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

Abstract

Serotonin receptor (5-HTR) agonists that target 5-HT 4(a) R and 5-HT 1A R can reverse μ-opioid receptor (μ-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 μ-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 μ-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.