It is well established that cannabinoids acting at presynaptic cannabinoid CB₁ receptors inhibit electrical field stimulated (EFS) contractions of the guinea pig ileum by a reduction in acetylcholine release (Coutts and Pertwee, 1997). In the rat, activation of CB₁ receptors inhibits gastrointestinal transit whereas selective antagonism of these receptors has the opposite effect suggesting the presence of endogenous cannabinoid tone (Izzo et al., 1999). Since CB₁ receptor immunoreactivity has been identified in both the guinea pig and rat ileum myenteric plexus (Coutts et al., 2002) the aim of the present study was to examine the effects of cannabinoids on electrically evoked contractions of the rat isolated ileal myenteric plexus longitudinal muscle (MPLM) preparation. Strips of ileal MPLM were dissected from male Wistar rats (350-550g) and mounted in organ baths as described for the guinea pig MPLM by Coutts & Pertwee, (1997). Periodic EFS (30 V intensity, 30 Hz frequency, and 0.5 ms pulse duration for 2 sec every min) evoked stable rebound contractile responses that were abolished by treatment with either tetrodotoxin (1 µM) or atropine (1 µM). The non-selective cannabinoid receptor agonists CP 55,940 (0.1-100 µM) and WIN 55,212-2 (1-30 µM) produced a concentration dependent inhibition of the response to EFS (EC₅₀: 4.4 µM (n=8) and 3.4 µM; (n=14) respectively) with no significant inhibitory effect on exogenously applied carbachol (1 µM) induced contractions. Values are expressed as mean inhibition of maximal response ± s.e.m. All drugs were dissolved in absolute ethanol. The inhibitory effect of CP 55,940 was not antagonised by 60 min pre-treatment with the selective CB₁ receptor ligand SR141716 (1 µM). However SR141716 (1 µM) induced a small but statistically significant (P<0.05; one way ANOVA) rightward displacement of the WIN 55212-2 log concentration inhibitory response curve (EC₅₀ 8.9 µM (n=10)). It was difficult to study the antagonistic action of SR141716 since it alone produced a concentration related (0.1-30 µM) inhibition of the EFS response (EC₅₀ 3.6 µM (n=9)). Two other selective CB₁ receptor antagonists AM 251 and O-2050 also inhibited the EFS evoked response. (EC₅₀ 3.3 µM (n=11) and EC₅₀ 3.5 µM (n=4) respectively).

These observations are in marked contrast to those on the guinea pig MPLM where SR141716 and AM 251 potentiate EFS responses. Thus the inhibitory effect of WIN 55,212-2 but not CP 55,940 is mediated by CB₁ receptors. Whether or not the selective CB₁ receptor antagonists are acting on rat ileal MPLM as cannabinoid receptor agonists or through another mechanism remains to be established.

Coutts AA et al., (2002) J Comp Neurol. 448(4):410-22.
Coutts AA & Pertwee RG., (1997) Br J Pharmacol. 121(8):1557-66.
Izzo AA et al., (1999) Naunyn-Schmiedeberg’s Arch Pharmacol359:65–70.

We would like to thank Pfizer for the kind gift of CP 55,940 and Sanofi for SR141716.