title: Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.
abstract: BACKGROUND
  5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 μg/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid.
  
  
  METHODS
  A dose-response curve of the repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate repinotan dose (10 μg/kg), and (2) remifentanil boluses (2.5 μg/kg) were given after repinotan (10 and 20 μg/kg).
  
  
  RESULTS
  (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by repinotan (10 μg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 μg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 μg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 μg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level).
  
  
  CONCLUSIONS
  Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.
authors.affiliation: Clinic of Anesthesiology and Intensive Care Medicine, Bonn University Hospital, Bonn, Germany. u.guenther@uni-bonn.de
authors.forename: Ulf
authors.initials: U
authors.lastname: Guenther
authors.forename: Nils U
authors.initials: NU
authors.lastname: Theuerkauf
authors.forename: Daniel
authors.initials: D
authors.lastname: Huse
authors.forename: Michael F
authors.initials: MF
authors.lastname: Boettcher
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
authors.forename: Christian
authors.initials: C
authors.lastname: Putensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D000077208:Remifentanil; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000517:prevention & control*; D015656:Respiratory Mechanics / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D001578:Benzopyrans; D006993:Hypnotics and Sedatives; D010880:Piperidines; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; C111221:repinotan hydrochloride; D000077208:Remifentanil