Antinociceptive Effect of Mirtazapine in Rats with Diabetic Neuropathy

Abstract

INTRODUCTIONDiabetic neuropathy is a chronic complication associated with diabetes that has a significant detrimental effect on the daily activities of patients. It occurs in approximately 50% of patients with diabetes within 20 years of diagnosis (1). Different drugs have been used in the treatment of neuropathy, such as tricyclic antidepressants (amitriptyline), selective serotonin reuptake inhibitors (fluoxetine), antiepileptics (carbamazepine, phenytoin), venlafaxine, amantadine, tramadol, oxycodone, gabapentin, bupropion, and capsaicin (1). Mirtazapine is a new antidepressant that acts in a manner that is different from other antidepressants and is notable for the low frequency of severe side effects when compared with other antidepressants (2).Mirtazapine blocks the presynaptic α-2 adrenoreceptors in both the central and peripheral nervous systems, while its affinity to α-1 adrenoreceptors is less marked. In addition, it weakly blocks serotonin-1 (5-hydroxytryptamine-1, 5-HT-1) receptors and strongly blocks 5-HT-2 and 5-HT-3 receptors. On the other hand, it has no effect on noradrenaline re-uptake and does not block the subtypes of β-adrenergic receptors to any significant degree (2).Mirtazapine, with its low side-effect profile, might be considered a good alternative in the treatment of diabetic neuropathy. This study investigated the antinociceptive effect of mirtazapine on diabetic neuropathy in rats and the role of opioidergic, serotoninergic, and adrenergic systems in this effect. Naloxone, a competitive opioid µ (mu) receptor antagonist that removes the respiratory depression effect resulting from opioid toxicity, was used to evaluate the role of the opioidergic system (3). Furthermore, a non-selective serotonin receptor antagonist, metergoline (4), and a α-2a adrenergic receptor antagonist, BRL44408 (5), were used to evaluate the roles of the serotoninergic and adrenergic systems, respectively. METHODSThis study was approved by the Local Ethics Board of Animal Research. Sprague Dawley rats weighing 170-225 g were used in the study. They were divided into 11 groups, each containing four males and four females. Rats were kept in a 12-h daylight and 12-h darkness cycle at a room temperature of 20°C and a humidity of 50%-60% and were administered standard pellet feed and water. Rats were brought to the experiment area 1 h prior to the start of experiments to enable them to adjust to the environment. Sensorimotor PerformanceA rotarod test was used to detect the motor activity of rats to be included in the study, with the adequacy of motor activity being defined as being able to stay on the rod for at least 120 s. Introduction: To evaluate the antinociceptive effect of mirtazapine and the mechanisms mediating this effect in neuropathic pain in rats with diabetes.

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“…The animal model induced by STZ is a well-recognized animal model of diabetes. 21 When the blood glucose levels of diabetic mice are significantly increased and body weights are significantly decreased after STZ injection, a supporting diabetes model is successfully established. After the diabetes model, when the paw withdrawal thresholds from diabetes mice are significantly decreased, the DNP model is successfully established.…”

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“…Особенность противоболевого эффекта миртазапина продемонстрирована в исследованиях Schreiber S, et al Доказано воздействие миртазапина на опиоидную систему через μ-и κ-рецепторы [59,81]. В работах других авторов данные эффекты подтверждены блокадой антиноцицептивных эффектов миртазапина при применении налоксона [82,83].…”