Pretreatment with clonidine caused desensitization to WIN 55,212-2 in guinea pig ileum

1. Considering the existence of cross-tolerance between clonidine and morphine besides the same interaction between morphine and WIN 55,212-2 persuaded us to verify this fact between WIN 55,212-2 and clonidine in guinea pig ileum, which is a well-known model to examine the mode of action of cannabinoids and α₂-adenoceptor agonists
2. The rectangular pulses were passed to the 0.5 g stretched ileum segments that were fixed in 20-ml organ bath. PowerLab system and Graphpad Prism were applied to record twitches and analyse the data. Electrically evoked contractions were dose-dependently inhibited by WIN 55,212-2 and clonidine (pD₂= 8.56 ± 0.41 and 7.65 ± 0.15, respectively).
3. Tolerance to this effect could be induced by 4-h incubation with WIN 55,212-2 (3 × IC₅₀) (pD₂ = 6.36 ± 0.26, degree of tolerance: 159.32) (P < 0.01) but not with clonidine (2 × IC₅₀ and 4 × IC₅₀) for different time courses. Dose–response curve for inhibitory action of WIN 55,212-2 was shifted to the right after 4-h incubation with clonidine (3 × 10⁻¹⁰m) comparing to the untreated tissues (pD₂ = 5.26 ± 0.69, degree of tolerance: 2000) (P < 0.001). This observation provides the evidence for the cannabinoid-noradrenergic systems interaction in the enteric nervous system as a simplified representative for central nervous system.