Targeting Excitatory Glutamate Receptors for Morphine Tolerance: A Narrative Review

Abstract

Background: Opioids remain a primary treatment for moderate-to-severe chronic pain, but prolonged use frequently induces analgesic tolerance. Excitatory glutamate receptors, ubiquitous in the central and peripheral nervous systems, are pivotal in physiological and pathological processes and are now recognized as significant contributors to opioid tolerance development. Methods: We comprehensively analyzed experimental data from our team's intensive investigations over the past 10 years, alongside relevant peer-reviewed studies on glutamate receptor mechanisms in opioid tolerance. Results: Excitatory glutamate receptors (including NMDA, AMPA, and metabotropic subtypes) fundamentally regulate neuroadaptations underlying morphine tolerance. Our work and others' demonstrate their involvement in synaptic plasticity, neuroinflammation, and downstream signaling pathways that drive tolerance. Conclusions: Targeting excitatory glutamate receptors presents a promising therapeutic strategy for mitigating opioid tolerance. Future research should prioritize elucidating receptor-specific mechanisms, peripheral-central nervous system crosstalk, and translating preclinical findings into clinically viable.