Acute antinociceptive effect of fish oil or its major compounds, eicosapentaenoic and docosahexaenoic acids on diabetic neuropathic pain depends on opioid system activation

Diabetic neuropathic pain is one of the most common and debilitating complications of diabetes whose available treatments are poorly effective. Currently, omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been widely studied as a treatment of many types of pain, including inflammatory, spontaneous and neuropathic pain. However, little is known about the potential antinociceptive effect of omega-3 PUFAs (fish oil; FO or its major fatty acids, eicosapentaenoic -EPA and docosahexaenoic acids-DHA), in diabetic neuropathic pain as well as the mechanisms involved. To test, streptozotocin (STZ) -induced diabetic male Wistar rats were submitted to acute treatment with FO, EPA or DHA at the second and fourth weeks after diabetes induction (at the beginning and peak of development of mechanical allodynia, respectively). The cumulative effect of these compounds after a sub-chronic treatment for two weeks was also evaluated as well as the role of central mu-opioid receptors. It was observed that acute oral treatment with FO (0.5, 1 or 3 g/kg), EPA or DHA (100, 200 or 400 mg/kg) at the 2nd or at the 4th week after STZ significantly reverted the mechanical allodynia of diabetic animals, without altering the hyperglycemia or reduced weight gain. Moreover, the sub-chronic treatment with FO, EPA or DHA induced a sustained antinociceptive effect in diabetic animals. Intriguingly, the intrathecal treatment with a mu-opioid receptor antagonist (CTOP; 10 mu g/rat) completely prevented the acute effect of FO, EPA or DHA. Taken together, our data suggest that omega-3 PUFAs may represent a promising therapeutic outcome for diabetic neuropathic pain, probably acting through the opioid system activation.