Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons.
Pain is normally evoked only by stimuli that are sufficiently intense to activate high-threshold A(delta) and C sensory fibres, which relay the signal to the spinal cord. Peripheral inflammation leads to profoundly increased pain sensitivity: noxious stimuli generate a greater response and stimuli that are normally innocuous elicit pain. Inflammation increases the sensitivity of the peripheral terminals of A(delta) and C fibres at the site of inflammation. It also increases the excitability of spinal cord neurons, which now amplify all sensory inputs including the normally innocuous tactile stimuli that are conveyed by low-threshold A(beta) fibres. This central sensitization has been attributed to the enhanced activity of C fibres, which increase the excitability of their postsynaptic targets by releasing glutamate and the neuropeptide substance P. Here we show that inflammation results in A(beta) fibres also acquiring the capacity to increase the excitability of spinal cord neurons. This is due to a phenotypic switch in a subpopulation of these fibres so that they, like C-fibres, now express substance P. A(beta) fibres thus appear to contribute to inflammatory hypersensitivity by switching their phenotype to one resembling pain fibres, thereby enhancing synaptic transmission in the spinal cord and exaggerating the central response to innocuous stimuli.
Neumann
S
S
Department of Anatomy and Developmental Biology, University College London, UK.
Doubell
T P
TP
Leslie
T
T
Woolf
C J
CJ
D000200:Action Potentials; D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism / Q000502:physiology*; D010146:Pain; D010641:Phenotype; D010784:Photomicrography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology; D013373:Substance P / Q000378:metabolism
D009414:Nerve Growth Factors; D013373:Substance P