Evidence that cannabinoid-induced inhibition of electrically evoked contractions of the myenteric plexus--longitudinal muscle preparation of guinea-pig small intestine can be modulated by Ca2+ and cAMP.
Cannabinoid receptor agonists inhibit electrically evoked isometric contractions of the myenteric plexus--longitudinal muscle preparation of the guinea-pig small intestine (MPLM), probably by reducing release of acetylcholine (ACh) through the activation of prejunctional CB1 receptors. As CB1 receptors are thought to be negatively coupled through Gi/o proteins to both N-type Ca2+ channels and adenylate cyclase, we have now further investigated the involvement of CB1 receptors by monitoring the effects of forskolin, 8-bromo-cAMP, 3-isobutyl-1-methylxanthine (IBMX), and extracellular Ca2+ on the ability of the cannabinoid agonist, (+)-WIN 55212 to inhibit electrically evoked contractions of the MPLM (0.1 Hz, 0.5 ms, and 110% maximal voltage). Some experiments were performed with normorphine instead of (+)-WIN 55212. At 10(-7) M, forskolin, 8-bromo-cAMP, and IBMX were found to reduce significantly the maximum inhibitory response to (+)-WIN 55212 by 49.4, 48.4, and 40.2%, respectively, without affecting control contractions or responses to exogenous ACh. Low external Ca2+ (0.64 mM) significantly increased the maximum response to (+)-WIN 55212 and shifted the curve slightly leftwards, whereas high external Ca2+ (5.08 mM) reduced the maximum response by 27.2%. The concentration-response curve to normorphine, which also reduces evoked contractions of this preparation as a result of a presynaptic inhibition of ACh release via opioid mu receptors, was affected similarly. These results support the hypothesis that cannabinoid-induced inhibition in the MPLM is mediated by CB1 receptors.
Department of Biomedical Sciences, University of Aberdeen, Scotland. a.a.coutts@abdn.ac.uk
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Pertwee
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009022:Morphine Derivatives / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009197:Myenteric Plexus / Q000187:drug effects* / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002186:Cannabinoids; D009022:Morphine Derivatives; D009025:Morpholines; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017450:Receptors, Opioid, mu; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000242:Cyclic AMP; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; C010616:normorphine