Research article summary (published 10 Sep 2009):

The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances.

Full Abstract

Serotonin receptor (5-HTR) agonists that target 5-HT(4(a))R and 5-HT(1A)R can reverse mu-opioid receptor (mu-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart-brainstem preparations in situ, we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT(4(a))R and 5-HT(1A)R in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the mu-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT(1A)R agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT(4(a))R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of mu-OR cardiorespiratory disturbance by 5-HT(1A)R than 5-HT(4(a))R is supported by the finding that 5-HT(1A)R was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT(4(a))R. We conclude that during treatment of severe pain, 5-HT(1A)R agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances.

Author information

Author/s: Dutschmann, M (M); Waki, H (H); Manzke, T (T); Simms, A E (AE); Pickering, A E (AE); Richter, D W (DW); Paton, J F R (JF);

Affiliation: Institute of Membrane and Systems Biology, University of Leeds, , Leeds LS2 9JT, UK.

Journal and publication information

Publication Type: Comparative Study; Journal Article

Journal: Philosophical transactions of the Royal Society of London. Series B, Biological sciences (Philos Trans R Soc Lond B Biol Sci), published in England. (Language: eng)

Reference: 2009-Sep; vol 364 (issue 1529) : pp 2611-23

Dates: Created 2009/08/04; Completed 2009/10/30;

PMID: 19651661, status: MEDLINE (last retrieval date: 10/30/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology Analgesics, Opioid - metabolism Aniline Compounds - pharmacology Animals Blood Pressure - drug effects Brain Stem - physiology Cardiovascular Physiological Processes - drug effects Diaphragm - drug effects; physiology Electromyography Fentanyl - pharmacology

Heart - physiology Heart Rate - drug effects Histocytochemistry Phrenic Nerve - drug effects Piperidines - pharmacology Rats Receptors, Opioid, mu - agonists; metabolism Serotonin Agonists - pharmacology Telemetry Vascular Resistance - drug effects

Associated Chemicals: Analgesics, Opioid (0) ; Aniline Compounds (0) ; Piperidines (0) ; Receptors, Opioid, mu (0) ; Serotonin Agonists (0) ; RS 67333 (160845-95-4) ; Fentanyl (437-38-7) ; 8-Hydroxy-2-(di-n-propylamino)tetralin (78950-78-4)

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