Assessing the emetic potential of PDE4 inhibitors in rats

Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha2‐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. 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 (alpha2‐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. Neither MK‐912 (3 mg kg−1) nor PMNPQ (0.1 – 1 mg kg−1) altered the duration of anaesthesia induced via a non‐alpha2‐adrenoceptor pathway (sodium pentobarbitone 50 mg kg−1, i.p.) Central NK1 receptors are involved in PDE4 inhibitor‐induced emesis. Consistently, [sar9, Met(O2)11]‐substance P (NK1 receptor agonist, 6 μg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. In summary, this model is functionally coupled to PDE4, specific to alpha2‐adrenoceptors and relevant to PDE4 inhibitor‐induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats. British Journal of Pharmacology (2002) 135, 113–118; doi:10.1038/sj.bjp.0704457