Objective: Diabetic neuropathy is a syndrome that develops with Diabetes mellitus only, in the absence of other factors that can cause neuropathy; it affects different components of the nervous system and can involve all types of nerve fibers. The drug groups most widely preferred for treating neuropathic pain in clinics are anticonvulsants and antidepressants. Based on the ability of antidepressants in the treatment of neuropathic pain, we planned to investigate possible effect of agomelatine, a new antidepressant drug, on hyperglycemia, metabolic alterations and neuropathic pain observed in diabetic rats.
Methods: Male Sprague-Dawley rats of the same age (weight: 250-300 g) were used for the experiments. Diabetes was induced by a single 50 mg/kg dose of intravenous streptozotocin administration. The experimental protocol was approved by the Anadolu University Animal Experiments Local Ethics Committee. Effects of 7 and 14 days agomelatine (40 and 80 mg/kg) administration on hyperglycemia were assessed by measuring fasting blood glucose levels and conducting oral glucose tolerance tests (OGTT). Changes in metabolic parameters such as food and water consumption and excretion of urine and feces were monitored using metabolic cages. Weekly changes in the body weights of animals were recorded as well. The effect of agomelatine treatment on hyperalgesia occurring due to peripheral diabetic neuropathy was examined using Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold-plate (4°C, thermal nociceptive stimulus) tests. The dynamic plantar esthesiometer, which measures the threshold values for mechanical stimuli, was used for allodynia studies; in addition, thermal allodynia was evaluated using warm-plate (38°C) test. Agomelatine administration was initiated 4 weeks after the induction of diabetes to permit development of nociceptive perception deficits in rats.
Results: Subacute administration of agomelatine did not cause any alterations in the blood glucose levels or metabolic parameters of diabetic rats with respect to the untreated diabetic animals. Moreover, body weights of diabetic rats were not affected by the agomelatine treatment. In contrast, subacute administration of agomelatine caused a significant increase in the reduced paw-withdrawal threshold, decreased paw-withdrawal latency and shortened reaction period of diabetic rats. Data obtained from OGTT, as well as blood glucose and metabolic cage measurements, suggest that agomelatine treatment does not induce a significant anti-hyperglycemic effect. On the other hand, findings of neuropathy tests indicated that subacute administration of agomelatine at doses of 40 and 80 mg/kg restored hyperalgesia and allodynia responses of the diabetic rats to the levels of normoglycemic control animals. Anti-hyperalgesic and antiallodynic effects of this new antidepressant were comparable to the reference drug pregabalin (10 mg/kg).
Conclusion: Considering its antidepressant, anxiolytic and antinociceptive effects, it seems that agomelatine may propose clinical advantages for providing an ability to avoid polypharmacy in treatment of painful diabetic neuropathy and diabetes-induced affective disorders such as depression and anxiety.