Previous data from our laboratory have shown that calcitonin gene-related peptide (CGRP) is released into the circulation during pathogenesis of endotoxic, hemorrhagic, and septic shock and appears to mediate in part the vascular problems of shock. Elevations in the levels of bradykinin (BK) and lactic acid and lowering of tissue pH also occur during shock and could be involved in CGRP release. In the present study, we have tested whether lactic acid, alone or in combination with BK or low pH, triggers release of CGRP-like immunoreactivity (CGRP-LI) from sensory nerves, using rat spinal cord slices as a tissue model. Lowering media pH from 7.4 to < or = 6.0 increased the release of CGRP-LI. Lactic acid (5 and 10 mM) by itself elevated CGRP-LI release from a control of 6.89 +/- 0.95 to 57.2 +/- 8.2 and 116 +/- 13 pg/mg protein, respectively. The combination of pH 6.0 and lactic acid (5 or 10 mM) caused more than additive stimulation of CGRP-LI release. BK (50 or 100 microM) elevated CGRP-LI release, which was greatly enhanced by lactic acid (2.5 or 5 mM). The data indicate that lactic acid potentiates BK- and low-pH-induced release of CGRP from sensory nerves in spinal cord. Similar mechanisms may occur at peripheral ends of sensory nerves, contributing to CGRP release during septic shock and other conditions with elevated lactic acid levels (e.g., strenuous exercise and tissue ischemia).