Intestinal inflammation and morphine tolerance alter the interaction between morphine and clonidine on gastrointestinal transit in mice

Background: Morphine and clonidine show synergy or antagonism inhibiting gastrointestinal transit depending on their proportion and level of effect. Their interaction during morphine tolerance and intestinal inflammation were assessed. Methods: Gastrointestinal transit in mice was evaluated with charcoal and antitransit effects expressed as percent mean values ± SEM. Tolerance was induced with a morphine pellet (75 mg) implanted for 72 h, and inflammation with intragastric croton oil. Dose-response curves for morphine and clonidine alone and combined at a 1:1 potency ratio were obtained, and doses producing a 50% and 60% inhibition were calculated (ED50, ED60). Interaction was established by isobolograms, interaction indexes, and analysis of variance. Results: In naive and tolerant mice, the combination induced linear dose-response curves up to the ED60 and then reached a plateau. In naive mice, ED50 values were as follows: morphine 1.52 ± 0.15 mg/kg, clonidine 0.09 ± 0.008 mg/kg, and combined 0.506 ± 0.084 mg/kg (0.478 ± 0.08 mg/kg morphine plus 0.028 ± 0.004 mg/kg clonidine). During tolerance, ED50 values were as follows: morphine 9.73 ± 0.8 mg/kg, clonidine 0.09 ± 0.007 mg/kg, combination 0.131 ± 0.09 mg/kg (morphine 0.13 ± 0.09 mg/kg plus clonidine 0.0013 ± 0.0005 mg/kg). In both groups, the interaction was synergistic up to the ED60 and antagonistic thereafter; synergy was enhanced during tolerance. During inflammation, ED50 values were as follows: morphine 0.17 ± 0.04 mg/kg, clonidine 0.015 ± 0.006 mg/kg, combined 0.62 ± 0.04 mg/kg (morphine 0.568 ± 0.04 mg/kg plus clonidine 0.052 ± 0.004 mg/kg); thus, potencies of morphine and clonidine increased 9.3 and 7.1 times, while the combination remained unaltered. Moreover, inflammation transformed synergy into antagonism. Conclusions: The interaction between morphine and clonidine was significantly altered during tolerance and inflammation. During tolerance, synergy was present up to 60% effect and then became antagonistic. Inflammation converted synergy to antagonism. A common pathway in signal transduction could partially explain the results.