Clinically relevant infusion rates of {mu}-opioid remifentanil causes bradypnea in decerebrate dogs but not via direct effects in the pre-Botzinger Complex Region. Journal of neurophysiology [J Neurophysiol] Journal article

Systemic administration of micro-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MOR) on pre-Bötzinger Complex (preBötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of preBötC 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 preBötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist DL-homocysteic acid (DLH, 20 mM) or the MOR agonist [D-Ala(2), N-Me-Phe(4), gly-ol(5)]-enkephalin (DAMGO, 100muM). Inspiratory and expiratory durations (TI and TE) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The preBötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (~ 60% decrease in central breathing frequency, fB), bilateral injections of NAL in the preBötC did not change TI, TE, fB and PPA. Also, NAL picoejected onto single preBötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, ~60 mug/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the preBötC increased fB 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 preBötC region.

Journal of neurophysiology [J Neurophysiol]