Nerve growth factor sensitizes nociceptors to C‐fibre selective supra‐threshold electrical stimuli in human skin

Abstract

BackgroundIntradermal injection of 1 µg nerve growth factor (NGF) causes sustained nociceptor sensitization. Slowly depolarizing electrical current preferentially activates C‐nociceptors.MethodsWe explored the differential contribution of A‐delta and C‐nociceptors in NGF‐sensitized skin using slowly depolarizing transcutaneous electrical current stimuli, CO2 laser heat, mechanical impact, and A‐fibre compression block. In 14 healthy volunteers, pain rating was recorded on a numeric scale at days 1–14 after NGF treatment. Ratings during A‐fibre conduction block were investigated at days 3 and 7 post‐NGF.ResultsPain ratings to electrical, CO2 heat and mechanical impact stimuli were enhanced (>30%, p < .0005, ANOVA) at NGF‐injection sites. Axon reflex erythema evoked by electrical stimulation was also larger at NGF‐injection sites (p < .02, ANOVA). Diminution of pain during continuous (1 min) sinusoidal current stimulation at 4 Hz was less pronounced after NGF (p < .05, ANOVA). Pain ratings to electrical sinusoidal and mechanical impact stimuli during A‐fibre conduction block were significantly elevated at the NGF sites compared to NaCl‐treated skin (p < .05, ANOVA).ConclusionsNGF‐induced sensitization of human skin to electrical and mechanical stimuli is primarily driven by C‐nociceptors with little contribution from A‐delta fibres. Less‐pronounced accommodation during ongoing sinusoidal stimulation suggests that NGF could facilitate axonal spike generation and conduction in primary afferent nociceptors in humans. Further studies using this sinusoidal electrical stimulation profile to investigate patients with chronic inflammatory pain may allow localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.SignificanceThe application of novel slowly depolarizing electrical stimuli demonstrated a predominant C‐nociceptor sensitization in NGF‐treated skin. Increased pain ratings, larger axon reflex erythema and less accommodation of C‐fibres to ongoing sinusoidal stimulation all indicated an enhanced nociceptor discharge after NGF. A‐fibre conduction block had little effect on electrical and mechanical hyperalgesia skin in NGF‐treated compared to NaCl‐treated skin. This electrical stimulus profile may be applicable for patients with chronic inflammatory pain, allowing localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.

Local hyperexcitability of C-nociceptors may predict responsiveness to topical lidocaine in neuropathic pain

“…Slowly depolarizing transcutaneous electrical stimulation (4 Hz sinusoidal profile and 500 ms half sine wave pulses) induced burning pain in healthy subjects, activated primary afferent C-nociceptors, and revealed substantial accommodation upon continuous 4 Hz sinusoidal stimulation [ 15 , 17 , 18 ]. We found in our patients that about 50% reported enhanced pain upon 4 Hz sinusoidal stimulation of their stimulated neuropathic skin sites.…”

“…The geometry of the electrodes and the temporal stimulation profile is critical for a selective activation of peripheral nerve fibers [ 10 – 14 ]. Slowly depolarizing transcutaneous currents of low-intensity with 4 Hz sinusoidal stimulation profile as well as single 500 ms half sine wave pulses can be used to stimulate nociceptors in human skin [ 15 – 18 ]. While single supra-threshold 500 ms half sine wave pulses induce a burst of action potentials, at 4 Hz sinusoidal stimulation single action potentials are evoked per sine wave [ 17 ].…”

Electrically Evoked Itch in Human Subjects

“…The uncertainty of matching stimulus configuration to the activated nerve fiber class, however, is rather unsatisfying. This issue can be addressed by employing slowly depolarizing electrical stimuli of halfsine and sine wave shape delivered transcutaneously via small punctate electrodes that selectively activate C-fibers (33)(34)(35)(36). Thereby, "polymodal" C-nociceptors are activated by a single 500 ms half-sine wave pulse responding with a current intensity dependent burst of action potential discharges (34).…”

“…Expression changes in nerve fibers are particularly hard to detect in punch biopsies, as they make up only a minute amount of the tissue's total RNA, are not specifically targetable by current single cell transcriptomic approaches (76) and only refer to axonally transported RNA. These problems also preclude to link global transcriptomic changes to specific nerve fiber classes, which is particularly warranted, given that sinusoidal transcutaneous electrical stimuli preferentially activate C-fibers (35,36). However, despite these technical difficulties, one study found the voltage-gated sodium channels Nav1.3, Nav1.7, and Nav1.9 to be overexpressed in eczematous skin of AD patients and, importantly, this overexpression correlated with pruritus severity (72).…”

Transient receptor potential vanilloid subtype 1 depletion mediates mechanical allodynia through cellular signal alterations in small-fiber neuropathy

“… 57 Particularly, the C-polymodal nociceptors are further categorized as mechano-heat-responsive units and mechano-insensitive units (CMi) according to the different electrical thresholds. Past studies suggested CMi became sensitized by tissue damage (ie, skin denervation), 130 nerve growth factor (NGF), 113 , 114 , 141 and capsaicin administration. 140 Therefore, the neuropathology of skin denervation provided a basis for evaluating the alteration of pain perception.…”