We examined the contribution of potassium channels to the inhibitory effect of morphine on the increase in substance P release and cutaneous blood flow evoked by antidromic stimulation of the sectioned sciatic nerve. Cutaneous blood flow in the instep of the rat hind paw was measured by the non-invasive technique of laser Doppler flowmetry. Antidromic stimulation of the sectioned sciatic nerve caused a biphasic flow response, an initial transient decrease followed by an increase and an increase in substance P release into the subcutaneous perfusate of the instep of the rat hind paw. Both the increases of substance P release and cutaneous blood flow evoked by antidromic stimulation of the sectioned sciatic nerve were significantly inhibited by intra-arterial (i.a.) infusion of morphine (30 mumol/kg). This inhibitory effect of morphine was antagonized by pretreatment with naloxone (2 mg/kg, i.p.) or potassium channels blockers such as tetraethylammonium (40 mg/kg, i.v.). apamin (0.5 mg/kg, i.v.) and charybdotoxin (0.12 mg/kg. i.v.) but not with cesium chloride (85 mg/kg, i.v.) and glibenclamide (25 mg/kg, i.v.). These results suggest that the calcium-activated potassium channels may be involved in the prejunctional inhibitory effects of morphine in the hind instep of rats.