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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.
Anesth Analg. 2009 Apr; 108(4):1169-76.A&A

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.

CONCLUSION

5-HT(1A)-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats.

Authors+Show Affiliations

Clinic of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany. ulf.guenther@ukb.uni-bonn.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19299781

Citation

Guenther, Ulf, et al. "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." Anesthesia and Analgesia, vol. 108, no. 4, 2009, pp. 1169-76.
Guenther U, Manzke T, Wrigge H, et al. 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. Anesth Analg. 2009;108(4):1169-76.
Guenther, U., Manzke, T., Wrigge, H., Dutschmann, M., Zinserling, J., Putensen, C., & Hoeft, A. (2009). 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. Anesthesia and Analgesia, 108(4), 1169-76. https://doi.org/10.1213/ane.0b013e318198f828
Guenther U, et al. 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. Anesth Analg. 2009;108(4):1169-76. PubMed PMID: 19299781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Guenther,Ulf, AU - Manzke,Till, AU - Wrigge,Hermann, AU - Dutschmann,Matthias, AU - Zinserling,Joerg, AU - Putensen,Christian, AU - Hoeft,Andreas, PY - 2009/3/21/entrez PY - 2009/3/21/pubmed PY - 2009/4/9/medline SP - 1169 EP - 76 JF - Anesthesia and analgesia JO - Anesth. Analg. VL - 108 IS - 4 N2 - 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. CONCLUSION: 5-HT(1A)-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/19299781/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_ L2 - http://dx.doi.org/10.1213/ane.0b013e318198f828 DB - PRIME DP - Unbound Medicine ER -