Modulatory effect of cilostazol on tramadol-induced behavioral and neurochemical alterations in rats challenged across the forced swim despair test

Pain-associated depression is encountered clinically in some cases such as cancer, chronic neuropathy, and after operations. Tramadol is an opioid analgesic drug that may modulate monoaminergic neurotransmission by inhibition of noradrenaline and serotonin reuptake that may contribute to its antidepressant-like effects. Clinically, tramadol is used either alone or in combination with other NSAIDs in the treatment of cases associated with pain and depression, e.g. low back pain, spinal cord injury, and post-operative pain management. However, tramadol monotherapy as an antidepressant is impeded by severe adverse effects including seizures and serotonin syndrome. Interestingly, phosphodiesterase-III inhibitors demonstrated novel promising antidepressant effects. Among which, cilostazol was reported to attenuate depression in post-stroke cases, geriatrics and patients undergoing carotid artery stenting. Therefore, this study was carried out to investigate the possible antidepressant-like effects of tramadol and/or cilostazol on the behavioral level in experimental animals, and to examine the neurochemical and biochemical effects of tramadol, cilostazol and their combination in rats, in order to explore the probable mechanisms of action underlying their effects. To achieve our target, male albino mice and rats were randomly allocated into five groups and administered either vehicle for control, fluoxetine (20 mg/kg, p.o.), tramadol HCl (20 mg/kg, p.o.), cilostazol (100 mg/kg, p.o.), or combination of both tramadol and cilostazol. At day 14, mice and rats were challenged in the tail suspension test and forced swim test, respectively. Rats were sacrificed and brains were isolated for determination of brain monoamines, MDA, NO, SOD, and TNF-α. The current results showed that concurrent administration of cilostazol to tramadol-treated animals modulated depression on the behavioral level, and showed ameliorative neurochemical and biochemical effects in rats exposed to FST