PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression

• Published in: The Journal of neuroscience 2011-01, Vol.31 (4), p.1292-1301
• Main Authors: Montandon, Gaspard, Qin, Wuxuan, Liu, Hattie, Ren, Jun, Greer, John J, Horner, Richard L
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - adverse effects; Anesthesia; Animals; Apnea - chemically induced; Brain Stem - drug effects; Brain Stem - metabolism; Depression, Chemical; In Vitro Techniques; Male; Medulla Oblongata - physiology; Neurons - physiology; Periodicity; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1 - biosynthesis; Receptors, Opioid, mu - agonists; Respiration - drug effects; Respiratory Rate - drug effects; Sleep; Synaptic Transmission
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4611-10.2011

The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of the neurons mediating this depression are unknown. By locally manipulating neurotransmission in the adult rat, we identify the critical site of the medulla, the preBötzinger complex, that mediates opioid-induced respiratory depression in vivo. Here we show that opioids at the preBötzinger complex cause respiratory depression or fatal apnea, with anesthesia and deep-sleep being particularly vulnerable states for opioid-induced respiratory depression. Importantly, we establish that the preBötzinger complex is fully responsible for respiratory rate suppression following systemic administration of opioid analgesics. The site in the medulla most sensitive to opioids corresponds to a region expressing neurokinin-1 receptors, and we show in rhythmically active brainstem section in vitro that neurokinin-1 receptor-expressing preBötzinger complex neurons are selectively inhibited by opioids. In summary, neurokinin-1 receptor-expressing preBötzinger complex neurons constitute the critical site mediating opioid-induced respiratory rate depression, and the key therapeutic target for its prevention or reversal.