Lofentanil, a very potent and long-acting opiate agonist, was used to evaluate the opioid control of substance P release from primary afferents. Substance P release from the central terminals of primary afferents was studied in the superfused isolated dorsal half of the rat spinal cord. Substance P release as initiated by electrical field stimulation and by capsaicin was found to be diminished by 50% by lofentanil (1 microM) in a naloxone-reversible manner. Substance P release from peripheral terminals of primary afferents was induced by antidromic saphenous nerve stimulation. Release was measured indirectly by its effect on blood flow and plasma extravasation in the rat hind paw. Both antidromic vasodilatation and plasma extravasation were dose dependently inhibited by lofentanil. The inhibition of antidromic vasodilatation by 10 micrograms X kg-1 lofentanil i.p. was completely prevented by 1 mg X kg-1 naloxone. On the other hand, vasodilatation and plasma extravasation induced by infusion of 3.7 pmol X min-1 substance P remained unaffected by lofentanil. It is concluded that lofentanil inhibits the release of substance P from central as well as peripheral terminals of substance P-containing primary afferent neurons.