tacrolimus and Morphine-Dependence

FK506 is an immunophilin-binding ligand that inhibits calcineurin and decreases nitric oxide (NO) production in the nervous tissues. We examined the effects in mice of systemic treatment with FK506 on the induction and expression of morphine (s.c.) tolerance and dependence and compared them with the effects of the non-specific NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and specific inducible NO synthase inhibitor, aminoguanidine. FK506 (0.5-10 mg/kg, s.c.) exerted inhibitory effects on both development and expression of tolerance to morphine-induced antinociception. FK506 also significantly decreased the expression of morphine dependence, as assessed by naloxone-precipitated (2 mg/kg, i.p.) withdrawal syndrome, but a similar effect was not found for the development of morphine dependence. A similar pattern of effects was observed with L-NAME (3-20 mg/kg, i.p.), while aminoguanidine (50-100 mg/kg, i.p.) did not alter tolerance or dependence. Examining the possible interaction between their inhibitory effects on tolerance and dependence, we combined the subeffective doses of FK506 (0.5 or 1 mg/kg) with L-NAME (3 mg/kg) or aminoguanidine (100 mg/kg). The combination of FK506 with L-NAME, but not with aminoguanidine, significantly decreased the development and expression of tolerance and expression of dependence. These data show the effectiveness of FK506 on morphine tolerance and dependence and suggest an additive effect between FK506 and the inhibition of constitutive NO synthesis in this regard.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Enzyme Inhibitors; Guanidines; Immunophilins; Injections, Intraperitoneal; Injections, Subcutaneous; Ligands; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain Measurement; Substance Withdrawal Syndrome; Tacrolimus

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.

Topics: Animals; Cyclosporine; Dose-Response Relationship, Drug; Drug Tolerance; Electric Stimulation; Guinea Pigs; Ileum; Immunophilins; In Vitro Techniques; Male; Morphine; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Narcotics; Tacrolimus