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. 2014 Jan 1;190:20-4.
doi: 10.1016/j.resp.2013.10.001. Epub 2013 Oct 11.

Intranodose Ganglion Injections of Dronabinol Attenuate Serotonin-Induced Apnea in Sprague-Dawley Rat

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Free PMC article

Intranodose Ganglion Injections of Dronabinol Attenuate Serotonin-Induced Apnea in Sprague-Dawley Rat

Michael W Calik et al. Respir Physiol Neurobiol. .
Free PMC article

Abstract

Obstructive sleep apnea represents a significant public health concern. Afferent vagal activation is implicated in increased apnea susceptibility by reducing upper airway muscle tone via activation of serotonin receptors in the nodose ganglia. Previous investigations demonstrated that systemically administered cannabinoids can be used therapeutically to decrease the apnea/hypopnea index in rats and in humans. However, cannabinoids have effects on both the central and peripheral nervous systems, and the exact mechanism of decreased apnea/hypopnea index with cannabinoids is unknown. Here, we hypothesized that intranodose ganglion injections of a cannabinoid will attenuate 5-HT-induced reflex apnea and increase upper airway muscle tone. We show that dronabinol injected locally into the nodose ganglia suppresses 5-HT-induced reflex apnea, and increases phasic, but not tonic, activation of the genioglossus. These data support the view that dronabinol stabilizes respiratory pattern and augments upper airway muscles by acting at the nodose ganglia. These findings underscore a therapeutic potential of dronabinol for the treatment of obstructive sleep apnea.

Keywords: Cannabinoids; Dronabinol; Genioglossus; Nodose ganglia; OSA; Serotonin.

Figures

Figure 1
Figure 1
Protocol of acute 5-HT-induced apneas. For baseline recording, rats under ketamine/xylazine anesthesia were instrumented with femoral I.V. catheters, genioglossus electrodes, and a piezoelectric strain gauges, and then infused with 5-HT to induce apneas and record genioglossus activity. After baseline recordings, surgical exposure of nodose ganglia was performed, and 5-HT infusion and surgery baseline recordings were performed to confirm that the nerves were functionally intact. After confirmation that nerves were intact, nodose injections of 100 µg or 10 µg of dronabinol or vehicle, or sham surgery were performed, and 5-HT infusion and nodose injection recordings were performed. EMGgg = genioglossus electromyogram.
Figure 2
Figure 2
Sample recordings from acute 5-HT-indudced apnea experiments. The left panels are from an acute experiment of dronabinol (100 µg) injections into the nodose ganglia. The right panels are from an acute experiment of vehicle (sesame oil) injections into the nodose ganglia. Genioglossus electromyogram and respiratory recordings were taken before surgery (Baseline, top panels), after surgery (Surgery Baseline, middle panels), and after nodose ganglia injections (Nodose Injection, bottom panels). Apnea was attenuated, and EMGgg was increased, in the dronabinol injections. Vertical line signifies femoral intravenous 5-HT (12.5 µg/kg) infusion to induce reflex apnea. A.U. = arbitrary units; EMGgg = genioglossus electromyogram; RESP = respiratory pattern.
Figure 3
Figure 3
Apnea duration quantified from acute 5-HT-induced apnea experiments. 100 µg of dronabinol injected into the nodose ganglia attenuated apnea duration compared to baseline and surgery baseline. 10 µg of dronabinol injected into the nodose ganglia attenuated apnea duration compared only to baseline. * p<0.05 compared to baseline recording; # p<0.05 compared to surgery baseline recording; two-way repeated measures ANOVA (treatment × time) with Tukey's post hoc multiple comparison test. Dronab = dronabinol.
Figure 4
Figure 4
Phasic and tonic genioglossus electromyogram amplitude quantified from acute 5-HT-induced apnea experiments. (A) 100 µg of dronabinol injected into the nodose ganglia increased phasic genioglossus muscle activity. (B) There were no differences in tonic genioglossus muscle activity among the treatment groups. * p<0.05 compared to baseline; # p<0.05 compared to surgery baseline recording; + p<0.05 compared to other nodose injection treatments; two-way repeated measures ANOVA (treatment × time) with Tukey's post hoc multiple comparison test. EMGgg = genioglossus electromyogram, Dronab = dronabinol.

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