J. Sevcik et al., EFFECTS OF THE CENTRAL ANALGESIC TRAMADOL AND ITS MAIN METABOLITE, O-DESMETHYLTRAMADOL, ON RAT LOCUS-CERULEUS NEURONS, British Journal of Pharmacology, 110(1), 1993, pp. 169-176
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.