C-Fiber mechanoheat (C-MH) nociceptors from the saphenous nerve were studied, in control rats and in rats that underwent surgical sympathectomy. Intradermal injection, alone, of either norepinephrine (NE) or the calcium ionophore, A23187, did not affect mechanical threshold. The combination of A23187 and NE, however, significantly decreased mechanical threshold. In the presence of the alpha 2-adrenergic antagonist, yohimbine, or the cyclooxygenase inhibitor, indomethacin, C-MHs were not sensitized by the combination of NE + A23187. One week after surgical sympathectomy, the number of C-MHs sensitized by NE + A23187 was significantly reduced. In summary, NE appears to sensitize nociceptors indirectly. These data are compatible with the suggestion that a sympathetic postganglionic neuron-dependent release of prostaglandins mediates the sensitization. NE appears to act at an alpha 2-adrenergic receptor, only in the presence of an increased intracellular Ca2+.