Aspirin-triggered lipoxin A4 reduces neuropathic pain and anxiety-like behaviours in male diabetic rats: antinociceptive enhancement by cannabinoid receptor agonists.

Neuropathy is the most common complication of diabetes, leading to painful symptoms like hyperalgesia. Current treatments for diabetic painful neuropathy often prove inadequate, necessitating the exploration of new pharmacological approaches. Therefore, this study aimed to investigate the potential antinociceptive effect of aspirin-triggered lipoxin A4 (ATL), a specialized pro-resolving lipid mediator, when administered alone or in combination with cannabinoid agonists, to alleviate diabetic neuropathic pain. Mechanical hyperalgesia in the hindpaws of streptozotocin (STZ)-induced diabetic (DBT) rats was assessed using the electronic Von Frey test (VFT), before diabetes induction and for up to 32 days after STZ administration and intraperitoneal ATL (0.3, 1, 3, 10, or 30 ng/rat) treatment, alone or in combination with intrathecal CB1 or CB2 receptor agonists (ACEA or JWH-133, respectively; 10 or 30 μg/rat). The effect of ATL treatment on locomotor activity and anxious or depressive-like behaviors was also evaluated. In comparison to control normoglycemic rats, control DBT rats developed: 1) mechanical hyperalgesia; 2) increase in anxious and depressive-like behaviors. ATL treatment attenuated mechanical hyperalgesia in DBT rats both acutely (at 30 ng) and cumulatively (at doses of 1, 3, 10, or 30 ng), without compromising locomotor activity. The antinociceptive effect of ATL (at 1 or 3 ng) was augmented when combined with ACEA or JWH-133 treatments (only at a dose of 30 μg/rat). While ATL treatment alone reduced anxious-like behavior in DBT rats, it did not affect depressive-like behavior. These findings underscore the therapeutic potential of ATL, in diabetic complications, suggesting a possible interaction with the endocannabinoid system.