Pontine μ-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs

Prkic I, Mustapic S, Radocaj T, Stucke AG, Stuth EA, Hopp FA, Dean C, Zuperku EJ. Pontine mu-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs. J Neurophysiol 108: 2430-2441, 2012. First published August 8, 2012; doi:10.1152/jn.00185.2012.-Life-threatening side effects such as profound bradypnea or apnea and variable upper airway obstruction limit the use of opioids for analgesia. It is yet unclear which sites containing mu-opioid receptors (mu ORs) within the intact in vivo mammalian respiratory control network are responsible. The purpose of this study was 1) to define the pontine region in which mu OR agonists produce bradypnea and 2) to determine whether antagonism of those mu ORs reverses bradypnea produced by intravenous remifentanil (remi; 0.1-1.0 mu g.kg(-1).min(-1)). The effects of microinjections of agonist [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO; 100 rho M) and antagonist naloxone (NAL; 100 mu M) into the dorsal rostral pons on the phrenic neurogram were studied in a decerebrate, vagotomized, ventilated, paralyzed canine preparation during hyperoxia. A 1-mm grid pattern of microinjections was used. The DAMGO-sensitive region extended from 5 to 7 mm lateral of midline and from 0 to 2 mm caudal of the inferior colliculus at a depth of 3-4 mm. During remi-induced bradypnea (similar to 72% reduction in fictive breathing rate) NAL microinjections (similar to 500 nl each) within the region defined by the DAMGO protocol were able to reverse bradypnea by 47% (SD 48.0%) per microinjection, with 13 of 84 microinjections producing complete reversal. Histological examination of fluorescent microsphere injections shows that the sensitive region corresponds to the parabrachial/Kolliker-Fuse complex.