Effects on breathing of agonists to μ-opioid or GABA A receptors dialyzed into the ventral respiratory column of awake and sleeping goats

Abstract

Pulmonary ventilation (V̇I) in awake and sleeping goats does not change when antagonists to several excitatory G protein-coupled receptors are dialyzed unilaterally into the ventral respiratory column (VRC). Concomitant changes in excitatory neuromodulators in the effluent mock cerebral spinal fluid (mCSF) suggest neuromodulatory compensation. Herein, we studied neuromodulatory compensation during dialysis of agonists to inhibitory G protein-coupled or ionotropic receptors into the VRC. Microtubules were implanted into the VRC of goats for dialysis of mCSF mixed with agonists to either μ-opioid (DAMGO) or GABAA (muscimol) receptors. We found: 1) V̇I decreased during unilateral but increased during bilateral dialysis of DAMGO, 2) dialyses of DAMGO destabilized breathing, 3) unilateral dialysis of muscimol increased V̇I, and 4) dialysis of DAMGO decreased GABA in the effluent mCSF. We conclude: 1) neuromodulatory compensation can occur during altered inhibitory neuromodulator receptor activity, and 2) the mechanism of compensation differs between G protein-coupled excitatory and inhibitory receptors and between G protein-coupled and inotropic inhibitory receptors.

Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats

“…Doi and Ramirez tested the concept of neuromodulator interdependence where changes in one or more neuromodulators are compensated for by changes in other modulators to maintain stability in the respiratory control network (7,8). Subsequent studies support this concept as compensatory neuromodulation was elicited by dialysis of agonists/antagonists in the respiratory rhythm/pattern-generating VRC of awake and sleeping goats (20,21,(32)(33)(34)(35). The objective herein was to study this concept as it applies to the motor neuron-rich HMN, focusing on effects of activating -opioid receptors (DAMGO) or inhibiting musca- rinic (atropine), neurokinin-1 (spantide) and select serotonergic receptors (5-HT 2A ; MDL 11,939).…”

“…Indeed, conformational changes in opioid receptors cause coupling to inhibitory G proteins when exposed to high opioid concentration, whereas the same receptor subtype might switch to a stimulatory G protein during exposure to low opioid concentrations (11,49). Opioids modulate neural activity throughout the central nervous system, including the preBötC and HMN (10,18,20,48). The effects of opioid administration in the preBötC, critical for the generation of respiratory rhythm and pattern (18,21), have been equivocal, where some studies found breathing increases (20,36), breathing decreases (28,29), or no effect (18,20).…”

“…Hour 1 was mCSF alone, hour 2 was mCSF alone or mCSF mixed with different drugs, and hour 3 was mCSF alone. One dialyzed drug was the -opioid agonist DAMGO at concentrations of 10 or 100 M, which is over the range and duration others used in dialysis studies on rats or dogs (29,36) and the same as in previous studies in the VRC (20). The second drug was 50 mM atropine, which was at the same concentrations during dialysis into the VRC (21,32).…”

“…Increased activity of inhibitory neuromodulatory receptors in the VRC of awake and sleeping goats does not elicit local increases in excitatory neuromodulators but still provides another example of compensatory neuromodulation. For example, dialysis of the -opioid receptor agonist [D-Ala 2 , N-MePhe 4 , Gly-ol]enkephalin (DAMGO) led to a dose-dependent decrease in the local, endogenous GABA in the effluent dialysate (20). The reduced GABA levels were concomitant with transient decreases in V I with unilateral DAMGO, whereas bilateral dialysis of 100 M DAMGO increased V I and f and increased the variability of V I (20), indicative of local neuromodulator compensation for the increased inhibition by the exogenously delivered opioid.…”

“…For example, dialysis of the -opioid receptor agonist [D-Ala 2 , N-MePhe 4 , Gly-ol]enkephalin (DAMGO) led to a dose-dependent decrease in the local, endogenous GABA in the effluent dialysate (20). The reduced GABA levels were concomitant with transient decreases in V I with unilateral DAMGO, whereas bilateral dialysis of 100 M DAMGO increased V I and f and increased the variability of V I (20), indicative of local neuromodulator compensation for the increased inhibition by the exogenously delivered opioid. Thus, collectively, the summarized results support the concept of neuromodulator interdependence in respiratory rhythm-and pattern-generating nuclei such as the preBötC of the VRC (7,8,20,21,(32)(33)(34)(35).…”