Tuning in C‐nociceptors to reveal mechanisms in chronic neuropathic pain

Jonas, Robin; Namer, Barbara; Stockinger, Lenka; Chisholm, Kim I.; Schnakenberg, Mark; Landmann, Gunther; Kucharczyk, M.; Konrad, Christoph; Schmidt, Roland; Carr, Richard W.; McMahon, Stephen B.; Schmelz, Martin; Rukwied, Roman

doi:10.1002/ana.25231

Cited by 42 publications

(96 citation statements)

References 33 publications

(55 reference statements)

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“…When the stimulation frequency is reduced to 5 Hz, activation of C-fibres is anticipated. However, for selective C-fibre stimulation in human skin, higher current density with small bipolar electrodes is required (19). Patients reported more throbbing, pounding and tingling after stimulation at 2,000 Hz compared with stimulation at 5 Hz.…”

Section: Discussionmentioning

confidence: 99%

Selective Nerve Fibre Activation in Patients with Generalized Chronic Pruritus: Hint for Central Sensitization?

Pereira¹,

Agelopoulos²,

Köllner³

et al. 2019

Acta Derm Venerol

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Mechanisms underlying chronic pruritus are not yet completely understood. We compared patients with chronic pruritus of different origins (atopic dermatitis, chronic itch on non-lesional skin, chronic prurigo) to healthy controls in regard to itch intensity and sensory symptoms elicited by electrical stimulation. Both stimulation at 5 Hz (targeting C-fibers) and 2,000 Hz (targeting Aβ-fibers) induced a higher itch intensity in patients compared to healthy individuals, regardless of the origin of the pruritus. Additionally diverse sensory symptoms were recorded between patients and controls upon electrical stimulation. These findings argue for common central sensitization mechanisms in chronic itch patients of different origins. Central sensitization induces pain augmentation in chronic pain states. An analogous mechanism is speculated for chronic pruritus. This study compared patients with chronic pruritus (n = 79) of different origins (atopic dermatitis, chronic pruritus on non-lesional skin, chronic prurigo) and healthy controls (HC, n = 54) with regard to itch intensity and qualities of sensory symptoms after selective peripheral nerve fibre activation by electrical stimulation at 5 Hz (surrogate for C-fibre function) and 2,000 Hz (surrogate for Aβ-fibre function) using a Neurometer ®. Electrically-induced itch was more intense in patients with chronic pruritus than in HC, but patients with chronic pruritus did not report "itch" more often than HC at 5 Hz. Stimulation at 2,000 Hz induced more pricking and tingling, but less throbbing in patients with chronic pruritus compared with HC. Treatment with cooling compound reduced clinical and experimental itch, but did not alter the distribution of sensory symptoms. These data show hyperknesis in chronic pruritus of various origins, arguing for common central sensitization mechanisms.

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Section: Discussionmentioning

confidence: 99%

Selective Nerve Fibre Activation in Patients with Generalized Chronic Pruritus: Hint for Central Sensitization?

Pereira¹,

Agelopoulos²,

Köllner³

et al. 2019

Acta Derm Venerol

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“…As shown by single nerve fibre recordings in pig and human, fewer sympathetic efferent neurons can be activated by sinusoidal pulses and their response to this stimulus is markedly weaker. Thus, 4 Hz sinusoidal stimuli even at 0.4 mA peak currents induce only a very weak sweat response (QSART) contrasting the development of an axon reflex erythema and pain already at 0.05 mA (Jonas et al, ). This mismatch might result from different levels of neuronal activity required to evoke nociceptor‐driven pain and axon reflex erythema versus sympathetically driven sweat response or from different axonal excitability related to the sine wave stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Single nerve fibre recordings in vivo reveal that a sinusoidal current can produce a slow electrical depolarization that preferentially activates unmyelinated primary afferent C‐nociceptors over A‐delta fibres when applied transcutaneously and causes a pronounced axon reflex erythema (Jonas et al, ). Yet, it is unknown whether slow depolarization would stimulate also unmyelinated efferent sympathetic neurons in the skin.…”

Section: Introductionmentioning

confidence: 99%

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Sympathetic efferent neurons are less sensitive than nociceptors to 4 Hz sinusoidal stimulation

Jonas

Namer

Schnakenberg

et al. 2019

European Journal of Pain

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Background Sinusoidal current stimuli preferentially activate C‐nociceptors. Sodium channel isoforms NaV1.7 and NaV1.8 have been implicated in this. Sympathetic efferent neurons lack NaV1.8 and were explored upon sinusoidal activation. Methods Quantitative Sudomotor Axon Reflex Test (QSART) was performed in hairy (n = 16) and glabrous (n = 12) skin. Responses of sympathetic efferents (n = 10) and nociceptive afferents (n = 21) to sinusoidal current stimulation (4 Hz, 0.05–0.15 mA) were recorded in humans by microneurography (n = 11). Activation of sympathetic units upon supra‐threshold sinusoidal currents (>0.8 mA) was recorded in pigs (n = 8). Results Sinusoidal stimuli (4 Hz, 0.4 mA) evoked weak sweat output (30 ml/h/m2) in hairy skin compared to rectangular pulses (4 Hz, 5 mA, 53 ml/h/m2, p < .00001, ANOVA). No change in sweat output was recorded from glabrous skin to sine wave stimuli. Sinusoidal current at intensities ranging from 0.05 to 0.15 mA activated almost all (85%) nociceptors but only 40% of sympathetic units in human. Stimuli lead to a significantly lower activation in sympathetic versus nociceptive fibres as measured by activity‐dependent slowing (ADS) of conduction (sympathetic efferents average ADS 100 ± 0.2% vs. C‐nociceptors average ADS 113 ± 4%, p < .003, ANOVA). Conclusions Sympathetic efferent neurons are less apt to convert slow depolarizations into action potentials as compared to nociceptors. Distinctive sodium channel expression patterns between nociceptors and sympathetic efferent neurons may account for this difference. Sinusoidal stimulation therefore provokes weak sweat responses and provides no alternative for clinical assessment of autonomic function. Significance C‐nociceptors in hairy skin are activated by 4 Hz sinusoidal current stimulation at lower intensities than myelinated fibres. Sympathetic efferent neurons—albeit also unmyelinated—are less responsive to sinusoidal activation than nociceptors within the same skin area. Cutaneous sympathetic efferent neurons apparently are less apt than nociceptors to convert slow depolarization into action potentials.

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“…迄今为止还没有研究发现痒感受特异性的初级感觉神经元 [12] , 大部分初级感觉传入纤维都是"多觉型纤维"(polymodal fiber) [13] , 一般根据其有无髓鞘和对机械刺激的敏感性来进行分类. 例如, 可以根据对机械刺激的敏感性分为机械敏感型传入纤维(mechanically sensitive afferents, MSAs)和机械不敏感型传入纤维(mechanically insensitive afferents, MIAs) [14] . 传导伤害性感受的无髓鞘纤维又称C纤维, 信号传导速度较慢, 主要传递施加在手部无毛皮肤的烧灼痛以及持续压痛, 即"慢痛".…”

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Neural similarities and differences between pain and itch: Reception, transmission and modulation

Wei¹,

Zhang²,

Kong³

2020

Chin. Sci. Bull.

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Tuning in C‐nociceptors to reveal mechanisms in chronic neuropathic pain

Cited by 42 publications

References 33 publications

Selective Nerve Fibre Activation in Patients with Generalized Chronic Pruritus: Hint for Central Sensitization?

Selective Nerve Fibre Activation in Patients with Generalized Chronic Pruritus: Hint for Central Sensitization?

Sympathetic efferent neurons are less sensitive than nociceptors to 4 Hz sinusoidal stimulation

Neural similarities and differences between pain and itch: Reception, transmission and modulation

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