Calcium influx through neuronal voltage-sensitive
calcium channels (VSCC S) mediates nociceptive information in the spinal dorsal horn. In fact, spinally administered VSCC S blockers, such as
omega-conotoxin MVIIA, have
analgesic effect apart of their low therapeutic index and many side effects. Here we study the
analgesic potential of Ph alpha 1beta, a
calcium channel blocker, in rodent models of acute and persistent
pain. Spinally administered Ph alpha 1beta showed higher efficacy and long-lasting
analgesia in a thermal model of
pain, when compared with
omega-conotoxin MVIIA. Moreover, Ph alpha 1beta was more effective and potent than
omega-conotoxin MVIIA not only to prevent, but especially to reverse, previously installed persistent chemical and
neuropathic pain. Furthermore, the
analgesic action of both toxins are related with the inhibition of Ca2+-evoked release of pro-nociceptive
neurotransmitter,
glutamate, from rat spinal cord synaptosomes and decrease of
glutamate overflow in cerebrospinal fluid. When side effects were assessed, we found that Ph alpha 1beta had a therapeutic index wider than
omega- conotoxin MVIIA. Finally, recombinant Ph alpha 1beta expressed in Escherichia coli showed marked
analgesic activity similar to the native toxin. Taken together, the present study demonstrates that native and recombinant Ph alpha 1beta have
analgesic effects in rodent models of
pain, suggesting that this toxin may have potential to be used as a
drug in the control of persistent pathological
pain.