Role of TRPA1 channels in hyperalgesia and tolerance induced by chronic morphine administration

• Grant number: 25/05902-0
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: October 01, 2025
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Natalia Pressuto Pennachioni
• Supervisor: Stuart John Bevan
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: King's College London, England
• Associated to the scholarship: 23/14271-8 - Molecular mechanisms involved in the adverse effects associated with the chronic use of morphine: role of the TRPA1 receptor and the aldehyde dehydrogenase-2 enzyme, BP.MS

Abstract

Chronic opioids often lead to tolerance and paradoxical hyperalgesia, limiting therapeutic efficacy. Transient receptor potential ankyrin 1 (TRPA1) ion channels, activated by reactive aldehydes, such as 4-hydroxynonenal (4-HNE), are involved in nociceptive signaling. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme responsible for 4-HNE detoxification. Previous data have shown that TRPA1 antagonists or Alda1, an ALDH2 activator, prevent morphine-induced pronociceptive effects, such as analgesic tolerance and hyperalgesia. Therefore, using TRPA1 knockout (TRPA1-KO) mice, this study aims to investigate the role of 4-HNE and TRPA1 in morphine-induced hyperalgesia and tolerance. We hypothesize that morphine-induced oxidative stress increases 4-HNE levels, which activates TRPA1, driving calcium-dependent pathways to promote pain. Wild type (WT) and TRPA1-KO animals will be treated with morphine to evaluate the impact of TRPA1 activation on morphine-induced side effects. We also aim to develop a primary cell culture model that recapitulates morphine-induced adverse effects. Thus, sensory neurons derived from naive WT and TRPA1-KO mice will be chronically treated with morphine and calcium influx will be assessed. A group of cells will be treated 4-HNE or Alda1 as control. We expect that TRPA1-KO mice will not develop morphine side-effects and the dorsal root ganglia (DRG) neurons obtained from these mice will lack sensitivity to morphine-induced calcium influx. (AU)