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

Date Published: January 19, 2010

Publisher: Public Library of Science

Author(s): Amanda R. Lorier, Gregory D. Funk, John J. Greer, Shawn Hochman.

Abstract: Hypoglossal (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.

Partial Text: Respiratory depression induced by opioid analgesics is a significant clinical problem [1]. This includes opiate-induced depression of hypoglossal motoneuron (XII MN) output, which activates the genioglossal muscle of the tongue and helps maintain an open airspace for effective breathing [2], [3]. Children and adults with obstructive sleep apnea (OSA) are particularly prone to opioid-induced apnea [4], [5], [6], [7], [8]. The mechanisms underlying opioid-induced suppression of XII nerve activity [9] are not well understood. Further, the current therapy to overcome the respiratory depression of administering μ-opiate receptor antagonists, such as naloxone, has the distinctly undesirable effect of removing analgesia. However, recent work [10], [11] has demonstrated that positive modulators of the AMPA sub-type of glutamate receptor, AMPAKINES, alleviate the opiate-induced depression of central respiratory rhythmogenesis [9], which is hypothesized to emanate from the preBötzinger complex (preBötC), without affecting analgesia. These data have led us to first assess whether an opiate-mediated inhibition of XII MNs contributes to the opiate-induced depression of breathing, and second, to examine the utility of AMPAKINES in reversing the opiate-mediated inhibition of XII inspiratory motor output. AMPAKINES are a family of compounds that modulate the actions of the excitatory neurotransmitter glutamate at AMPA receptors by altering channel kinetics [12], [13]. AMPA-receptor mediated currents are important for transmitting inspiratory drive to XII MNs [14], [15]. Thus, we hypothesized that increasing the charge transfer of inspiratory drive currents with AMPAKINES would counter μ-opiate receptor-mediated suppression of XII MN excitability. In this study we used medullary slice preparations from neonatal rats that produce inspiratory-related output in vitro to: i) determine the action of μ-opioid receptor activation on XII MN inspiratory activity; ii) determine the mechanism and sites of actions of μ-opioids within the XII motor nucleus, and iii) test the hypothesis that AMPAKINES counter opioid-induced depression of XII MN activity.