title: Inhibition by immunophilin ligands of morphine-induced tolerance and dependence in guinea pig ileum.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Shahram Ejtemaei
authors.initials: SE
authors.lastname: Mehr
authors.forename: Morteza
authors.initials: M
authors.lastname: Samini
authors.forename: Khodadad
authors.initials: K
authors.lastname: Namiranian
authors.forename: Houman
authors.initials: H
authors.lastname: Homayoun
authors.forename: Seyed Ali
authors.initials: SA
authors.lastname: Gaskari
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D020104:Immunophilins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D009020:Morphine; D016572:Cyclosporine; D020104:Immunophilins; D016559:Tacrolimus