title: Pontine μ-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs.
abstract: 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 μ-opioid receptors (μORs) 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 μOR agonists produce bradypnea and 2) to determine whether antagonism of those μORs reverses bradypnea produced by intravenous remifentanil (remi; 0.1-1.0 μg·kg(-1)·min(-1)). The effects of microinjections of agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO; 100 μM) and antagonist naloxone (NAL; 100 μM) 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 (~72% reduction in fictive breathing rate) NAL microinjections (~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/Kölliker-Fuse complex.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Prkic
authors.forename: Sanda
authors.initials: S
authors.lastname: Mustapic
authors.forename: Tomislav
authors.initials: T
authors.lastname: Radocaj
authors.forename: Astrid G
authors.initials: AG
authors.lastname: Stucke
authors.forename: Eckehard A E
authors.initials: EA
authors.lastname: Stuth
authors.forename: Francis A
authors.initials: FA
authors.lastname: Hopp
authors.forename: Caron
authors.initials: C
authors.lastname: Dean
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Zuperku
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D018686:Anesthetics, Intravenous / Q000633:toxicity*; D000818:Animals; D001931:Brain Mapping; D003964:Diaphragm / Q000294:innervation; D004285:Dogs; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D018496:Hyperoxia; D007262:Infusions, Intravenous; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology; D010880:Piperidines / Q000633:toxicity*; D011149:Pons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077208:Remifentanil; D056152:Respiratory Rate / Q000187:drug effects* / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D009292:Narcotic Antagonists; D010880:Piperidines; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D000077208:Remifentanil