Opioid-induced Respiratory Depression Is Only Partially Mediated by the preBötzinger Complex in Young and Adult Rabbits In Vivo.
BACKGROUND
The preBötzinger Complex (preBC) plays an important role in respiratory rhythm generation. This study was designed to determine whether the preBC mediated opioid-induced respiratory rate depression at clinically relevant opioid concentrations in vivo and whether this role was age dependent.


METHODS
Studies were performed in 22 young and 32 adult New Zealand White rabbits. Animals were anesthetized, mechanically ventilated, and decerebrated. The preBC was identified by the tachypneic response to injection of D,L-homocysteic acid. (1) The μ-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO, 100 μM) was microinjected into the bilateral preBC and reversed with naloxone (1 mM) injection into the preBC. (2) Respiratory depression was achieved with intravenous remifentanil (0.08 to 0.5 μg kg(-1) min(-1)). Naloxone (1 mM) was microinjected into the preBC in an attempt to reverse the respiratory depression.


RESULTS
(1) DAMGO injection depressed respiratory rate by 6 ± 8 breaths/min in young and adult rabbits (mean ± SD, P < 0.001). DAMGO shortened the inspiratory and lengthened the expiratory fraction of the respiratory cycle by 0.24 ± 0.2 in adult and young animals (P < 0.001). (2) During intravenous remifentanil infusion, local injection of naloxone into the preBC partially reversed the decrease in inspiratory fraction/increase in expiratory fraction in young and adult animals (0.14 ± 0.14, P < 0.001), but not the depression of respiratory rate (P = 0.19). PreBC injections did not affect respiratory drive. In adult rabbits, the contribution of non-preBC inputs to expiratory phase duration was larger than preBC inputs (3.5 [-5.2 to 1.1], median [25 to 75%], P = 0.04).


CONCLUSIONS
Systemic opioid effects on respiratory phase timing can be partially reversed in the preBC without reversing the depression of respiratory rate.
From the Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (A.G.S., J.R.M., I.P., E.J.Z., F.A.H., E.A.E.S.); Children's Hospital of Wisconsin, Milwaukee, Wisconsin (A.G.S., E.A.E.S.); and the Zablocki VA Medical Center, Milwaukee, Wisconsin (E.J.Z., F.A.H.).
Astrid G
AG
Stucke
Justin R
JR
Miller
Ivana
I
Prkic
Edward J
EJ
Zuperku
Francis A
FA
Hopp
Eckehard A E
EA
Stuth
D000375:Aging; D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D011817:Rabbits; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D006710:Homocysteine; C007956:homocysteic acid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone