Structure and mechanism of action

Fluoxetine, paroxetine, and citalopram inhibit serotonin reuptake but differences in structure and activity exist. Compared to fluoxetine, paroxetine and citalopram are more potent serotonin reuptake inhibitors, whereas par-oxetine is a weak inhibitor of norepinephrine reuptake (Table 18.1 ).103 The antinociceptive mechanisms of SSRIs are poorly understood. In general, SSRIs block ser-otonergic reuptake which desensitizes feedback receptors leading to accumulation of serotonin in the synaptic cleft. Apart from serotonergic mechanisms, animal studies suggest the analgesic effects of SSRIs are also mediated by opioid and cholinergic pathways,104,105 inhibition of sodium channels,106 and activation of the descending inhibitory pathways.103

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