Serotonin Receptor Agonists
The neurotransmitter serotonin (5HT) plays an important role in inspiratory and expiratory respiratory control with actions in the opposite direction from the μ-opioid receptors. We earlier summarized data on seven different serotonin agonists aimed at receptor subtypes 1a, 4a, and 7a. Irrespective of the targeted subtype, all agonists caused reversal or prevention of μ-opioid–induced respiratory depression in animal studies. In two recent studies, the effect of the 5HT4a receptor agonist BIMU8 was tested on etorphine- and sufentanil-induced respiratory depression.[26,44] In etorphine-immobilized goats, BIMU8 reduced etorphine toxicity with a reversal of the drop in respiratory rate and normalization of blood gasses. In the animals, blood pressure dropped after infusion of BIMU8, and some goats developed muscle rigidity or muscle spasms. In conscious rats, however, BIMU8 failed to counter sufentanil-induced respiratory depression, although this may be dose-related. This stands in contrast to 8-OH-DPAT, a 5HT1a and weak 7a receptor agonist that does reverse sufentanil-induced respiratory depression in the conscious rat by increasing respiratory rate and tidal volume. The development of muscle rigidity may be an additional cause of respiratory depression. Reducing muscle rigidity by adding the α1-adrenoreceptor agonist prazosin to 8-OH-DPAT treatment further improved tidal volume and oxygenation, albeit respiratory rate decreased by about 25%. This again highlights the importance of addressing muscle rigidity, the so-called wooden chest syndrome, in the light of opioid-induced respiratory depression. Importantly, and in contrast to the animal studies, in humans, the two studies that tested the effect of serotonin agonists selectively targeting the 1a- and the 4a-receptor subtypes failed to show efficacy in morphine-induced respiratory depression.[45,46] This may be related to insufficient dosing or due to insufficient exposure of the 5HT agonists at their receptor within the brainstem due to inability to pass the blood–brain barrier. Further studies on selective and permeable 5HT agonists are warranted.
Anesthesiology. 2022;136(4):618-632. © 2022 American Society of Anesthesiologists | Lippincott Williams & Wilkins