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ANESTHETIC PHARMACOLOGY

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

Ulf Guenther, MD^*, Till Manzke, PhD, Hermann Wrigge, PhD^*, Matthias Dutschmann, PhD, Joerg Zinserling, PhD^*, Christian Putensen, PhD^*, and Andreas Hoeft, PhD^*

From the *Clinic of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany; and DFG Research Center Molecular Physiology of the Brain (CMPB), Goettingen, Humboldtallee 23, Goettingen, Germany.

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 µM in situ, 0.1 µg/kg in vivo) enhanced nociceptive reflexes but did not activate spontaneous ventilation. On the contrary, high doses of 8-OH-DPAT (1 µM in situ and 10–100 µg/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 µM in situ, and 10 µg/kg in vivo), whereas antinociception sustained. Selective 5-HT_1A-R-antagonist WAY 100 635 (1 µM) 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.

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