In the present study we have investigated the effects of nicotine, capsaicin, potassium, glutamate and aspartate on release of calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) from guinea-pig dorsal root ganglion (DRG) cultures. In addition the possible influence of Ruthenium red (RR), neuropeptide Y (NPY) and noradrenaline (NA) on the CGRP-LI outflow has been evaluated. Nicotine, capsaicin and potassium, but not glutamate or aspartate, evoked a Ca2+-dependent increase in the culture medium, suggesting release of CGRP-LI. RR inhibited the effect of both capsaicin and nicotine but did not influence potassium-induced CGRP-LI release. Furthermore, the nicotine- but not capsaicin-evoked CGRP-LI release was inhibited by NPY. It is concluded that DRG cultures represent an experimental model where regulation of CGRP-LI release can be studied. The ability of RR to inhibit not only capsaicin but also nicotine effects indicate that the proposed selectivity of RR may depend on the agent used to evoke peptide release and/or concentrations used.