The antihyperalgesic effect of docosahexaenoic acid in streptozotocin-induced neuropathic pain in the rat involves the opioidergic system

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that has shown an antinociceptive effect in multiple pain models, such as inflammatory and neuropathic pain by chronic constriction injury in rats; however, its mechanism of action is still not well-understood. Reports suggest that DHA activates opioid signaling, but there is no information on this from a model of neuropathic pain. As a result, the aims of this study were (1) to determine the antihyperalgesic and antiallodynic effect of peripheral DHA administration, and (2) to evaluate the participation of the opioid receptors in the antihyperalgesic effect of DHA on streptozotocin-induced neuropathic pain in the rat. Female Wistar rats were injected with streptozotocin (50 mg/kg, i.p.) to induce hyperglycemia. The formalin, Hargreaves, and von Frey filaments tests were used to assess the nociceptive activity. Intraplantar administration of DHA (100–1000 μg/paw) or gabapentin (562–1778 μg/paw) decreased formalin-evoked hyperalgesia in diabetic rats, in a dose-dependent manner. Furthermore, DHA (562 μg/paw) and gabapentin (1000 μg/paw) reduced thermal hyperalgesia and allodynia. Local peripheral administration of naloxone (non-selective opioid receptor antagonist; 100 μg/paw), naltrindole (selective δ receptor antagonist; 1 μg/paw), and CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, μ receptor antagonist; 20 μg/paw) prevented formalin-evoked hyperalgesia in diabetic rats but not by GNTI (guanidinonaltrindole, κ receptor antagonist;1 µg/paw). It is suggested that peripheral DHA shows an antihyperalgesic effect in neuropathic pain in the rat. Furthermore, δ and μ receptors are involved in the antihyperalgesic peripheral effect of DHA in diabetic rats.