Blockade of TRPV1 Attenuates the Immediate Apneic Response to Intravenously Bolus (IVb) Injection of Fentanyl (FNT)

Our previous study has demonstrated that IVb injection of FNT leads to an immediate persistent apnea that is primarily mediated by activation of vagal afferents’ opioid mu-receptors (MORs) in rats. Recent accumulating evidence shows that pharmacological blockade of TRPV1 receptor selectively diminishes the MOR-mediated antinociception, tolerance, and dependence, indicating an interaction between the two receptors. Because both MORs and TRPV1 receptor are abundantly localized in vagal afferents, this study aimed to define the functional interaction of MOR and TRPV1 receptors in FNT-induced immediate apneic response in conscious rats. IVb injection of FNT (50 µg/kg) was conducted without and with pretreatment of capsazepine (a TRPV1 receptor antagonist) administered via IV injection (IV CAPZ ) and intra-vagal microinjection (Vagal CAPZ ) to systemically and locally block TRPV1 receptor respectively. FNT triggered an immediate (<3 sec latency) persistent apnea usually lasting for >1 min associated with bradycardia (40%↓). The apnea was followed by subsequent cardiorespiratory depression, in which bradypnea and bradycardia were fully recovered 5 min postinjection, meanwhile V E and V T were largely (80%) recovered and the remained V E depression maintained 60 min postinjection. In contrast, IV CAPZ shortened the apneic duration by 85% and blocked the bradycardia, and Vagal CAPZ shortened the apneic duration by 65% and improved bradycardia by 20%. In addition, both pretreatments promoted the full recovery of the V E depression. Our results suggest an interaction of MOR and TRPV1 receptor in FNT-induced cardiorespiratory responses. In other words, antagonizing TRPV1 receptors, especially locally in vagal afferents, significantly blunts the FNT-triggered immediate apnea and promotes subsequent V E depression. This study is supported by National Institutes of Health (NIH), Bethesda. Grant numbers: DA059063 and HL163512. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.