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Review
. 2018 Nov 1;125(5):1511-1525.
doi: 10.1152/japplphysiol.00477.2018. Epub 2018 Aug 23.

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

Hubert V Forster  1
Affiliations
Review

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

Hubert V Forster. J Appl Physiol (1985). .

Abstract

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.

Keywords: breathing; compensation; neuromodulation.

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Figures

Fig. 1.
Fig. 1.
Unilateral dialysis of 50 mM atropine (ATR; a muscarinic receptor antagonist) into the pre-Bötzinger complex (preBötC) during the day increased (P < 0.001) pulmonary ventilation (V̇I; A) and breathing frequency (B) above dialysis of mock cerebrospinal fluid (mCSF), but tidal volume (VT; C) was not altered. The F and P values are from two-way repeated measures ANOVA. *Holm-Sidak post hoc test. Shown here (and in subsequent figures) are data binned at 15-min intervals, and the x-axis is time in minutes from start of dialysis. Open circles are data when mCSF was dialyzed over the entire period, and open squares are when 50 mM atropine was dialyzed between 60 and 120 min (closed squares and black line indicate period of atropine dialysis).
Fig. 2.
Fig. 2.
There is a state-dependent effect on pulmonary ventilation (V̇I); A and breathing frequency (B) of a muscarinic receptor antagonist unilaterally dialyzed into the ventral respiratory column (VRC) as 50 mM atropine increased V̇I and breathing frequency in the awake state but not during nonrapid eye movement (NREM) sleep (two-way repeated-measures ANOVA). Circles are data during the awake state, and squares are data during NREM sleep. Closed symbols and black line indicate period of atropine dialysis. *P < 0.005, significant difference between state; †P < 0.05, comparing values with 1 or more points in the predialysis period by post hoc analysis (Holm-Sidak).
Fig. 3.
Fig. 3.
Dialysis of the muscarinic receptor antagonist atropine (ATR) into the ventral respiratory column (VRC) elicits apparent compensatory changes in other neuromodulators. Compared with dialysis of mock cerebral spinal fluid (mCSF) alone, the concentrations of serotonin (5-HT; A), glycine (GLY; B), γ-aminobutyric acid (GABA; C) were increased (P < 0.05) in the effluent mCSF during daytime unilateral dialysis into the VRC of 50 mM atropine. The x-axis is hour of dialysis. The 1st bar for each hour is when mCSF was dialyzed all 3 h while the 2nd bar is when 50 mM atropine was dialyzed during the 2nd hour (closed bar). F and P values are from two-way ANOVA. *P < 0.05, significant difference between treatments; **P < 0.001 between groups; †P < 0.001 comparisons with hour 1; §P < 0. 001, comparisons with hour 2 by by post hoc analysis (Holm-Sidak).
Fig. 4.
Fig. 4.
The effect of unilateral dialysis of 50 mM atropine into the ventral respiratory column (VRC) appears state-independent as shown by the finding that the mock cerebral spinal fluid (mCSF) effluent concentration of serotonin (5-HT; A), γ-aminobutyric acid (GABA; B), and glycine (GLY; C) did not differ (P > 0.05) between day and night studies even though the goats were in nonrapid eye movement for extended periods at night. The 1st and 2nd bars for each hour represent day and night studies, respectively. The shaded gray represents when 50 mM atropine (ATR) was dialyzed. F and P values are from two-way repeated measures ANOVA comparing day and night values *P < 0.05 between treatment groups, †P < 0.05 vs. hour 1.
Fig. 5.
Fig. 5.
The effect on compensatory neuromodulators of a muscarinic receptor antagonists dialyzed into the ventral respiratory column is state independent as indicated by the finding that the mock cerebral spinal fluid (mCSF) effluent concentration of serotonin (5-HT; A), glycine (B), γ-aminobutyric acid (GABA; C) did not differ (P > 0.05) between awake and isoflurane anesthesia studies. The 1st and 2nd bars for each hour represent awake and anesthetized states, respectively. F and P values are from two-way repeated measures ANOVA.
Fig. 6.
Fig. 6.
Release of compensatory neuromodulators in response to a muscarinic receptor antagonist is locally mediated and not reflex as indicated by increases in serotonin (5-HT; A) and glycine (B) at the site of 50 mM atropine (ATR) dialysis but not at the contralateral site. Data are from an individual goat studied on 2 different dates with mock cerebral spinal fluid (mCSF) dialyzed for 3 h at one site, and on alternate days, 50 mM atropine were dialyzed at the contralateral site during hour 2 of dialysis.
Fig. 7.
Fig. 7.
The effect on pulmonary ventilation (V̇I; A) and breathing frequency (B) of atropine dialysis is dose-dependent as indicated by the finding that in contrast to dialysis of 50 mM atropine (Fig. 1), dialysis of 5 mM atropine (this figure) into the ventral respiratory column did not affect V̇i and breathing frequency differently (P > 0.028) from dialysis of mock cerebral spinal fluid (mCSF) (two-way repeated measures ANOVA). Open circles are data when mCSF was dialyzed over the entire period, and squares are when 5 mM atropine was dialyzed between 60 and 120 min (closed squares and black line indicate period of atropine dialysis).
Fig. 8.
Fig. 8.
Simultaneous blockade of 3 excitatory receptor neuromodulators was insufficient to alter pulmonary ventilation (V̇I; A) and breathing frequency (B) as indicated by the finding that unilateral dialysis into the ventral respiratory column during the day of a triple mixture of antagonist [5 mM atropine (ATR), 500 µM spantide (SPA), and 0.5 mM MDL 11939] had no effect on V̇I or breathing frequency. The x-axis is time from start of dialysis. Open triangles are data when mock cerebral spinal fluid (mCSF) was dialyzed over the entire period, and circles are when the mixture was dialyzed during hour 2 of dialysis (closed squares and black line indicate period of cocktail dialysis). F and P are values from interaction term of two-way repeated measures ANOVA. mAChRs, muscarinic acetylcholine receptors.
Fig. 9.
Fig. 9.
Bilateral dialysis into the ventral respiratory column (VRC) of a triple mixture of excitatory receptor antagonists had a paradoxical effect as indicated by an increased pulmonary ventilation (V̇I; A), metabolic rate (V̇o2; B), and ventilatory drive (Vt/Ti; C). Open circles are when mock cerebral spinal fluid (mCSF) was dialyzed for 3 hours and closed circles are when the cocktail was dialyzed during hour 2 of dialysis. The x-axis is time from beginning of dialysis. F and P are values from interaction term of two-way repeated measures ANOVA. *P < 0.05, post hoc significant difference between treatments.
Fig. 10.
Fig. 10.
Bilateral dialysis into the ventral respiratory column of the triple mixture of excitatory receptor antagonists increased the concentration of 5-HT in the effluent mock cerebral spinal fluid (mCSF) over values when mCSF was dialyzed for 3 h. The 1st bar for each hour is when mCSF was dialyzed all 3 h while the 2nd bar is when the triple mixture was dialyzed during the 2nd hour (closed bar). *During the hour of and the hour after antagonists dialysis, 5-HT was significantly increased above mCSF dialysis.
Fig. 11.
Fig. 11.
There is a site- dependent effect on pulmonary ventilation (V̇I; A) and breathing frequency (B) of unilateral dialysis of 50 mM atropine as dialysis into the hypoglossal motor nuclei did not (P = 0.905) alter V̇I and breathing frequency which contrast to the marked hyperpnea after atropine dialysis into the ventral respiratory column (Fig. 1). The black line denotes when atropine was dialyzed.
Fig. 12.
Fig. 12.
Unilateral dialysis of 50 mM atropine has an apparent site-independent effect on release of 5-HT ventral respiratory column as indicated by increased 5-HT after atropine dialysis into both the hypoglossal motor nuclei (this figure) and the ventral respiratory column (Fig. 3). Values are presented for the 3 h of dialysis when atropine was dialyzed during hour 2. *P < 0.001, comparisons with hour 1 by post hoc analysis (Holm-Sidak),
Fig. 13.
Fig. 13.
Increased activation of µ-opioid inhibitory receptors by unilateral dialysis of 100 µM of [d-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO; closed circles) into the ventral respiratory column did not (P = 0.758) alter pulmonary ventilation (V̇i; A) and breathing frequency (B) compared with dialysis of mock cerebral spinal fluid (mCSF) (open circles). The black line denotes when DAMGO was dialyzed.
Fig. 14.
Fig. 14.
Increased activation of µ-opioid inhibitory receptors by bilateral dialysis of 100 µM d-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO) into the ventral respiratory column paradoxically increased pulmonary ventilation (V̇i; A), breathing frequency (B), and ventilatory drive (Vt/Ti; C). Open circles are when mCSF was dialyzed for 3 h and closed circles are when DAMGO was dialyzed during hour 2 of dialysis. F and P are values from interaction term of two-way repeated measures. *P < 0.001 comparisons to the pre DAMGO dialysis period by post hoc analysis (Holm-Sidak).
Fig. 15.
Fig. 15.
There was a dose-dependent decrease in the concentration of the endogenous inhibitory receptor agonist GABA when the exogenous inhibitory receptor agonist [d-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO) was dialyzed into the ventral respiratory column. F and P values are from a one-way ANOVA.
Fig. 16.
Fig. 16.
Increased activation of µ-opioid inhibitory receptors by unilateral dialysis of 100 µM [d-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO) into the hypoglossal motor nuclei decreased activation of the genioglossal muscle (closed circles), but did not alter activation of the diaphragm (open circles). F and P values are from two-way ANOVA comparing dialysis of DAMGO during hour 3 and dialysis of mCSF all 3 h. *P < 0.001 comparisons to the pre DAMGO dialysis period by post hoc analysis (Holm-Sidak).
Fig. 17.
Fig. 17.
There is a site-dependent effect on pulmonary ventilation (V̇i; A and C) and breathing frequency (B and D)of dialysis of a µ-opioid inhibitory receptor agonist. Unilateral (A and B) and bilateral (C and D) dialysis of the agonist (closed circles) into the HMN decreased P < 0.016) or did not change (P = 462) V̇i and breathing frequency. These findings contrast to unchanged V̇i and breathing frequency (Fig. 13) or increased values (Fig. 14) during dialysis into the ventral respiratory column (VRC). The black line denotes when DAMGO was dialyzed.
Fig. 18.
Fig. 18.
Unilateral dialysis into the ventral respiratory column of 1 mM muscimol (closed circles), an ionotropic GABA receptor agonist paradoxically increased pulmonary ventilation (V̇i; A) and breathing frequency (B) compared with dialysis of mCSF (open circles). The black line denotes when muscimol was dialyzed. *P < 0.001, comparisons with the pre DAMGO dialysis period by post hoc analysis (Holm-Sidak).
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