title: Clinically relevant infusion rates of mu-opioid agonist remifentanil cause bradypnea in decerebrate dogs but not via direct effects in the pre-Bötzinger complex region.
abstract: Systemic administration of mu-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Bötzinger Complex (pre-BötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BötC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent mu-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record pre-BötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist D-homocysteic acid (DLH, 20 mM), or the MOR agonist [D-Ala(2), N-Me-Phe(4), gly-ol(5)]-enkephalin (DAMGO, 100 microM). Inspiratory and expiratory durations (T(I) and T(E)) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (approximately 60% decrease in central breathing frequency, f(B)), bilateral injections of NAL in the pre-BötC did not change T(I), T(E), f(B), and PPA. Also, NAL picoejected onto single pre-BötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, approximately 60 microg/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BötC increased f(B) by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that mu-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BötC region.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Clement J. Zablocki VA Medical Center, 5000 W. National Ave., Milwaukee, WI 53295, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Mustapic
authors.forename: Tomislav
authors.initials: T
authors.lastname: Radocaj
authors.forename: Antonio
authors.initials: A
authors.lastname: Sanchez
authors.forename: Zoran
authors.initials: Z
authors.lastname: Dogas
authors.forename: Astrid G
authors.initials: AG
authors.lastname: Stucke
authors.forename: Francis A
authors.initials: FA
authors.lastname: Hopp
authors.forename: Eckehard A E
authors.initials: EA
authors.lastname: Stuth
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Zuperku
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D003655:Decerebrate State; D004285:Dogs; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007839:Functional Laterality; D006710:Homocysteine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D000077208:Remifentanil; D056152:Respiratory Rate / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D018690:Excitatory Amino Acid Agonists; D009292:Narcotic Antagonists; D010880:Piperidines; D006710:Homocysteine; C007956:homocysteic acid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D000077208:Remifentanil