Cited by 267Phosphodiesterase function and regulationPharmacogenetics and Drug MetabolismVeterinary Pharmacology and Anesthesia

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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

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Robichaud, Annette, Stamatiou, Panagiota B., Jin, S.-L.Catherine, Lachance, Nicholas, MacDonald, Dwight, Laliberté, France, Liu, Susana, Huang, Zheng, Conti, Marco, Chan, Chi-Chung·2002·Journal of Clinical Investigation

DOI 10.1172/jci15506PMC PMC151147

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Abstract

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.

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“However, the deletion of PDE4D specifically results in a behavior correlated to emesis, supporting the hypothesis that the inhibition of PDE4D is likely responsible for emesis induced by PDE4 inhibitors (Robichaud et al., 2002).”
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Authors: Robichaud, A., Stamatiou, P. B., Jin, S.-L. C., Lachance, N., MacDonald, D., Laliberté, F., Liu, S., Huang, Z., Conti, M., & Chan, C.-C.
Affiliations: Merck Canada Inc. (Canada) (CA)
Stanford Medicine (US)
Corresponding author: Robichaud, Annette
ORCID: MacDonald, Dwight
Huang, Zheng
Conti, Marco
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2002-10-01
Volume: 110
Issue: 7
Pages: 1045-1052
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci15506
PMC: PMC151147
OpenAlex: W2170451911
Cited by: 267
References: 44
Citations by year: 2026: 4 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 7 · 2017: 14 · 2016: 10 · 2015: 11 · 2014: 22 · 2013: 11 · 2012: 19
FWCI: 3.83
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Child Health and Human Development
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD020788, HD20788)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Veterinary › Small Animals › Veterinary Pharmacology and Anesthesia
Keywords: PDE4D, PDE4B, phosphodiesterase-4 inhibitors, vomiting, ketamine-xylazine anesthesia, rolipram, sleep duration, cAMP signaling
MeSH terms: Anesthesia, Animals, Male, Mice, Inbred C57BL, Pentobarbital, Phosphodiesterase Inhibitors, Time Factors, Vomiting, 3',5'-Cyclic-AMP Phosphodiesterases, Receptors, Adrenergic, alpha-2, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4

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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

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