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.