Novel classes of responsive and unresponsive C nociceptors in human skin

Schmidt, Roland; Schmelz, Martin; Forster, Clemens; Ringkamp, Matthias; Torebjörk, Erik; Handwerker, Hermann O.

doi:10.1523/jneurosci.15-01-00333.1995

Cited by 417 publications

(267 citation statements)

References 52 publications

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“…[11][12][13][14] The two may have different sensory/efferent pathways, and/or different sub-sets of nociceptors. 15,33 The difference in the flare and pain response to a heat-ramp stimulus among the normal and obese subjects may be indicative of such a dissociation and, in fact, would favor a concept that the organism attempts to elicit an early protective reaction (neurogenic vasodilatation) at a temperature (441C) just below that which will become injurious to tissue. 14 Flare can be suppressed or abolished by denervation, 21,42 local anesthetics, 12,21 capsaicin-desensitization, 22,34 disease (diabetes, post-herpetic neuralgia), 21,43 and aging.…”

Section: Discussionmentioning

confidence: 99%

“…21,31,32 All four of these reactions, acute heat pain, pruritis, sensitization and flare reactions, are C-fiber mediated, apparently by utilizing different sub-sets of C-fibers. 15,33 Specific noxious and non-noxious stimuli are applied to the skin to activate nociceptive afferent neurons to induce a spreading hyperemia, which is visible as a neurogenic vasodilatory, or flare, response. 12,21,31,32,34 Assessment of the axon-reflex flare by noxious heat-and capsaicinstimulation and by non-noxious transcutaneous electrical stimulation can be used to measure C-fiber function.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence of somatic small fiber neuropathy in obesity

et al. 2006

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Background: Somatic cutaneous small sensory fiber neuropathy (SSFN) can be an early manifestation of impaired glucose tolerance and diabetes mellitus and/or insulin resistance among obese subjects and is often associated with pain, wound occurrence and impaired wound healing. It is yet unclear as to whether SSFN is prevalent among obese individuals without glucose and/or insulin dysregulation despite abundant evidence of delayed wound healing. Objective: To observe whether there is hypofunctioning of stimulated capsaicin-sensitive cutaneous nerves (small sensory fibers) in obese subjects with/without hyperglycemia and hyperinsulinemia. Design, setting and participants: Fifty-eight morbidly obese and 15 lean subjects were recruited for small fiber testing of the forearm in a cross-sectional study. Hyperglycemia was observed in 35 obese subjects. Of 25 obese subjects, hyperinsulinemia was noted in 15, 14 of which were hyperglycemic. No subjects demonstrated symptoms/signs of neuropathy over the hairy skin of the forearm. In fact, a neurological examination revealed that 37 subjects were asymptomatic in the legs and only four complained of a neuropathic pain in the foot. Virtually all subjects were exposed to a set of capsaicin-sensitive tests and measures which were identified by capsaicin desensitization procedures. These tests, conducted while in a supine position in bed at the Banner Good Samaritan Medical Center, Phoenix, examined the two principle roles of cutaneous SSFs, namely conveying pain signals to the CNS and controlling local neurogenic vasodilatation (flare; axon-reflex). Main outcome measures: Heat-induced pain was assessed by verbal reports of sensation after accommodation and heat-, capsaicin-, and transcutneous stimulation-induced blood flow was measured by laser Doppler flowmetry with probes placed at the site of stimulation and 1 cm remote from the site, the latter to evaluate flare latency and intensity of flare. Results: Significant depression of pain and flare responses were observed in the obese subjects in all but one test. Decreased pain and flare responses were noted in all subjects without hyperglycemia and hyperinsulinemia. Age negatively correlated with capsaicin-induced flare in both the obese and normal groups. Conclusion: SSFN was prevalent in the cohort of morbidly obese subjects in a skin area without neurological symptoms or signs and in subjects with/without hyperglycemia and hyperinsulinemia. SSFN may be a serious factor in observations of impaired wound healing among obese subjects, a particularly worrisome problem in an obese aging population given the propensity for small fiber impairment in aging subjects. Small fiber impairment in the younger obese population may signal an early aging phenomenon.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prevalence of somatic small fiber neuropathy in obesity

et al. 2006

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“…A large variety of substances feed back onto nociceptors innervating the injured region and sensitize peripheral terminals by direct and indirect actions at ion channels, receptors, and second messenger cascades (87,102,111,112). The mechanisms by which inflammatory mediators recruit "silent" C-M i H i fibers by endowing these fibers with prolonged mechanical and heat sensitivity (25,60) is unknown but may involve long-lasting alterations in second messenger signaling cascades and sensitization of nocisensors. Decreased thermal and chemical thresholds in the primary area are due in part to sensitization of TRPV1 and TRPA1 by numerous components of the "inflammatory soup" including BK (36,(85)(86)(87)112).…”

Section: Adaptive and Maladaptive Shifts In Pain Thresholdmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

1,014

856

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Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.

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“…Heat nociceptor units are reported to be present in significant numbers in primate cutaneous nerves. Microneurography studies in the peroneal nerve of man have shown that 6% of C fibre afferents are heat nociceptor units (Schmidt, Schmelz, Forster, Ringkamp, Torebj ork & Handwerker, 1995). In monkey hairy skin it is reported that heat nociceptor afferents make up 7% of C fibres (Baumann, Simone, Shain & LaMotte, 1991), and in monkey glabrous skin they make up 5·5% of nociceptive C fibres (Georgopoulos, 1976).…”

Section: Species Differencesmentioning

confidence: 99%

The Relationship between Cutaneous C Fibre Type and Antidromic Vasodilatation in the Rabbit and the Rat

Gee

Lynn

Cotsell

1997

The Journal of Physiology

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Skin blood flow was monitored during antidromic stimulation of identified cutaneous C fibres in fine filaments dissected from the saphenous nerve of anaesthetized rabbits and rats. The techniques used to monitor skin blood flow were laser Doppler perfusion imaging and laser Doppler flowmetry. In the rabbit filaments a total of thirty‐three C fibres were tested for their ability to produce antidromic vasodilatation. The only C fibres found to have vasodilator actions were of the polymodal nociceptor afferent class, and fourteen (50%) of the twenty‐eight polymodal nociceptor units tested were vasoactive. The afferent receptive fields of polymodal nociceptor afferents were mapped carefully using suprathreshold mechanical stimuli, and there was a good correlation between afferent receptive field area and area of vasodilatation. In the rat, eleven of the fifty‐four C fibres antidromically stimulated had vasodilator actions. All eleven vasoactive C fibres were nociceptive and comprised seven polymodal nociceptor units, two heat nociceptor units and two incompletely classified nociceptor units. The area of increased blood flow was always coincident with the afferent field of the stimulated unit. In the rat the vasodilator units were not evenly distributed over the saphenous nerve receptive field. Nine of the eleven vasoactive C fibres had receptive fields located on the foot or the digits, and only two were on the ankle or lower leg. Overall, the population of nociceptive C fibres was evenly distributed over the saphenous nerve receptive field. In both the rabbit and the rat, a subclass of polymodal nociceptor afferents form the majority of the vasoactive units and will make the main contribution to axon reflex flare and other neurogenic inflammatory responses involving vasodilatation. The vasoactive polymodal nociceptor units tend to have relatively low mechanical sensitivity, although they have typical heat thresholds. In the rat heat nociceptor units also have vasodilator actions. However, such heat nociceptor units form a minor functional class of afferent C fibre in the rat saphenous nerve, and are not found in the rabbit saphenous nerve. The findings from this study in the rabbit and the rat are compared with the situation in pig skin. The close relationship between afferent receptive field area and spread of flare across species is noted, and the way these measures increase with body size is discussed.

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Novel classes of responsive and unresponsive C nociceptors in human skin

Cited by 417 publications

References 52 publications

Prevalence of somatic small fiber neuropathy in obesity

Prevalence of somatic small fiber neuropathy in obesity

Nociceptors: the sensors of the pain pathway

The Relationship between Cutaneous C Fibre Type and Antidromic Vasodilatation in the Rabbit and the Rat

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