Tramadol is an atypical
analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of
noradrenaline (NA) and
serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-
opioid receptors. Here, we present data for the novel compound
NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-
opioid receptors and inhibited reuptake of
5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively).
NS7051 (1-30mg/kg, s.c.) produced a dose-dependent
naloxone-reversible increase in the hot plate withdrawal latency, and was also
analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception,
NS7051 reversed flinching behaviours during interphase and second phase of the
formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete
Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of
neuropathic pain,
mechanical allodynia and
hyperalgesia were both reversed by
NS7051 (ED50=6.7 and 4.9mg/kg, s.c.).
Tramadol was also active in all
pain models although at considerably higher doses (20-160mg/kg, s.c.). No
ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for
NS7051 and
tramadol. The combined
opioid receptor agonism and monoamine reuptake inhibitory properties of
NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike
tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.