Ampakines alleviate respiratory depression in rats.
BACKGROUND
There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the pre-Bötzinger 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 in the following rat models: (1) perinatal in vitro brainstem-spinal cord, (2) neonatal in vitro medullary slice, (3) juvenile in situ perfused, working heart-brainstem preparation, and (4) newborn and adult in vivo.


RESULTS
Administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not in older animals (greater than Postnatal Day 0). Furthermore, pharmacologic depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ, and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus.


CONCLUSIONS
CX546 effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify the potential of ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.
Ren
Jun
J
Department of Physiology, University of Alberta, 513 HMRC, Edmonton, AB, T6G 2S2 Canada.
Poon
Betty Y
BY
Tang
Yun
Y
Funk
Gregory D
GD
Greer
John J
JJ
D000701:Analgesics, Opioid; D000818:Animals; D000831:Animals, Newborn; D001463:Barbiturates; D004149:Dioxoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology*; D010991:Plethysmography; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D000701:Analgesics, Opioid; D001463:Barbiturates; D004149:Dioxoles; D010880:Piperidines