Tramadol safety--cholinergic system of rat brain without nociception

In the present investigation, changes in the levels of acetylcholinesterase (AChE) activity, acetylcholine (ACh) content, and the activity levels of plasma (PChE) and erythrocyte (EChE) cholinesterases as representatives of pseudocholinesterases were examined in different areas of the rat brain during the administration of the synthetic opioid analgesic drug tramadol (Ultram) without induction of pain. Male adult Wistar rats weighing 150 +/- 20 g were used. Tramadol was injected subcutaneously (s.c.) into the rats at 0, 24 and 48 h, and the changes in the above cholinergic parameters were recorded after the completion of 3, 6, 12, 24, 48 and 72 h. Following administration of single dose (for rats sacrificed at 24 h) and multiple doses (for rats sacrificed at 48 and 72 h) of tramadol, the ACh content showed an increase in all brain areas. Concurrently, the AChE activity was found to decrease in all the areas. PChE and EChE showed higher activity levels, with EChE showing a higher level of activity than PChE. The levels of all the parameters examined returned towards the control levels by about 24 h after the administration of single dose of tramadol. However, the ACh levels showed an elevation at 48 and 72 h (following double and triple doses, respectively). The AChE activity levels also showed a simultaneous increase at 48 and 72 h, presumably to balance the increase in ACh levels on longer treatment with tramadol. The observed changes in the cholinergic segment presumably do not cause any physiological lesion since they reverted to control levels after the time limit of change under tramadol influence. This observation indicates that tramadol can be administered safely both under nociceptive and non-nociceptive conditions.