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Tramadol hydrochloride (TH) is an atypical opioid synthetic agent which is a centrally acting analgesic, used for treating moderate to severe pain with fewer side effects than traditional opioid medications. The present work aimed to study the dose-dependent possible deleterious effect of long-term administration of TH as well as a 4-weeks spontaneous recovery period to evaluate the reversibility of the toxic effects on the brain tissues of the rats. Forty adult male albino rats were divided into 4 groups. Group I (control), group II (low dose) was treated orally with TH (30 mg/kg/day) and group III (high dose) was treated orally with TH (60 mg/kg/day) for 4 weeks. Group IV (follow up) was treated as group III and then held for 4-weeks recovery period. At the end of experimental period, rats were sacrificed, histopathological and immunohistolochemical (IHC) examinations of the brains were carried out. The obtained results revealed that both low and high doses of TH produced remarkable histomorphological changes in rats’ brains (cerebral cortex {CC} and hippocampus {HC}) as compared to control and were more pronounced in high than low dose group and in both doses when compared to that of control. On the other hand, group IV showed remarkable regression of the total degenerative changes induced by TH with some residual effect. This was noted by nearly normal morphology of brain tissues and marked significant decrease of p53 and Bax along with significant increase of Bcl-2 protein expressions when compared to those of group II and III treated rates. Khodeary et al ... 2 Vol. XVIII, No. 1, Jan. 2010 Mansoura J. Forensic Med. Clin. Toxicol. The molecular mechanisms of opioidinduced apoptosis have not been established yet. Various key proteins are involved in the regulation of programmed cell death (Sastry and Rao, 2000). Some members of the Bcl family, such as Bcl-2 and Bcl-xL are known anti-apoptotic proteins that suppress apoptosis. Whereas, the cytoplasmic expression of Bax is proapoptotic that enhance apoptosis. Bcl-2 protein localized mainly in the mitochondrial membrane has been shown to play an important role in protecting tissues from apoptotic cell death (Yuan and Yankner, 2000). The p53 tumor suppressor protein also plays a central role in cell cycle arrest and apoptosis (Polyak et al., 1997). p53 is a pro-apoptotic short-lived protein (its half life is approximately 10-30 min) and constitutively expressed at low levels in most cell types including neurons (Soussi, 2000). Normally, several negative regulatory mechanisms that control p53 function were reported. Cytoplasmic p53 directly binds to Bcl-xL forming complex (Chipuk et al., 2005). Also, within the nucleus, human homolog double minute-2 / murine double minute-2 (HDM2/MDM2) binds p53 and mediates its transport into the cytosol, where it is ubiquitinated and then degraded by the proteasome (Prives and Hall, 1999). Bax has been shown to contain p53neuropathic, fibromyalgia, migraine ..etc) is well established (Babul et al., 2004). Also, it has been suggested that TH could be effective for alleviating symptoms of depression, anxiety, and phobias (RojasCorrales et al., 2004). Additionally, TH seems to have a specific role in the treatment of opiate withdrawal (Threlkeld et al., 2006) and premature ejaculation (Salem et al., 2008). The most frequent adverse effects of TH include constipation, nausea, dizziness, headache, somnolence and vomiting (Stitik et al., 2006). The most serious adverse reactions include confusion, hallucinations, convulsions, serotonin syndrome, and hypersensitivity reactions. Also, several reports of withdrawal symptoms with long-term TH usage were reported (ADRAC, 2003). A better understanding of the fundamental mechanisms involved in apoptosis has made it possible to define its real significance in many areas of cell biology and, more recently, in pharmacology and toxicology (Feldmann, 2006). Apoptosis provides a mechanism for the disposal of cells damaged by toxicants without perturbing the homeostatic balance of their environment. However, the importance of apoptosis in toxicology has been underestimated given the difficulty of identifying apoptotic cells either in vivo or in vitro models (Gómez-Lechón et al., 2008).

a Histopathological and Immunohistochemical Study of Adult rats’ Brain after Long-term Exposure to Amadol (Tramadol Hydrochloride)