Beyond Symptom Suppression: The Multitargeted Reversal of Chronic Pain by Maresin1

The transition from acute inflammation to chronic pain represents a significant clinical challenge, often driven by a failure of endogenous resolution programs. Specialized pro-resolving mediators (SPMs), derived from polyunsaturated fatty acids, are crucial for actively terminating inflammation and restoring tissue homeostasis. Maresin 1 (MaR1), a prototypical SPM biosynthesized from docosahexaenoic acid (DHA), has emerged as a powerful modulator of pain. This review comprehensively synthesizes the current preclinical evidence, primarily derived from preclinical animal models, detailing the analgesic effects of MaR1 across a spectrum of pain models, including inflammatory, neuropathic, postoperative, osteoarthritis-related pain, etc. We dissect the multifaceted mechanisms underlying its efficacy, which extend beyond simple anti-inflammation. MaR1 exerts its effects by: (1) attenuating neuroinflammation including the suppression of glial (microglia and astrocyte) activation and reprogramming macrophage phenotypes; (2) directly modulating neuronal function by inhibiting nociceptive ion channels (e.g. TRPV1) and reversing central synaptic plasticity; and (3) promoting robust tissue repair, including peripheral nerve regeneration. These actions are mediated through potential specific receptors, notably G-protein-coupled receptor 37-like 1 (GPR37L1) on glial cells and retinoic acid-related orphan receptor α (RORA) on neurons. While MaR1 demonstrates significant therapeutic potential, challenges related to its pharmacokinetic instability and observed sex-dependent analgesic effects must be addressed for successful clinical translation. This review provides a comprehensive mechanistic framework supporting MaR1 as a next-generation therapeutic candidate for pain management, and outlines the core research directions to overcome key translational barriers for MaR1-based therapies.