Opioid-induced Respiratory Depression: Are 5-HT_4a Receptor Agonists the Cure?

Abstract

μ-Opioid receptor agonists are commonly utilized as analgesics for treatment of acute pain and some chronic pain syndromes. In addition to their outstanding effectiveness, opioids, unfortunately, promote respiratory depression. Indeed, opioid–induced respiratory depression can result in hypoventilation and neurologic injury, and may arise as a consequence of μ-opioid receptor–mediated blockade of specialized respiratory neurons in the brainstem. Manzke and coworkers have suggested that the serotonin receptor subtype 5-HT_4a (5-HT_4aR) could serve as a useful therapeutic target for the treatment or prevention of opioid–induced respiratory depression. This hypothesis derives from the finding that the 5-HT_4aR and the μ-opioid receptors affect the intracellular concentration of cyclic AMP in opposing ways. The findings are a significant milestone in ongoing efforts to understand the analgesia–ventilation link.