Neurokinin-1 receptor (NK-1) plays an important role in nociception. The present study was to explore whether activation of peripheral NK-1 receptor, especially expressed on primary sensory afferent, could induce hyperalgesia and sensitize C-type sensory afferents. (1) Intraplantar administration of NK-1 agonist [Sar(9), Met(O-2)(11)]SP (Sar-SP, 0.2, 1 nmol, 20 mu l) produced significant thermal hyperalgesia edema, which was blocked by co-injection of NK-1 antagonist WIN51,708 (10 nmol). But in the rats with compound 48/80 treatment for mast cell depletion, the Sar-SP-induced edema, but not hyperalgesia, was attenuated. (2) Close-arterial injection of Sar-SP (1 nmol, 0.1 ml) excited and sensitized sensory C afferents of the sural nerve to heat stimuli. The results suggest involvement of NK-1 receptors expressed on the peripheral afferent terminals in thermal hyperalgesia mediated by directly sensitizing C-type sensory afferents. (c) Elsevier Inc. All rights reserved.