Maresin 2 reduces nociceptive and anxious-like behaviors inhibiting IL-1β in spinal and prefrontal cortex of type 1-diabetic rats

Abstract

Neuropathic pain and anxiety, or depression are common and debilitating complications of diabetes mellitus (DM), with few effective therapeutic options available. Given the significant role of neuroinflammation in the development and persistence of these complications, in addition to the known antinociceptive effects in inflammatory pain models induced by Maresin 2 (MaR2), a specialized pro-resolving mediator, we aimed to explore its therapeutic potential in mitigating mechanical hypersensitivity and anxiety/depressive-like behaviors in chemically induced DM male Wistar rats. Following the induction of experimental type-1 diabetes mellitus (T1DM) using streptozotocin (60 mg/kg, i.p.), rats were treated with MaR2 (1, 3, or 10 ng/rat, i.p.) or vehicle (VEH), starting 14 days after T1DM induction and continuing until the fourth week. Mechanical allodynia was assessed using the electronic Von Frey test (VFT) one day before STZ administration (baseline) and at multiple time points during MaR2 treatment. In the fourth week after STZ induction, behavioral assessments were performed using the open-field test (OFT), elevated plus-maze (EPM), and modified forced swimming test (MFST). Furthermore, samples from the spinal cord (L4-L6), hippocampus, and prefrontal cortex (pFC) were analyzed to measure levels of the pro-inflammatory cytokine IL-1β. MaR2 treatment significantly reduced mechanical allodynia (at all tested doses) and anxiety-like behavior (only at a dose of 3 ng) in diabetic rats, normalizing IL-1β expression in the pFC and spinal cord. However, it did not reverse depressive-like behavior. These results highlight MaR2's potential as a therapeutic agent for pain and anxiety in experimental diabetes, likely via its anti-inflammatory effects.