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Effects of the central analgesic tramadol and its main metabolite, O‐desmethyltramadol, on rat locus coeruleus neurones
Author(s) -
Sevcik Jan,
Nieber Karen,
Driessen Bernd,
Illes Peter
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13788.x
Subject(s) - rauwolscine , locus coeruleus , tramadol , chemistry , (+) naloxone , analgesic , pharmacology , metabolite , opioid receptor , endocrinology , medicine , antagonist , receptor , central nervous system , biochemistry , prazosin
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 (0.1–100μ m ), (+)‐tramadol (0.1–100 μ m ), (−)‐O‐desmethyltramadol (0.1–100 μ m ) and (+)‐O‐desmetnyltramadol (0.01–1 μ m ) 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 μ m ) 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 μ m ) was abolished in the presence of the α 2 ‐adrenoceptor antagonist, rauwolscine (1 μ m ), whilst that of (+)‐O‐desmetnyltramadol (0.3 μ m ) virtually disappeared in the presence of the opioid antagonist, naloxone (0.1 μ m ). (+)‐Tramadol (30 μ m ) and (−)‐O‐desmethyltramadol (10 μ m ) became inactive only in the combined presence of naloxone (0.1 μ m ) and rauwolscine (1 μ m ). 5 In another series of experiments, the membrane potential of LC neurones was determined with intracellular microelectrodes. (−)‐Tramadol (100 μ m ) inhibited the spontaneous firing and hyperpolarized the cells; this effect was abolished by rauwolscine (1 μ m ). (+)‐O‐desmethyltramadol (10 μ m ) had a similar but somewhat larger effect on the membrane potential than (−)‐tramadol. The (+)‐O‐desmethyltramadol‐ (10 μ m ) induced hyperpolarization was abolished by naloxone (0.1 μ m ). 6 The hyperpolarizing effect of noradrenaline (30 μ m ) was potentiated in the presence of (−)‐tramadol (100 μ m ), but not in the presence of (+)‐O‐desmethyltramadol (10 μ m ). There was no potentiation of the noradrenaline (30 μ m ) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (−)‐tramadol (100 μ m ). 7 Both noradrenaline (100 μ m ) and (−)‐tramadol (100 μ m ) 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 α 2 ‐adrenoceptors. (+)‐O‐desmethyltramadol seems to stimulate directly opioid μ‐receptors. The effects of (+)‐tramadol and (−)‐O‐desmetnyltramadol consist of combined μ‐opioid and α 2 ‐adrenergic components.