Opioid-oxytocin interaction in respiratory control: from physiological role to respiratory depression

• Grant number: 25/06864-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Thiago dos Santos Moreira
• Grantee: Emmanuel Veríssimo de Araújo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/05299-0 - Control of the respiratory rhythm and chemosensitivity by the brainstem: role of molecular, cellular and physiopathology aspects, AP.TEM

Abstract

The abusive use of opioids such as fentanyl and morphine is increasing worldwide each year, leading users to develop respiratory depression (RD), which can result in respiratory arrest and death. It is suggested that opioids exert their depressive effects by inhibiting the activity of key respiratory nuclei, such as the pre-Bötzinger complex (pre-BötC). The main pharmacological agent used to counteract RD is naloxone, an opioid receptor antagonist; however, this drug has a short half-life and significantly reduces the analgesic effects of opioids in clinical settings.Interestingly, some studies have shown that the hormone and neuropeptide oxytocin, when intravenously administered in rats, can reverse RD. Additionally, it is known that naloxone increases oxytocin secretion, whereas both endogenous and exogenous opioids can inhibit oxytocinergic neurons. Based on this, the main hypothesis of the present study is that endogenous opioids inhibit oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN), reducing oxytocin release in the pre-BötC-a key respiratory rhythm-generating nucleus. Exogenous opioids exacerbate this inhibition, contributing to respiratory depression by reducing the excitatory effect of oxytocin in the pre-BötC.Our goal is to investigate the role of opioids in the modulation of oxytocinergic neurons in the PVN and to assess the contribution of PVN oxytocinergic pathways to the pre-BötC in the context of fentanyl-induced respiratory depression.