Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones.

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 O-desmethyltramadol were tested on rat central noradrenergic neurones of the nucleus locus coeruleus (LC), which are involved in the modulation of nociceptive afferent stimuli. 2. In pontine slices of the rat brain the spontaneous discharge of action potentials of LC cells was recorded extracellularly. (-)-Tramadol (0.1-100 microM), (+)-tramadol (0.1-100 microM), (-)-O-desmethyl-tramadol (0.1-100 microM) and (+)-O-desmethyltramadol (0.01-1 microM) inhibited the firing rate in a concentration-dependent manner. (+)-O-desmethyltramadol had the highest potency, while all other agonists were active at a similar range of concentrations. 3. (-)-Tramadol (10, 100 microM) was less inhibitory in brain slices of rats pretreated with reserpine (5 mg kg-1, 5 h before decapitation) than in controls. 4. The effect of (-)-tramadol (10 microM) was abolished in the presence of the alpha 2-adrenoceptor antagonist, rauwolscine (1 microM), whilst that of (+)-O-desmethyltramadol (0.3 microM) virtually disappeared in the presence of the opioid antagonist, naloxone (0.1 microM). (+)-Tramadol (30 microM) and (-)-O-desmethyl-tramadol (10 microM) became inactive only in the combined presence of naloxone (0.1 microM) and rauwolscine (1 microM). 5. In another series of experiments, the membrane potential of LC neurones was determined with intracellular microelectrodes. (-)-Tramadol (100 microM) inhibited the spontaneous firing and hyper-polarized the cells; this effect was abolished by rauwolscine (1 microM). (+)-O-desmethyltramadol (10 microM)had a similar but somewhat larger effect on the membrane potential than (-)-tramadol. The (+)-O-desmethyltramadol-(10 microM) induced hyperpolarization was abolished by naloxone (0.1 microM).6. The hyperpolarizing effect of noradrenaline (30 microM) was potentiated in the presence of (-)-tramadol(100 microM), but not in the presence of (+)-O-desmethyltramadol (10 microM). There was no potentiation of the noradrenaline (30 microM) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (-)-tramadol (100 microM).7. Both noradrenaline (100 microM) and (- )-tramadol (100 microM) 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 alpha2-adrenoceptors. (+)-0-desmethyltramadol seems to stimulate directly opioid micro-receptors. The effects of (+)-tramadol and(-)-O-desmethyltramadol consist of combined micro-opioid and alpha2-adrenergic components.