1. The amount of calcitonin gene-related peptide (CGRP) released from the isolated rat soleus muscle was measured by enzyme immunonoassay.
2. When the soleus muscle was exposed to a solution containing high K+ (20-100 mM) in the presence of tetrodotoxin, the amount of CGRP released into the bathing medium increased with an increase in the K+ concentration.
3. The exposure to 100 mM-K+ did not increase CGRP release from chronically' denervated soleus muscles or from pieces of the soleus nerve separated from the muscle.
4. The amount of CGRP released from the isolated muscle by 100 mM-K+ depended on the external Ca2+ concentration. The slope of the relation between the amount of CGRP release and the Ca2+ concentration was less than one on double logarithmic co-ordinates.
5. Following chronic section of the lumbar ventral roots, the mean amount of CGRP released from the soleus muscle by 100 mM-K+ was reduced by 28%, compared with that observed in normal muscle.
6. Antidromic stimulation of the lumbar dorsal roots at an intensity three times the threshold for most excitable sensory fibres failed to induce CGRP release from the soleus muscle, whereas stimulation at intensities 50-100 times the threshold increased significantly the amount of CGRP release from the muscle.
7. Stimulation of the muscle nerve at an intensity sufficient to activate the alpha-motor fibres did not release CGRP from the soleus muscle or from the diaphragm.
8. It is concluded that the major source of CGRP released from skeletal muscle is A-delta-and/or C sensory terminals and that the Ca2+ dependence of CGRP release is less steep than that reported for acetylcholine release at neuromuscular junctions.