Mehr Shahram Ejtemaei, Samini Morteza, Namiranian Khodadad, Homayoun Houman, Gaskari Seyed Ali, Dehpour Ahmad Reza
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Eur J Pharmacol. 2003 Apr 25;467(1-3):205-10. doi: 10.1016/s0014-2999(03)01632-7.
Immunophilin ligands, cyclosporine A and FK506 (tacrolimus), besides their immunosuppressive action, have several effects on different neural functions, such as modulation of the release of many neurotransmitters, the reduction of nitric oxide (NO) production by the inhibition of dephosphorylation of neuronal nitric oxide synthase (nNOS) and the alteration of the expression of certain genes. Many of these actions apparently occur through the inhibition of calcineurin, a calcium-calmodulin-dependent phosphatase. On the other hand, several studies have shown that NO has a critical role in opioid-induced tolerance and dependence in both in vivo and in vitro models. In the present study, the effect of cyclosporine A and FK506 on the development of tolerance to and dependence on morphine in the guinea pig ileum was assessed. Morphine inhibited electrically stimulated twitch of ileum in a concentration-dependent manner (pD(2)=7.45+/-0.07). Tolerance to this effect was induced by incubation of ileum with 2 x IC(50) or 4 x IC(50) of morphine for 2 h that induced a degree of tolerance of 6.81 and 18.10, respectively. The co-incubation of ileum with morphine along with either cyclosporine A or FK506 reduced the degree of tolerance significantly (P<0.05) and restored the sensitivity of ileum to the morphine inhibitory effect. Dependence was induced by incubation with 4 x IC(50) of morphine for 2 h and was assessed based on naloxone-induced contractions (10(-5) M). Cyclosporine A (10(-9) M) and FK506 (10(-9) M) can attenuate the development of dependence to morphine as shown by the significant decrease in naloxone-induced contractions (P<0.05). These results suggest that immunophilin ligands at very low concentrations (nanomolar) can reduce the induction of acute tolerance to and dependence on morphine in the myenteric plexus of guinea pig ileum.
免疫亲和素配体环孢素A和FK506（他克莫司），除了具有免疫抑制作用外，还对不同的神经功能有多种影响，如调节多种神经递质的释放、通过抑制神经元型一氧化氮合酶（nNOS）的去磷酸化来减少一氧化氮（NO）的产生以及改变某些基因的表达。这些作用许多显然是通过抑制钙调神经磷酸酶（一种钙 - 钙调蛋白依赖性磷酸酶）而发生的。另一方面，多项研究表明，在体内和体外模型中，NO在阿片类药物诱导的耐受性和依赖性中起关键作用。在本研究中，评估了环孢素A和FK506对豚鼠回肠中吗啡耐受性和依赖性发展的影响。吗啡以浓度依赖性方式抑制回肠的电刺激抽搐（pD(2)=7.45±0.07）。通过将回肠与2倍IC(50)或4倍IC(50)的吗啡孵育2小时诱导对该作用的耐受性，分别诱导出6.81和18.10程度的耐受性。回肠与吗啡以及环孢素A或FK506共同孵育显著降低了耐受性程度（P<0.05），并恢复了回肠对吗啡抑制作用的敏感性。通过与4倍IC(50)的吗啡孵育2小时诱导依赖性，并基于纳洛酮诱导的收缩（10(-5) M）进行评估。环孢素A（10(-9) M）和FK506（10(-9) M）可减轻对吗啡的依赖性发展，纳洛酮诱导的收缩显著减少表明了这一点（P<0.05）。这些结果表明，极低浓度（纳摩尔）的免疫亲和素配体可减少豚鼠回肠肌间神经丛中对吗啡的急性耐受性和依赖性的诱导。
