Figure 8. Summary and translational mechanisms for nociceptive presynaptic inhibition.

Upper left: a simplified schematic of vesicle fusion showing SNARE complex and the tethered calcium channel. Depolarization of the terminal causes an influx of calcium through voltage-gated calcium channels and initiates vesicle fusion. Lower right: overexpression of STX1A interferes with the fusion machinery through multiple interactions, which occlude fusion and interrupt neuropeptide release from primary afferents. The resulting phenotype is profound analgesia. The blue panel depicts multiple mechanisms for inhibition of presynaptic vesicle fusion ranging from competition, to disruption of STX1A-calcium channel tethering (52, 76), to enzymatic cleavage with botulinum toxins (59). Three interventions, botulinum toxin, morphine, and the calcium channel blocker ziconotide (77, 78), are currently used therapeutic agents. Intrathecal administration of morphine or ziconotide produces potent and effective analgesia.