US EPA

1984898 

Journal Article 

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 

Guenther, Ulf; Manzke, T; Wrigge, H; Utschmann, M; Zinserling, J; Putensen, C; Hoeft, A 

2009 

Yes 

Anesthesia and Analgesia
ISSN: 0003-2999
EISSN: 1526-7598 

108 

4 

1169-1176 

English 

19299781 

10.1213/ane.0b013e318198f828 

WOS:000264534700022 

http://://WOS:000264534700022
Exit
 

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 viva anesthetized rats.



RESULTS: Low-dose 8-OH-DPAT (0.001 and 0.01 mu M in situ, 0.1 mu g/kg in vivo) enhanced nociceptive reflexes but did not activate spontaneous ventilation. On the contrary, high doses of 8-OH-DPAT (1 mu M in situ and 10-100 mu g/kg in viva) stimulated ventilation, whereas nociceptive CFR amplitude in situ returned to baseline and tail-flick reflex was depressed in viva. Opioid-induced ventilatory depression was antagonized by 8-OH-DPAT (1 mu M in situ, and 1.0 mu g/kg in viva), whereas antinociception sustained. Selective 5-HT(1A)-R-antagonist WAY 100 635 (1 AM) prevented the effects of 8-OH-DPAT in situ.



CONCLUSION: 5-HT(1A)-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats. (Anesth Analg 2009;108:1169-76) 

induced respiratory depression; postoperative pain management; pressure; release ventilation; tonic nociceptive pain; 5-ht1a agonist f-13640; acute lung injury; spinal-cord; withdrawal reflex; receptor agonist; formalin model