Which nerve fibers mediate the axon reflex flare in human skin?

Schmelz, Martin; Michael, K; Weidner, Christian; Schmidt, Roland; Torebjörk, H. E.; Handwerker, H. O.

doi:10.1097/00001756-200002280-00041

Cited by 271 publications

(214 citation statements)

References 6 publications

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“…In human skin, axon reflex vasodilatation is thought to be mediated by a subset of nociceptive C-fibres that become responsive to mechanical and/or heat stimulation only after sensitization (Schmelz et al, 2000). In general, pain ratings were low and some of the participants described the sensations experienced during the iontophoreses as a sharp feeling or an itch rather than pain.…”

Section: Discussionmentioning

confidence: 99%

“…This has implications for pain control, as inhibitory  2 -effects of noradrenaline usually outweigh excitatory  1 -influences on spinal and supra-spinal nociceptive neurotransmission. thought to be mediated by neural discharge that spreads retrogradely through the terminal network of mechano-insensitive nociceptive C-fibres (termed an axon reflex), ultimately releasing neuropeptides that act on mast cells, immune cells and vascular smooth muscle to increase local blood flow (Schmelz et al, 2000;Schmelz and Petersen, 2001;Richardson and Vasko, 2002). Intradermal administration of noradrenaline by microdialysis on the dorsal aspect of the human hand did not induce axon reflex vasodilatation (Zahn et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Drummond

2011

Autonomic Neuroscience

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experiments, skin sites were treated with the vasodilator sodium nitroprusside (to counteract vasoconstriction and disperse inflammatory mediators produced during the iontophoresis of phenylephrine); local anaesthetic agent (to determine whether the axon reflex to phenylephrine was neurally-mediated); or the  2 -adrenoceptor agonist clonidine (to investigate the specificity of the adrenergic axon reflex). Phenylephrine evoked marked vasodilatation 8 mm from the site of iontophoresis whereas clonidine and saline-control did not (mean flux increase + S.E. 485 + 132% for phenylephrine; 44 + 24% for clonidine; 39 + 19% for saline-control; p<0.05 for phenylephrine versus control). Axon reflex vasodilatation to phenylephrine was unaffected by variations in blood flow at the site of phenylephrine iontophoresis, but was reduced by ibuprofen pretreatment and abolished by local anaesthetic pretreatment. These findings suggest that prostaglandin synthesis at the site of iontophoresis contributes to but does not account entirely for axon reflex vasodilatation to phenylephrine. Alpha-1 adrenoceptor mediation of axon reflexes could play a role in aberrant sensorysympathetic coupling in neuro-inflammatory diseases.3 Introduction Stimulation of  1 -adrenoceptors generally increases neural discharge in the dorsal horn of the spinal cord whereas  2 -adrenoceptor stimulation is inhibitory (Holden et al., 1999; Pertovaara, 2006). This has implications for pain control, as inhibitory  2 -effects of noradrenaline usually outweigh excitatory  1 -influences on spinal and supra-spinal nociceptive neurotransmission.The effects of -adrenoceptor stimulation on peripheral nociceptive afferents are less clear. In uninjured animals, neither stimulation of the sympathetic chain nor close arterial injection of noradrenaline had any discernable effect on activity of Cfibre nociceptors (Sato and Perl, 1991). Similarly, in humans, sympathetic activity did not affect neural discharge of C-fibre cutaneous nociceptive afferents primed with mustard oil (Elam et al., 1999). Nevertheless, there is evidence that  1 -adrenoceptors influence nociceptive discharge. For example, in uninjured rats blockade of  1 -adrenoceptors inhibited behavioural signs of pain induced by subcutaneous injection of the  1 -adrenoceptor agonist phenylephrine and β-methylene-ATP (an agonist for purinergic P2X3 receptors) (Meisner et al., 2007), whereas blockade of  2 -adrenoceptors was ineffective. Similarly, blockade of  1 -but not  2 -adrenoceptors abolished hyperalgesia and C-fibre discharge evoked by intradermal injection of capsaicin (Kinnman and Levine;1995;Ren et al., 2005). In studies on healthy humans, intradermal injection of  1 -and  2 -adrenergic agonists increased sensitivity to heat-pain (Fuchs et al., 2001), as did iontophoresis of noradrenaline and phenylephrine in mildly burnt or inflamed skin (Drummond, 1995;Drummond, 1998;Drummond, 2009a).Animal studies have shown that  1 -adrenoceptors may also influence the flare that develops around the sit...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Drummond

2011

Autonomic Neuroscience

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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. 35,36 While objective measurement of the flare reaction can be accomplished by visual assessment, introduction of laser Doppler flowmetry (LDF) has made it possible to monitor the flare response continuously in a small area of the skin, thereby facilitating the study of the axon-reflex in terms of flux.…”

Section: Introductionmentioning

confidence: 99%

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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“…These unmyelinated, histamine sensitive sensory neurons have large receptive fields and poor discrimination threshold for histamine induced itch. Furthermore, they are characterized by a particularly low conduction velocity and high transcutaneous electrical thresholds [7,[16][17][18][19][20]. These Cfibers are also suggested to be involved in the generation of the axon reflex erythema [17].…”

Section: Pruriceptive Sensory Fibersmentioning

confidence: 99%

TRP Channels and Pruritus

Tóth¹,

Bı́ró²

2013

TOPAINJ

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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

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Which nerve fibers mediate the axon reflex flare in human skin?

Cited by 271 publications

References 6 publications

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Prevalence of somatic small fiber neuropathy in obesity

TRP Channels and Pruritus

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