title: The counteraction of opioid-induced ventilatory depression by the serotonin 1A-agonist 8-OH-DPAT does not antagonize antinociception in rats in situ and in vivo.
abstract: BACKGROUND
  Spontaneous breathing during mechanical ventilation is gaining increasing importance during intensive care but is depressed by narcotics, such as opioids. Serotonin 1A-receptor (5-HT(1A)-R) agonists have been shown to antagonize opioid-induced ventilatory depression, but both enhancement and attenuation of nociceptive reflexes have been found with different experimental models. To clarify contradictory findings, we simultaneously determined dose-response functions of the standard 5-HT(1A)-R-agonist 8-OH-DPAT and two different opioids for spontaneous ventilation and nociception. Two hypotheses were tested: 1) 8-OH-DPAT at a dose to stimulate spontaneous breathing does not activate nociceptive reflexes. 2) 8-OH-DPAT does not diminish opioid-induced antinociception.
  
  
  METHODS
  (A) A dose-response relationship of 8-OH-DPAT, spontaneous phrenic nerve activity and a nociceptive C-fiber reflex (CFR) were established simultaneously in an in situ perfused, nonanesthetized, rat brainstem-spinal cord preparation. (B) Fentanyl was administered in situ to investigate the interaction with 8-OH-DPAT on phrenic nerve activity and nociceptive CFR. Additional experiments involved the selective 5-HT(1A)-R-antagonist WAY 100 635 to exclude effects of receptors other than 5-HT(1A)-R. (C) The effects of 8-OH-DPAT on spontaneous ventilation and nociceptive tail-flick reflex with and without morphine were verified in in vivo anesthetized rats.
  
  
  RESULTS
  Low-dose 8-OH-DPAT (0.001 and 0.01 microM in situ, 0.1 microg/kg in vivo) enhanced nociceptive reflexes but did not activate spontaneous ventilation. On the contrary, high doses of 8-OH-DPAT (1 microM in situ and 10-100 microg/kg in vivo) stimulated ventilation, whereas nociceptive CFR amplitude in situ returned to baseline and tail-flick reflex was depressed in vivo. Opioid-induced ventilatory depression was antagonized by 8-OH-DPAT (1 microM in situ, and 10 microg/kg in vivo), whereas antinociception sustained. Selective 5-HT(1A)-R-antagonist WAY 100 635 (1 microM) prevented the effects of 8-OH-DPAT in situ.
  
  
  CONCLUSIONS
  5-HT(1A)-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats.
authors.affiliation: Clinic of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany. ulf.guenther@ukb.uni-bonn.de
authors.forename: Ulf
authors.initials: U
authors.lastname: Guenther
authors.forename: Till
authors.initials: T
authors.lastname: Manzke
authors.forename: Hermann
authors.initials: H
authors.lastname: Wrigge
authors.forename: Matthias
authors.initials: M
authors.lastname: Dutschmann
authors.forename: Joerg
authors.initials: J
authors.lastname: Zinserling
authors.forename: Christian
authors.initials: C
authors.lastname: Putensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010791:Phrenic Nerve / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D012123:Pulmonary Ventilation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D009020:Morphine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005283:Fentanyl