Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea‐pig small intestine

Abstract

1 The psychoactive cannabinoids (-)-A9-tetrahydrocannabinol ((-)-A9-THC) and the 1,l-dimethylheptyl homologue of (-)-11-hydroxy-A8-tetrahydrocannabinol ((-)-DMH) both inhibited electricallyevoked contractions of the mouse isolated vas deferens and the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine. 2 Concentrations of (-)-A9-THC and (-)-DMH that decreased twitch heights by 50% were 6.3 and 0.15nM respectively in the mouse vas deferens and 60nM and 1.4nM respectively in the myenteric plexus preparation. (-)-DMH was about 40 times more potent than (-)-A9-THC in both preparations, supporting the notion that their mode of action in each tissue is the same. 3 The psychically inactive cannabinoid, (+)-DMH, had no inhibitory effect in the mouse vas deferens at a concentration of 30 nM, showing it to be at least 1000 times less potent than (-)-DMH. In the myenteric plexus preparation, (+)-DMH was about 500 times less potent than its (-)-enantiomer. 4 The inhibitory effects of sub-maximal concentrations of (-)-A9-THC were not attenuated by 300 nM naloxone. 5 The findings that (-)-A9-THC and (-)-DMH are highly potent as inhibitors of the twitch response of the mouse vas deferens and guinea-pig myenteric plexus preparation and that DMH shows considerable stereoselectivity suggest that the inhibitory effects of cannabinoids in these preparations are mediated by cannabinoid receptors.

Modulation of Excitatory Synaptic Transmission by Δ9-Tetrahydrocannabinol Switches from Agonist to Antagonist Depending on Firing Rate

“…We speculate that the high sensitivity of THC-mediated inhibition of synaptic transmission to firing frequency contributes to the variable effects reported for this drug in in vitro models. The only experiments to describe THC-mediated inhibition of synaptic transmission were performed at a stimulus rate of 0.1 Hz or less (Pertwee et al, 1996;Shen and Thayer, 1999;Azad et al, 2008) or used intermittent burst-type stimulus protocols with prolonged interstimulus intervals (Pertwee et al, 1992). It is noteworthy that a partial agonist at 5-hydroxytryptamine-3 receptors was shown previously to display a frequency-dependent reduction in the efficacy for inhibition of neurotransmitter release (Van der Vliet et al, 1988), suggesting that a general property of presynaptic inhibition produced by agonists of low intrinsic activity may be an especially high sensitivity to firing rate.…”

Acute Δ9-Tetrahydrocannabinol-Induced Deficits in Reversal Learning: Neural Correlates of Affective Inflexibility

“…Each cohort was then further subdivided into three treatment groups receiving vehicle (1% Tween 80 in saline), 0.01 mg/kg THC, or 1.0 mg/kg THC (Sigma, UK). THC was prepared according to a previously published method (Pertwee et al, 1992). To permit counterbalancing in the behavioral task, an n ¼ 12 per treatment group was employed for behavior-positive animals, but, to reduce animal use, an n ¼ 8 per treatment group was employed in the behavior-negative animals, which were paired as far as group numbers permitted with behavior-positive animals receiving the same drug treatment.…”

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

“…Cumulative concentration-response curves were constructed to the cannabinoid ligands with a 20 or 30 min dosing interval on tissues stimulated with 0.05 or 0.1 and 30 Hz respectively. Only one concentration-response curve was constructed per tissue as previous studies have shown that cannabinoids cannot be washed from the tissue by replenishing the bath with drug-free Krebs-Henseleit solution (Pertwee et al, 1992). When competition studies were performed, the cannabinoid receptor antagonists/inverse agonists were administered 30 min prior to the addition of the cannabinoid receptor agonists.…”