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

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Abstract
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 (0.1–100μm), (+)-tramadol (0.1–100 μm), (−)-O-desmethyltramadol (0.1–100 μm) and (+)-O-desmetnyltramadol (0.01–1 μm) inhibited the firing rate in a concentration-dependent manner. (+)-O-desmetnyltramadol had the highest potency, while all other agonists were active at a similar range of concentrations. 3 (−)-Tramadol (10, 100 μm) 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 μm) was abolished in the presence of the α2-adrenoceptor antagonist, rauwolscine (1 μm), whilst that of (+)-O-desmetnyltramadol (0.3 μm) virtually disappeared in the presence of the opioid antagonist, naloxone (0.1 μm). (+)-Tramadol (30 μm) and (−)-O-desmethyltramadol (10 μm) became inactive only in the combined presence of naloxone (0.1 μm) and rauwolscine (1 μm). 5 In another series of experiments, the membrane potential of LC neurones was determined with intracellular microelectrodes. (−)-Tramadol (100 μm) inhibited the spontaneous firing and hyperpolarized the cells; this effect was abolished by rauwolscine (1 μm). (+)-O-desmethyltramadol (10 μm) had a similar but somewhat larger effect on the membrane potential than (−)-tramadol. The (+)-O-desmethyltramadol- (10 μm) induced hyperpolarization was abolished by naloxone (0.1 μm). 6 The hyperpolarizing effect of noradrenaline (30 μm) was potentiated in the presence of (−)-tramadol (100 μm), but not in the presence of (+)-O-desmethyltramadol (10 μm). There was no potentiation of the noradrenaline (30 μm) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (−)-tramadol (100 μm). 7 Both noradrenaline (100 μm) and (−)-tramadol (100 μm) 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 α2-adrenoceptors. (+)-O-desmethyltramadol seems to stimulate directly opioid μ-receptors. The effects of (+)-tramadol and (−)-O-desmetnyltramadol consist of combined μ-opioid and α2-adrenergic components.