title: Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats.
abstract: Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates.
authors.affiliation: Numedicus Limited, Cambridge CB1 2DX, United Kingdom; Revive Therapeutics Ltd., 5 Director Court, Suite 105, Vaughan, Ontario L4L 4S5, Canada. Electronic address: david.cavalla@numedicus.co.uk.
authors.forename: David
authors.initials: D
authors.lastname: Cavalla
authors.affiliation: Revive Therapeutics Ltd., 5 Director Court, Suite 105, Vaughan, Ontario L4L 4S5, Canada. Electronic address: fabio@revivethera.com.
authors.forename: Fabio
authors.initials: F
authors.lastname: Chianelli
authors.affiliation: Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. Electronic address: a.korsak@ucl.ac.uk.
authors.forename: Alla
authors.initials: A
authors.lastname: Korsak
authors.affiliation: Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Hosford
authors.affiliation: Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. Electronic address: a.gourine@ucl.ac.uk.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
authors.affiliation: UCL Department of Clinical Pharmacology, University College London, London WC1E 6JF, United Kingdom. Electronic address: n.marina@ucl.ac.uk.
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
mesh_terms: D000818:Animals; D004146:Dioxanes / Q000494:pharmacology; D004149:Dioxoles; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009020:Morphine; D017288:Pain Threshold / Q000187:drug effects*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D010993:Plethysmography, Whole Body; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D012119:Respiration / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D004146:Dioxanes; D004149:Dioxoles; D018690:Excitatory Amino Acid Agonists; D010880:Piperidines; D018091:Receptors, AMPA; D013841:Thiazepines; C050504:tianeptine; D009020:Morphine
keywords: Ampakines; Analgesia; Morphine; Nociception; Opiates; Respiratory depression; Tianeptine