FURTHER EVIDENCE FOR THE PRESENCE OF CANNABINOID CBI RECEPTORS IN GUINEA-PIG SMALL-INTESTINE

1 CP 50,556, CP 55,940, nabilone, CP 56,667, Delta(9)-tetrahydrocannab inol (THC) and cannabinol each inhibited electrically-evoked contracti ons of the myenteric plexus-longitudinal muscle preparation of guinea- pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.36, 30.61, 162.94, 214.63 , and 3913.5 nM, correlate well with previously obtained potency value s for displacement of [H-3]-CP 55,940 from cannabinoid binding sites. 2 Electrically-evoked contractions of the myenteric plexus-longitudina l muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline ) and by WIN 55,212-2 (IC50=1923.0 and 5.54 nM, respectively). The pre sent finding that AM 630 is an agonist, contrasts with a previous obse rvation that it behaves as a cannabinoid receptor antagonist in the mo use isolated vas deferens. 3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940 , WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked c ontractions of the myenteric plexus-longitudinal muscle preparation. S R141716A (1 mu M) did not reverse the inhibitory effects of normorphin e and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine. 4 Doses of naloxone and yohimbi ne that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,2 12-2. 5 Electrically-evoked release of acetylcholine from strips of my enteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 a nd this inhibitory effect was almost completely reversed by 1 mu M SR1 41716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940. 6 These results support the hypothesis that guinea-pig sma ll intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine. 7 THC was found to be more susceptible to antagonism by SR141716A than CP 55 ,940 or AM 630, raising the possibility that guinea-pig small intestin e contains more than one type of cannabinoid receptor. 8 At concentrat ions of 10 nM and above, SR141716A produced small but significant incr eases in the amplitude of electrically-evoked contractions of the myen teric plexus-longitudinal muscle preparation suggesting that this tiss ue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716 A can reduce the number of receptors in this state.