Assessing the emetic potential of PDE4 inhibitors in rats

1 Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2 Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.) PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01-3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01-3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1-10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3 Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1-1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4 Central NK1, receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O-2)(11)]-substance P (NK1 receptor agonist, 6 mug i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5 In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.