Spinal neurotransmission plays an important role in the perception of pain 
signaling. In the present study, we investigated the spinal anti-nociceptive 
mechanism of current standard analgesics in mouse models of tactile allodynia 
induced by intrathecal administration of N-methyl-D-aspartic acid (NMDA), 
prostaglandin E2 (PGE2), and bicuculline. NMDA-induced allodynia is induced by 
postsynaptic NMDA receptor activation, while PGE2-induced allodynia is triggered 
by the enhancement of presynaptic glutamate release via EP1 receptor activation. 
In contrast, bicuculline induces allodynia by the blockade of gamma-aminobutyric 
acid (GABA)A receptor-mediated inhibitory system. As the clinically available 
analgesics, pregabalin (alpha2delta-subunit calcium channel ligand), ziconotide 
(N-type calcium channel blocker), mexiletine (sodium channel blocker), and 
duloxetine (serotonin and norepinephrine reuptake inhibitors) were evaluated in 
these neurochemically-induced allodynia models. Pregabalin almost completely 
alleviated NMDA-, PGE2-, and bicuculline-induced allodynia. Despite being 
classified as an agent with a similar molecular target mechanism, ziconotide 
could only alleviate PGE2-induced allodynia, but not NMDA- or 
bicuculline-induced allodynia, as did mexiletine and duloxetine. These results 
taken together suggest that ziconotide, mexiletine, and duloxetine suppress 
spinal hyperactivity via the presynaptic site mechanism. In contrast, pregabalin 
could suppress via the downstream step during spinal hyperactivation such as 
postsynaptic NMDA activation or dysfunction of GABAergic control in addition to 
presynaptic mechanism. In conclusion, present findings provide implication that 
the spinal anti-nociceptive mechanistic site of pregabalin is different from 
that of ziconotide, mexiletine, and duloxetine, and pregabalin could have a 
broader anti-nociceptive mechanism other than N-type calcium channel blockade.