ca2+通道调节剂尼莫地平（Ca2+阻滞剂）和Bay K 8644（Ca2+激活剂）对已对舒芬太尼产生耐受性的豚鼠回肠中μ和κ阿片样激动剂抑制作用耐受性表达的影响。用尼莫地平（2微克/微升/小时，持续7天）或Bay K 8644（0.5微克/微升/小时，持续7天）对豚鼠进行慢性灌注，并未引起未处理动物的肌间神经丛-纵行肌（MPLM）条电刺激所诱导收缩高度的任何改变。通过皮下植入渗透微型泵7天（以2微克/微升/小时给药）诱导对舒芬太尼（一种选择性μ激动剂）的耐受性，对照组给予生理盐水。在用舒芬太尼进行慢性治疗后，观察到对舒芬太尼以及U-50,488H（选择性κ激动剂）的耐受性，表现为浓度-反应曲线向右移位。在用Ca2+拮抗剂尼莫地平对豚鼠进行慢性灌注的同时给予慢性舒芬太尼，显著阻断了对舒芬太尼的耐受性表达以及舒芬太尼和U-50,488H之间的交叉耐受性。相反，当豚鼠在给予舒芬太尼的同时用Ca2+激动剂Bay K 8644进行灌注时，它增强了对舒芬太尼和U-50,488H两者的耐受性程度。这些结果表明，在豚鼠回肠中，长期暴露于阿片类药物可能涉及L型Ca2+通道的激活，这表明细胞内Ca2+可能是肌间神经丛神经元适应长期阿片类药物暴露的最终途径之一。
