1 Tramadol is a centrally acting analgesic with low opioid receptor affinity and, therefore, presumably additional mechanisms of analgesic action. Tramadol and its main metabolite 0-desmethyltramadol were tested on rat central noradrenergic neurones of the nucleus locus coeruleus (LC), which are involved in the modulation of nociceptive afferent stimuli. 6 The hyperpolarizing effect of noradrenaline (30 JM) was potentiated in the presence of (-)-tramadol (100 JM), but not in the presence of (+ )-O-desmethyltramadol (10 JAM). There was no potentiation of the noradrenaline (30 iAM) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (-)-tramadol (100 JM). 7 Both noradrenaline (100 JM) and (-)-tramadol (1I00 jaM) decreased the input resistance.8 The results confirm that the analgesic action of tramadol involves both opioid and non-opioid components. It appears that (-)-tramadol inhibits the uptake of noradrenaline and via a subsequent increase in the concentration of endogenous noradrenaline indirectly stimulates a2-adrenoceptors. (+ )-0-desmethyltramadol seems to stimulate directly opioid "-receptors. The effects of (+)-tramadol and (-)-O-desmethyltramadol consist of combined J-opioid and a2-adrenergic components.