There is evidence in experimental animals that deep and superficial pain exert differential effects on cutaneous sympathetic activity. Skin sympathetic nerve activity (SSNA) was recorded from the common peroneal nerve of awake human subjects and injections of 0.5 ml hypertonic saline was made into the tibialis anterior muscle (causing a deep, dull ache) or 0.2 ml into the overlying skin (causing a sharp burning pain) at unexpected times. Both deep and superficial pain caused increases in SSNA immediately on injection and preceding the onset of pain for both muscle and skin pain (10.1 +/- 2.4 vs. 15.3 +/- 5.3 s; muscle versus skin, respectively). SSNA increases were short lasting (104.2 +/- 13.4 vs. 81.8 +/- 11.7 s; muscle versus skin pain) and did not follow muscle and skin pain profiles. Sweat release occurred following both intramuscular and subcutaneous injections of hypertonic saline. While muscle or skin pain invariably caused changes in skin blood flow as well as increases in sweat release, skin blood flow increased in females and decreased in males. We conclude that both acute muscle and skin pain cause an increase in SSNA, sweat release and gender-dependent changes in skin blood flow.