EFFECTS OF THE CENTRAL ANALGESIC TRAMADOL AND ITS MAIN METABOLITE, O-DESMETHYLTRAMADOL, ON RAT LOCUS-CERULEUS NEURONS

1 Tramadol is a centrally acting analgesic with low opioid receptor af finity and, therefore, presumably additional mechanisms of analgesic a ction. Tramadol and its main metabolite O-desmethyltramadol were teste d on rat central noradrenergic neurones of the nucleus locus coeruleus (LC), which are involved in the modulation of nociceptive afferent st imuli. 2 In pontine slices of the rat brain the spontaneous discharge of action potentials of LC cells was recorded extracellularly. (-)-Tra madol (0.1 100 muM), (+)-tramadol (0.1 100 mum), (-)-O-desmethyltramad ol (0.1-100 mum) and (+)-O-desmethyltramadol (0.01-1 mum) inhibited th e firing rate in a concentration-dependent manner. (+)-O-desmethyltram adol had the highest potency, while all other agonists were active at a similar range of concentrations. 3 (-)-Tramadol (10, 100 mum) was le ss inhibitory in brain slices of rats pretreated with reserpine (5 mg kg-1, 5h before decapitation) than in controls. 4 The effect of (-)-tr amadol (10 mum) was abolished in the presence of the alpha2-adrenocept or antagonist, rauwolscine (1 mum), whilst that of (+)-O-desmethyltram adol (0.3 mum) virtually disappeared in the presence of the opioid ant agonist, naloxone (0.1 mum). (+)-Tramadol (30 mum) and (-)-O-desmethyl tramadol (10 mum) became inactive only in the combined presence of nal oxone (0.1 mum) and rauwolscine (1 muM). 5 In another series of experi ments, the membrane potential of LC neurones was determined with intra cellular microelectrodes. (-)-Tramadol (100 mum) inhibited the spontan eous firing and hyperpolarized the cells; this effect was abolished by rauwolscine (1 mum). (+)-O-desmethyltramadol (10 mum) had a similar b ut somewhat larger effect on the membrane potential than (-)-tramadol. The (+)-O-desmethyltramadol- (10 mum) induced hyperpolarization was a bolished by naloxone (0.1 mum). 6 The hyperpolarizing effect of noradr enaline (30 mum) was potentiated in the presence of (-)-tramadol (100 mum), but not in the presence of (+)-O-desmethyltramadol (10 mum). The re was no potentiation of the noradrenaline (30 mum) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (-)-tramadol (100 mum). 7 Both noradrenaline (100 mu m) and (-)-tramadol (100 mum) decreased the input resistance. 8 The re sults confirm that the analgesic action of tramadol involves both opio id and non-opioid components. It appears that (-)-tramadol inhibits th e uptake of noradrenaline and via a subsequent increase in the concent ration of endogenous noradrenaline indirectly stimulates alpha2-adreno ceptors. (+)-O-desmethyltramadol seems to stimulate directly opioid mu -receptors. The effects of (+)-tramadol and (-)-O-desmethyltramadol co nsist of combined mu-opioid and alpha2-adrenergic components.