The present study investigated the effects of pharmacological spinal inhibition of voltage-gated
calcium channels (VGCC) in mouse
pruritus. The epidural administration of P/Q-type MVIIC or
PhTx3.3, L-type
verapamil, T-type
NNC 55-0396 or R-type
SNX-482 VGCC blockers failed to alter the scratching behavior caused by the
proteinase-activated receptor 2 (PAR-2) activator
trypsin, injected into the mouse nape skin. Otherwise,
trypsin-elicited
pruritus was markedly reduced by the spinal administration of preferential N-type VGCC inhibitors MVIIA and Phα1β. Time-course experiments revealed that Conus magus-derived toxin MVIIA displayed significant effects when dosed from 1h to 4h before
trypsin, while the anti-pruritic effects of Phα1β from Phoneutria nigriventer remained significant for up to 12h. In addition to reducing
trypsin-evoked
itching, MVIIA or Phα1β also prevented the
itching elicited by intradermal (i.d.) injection of
SLIGRL-NH2,
compound 48/80 or
chloroquine, although they did not affect H2O2-induced scratching behavior. Furthermore, the co-administration of MVIIA or Phα1β markedly inhibited the
pruritus caused by the
spinal injection of
gastrin-releasing peptide (GRP), but not
morphine. Notably, the epidural administration of MVIIA or Phα1β greatly prevented the chronic
pruritus allied to dry skin model. However, either tested toxin failed to alter the
edema formation or neutrophil influx caused by
trypsin, whereas they significantly reduced the c-Fos activation in laminas I, II and III of the spinal cord. Our data bring novel evidence on
itching transmission mechanisms, pointing out the therapeutic relevance of N-type VGCC inhibitors to control refractory
pruritus.