Depression of respiratory rate by intravenous opioids is not due to direct opioid effects on neurons within the preBotzinger Complex (pBC) region

Abstract

Clinical doses of i.v. mu‐opioids profoundly depress breathing rate. Mu‐opioid receptors (MORs) on pBC neurons, the putative kernel of rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pBC MORs to respiratory depression by i.v. remifentanil (remi), a short‐acting, selective MOR agonist. Multi‐barrel micropipettes were used to record pBC neuronal activity and picoeject naloxone (NAL) in decerebrate, vagotomized, paralyzed and ventilated dogs during isocapnic hyperoxia. Remi was infused i.v. at a rate (0.2–0.4 mcg/kg/min) that produced a marked steady‐state bradypnea as determined from the phrenic neurogram (PNG). In study 1, NAL (5 mM) was picoejected onto single pBC neurons to determine the level of direct remi depression. In study 2, bilateral injections of NAL (100 nl each), 3 each side, centered in the pBC and 1‐mm rostral and caudal were used to locally block MORs. The results show that antagonism of MOR in the pBC region had no effect on neuronal and PNG patterns, but i.v. NAL (0.3 ml; 5 mM) completely reversed bradypnea. We conclude that opioids at plasma concentrations used for profound clinical analgesia depress breathing via MORs outside of the pBC region, which does not exclude that effects may be mediated indirectly via the pBC. Support: VA Med. Res. Funds & NIH R01 GM59234.