1. Psychophysical studies were made, in humans, of the sensory characteristics and underlying mechanisms of the hyperalgesia (often termed "secondary hyperalgesia") that occurs in uninjured skin surrounding a local cutaneous injury. The hyperalgesia was characterized by lowered pain thresholds and enhanced magnitude of pain to normally painful stimuli. The "injury" was produced by a single intradermal injection of 10 microliters of 100 micrograms of capsaicin, the algesic substance in hot chili peppers. 2. On injection of capsaicin into the volar forearm, the subjects experienced intense burning pain, accompanied immediately by the formation of three areas of hyperalgesia surrounding the injection site. The largest mean area (55 cm2) was hyperalgesic to a normally painful punctate stimulation of the skin. Nested within this was an area of tenderness to gentle stroking (38 cm2) and a much smaller area of hyperalgesia to heat (2 cm2). An area of analgesia to pinprick, approximately 4 mm in diameter and centered on the injection site, developed within minutes and typically disappeared within 24 h. The hyperalgesia to heat and to stroking disappeared within 1-2 h, whereas the hyperalgesia to punctate stimuli, although gradually decreasing in area, lasted from 13 to 24 h. 3. The radial spread of the mechanical hyperalgesia (to punctate and stroking stimuli) away from the injury was dependent on neural activity and not produced, for example, by algesic substances transported away from the injury. The injection of capsaicin into a small area of anesthetized skin did not produce hyperalgesia in the surrounding, unanesthetized skin. Also, the hyperalgesia in normal skin readily crossed a tight arm band that blocked the circulation of blood and lymph. 4. The spread of mechanical hyperalgesia away from the injury was peripherally mediated via cutaneous nerve fibers because it was blocked by a thin mediolateral strip of cutaneous anesthesia placed 1 cm away from the capsaicin injection site. Hyperalgesia developed normally on the capsaicin side of the strip but not on the other side. 5. Heat stimulation of the skin that produced pain that was equivalent in magnitude and time course to that produced by an injection of capsaicin (10 micrograms) resulted in much smaller areas of mechanical hyperalgesia. It was postulated that there exist special chemosensitive primary afferent nerve fibers that are more effective in producing mechanical hyperalgesia than are the known thermo- and mechanosensitive nociceptive nerve fibers. 6. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Substance P is released in the spinal cord in response to painful stimuli, but its role in nociceptive signaling remains unclear. When a conjugate of substance P and the ribosome-inactivating protein saporin was infused into the spinal cord, it was internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor. This treatment left responses to mild noxious stimuli unchanged, but markedly attenuated responses to highly noxious stimuli and mechanical and thermal hyperalgesia. Thus, lamina I spinal cord neurons that express the substance P receptor play a pivotal role in the transmission of highly noxious stimuli and the maintenance of hyperalgesia.