Effects of Intra‐arterial Fentanyl and Codeine on Medullary Respiratory Network Organization

Abstract

The actions of mu‐opioid agonists to depress breathing are currently controversial, encompassing several proposed mechanisms that are focused on preferential effects in specific locations in the brainstem. We hypothesized that opioids have multiple actions at the respiratory network scale which include loss of synchrony and/or network dynamics. Experiments were conducted in 4 anesthetized, spontaneously breathing and 11 decerebrated, artificially ventilated, paralyzed and vagal intact cats. In spontaneously breathing animals, EMGs were recorded from diaphragm, parasternal, abdominal and upper airway muscles. In paralyzed animals, neurograms were recorded from phrenic and abdominal nerves. Fentanyl or codeine were administered via the vertebral artery (i.a.; fentanyl, 1‐10 ng/kg, codeine 1‐3000 μg/kg) while simultaneously recording from multiple medullary neurons. Analyses included assessment of autocorrelation histograms (ACH), significant features in cross correlation histograms (CCHs), and discharge identity (phenotype of firing frequency of a neuron during the breathing cycle). Qualitatively similar opioid‐induced changes in neuron firing rates, ACHs, CCHs, and discharge identity were observed during either fentanyl or codeine dose responses. Some neurons lost or gained excitability during the dose responses. ACHs of some neurons exhibited changes in spiking periodicity. Features in CCHs changed during administration of opioids including loss of some central or offset peaks. Detectability index (a metric of the magnitude of significant functional interactions) in some neuron pairs increased during opioid administration. Further, the discharge identity of many neurons changed during the dose responses with most of these changes occurring in neurons with tonic discharge during breathing. The extent of these changes strongly suggest that opioids induce significant changes in network organization including reduced synchrony and altered discharge identity of network members. These changes can occur at low doses of opioids that do not profoundly alter the breathing pattern.