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Ampakines alleviate respiratory depression in rats
Author(s) -
Greer John James,
Ren Jun,
Poon Betty,
Funk Greg D
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a558-b
Subject(s) - respiratory system , respiratory center , barbiturate , medicine , pharmacology , opioid , anesthesia , brainstem , ketamine , in vivo , depression (economics) , receptor , biology , microbiology and biotechnology , macroeconomics , economics
Rationale: There is a need for improved therapeutic interventions to treat both drug‐ and sleep‐induced respiratory depression. Activation of AMPA‐type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the preBötzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. Objective: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid‐ and barbiturate‐induced respiratory depression. Methods: Respiratory frequency and amplitude were measured using the following rat models; perinatal in vitro brainstem‐spinal cord, neonatal in vitro medullary slice, juvenile in situ perfused, working heart‐brainstem preparation and, newborn and adult in vivo.Results: The administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not older animals. Pharmacological depression of respiratory frequency and amplitude was countered at all ages studied by CX546 in vitro, in situ and in vivo. Significantly, CX546 countered opioid‐induced breathing depression in all preparations, without altering suppressing analgesia. Conclusions: CX546 effectively reverses opioid‐ and barbiturate‐induced respiratory depression without reversing analgesic response. These studies suggest that ampakines may be useful in preventing or reversing drug‐induced respiratory depression and identify a potential for ampakines for alleviating other forms of respiratory depression. Funded by CIHR, CFI, ASRAP and AHFMR.