In the 1960s, researchers found that tricyclic antidepressants (TCAs) alleviated neuropathic pain, such as postherpetic neuralgia. For 40 years, however, TCAs' mode of action remained mysterious. Now some hints as to a possible mechanism, which encompasses actions at Na+ channels and neuronal plasticity, are beginning to emerge.

TCAs alleviate depression by inhibiting reuptake of serotonin and noradrenaline, although they interact with a plethora of transporters, receptors, and channels. Juan-Antonio Micó, University of Cádiz, Spain, notes that in addition to serotonin and noradrenaline reuptake, TCAs modulate sodium and potassium channels and N-methyl D-aspartate and adenosine receptors, and they inhibit production of tumor necrosis factor in the brain. This complex pharmacology means that is unclear what underlies their analgesic actions.

Researchers' poor understanding of neuropathic pain exacerbates the lack of understanding of TCAs' mechanism. David Bowsher, University Hospital Aintree, Liverpool, UK, for example, notes that only 15% of people with...

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