TANGERETIN ATTENUATES DIABETES-INDUCED NEUROPATHIC PAIN IN RATS: EVIDENCE FOR ADRENOCEPTOR INVOLVEMENT.

In this study, the efficacy of tangeretin, a pentamethoxyflavone abundantly found in citrus peels, was investigated in male Sprague-Dawley rats with experimental diabetes-induced neuropathic pain. Its antihyperglycaemic effect was evaluated by measuring fasting blood glucose and HbA1c levels, whereas its effects on neuropathic pain were assessed using the Randall-Selitto, Dynamic Plantar, Hargreaves plantar, and warm plate tests. Locomotor activity was evaluated using an activity-meter. Both 7- and 14-day tangeretin administration (10 and 20 mg/kg) significantly reduced fasting blood glucose and HbA1c levels in diabetic rats. Tangeretin, at both doses, attenuated mechanical and thermal hyperalgesia and allodynia, with efficacy comparable to that of gabapentin. No statistically significant difference was observed between the 10 and 20 mg/kg doses in terms of anti-allodynic or anti-hyperalgesic efficacy. Tangeretin did not significantly alter total or ambulatory activity, suggesting that its beneficial effects were unlikely to be secondary to nonspecific changes in motor function. Mechanistic studies showed that pretreatment with the α2-adrenoceptor antagonist yohimbine and the β2-adrenoceptor antagonist ICI 118,551 reversed the anti-hyperalgesic and anti-allodynic effects of tangeretin (10 mg/kg), whereas the 5-HT1A receptor antagonist WAY 100635, the CB1 receptor antagonist AM251, the CB2 receptor antagonist AM630, and the non-selective opioid receptor antagonist naloxone had no effect. These findings suggest that α2- and β2-adrenoceptors contribute to the antinociceptive effects of tangeretin in diabetes-associated neuropathic pain. To our knowledge, this is the first study to indicate an adrenoceptor-related mechanism underlying the efficacy of tangeretin in this model. These findings warrant further investigation through comprehensive preclinical and clinical studies to clarify the therapeutic relevance of tangeretin in diabetic neuropathy.