The nociceptive C-fibers of the dorsal root ganglion express several sodium channel isoforms that associate with one or more regulatory beta-subunits (beta(1)-beta(4)). To determine the effects of individual and combinations of the beta-subunit isoforms, we co-expressed Na(v)1.8 in combination with these beta-subunits in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two-microelectrode voltage clamp method. Our studies revealed that the co-expression beta(1) alone or in combination with other beta-subunits enhanced current amplitudes, accelerated current decay kinetics, and negatively shifted the steady-state curves. In contrast, beta(2) alone and in combination with beta(1) altered steady-state inactivation of Na(v)1.8 to more depolarized potentials. Co-expression of beta(3) shifted steady-state inactivation to more depolarized potentials; however, combined beta(1)beta(3) expression caused no shift in channel availability. The results in this study suggest that the functional behavior of Na(v)1.8 will vary depending on the type of beta-subunit that expressed under normal and disease states. (C) 2004 Elsevier Inc. All rights reserved.