Modulation of the exocytotic and carrier-mediated transmitter release by endogenous and exogenously added cannabinoids
Final Report Abstract
This project was dedicated to the delineation of the effects of endocannabinoids in tissues. It was shown previously that virodhamine is converted to a prostacyclin-like compound and the question arose whether a conversion to prostaglandins of the E series might occur as well. However, unlike prostaglandin E2, which markedly inhibited transmitter release in mouse tissues, virodhamine failed to do so. Next, the metabolically stable analogue of anandamide (R-methandamide) and a synthetic cannabinoid agonist showed an attenuated effect in a CB1 receptor model in rats anaesthetized with urethane when compared to rats treated with pentobarbital instead. We have shown in two in vitro CB1 receptor models that this discrepancy cannot be ascribed to an affinity or potency of urethane at CB1 receptors. The second part of the project was dedicated to the inverse CB1 receptor agonist rimonabant. This compound increased noradrenaline release in guinea pig hippocampal slices and this effect was mimicked by the neutral CB1 receptor antagonist O-2050, suggesting that the stimulatory effect is caused by the interruption of a tonical inhibition of transmitter release elicited by endogenously formed endocannabinoids and not by the inverse agonistic effect of rimonabant. Finally, the inhibition of acetylcholine release by a muscarinic receptor agonist was more pronounced in hippocampal slices from mice in which the CB1 receptor was genetically ablated or blocked by rimonabant, suggesting that the presynaptic muscarinic and CB1 receptors do not act independently from each other.
Publications
- (2009). Urethane, but not pentobarbitone, attenuates presynaptic receptor function in pithed rats: a contribution to the choice of anaesthetic. Brit. J. Pharmacol., 157: 1474-1482
Kurz CM, Baranowska U, Łupiński S, Göthert M, Malinowska B, Schlicker E
(See online at https://doi.org/10.1111/j.1476-5381.2009.00315.x) - (2010). A cannabinoid receptor, sensitive to O-1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats. Brit J Pharmacol 160:574-584
Zakrzeska A, Schlicker E, Baranowska M, Kozłowska H, Kwolek G, Malinowska B
(See online at https://doi.org/10.1111/j.1476-5381.2009.00579.x) - (2010). Involvement of central ß2-adrenergic, NMDA and thromboxane A2 receptors in the pressor effect of anandamide in rats. Naunyn-Schmiedeberg's Arch Pharmacol 381:349-360
Malinowska B, Zakrzeska A, Kurz CM, Göthert M, Wielgat P, Braszko JJ, Schlicker E
(See online at https://doi.org/10.1007/s00210-010-0497-6) - (2010). Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L- 826,266. Naunyn-Schmiedeberg's Arch Pharmacol., 381: 21-31
Günther J, Schulte K, Wenzel D, Malinowska B, Schlicker E
(See online at https://doi.org/10.1007/s00210-009-0478-9) - (2012). Acute myocardial ischemia enhances the vanilloid TRPV1 and serotonin 5-HT3 receptor-mediated Bezold-Jarisch reflex in rats. Pharmacol Rep, 63(6):1450-9
Łupiński SŁ, Schlicker E, Pędzińska-Betiuk A, Malinowska B
(See online at https://doi.org/10.1016/S1734-1140(11)70709-5) - (2012). Cannabinoid CB1 receptor activation, pharmacological blockade or genetic ablation affects the function of the muscarinic auto- and heteroreceptor. Naunyn-Schmiedeberg´s Arch Pharmacol, 385(4):385-96
Schulte K, Steingrüber N, Jergas B, Redmer A, Kurz CM, Buchalla R, Lutz B, Zimmer A, Schlicker E
(See online at https://doi.org/10.1007/s00210-011-0717-8) - (2012). Triphasic blood pressure responses to cannabinoids: do we understand the mechanism? Brit J Pharmacol, 165(7):2073-88
Malinowska B, Baranowska-Kuczko M, Schlicker E
(See online at https://doi.org/10.1111/j.1476-5381.2011.01747.x)
