Objective: Our research group previously reported that mianserin has the ability to reduce diabetic neuropathic pain at doses of 30 and 45 mg/kg, comparable to a widely prescribed drug, pregabalin (10 mg/kg), used in the clinical treatment of neuropathic pain. Based on this finding, in this study we planned to investigate possible mechanisms underlying this beneficial effect of mianserin on diabetic neuropathic allodynia.
Methods: Male Wistar 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 streptozotocine administration. Mianserin treatment (30 mg/kg) was initiated 4 weeks after the induction of diabetes to permit development of nociceptive perception deficits in rats. The dynamic plantar esthesiometer, which measures the threshold values for mechanical stimuli, was used for allodynia studies. Further, thermal allodynia was evaluated with the warm-plate (38°C) test. The potential contribution of the serotonergic system to the effect of mianserin was investigated using p-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis, 600 mg/kg, administered for 2 consecutive days, i.p.), whereas a possible involvement of the catecholaminergic systems was examined using α-methyl-para-tyrosine methyl ester (AMPT; an inhibitor of catecholamine synthesis, daily 200 mg/kg x 2 times, i.p.). In independent experiments, involvement of the adrenoceptors in the observed antiallodynic effects of mianserin were evaluated with phentolamine (a non-selective α-adrenoceptor antagonist, 5 mg/kg, i.p.) and propranolol (a non-selective β-adrenoceptor antagonist, 5 mg/ kg, i.p.). The experimental protocol was approved by the Anadolu University Animal Experiments Local Ethics Committee.
Results: Subacute administration of mianserin at a dose of 30 mg/kg reduced diabetes-associated mechanical and thermal allodynia. The antiallodynic effect of mianserin was reversed with AMPT, phentolamine, and propranolol. The same effects were not reversed, however, by PCPA. The results suggest that the observed beneficial effect of mianserin on diabetic neuropathic pain is unrelated to the level of 5-HT in the synapse. Instead, it is mediated through an increase in catecholamine levels in the synaptic cleft, as well as through interactions with both subtypes of adrenoceptors. However, other mechanisms, e.g. mechanisms involving the GABAergic, glutaminergic and nitrergic systems, may also have contributed to the observed pharmacological effect of mianserin in the present study.
Conclusion: Considering the simultaneous antidepressant and antinociceptive effects of mianserin, it is possible to recommend this drug as a good alternative for treatment of pain associated to diabetic neuropathy and mood disorders caused directly by diabetes.