Neurogenic hyperalgesia: Psychophysical studies of underlying mechanisms

R. H. LaMotte, C. N. Shain, D. A. Simone, E. F.P. Tsai

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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 μl of 100 μg of capsaicin, the algesic substance in hot chili peppers. 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, ~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. 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. 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. 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 μg) 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. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury. Cooling the injection site to 1°C for several minutes reduced but did not eliminate the area of hyperalgesia to stroking, whereas rewarming brought it back. After capsaicin injection, a proximal, mediolateral strip of anesthetic reduced or eliminated the hyperalgesia to stroking on the proximal but not the distal side of the strip. These procedures were generally less effective in reducing the area of hyperalgesia to punctate stimuli. A proximal nerve block before the injection of capsaicin into the distal anesthetic skin prevented the occurrence of any hyperalgesia after recovery from the anesthetic 1-3 h later. A shorter lasting anesthetic greatly reduced or completely eliminated the areas of hyperalgesia to heat and to mechanical stimuli after recovery from the anesthetic. Thus the neurons that are 'sensitized' by capsaicin-activated nerve fibers reside in the central and not the peripheral nervous system. This sensitization of one set of neurons by neural activity in another is termed 'neurogenic hyperalgesia.' A neuronal model of neurogenic hyperalgesia was proposed in which chemospecific peripheral nerve fibers (that either branch widely or are functionally coupled together in the periphery) sensitize low- and high-threshold mechanoreceptive interneurons in the dorsal horn. These, in turn, differentially facilitate the responses of certain projection neurons to innocuous and noxious mechanical stimulation of the skin within the area of mechanical hyperalgesia. Heat-sensitive afferents from the area of heat hyperalgesia are hypothesized to sensitize heat-receptive interneurons, which also converge onto these projection neurons.

Original languageEnglish (US)
Pages (from-to)190-211
Number of pages22
JournalJournal of neurophysiology
Issue number1
StatePublished - 1991


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