Local microejection of mu‐opioids into the pre‐Bötzinger complex (pBC) region produces opposite effects on breathing rate to systemic mu‐opioid infusion in decerebrate dogs

Abstract

Systemic administration of mu‐opioids at clinical doses typically produces bradypnea. This study evaluated whether mu‐opioid receptors within the pBC region mediate this response. The effects of local microinjections of the selective mu‐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 tachypneic phrenic response to glutamate agonist (DLH) microejections. 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 mu‐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 support our previous study indicating that clinical doses of mu‐opioids produce their bradypneic effect via mu‐opioid receptors that are located outside the pBC. In contrast activation of mu‐opioid receptors within the pBC region produces tachypnea in vivo. Supported by VA Medical Research and NIH GM059234 funds.