Julius H. Comroe Distinguished Lecture: Interdependence of neuromodulators in the control of breathing.

In vitro and in vivo anesthetized studies led to the conclusion that "deficiencies in one neuromodulator are immediately compensated by the action of other neuromodulators," which suggests an interdependence among neuromodulators. This concept was the focus of the 2018 Julius H. Comroe Lecture to the American Physiological Society in which I summarized our published studies testing the hypothesis that if modulatory interdependence was robust, breathing would not decrease during dialysis of antagonists to G protein-coupled excitatory receptors or agonists to inhibitory receptors into the ventral respiratory column (VRC) or the hypoglossal motor nuclei (HMN). We found breathing was not decreased during unilateral VRC dialyses of antagonists to excitatory muscarinic, serotonergic, and neurokinin-1 receptors alone or in combinations nor was breathing decreased with unilateral VRC dialysis of a µ-opioid receptor agonist. Analyses of the effluent dialysate revealed locally increased serotonin (excitatory) during muscarinic receptor blockade and decreased γ-aminobutyric acid (inhibitory) during dialysis of opioid agonists, suggesting an interdependence of neuromodulators through release of compensatory neuromodulators. Bilateral dialysis of receptor antagonists or agonist in the VRC increased breathing, which does not support the concept that unchanged breathing with unilateral dialyses was due to contralateral compensation. In contrast, in the HMN neither unilateral nor bilateral dialysis of the excitatory receptor antagonists altered breathing, but unilateral dialysis of the opioid receptor agonist decreased breathing. We conclude: 1) there is site-dependent interdependence of neuromodulators during physiologic conditions, and 2) attributing physiologic effects to a specific receptor perturbation is complicated by local compensatory mechanisms.