Barbara Palkovic1, Denise Cook-Snyder2, Jennifer J Callison3, Thomas M Langer3, Riley Nugent4, Eckehard A E Stuth5, Edward J Zuperku6, Astrid G Stucke7. 1. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Faculty of Medicine, University of Osijek, Osijek, Croatia. 2. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Department of Neuroscience, Carthage College, Kenosha, WI, United States; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States. 3. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States. 4. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Carroll University, Waukesha, WI, United States. 5. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Children's Wisconsin, Milwaukee, WI, United States. 6. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Zablocki VA Medical Center, Milwaukee, WI, United States. 7. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States; Children's Wisconsin, Milwaukee, WI, United States. Electronic address: astucke@mcw.edu.
Abstract
BACKGROUND: Opioid-induced respiratory depression can be partially antagonized in the preBötzinger Complex and Parabrachial Nucleus/Kölliker-Fuse Complex. We hypothesized that additional opioid antagonism in the caudal medullary raphe completely reverses the opioid effect. METHODS: In adult ventilated, vagotomized, decerebrate rabbits, we administrated remifentanil intravenously at "analgesic", "apneic", and "very high" doses and determined the reversal with sequential naloxone microinjections into the bilateral Parabrachial Nucleus/Kölliker-Fuse Complex, preBötzinger Complex, and caudal medullary raphe. In separate animals, we injected opioid antagonists into the raphe without intravenous remifentanil. RESULTS: Sequential naloxone microinjections completely reversed respiratory rate depression from "analgesic" and "apneic" remifentanil, but not "very high" remifentanil concentrations. Antagonist injection into the caudal medullary raphe without remifentanil independently increased respiratory rate. CONCLUSIONS: Opioid-induced respiratory depression results from a combined effect on the respiratory rhythm generator and respiratory drive. The effect in the caudal medullary raphe is complex as we also observed local antagonism of endogenous opioid receptor activation, which has not been described before.
BACKGROUND: Opioid-induced respiratory depression can be partially antagonized in the preBötzinger Complex and Parabrachial Nucleus/Kölliker-Fuse Complex. We hypothesized that additional opioid antagonism in the caudal medullary raphe completely reverses the opioid effect. METHODS: In adult ventilated, vagotomized, decerebrate rabbits, we administrated remifentanil intravenously at "analgesic", "apneic", and "very high" doses and determined the reversal with sequential naloxone microinjections into the bilateral Parabrachial Nucleus/Kölliker-Fuse Complex, preBötzinger Complex, and caudal medullary raphe. In separate animals, we injected opioid antagonists into the raphe without intravenous remifentanil. RESULTS: Sequential naloxone microinjections completely reversed respiratory rate depression from "analgesic" and "apneic" remifentanil, but not "very high" remifentanil concentrations. Antagonist injection into the caudal medullary raphe without remifentanil independently increased respiratory rate. CONCLUSIONS: Opioid-induced respiratory depression results from a combined effect on the respiratory rhythm generator and respiratory drive. The effect in the caudal medullary raphe is complex as we also observed local antagonism of endogenous opioid receptor activation, which has not been described before.
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