5-HT 2C blockade may also account for its lowering of the seizure threshold, as 5-HT 2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. Antagonism of 5-HT 2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses. Tramadol has inhibitory actions on the 5-HT 2C receptor. Tramadol is also thought to have some NMDA antagonistic effects, which has given it a potential application in neuropathic pain states. There is an increased risk of serotonin toxicity when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents. These actions appear to produce a synergistic analgesic effect, with (1 R,2 R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1 S,2 S)-(–)- tramadol (Goeringer et al., 1997). The (1 R,2 R)-(+)-enantiomer is approximately four times more potent than the (1 S,2 S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1 S,2 S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000).

Tramadol is marketed as a racemic mixture of the (1 R,2 R)- and (1 S,2 S)-enantiomers with a weak affinity for the μ- opioid receptor (approximately 1/6000th that of morphine Gutstein & Akil, 2006).

The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist naloxone. The analgesic action of tramadol is not fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its relatively weak μ-opioid receptor agonism. Tramadol acts as a μ- opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist (IC 50=16.5 μM), 5-HT 2C receptor antagonist (EC 50=26nM), (α7) 5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist, and M 1 and M 3 muscarinic acetylcholine receptor antagonist.

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