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GABAB agonists block morphine-induced emesis in the ferret and the dog
The emetic reflex is complex and 5-HT, substance P and dopamine are involved in the integration of vomiting, retching and nausea (Miner et al., 1986; Bountra et al., 1996; Miner et al., 1987). Whilst GABA is the major inhibitory neurotransmitter in the CNS, its role in emetic pathways in the medullary “vomiting centre” has not been investigated. GABAB receptor agonists reduce release of substance P from spinal cord neurons by presynaptic inhibition (Riley et al., 2001). Release of tachykinins is of major importance in the emetic reflex of animals, as NK1 receptor antagonists are potent anti-emetic drugs . Therefore studies were conducted in the dog and the ferret to investigate the effect of GABAB agonists on opioid-induced emesis. Male albino and polecat ferrets (1.0–1.6kg) and female beagle dogs (10-15kg) were dosed subcutaneously (sc.) with morphine sulphate (Sigma) at a dose previously shown to induce a maximal emetic response, (ferret: 0.25mg kg-1; dog: 0.40mg kg-1). GABAB agonists (R,S-baclofen ;0.03–1mg kg-1 or SKF 97541 ;0.001 –0.1mg kg-1), were dosed (ferret sc. ; dog iv.)15-30 min before morphine challenge. Also, in a limited study in ferrets, the CNS penetrant GABAB antagonists CGP-35348 (50mg kg-1 sc.) and CGP-55845 (0.15mg kg-1 sc.) were dosed 15 and 30 min before dosing with baclofen and morphine, respectively. All animals were observed continuously for 6 hr following dosing with morphine, with retching and vomiting recorded. Morphine induced a consistent and marked emetic response in all animals (group mean ± s.e. of mean: ferret: 46.5 ± 3.0 retches; 8.3 ± 0.6 vomits; n =39; dog: 35.0 ± 5.1 retches; 4.0 ± 0.7 vomits; n =5). In the ferret, baclofen dose-dependently reduced morphine-induced retching and vomiting (0.1mg kg-1: -50%; 0.3mg kg-1: -99%) with 100% inhibition at 1mg kg-1 (n = 3). Also in the ferret, SKF-97541 dose-dependently reduced retching and vomiting (0.003mg kg-1, -80%) with 100% inhibition of morphine-induced emesis at a 0.01mg kg-1 (n = 3). In the dog, baclofen dose-dependently decreased emesis (0.03mg kg-1, -26% ; 0.1mg kg-1, -70% ; 0.3 mg kg-1 -100%, n =5), while SKF-97541 (n=2) completely blocked emesis at 0.01 and 0.001mg kg-1. In the ferret, CGP-35348 (50mg kg-1sc.) or CGP-55845 (0.15mg kg-1 sc.) attenuated the anti-emetic activity of baclofen (0.3–1mg kg-1sc.) by 75%. These results demonstrate that GABAB agonists have potent anti-emetic activity against opioid-induced emesis in two species. Since GABA is a major neuronal inhibitory transmitter the possibility exists that this class of compound may possess anti-emetic activity against diverse emetic stimuli, and may be of use in clinical conditions where emesis remains a problem.
Miner W.D. et al., (1986). Brit. J. Pharmacol., 88, 497-499. |
