Acute effects of fentanyl on carotid body sensory activity

Abstract

Opioid drugs have long served as important agents for pain management in the clinic, but misuse of opioids, especially of illicit ultra-potent synthetic opioids like fentanyl, is driving the growing opioid epidemic. Like the natural opioid morphine, fentanyl targets μ-opioid receptor signaling in the central nervous system. However, the pharmacology of fentanyl on the opioid receptors differs from morphine, and clinical symptoms of fentanyl overdose like opioid-induced respiratory depression (OIRD) are more severe and less well-managed by reversal agents like naloxone. Hypoventilation due to OIRD stimulate peripheral chemoreceptors like the carotid body (CB). Previous reports suggest that morphine has minor effects on CB sensory output or the hypoxic ventilatory response mediated by the CB in animal models. Denervation of the CB significantly attenuates the hypoxic ventilatory response of unaesthetized rats after morphine treatment, suggesting that CB sensory activity persists in the presence of morphine to defend against OIRD. However, the effect of fentanyl on CB sensory responses has been little explored. Our goal was to determine how fentanyl regulates CB activity at the level of glomus cells, neuroendocrine sensory cells in the CB that signal to afferent nerves that project to the brainstem to increase ventilation. Sensory stimuli like hypoxia induce calcium transients in glomus cells across all species studied, including human. By two-photon imaging, we performed calcium imaging of mouse glomus cells expressing the genetically encoded calcium indicator GCaMP3 in intact CBs. Whereas morphine suppresses the activity of neurons in the central nervous system, application of fentanyl at levels sufficient to induce OIRD in mice acutely increased calcium transients in CB glomus cells. This increase in intracellular calcium was suppressed by naloxone, indicating that the stimulatory effect of fentanyl was mediated through opioid receptor signaling. In addition, we tested if glomus cells could respond to sensory stimuli in the presence of fentanyl. We found that the combination of fentanyl and hypoxia (PO2~25 mmHg) increased calcium responses over either fentanyl or hypoxia alone. These results suggest that CB stimulation through sensory pathways could potentially be targeted to increase ventilation in OIRD. Experimental groups contained 22-73 cells from least two preparations from different animals, and p<0.05 was set as a significant difference using appropriate statistical test. This work is funded by a UCSF Innovation Ventures Catalyst Grant and NIH Grant R41DA056270. AJC is a co-founder of Olfa Thera, Inc. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.