title: Ampakine therapy to counter fentanyl-induced respiratory depression.
abstract: Opioid analgesics are the most widely used and effective pharmacological agents for the treatment of acute, postoperative and chronic pain. However, activation of opiate receptors leads to significant depression of respiratory frequency in a subpopulation of patients. Here we test the hypothesis that the AMPAKINE CX717 is effective for alleviating fentanyl-induced respiratory depression without interfering with analgesia. Ampakines are a relatively new class of compounds that are in Phase II clinical trials as potential treatments for cognitive disorders and the enhancement of memory and attentiveness. They function by allosterically binding to amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA)-type glutamate receptors and modulating the kinetics of channel closing, transmitter dissociation and desensitization. AMPA receptor mediated conductances play a central role in controlling respiratory rhythmogenesis and drive to motoneurons. Here, we demonstrate that CX717 counters fentanyl-induced respiratory depression without significantly altering analgesia and sedation, or noticeably affecting the animals' behavior. Collectively, the preclinical data demonstrate the significant potential for the use of ampakines in respiratory medicine.
authors.affiliation: Department of Physiology, Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. john.greer@ualberta.ca
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005283:Fentanyl; D006339:Heart Rate / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010147:Pain Measurement; D010791:Phrenic Nerve / Q000502:physiology; D010991:Plethysmography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy*; D013997:Time Factors
chemical_list: C542518:CX717; D007555:Isoxazoles; D018091:Receptors, AMPA; D005283:Fentanyl