The neuropeptide calcitonin gene-related peptide (CGRP) binds to a subpopulation of dorsal root ganglion (DRG) neurons, elevates intracellular calcium, and causes inward currents in about 30% of lumbar DRG neurons. Using whole-cell patch clamp recordings, we found in the present study that application of CGRP to isolated and cultured DRG neurons from the adult rat enhances voltage-gated TTX-resistant (TTX-R) Na + inward currents in about 30% of small- to medium-sized DRG neurons. During CGRP, peak densities of Na + currents increased significantly. CGRP shifted the membrane conductance of the CGRP-responsive cells towards hyperpolarization without changing the slope of the peak conductance curve. The effect of CGRP was blocked by coadministration of CGRP 8–37 , an antagonist at the CGRP receptor. The effect of CGRP was also blocked after bath application of PKA 14–22 , a membrane-permeant blocker of protein kinase A, and PKC 19–31 , a PKC inhibitor, in the recording pipette. These data show pronounced facilitatory effects of CGRP on TTX-R Na + currents in DRG neurons which are mediated through CGRP receptors and intracellular pathways involving protein kinases A and C. Thus, in addition to prostaglandins, CGRP is another mediator that affects TTX-R Na + currents which are thought to occur mainly in nociceptive DRG neurons.