The concept that NK1 receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK1 receptor knockout mice and an NK1 receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve. The results reveal that in the dorsal horn preparation, basal release of SP is significantly higher in NK1-/- mice than NK1+/+ mice (P <0.05, n = 7 mice/strain). However, a difference in SP release evoked in the dorsal horn by electrical stimulation of the dorsal roots or capsaicin application was not observed. In contrast, antidromic electrical stimulation of the saphenous nerve caused a substantially greater release of SP in the skin of NK1-/- mice than in NK1+/+ mice (P <0.05, n = 5 to 6 mice/strain). These results provide evidence for the existence of NK1 autoreceptors on sensory nerves in skin, which may be relevant to the modulation of their peripheral pathophysiological effector functions. (C) 2003 Elsevier Ltd. All rights reserved.