Assessing the emetic potential of PDE4 inhibitors in rats

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. 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. 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 2 ‐adrenoceptor pathway (sodium pentobarbitone 50 mg kg −1 , i.p.) Central NK 1 receptors are involved in PDE4 inhibitor‐induced emesis. Consistently, [sar 9 , Met(O 2 ) 11 ]‐substance P (NK 1 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 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.British Journal of Pharmacology (2002) 135 , 113–118; doi: 10.1038/sj.bjp.0704457