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

Abstract

Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the µ-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 µM) decreased pulmonary ventilation (V̇i), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered V̇i or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased V̇i and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory µ-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions.