Nociceptors are excited or sensitized by many inflammatory mediators as well as by elevation of tissue temperature. We have shown that there is a facilitatory synergistic interaction between norepinephrine (NE) and bradykinin (BK) on cutaneous C-fiber nociceptors in normal Lewis rats. These interactions may play an important role in the mechanism of sympathetically maintained pain. In the present experiment, using skin-saphenous nerve in vitro preparations, we tested the effect of NE on the activity of nociceptive fibers and their response to heat in normal Sprague-Dawley rats. For comparison with the previous data on Lewis rats, we also examined the effect of NE on BK response. NE (10(-5) or 10(-6) M) did not excite nociceptive fibers before repeated heat stimuli or BK superfusion (10(-5) or 10(-6) M) to the receptive field. In contrast, after a few applications of heat or BK, NE excited 20-43% of nociceptive fibers to similar magnitudes. We also found that NE sensitized subsequent BK responses, but somewhat unexpectedly that it suppressed subsequent heat responses. This occurred regardless of the presence or absence of NE-induced excitation. These results suggest different mechanisms of NE modification to the BK and heat responses of cutaneous C-fiber nociceptors. (c) 2004 Elsevier Ireland Ltd. All rights reserved.