Tramadol is one of typical centrally acting opioids. It is indicated for management of moderate to severe pain. Now it is considered to be the most widely sold analgesic in the world. Aim: To detect the effect of subchronic administration of tramadol on brain and spinal cord of the experimental animals as histopathologic changes in brain cells. Methods: Sixty adult male albino rats were divided into three equal groups each was 20 rats. Control group, group I that received Tramadol orally at increasing doses 1/10 LD50, 1/5 LD50 and lastly four times the initial dose for the first, second and third months respectively, and Group II that received 1/10 LD50 for one month. All rats were scarified after 24 hours of the last dose at the end of each experimental period under ether anesthesia. Craniotomy and laminectomy were performed for histopathological studies. The presences of number of red neurons which are histological marker of apoptosis were investigated in brain and spinal cord.  Results: The number of small sized neurons was greater in group II than in group I. There was statistical difference regarding neuopil density and color staining among three groups. Neuopil was lighter in staining and less dense in groups I and II comparing to control (p≤0.002 and p≤0.001) using SPSS program. The highest number of red neurons was found in hippocampal region followed by occipital and frontal regions. The abnormalities regions in the spinal cord tissue were less than those in the brain tissue. Conclusions: chronic use of Tramadolis an important factor responsible for histopathological changes inneurons.