Crosstalk Inhibition Between 5-HT2A and Adenosine 2A Receptor-Induced Phrenic Motor Facilitation

Abstract

Episodic spinal serotonin receptor activation elicits phrenic motor facilitation (pMF), a form of respiratory motor plasticity. Although both intermittent 5-HT2 and 5-HT7 receptor activation elicit pMF, they do so via distinct cellular mechanisms known as the Q (5-HT2A/B) and S (5-HT7) pathways. The Q and S pathways interact via powerful crosstalk inhibition; thus, concurrent activation of both receptor subtypes diminishes/abolishes pMF. At least some of the molecules giving rise to mutually inhibitory interactions between 5-HT2 and 5-HT7 receptors have been identified. Although episodic spinal adenosine 2A (A2A) receptor activation also elicits pMF via the S pathway, we do not know: 1) if 5-HT2 and A2A receptors interact via similar crosstalk inhibition, nor 2) if they do so via the same signaling mechanisms. Thus, we tested the hypothesis that concurrent 5-HT2 and A2A receptor activation diminishes pMF via crosstalk inhibition. Selective 5-HT2A (DOI) and A2A receptor agonists (CGS21680) were delivered to the C4 intrathecal space (3, 6 μl injections, 5-min intervals) in urethane anesthetized, artificially ventilated, vagotomized and paralyzed Sprague Dawley rats. Integrated phrenic nerve burst activity was measured before (baseline), during and 90 minutes post-drug injection. Spinal 5-HT2A and A2A receptor activation both increased phrenic nerve burst amplitude when delivered alone (i.e., pMF); however, pMF was no longer apparent with concurrent receptor activation. The magnitude of pMF, expressed as a % change in phrenic burst amplitude from baseline to 90-min post-injection, was significantly lower with concurrent receptor activation (5-HT2A + A2A= 15 ± 7.7%; n=5) versus 5-HT2A (84 ± 12%; n=5, p=0.0047) and A2A (88 ± 16%; n=5, p=0.0085) alone. Thus, 5-HT2A and A2A receptors interact via crosstalk inhibition similar to 5-HT2 and 5-HT7 receptors. However, the mechanism underlying this crosstalk inhibition remains unknown. NIH HL148030. This is the full abstract presented at the American Physiology Summit 2024 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.