Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.
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.
Robichaud
Annette
A
Merck Frosst Centre for Therapeutic Research, Pointe-Claire - Dorval, Quebec, Canada. annette_robichaud@merck.com
Stamatiou
Panagiota B
PB
Jin
S-L Catherine
SL
Lachance
Nicholas
N
MacDonald
Dwight
D
Laliberté
France
F
Liu
Susana
S
Huang
Zheng
Z
Conti
Marco
M
Chan
Chi-Chung
CC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000145:classification / Q000502:physiology*; D000758:Anesthesia; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010424:Pentobarbital / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced*
D010726:Phosphodiesterase Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010424:Pentobarbital