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Tuning in C‐nociceptors to reveal mechanisms in chronic neuropathic pain
Author(s) -
Jonas Robin,
Namer Barbara,
Stockinger Lenka,
Chisholm Kim,
Schnakenberg Mark,
Landmann Gunther,
Kucharczyk Mateusz,
Konrad Christoph,
Schmidt Roland,
Carr Richard,
McMahon Stephen,
Schmelz Martin,
Rukwied Roman
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25231
Subject(s) - nociceptor , neuropathic pain , medicine , stimulation , nociception , axon reflex , microneurography , anesthesia , hyperalgesia , axon , neuroscience , anatomy , psychology , receptor , baroreflex , heart rate , blood pressure
Objective Develop and validate a low‐intensity sinusoidal electrical stimulation paradigm to preferentially activate C‐fibers in human skin. Methods Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of “silent” C‐nociceptors. Synchronized C‐fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small‐diameter neurons during transcutaneous 4‐Hz stimulation of the hindpaw (0.4mA). Results Transcutaneous sinusoidal current (0.05–0.4mA, 4Hz) activated “polymodal” C‐fibers (50% at ∼0.03mA) and “silent” nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1‐ms rectangular pulses (“polymodal” ∼3mA, “silent” ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon‐reflex erythema, both indicative of C‐nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) –3 and nonpainful skin sites of neuropathic pain patients by NRS –0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2. Interpretation Sinusoidal electrical stimulation at 4Hz enables preferential activation of C‐nociceptors in pig and human skin that accommodates during ongoing (1‐minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment. Ann Neurol 2018;83:945–957