Effects of tramadol and its enantiomers on Concanavalin-A induced-proliferation and NK activity of mouse splenocytes: involvement of serotonin.

The centrally acting analgesic drug tramadol is a 1:1 racemic mixture of two enantiomers, with different pharmacological properties. The (-)-tramadol preferentially inhibits noradrenaline uptake, whereas the (+)-tramadol inhibits serotonin uptake and binds to opioid receptors. Since tramadol has been shown to stimulate some immune responses in mice, in the present work we analyzed the effects of its enantiomers on the same parameters, with the aim to better characterize the mechanisms involved in such action of tramadol. The acute administration of 20 and 40 mg/kg of racemic tramadol and of 10 and 20 mg/kg of (+)-tramadol induced a significant and comparable stimulation of Concanavalin-A (Con-A) induced proliferation and of Natural Killer (NK) activity of splenocytes. On the contrary, the (-)-tramadol was devoid of any effect. The pretreatment with the serotoninergic antagonist metergoline (3.0 mg/kg) completely blocked the effects of both tramadol and (+)-tramadol. We suggest that the enhancement of the serotoninergic tone could be at the basis of the stimulatory effects exerted by tramadol on Con-A induced lymphoproliferation and NK activity.