Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis

• Published in: The Journal of clinical investigation 2002-10, Vol.110 (7), p.1045-1052
• Main Authors: Robichaud, Annette, Stamatiou, Panagiota B, Jin, S-L Catherine, Lachance, Nicholas, MacDonald, Dwight, Laliberté, France, Liu, Susana, Huang, Zheng, Conti, Marco, Chan, Chi-Chung
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - classification; 3',5'-Cyclic-AMP Phosphodiesterases - physiology; Anesthesia; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Male; Mice; Mice, Inbred C57BL; Pentobarbital - pharmacology; Phosphodiesterase Inhibitors - adverse effects; Receptors, Adrenergic, alpha-2 - physiology; Time Factors; Vomiting - chemically induced
• ISSN: 0021-9738
• DOI: 10.1172/JCI200215506

A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.