Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

Abstract

BackgroundHypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of μ-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.Methodology/Principal FindingsA medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the μ-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.Conclusions/SignificanceThe inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract μ-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

“…In addition, brainstem histology confirmed extensive motoneuron pathology in Gaa 2/2 mice, and showed, for the first time, histopathology in medullary respiratory control neurons. The dramatic impact of CX717 on efferent respiratory motor output in Gaa 2/2 mice supports the hypothesis that respiratory neuropathology has a functional impact in Pompe disease (4), as ampakines stimulate breathing most effectively when respiratory neuromotor activity is blunted (13,20).…”

“…Ampakines are positive modulators of the AMPA glutamate receptor subtype, and act to increase the duration of AMPA receptor gated-inward currents (20,46). The ampakine used in this study, CX717, is metabolically stable, clinically safe, and effectively crosses the blood-brain barrier (11,14,47,48).…”

“…The ampakine used in this study, CX717, is metabolically stable, clinically safe, and effectively crosses the blood-brain barrier (11,14,47,48). CX717 has been used in both animal models (15,17,20) and clinical trials to alleviate respiratory depression due to opioids (14). CX717 does not directly antagonize opioid receptors, because, in both rats and humans, CX717 counteracts respiratory depression without influencing analgesia (15)(16)(17)20).…”

“…CX717 has been used in both animal models (15,17,20) and clinical trials to alleviate respiratory depression due to opioids (14). CX717 does not directly antagonize opioid receptors, because, in both rats and humans, CX717 counteracts respiratory depression without influencing analgesia (15)(16)(17)20). Animal studies have confirmed that CX717 stimulates breathing by potentiating AMPA currents in respiratory neurons, including both motor and premotor neurons (15,20).…”

“…This is a fundamental consideration, as delineation of the neuronal mechanisms contributing to respiratory failure in Pompe disease is a prerequisite for optimizing therapeutic strategies. Mechanistically, ampakines can act on both respiratory premotor circuits and motoneurons (13,20), and, accordingly, we believed it was important to determine if pathology was present in premotor respiratory control neurons, and to compare and contrast the histological appearance of these cells with respiratory motoneurons.…”