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October 17, 2009
2:00 PM - 4:00 PM
Room Area J
Direct Microejection of µ-Opioids into preBötzinger Complex Region In Vivo Produces Tachypnea
  **   Sanda Mustapic, M.D., Eckehard Stuth, M.D., Tomislav Radocaj, M.D., Edward Zuperku, Ph.D., Astrid Stucke, M.D.
Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Systemic administration of µ-opioids at clinical doses typically produces bradypnea in humans and other mammals in vivo. Studies in brain slices of immature rodents that contain the preBötzinger (pBC), the putative respiratory rhythm generating center, show that µ-opioids markedly slow the burst rate of respiratory-related output (Gray et al. 1999). We previously showed that local microinjections of the opioid antagonist naloxone into the pBC could not reverse the bradypnea of systemic remifentanil. This study evaluated whether µ-opioid receptor activation within the pBC region in vivo has any effects on respiratory timing.

The studies were approved by the institutional Animal Care Committee and conformed with the standards set forth by National Institutes of Health. The effects of local microinjections of the selective µ-opioid agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO;100 µM) into the pBC region on the phrenic neurogram were studied in a decerebrate, vagotomized, mechanically-ventilated, paralyzed canine preparation during hyperoxia. The location of the pBC was determined by ventral respiratory column neuronal recordings and the maximum tachyneic phrenic response to glutamate agonist (DLH) microejections. Effects were assessed with ANOVA.

Following unilateral DAMGO microejections (190±13 nl), the maximum increase in respiratory rate was 44±5% (SE) in 16 dogs. Bilateral DAMGO microejections (4 dogs) did not cause additional increases in respiratory rate compared to unilateral ejection. Subsequent i.v. infusion of the µ-agonist remifentanil typically produced a marked reduction in rate to 44.5±8.0% of control that more than offset the DAMGO induced tachypnea.

These findings further support our previous study indicating that clinical doses of systemic µ-opioids produce their bradypneic effect via µ-opioid receptors that are located outside the pBC, the putative rhythm generating center. In contrast activation of µ-opioid receptors within the pBC region produces tachypnea in vivo. Supported by VA Medical Research and NIH GM059234 funds.

From Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists.