Ikoma A, Fartasch M, Heyer G et al.Painful stimuli evoke itch in patients with chronic pruritus: Central sensitization for itch. Neurology 62:212-217

Department of Dermatology, Kyoto University, Japan.
Neurology (Impact Factor: 8.29). 01/2004; 62(2):212-7. DOI: 10.1212/WNL.62.2.212
Source: PubMed


Central sensitization for pain is important for patients with chronic pain. The authors investigated a possible role of central sensitization for itch in patients with chronic pruritus.
Noxious stimuli were applied in lesional and visually nonlesional skin areas of 25 patients with atopic dermatitis, in lesional skin areas of 9 patients with psoriasis vulgaris, and in 20 healthy subjects. The stimuli included mechanical pinpricks, electrical stimuli, contact heat, and injection of low-pH solution. Intensities of itch and pain were assessed separately on a numeric rating scale.
All the noxious stimuli primarily evoked pain in control subjects and patients with psoriasis vulgaris. In patients with atopic dermatitis, however, itch was evoked instead of burning pain. In their lesional skin, itch was the predominant sensation. Chemical stimuli evoked intense itch in lesional and visually healthy skin areas (the area under the curve of itch rating compared with the control, mean +/- SEM, 668 +/- 166 and 625 +/- 192 vs 38 +/- 23; p < 0.001; p < 0.01). Chemically induced itch also was observed in healthy subjects after a conditioning histamine stimulus of 15 minutes, but not after a conditioning histamine stimulus of 2 minutes.
The chronic barrage of pruriceptive input may elicit central sensitization for itch so that nociceptive input no longer inhibits itch but on the contrary is perceived as itch. In contrast to the well-known A-fiber-mediated alloknesis and hyperknesis, this type of central sensitization appears to be elicited by C-nociceptors.

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Available from: Manigé Fartasch, Jun 04, 2014
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    • "Histamine reaction test was performed by skin prick of 0.1% histamine using a 30-gauge needle at the dorsum of the shoulder in the index patient [15]. Reaction was evaluated during 30 minutes of observation and the intensity of evoked sensations measured by the NRS. "
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    ABSTRACT: Itch is a common experience. It can occur in the course of systemic diseases and be one manifestation of allergies, or the consequence of diseases affecting the somatosensory pathway. We describe a kindred characterized by paroxysmal itch caused by a variant in SCN9A gene encoding for the Nav1.7 sodium channel. Patients underwent clinical and somatosensory profile assessment by quantitative sensory testing, nerve conduction study, autonomic cardiovascular reflex and sympathetic skin response examination, skin biopsy with quantification of intraepidermal nerve fiber density and SCN9A mutational analysis. The index patient, her mother and a sister presented with a stereotypical clinical picture characterized by paroxysmal itch attacks involving the shoulders, upper back and upper limbs, followed by transient burning pain, triggered by environmental warmth, hot drinks and spicy food. Somatosensory profile assessment demonstrated a remarkably identical pattern of increased cold and pain thresholds and paradoxical heat sensation. Autonomic tests were negative, whereas skin biopsy revealed decreased intraepidermal nerve fiber density in two of the three patients. All affected members harbored the 2215A>G I739V substitution in exon 13 of SCN9A gene. Pregabalin treatment reduced itch intensity and attack frequency in all patients. The co-segregation of the I739V variant in the affected members of the family provides evidence, for the first time, that paroxysmal itch can be related to a mutation in sodium channel gene.
    Pain 05/2014; 155(9). DOI:10.1016/j.pain.2014.05.006 · 5.21 Impact Factor
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    • "And the pruritogen, histamine, evoked pain but not itch when delivered to an area of hyperalgesia in patients with postherpetic neuralgia [8]. These alterations in sensory qualities may result from the sensitization of neurons mediating itch or pain in the peripheral and/or central nervous system [5] [6] [7] [8] [9] [10]. "
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    ABSTRACT: Chemical pruritogens and algogens evoke primarily itch and pain, respectively, when administered to the skin of healthy human subjects. However, the dominant sensory quality elicited by an algesic chemical stimulus may change in patients with chronic itch where bradykinin, elicits itch in addition to pain. Here we tested whether normally pruritic and algesic chemicals evoked abnormal itch- or pain-like behaviors in the mouse after the development of contact hypersensitivity (CHS), an animal model of allergic contact dermatitis. Mice previously sensitized to a hapten (squaric acid dibutylester) applied to the abdomen, exhibited spontaneous itch-like scratching and pain-like wiping directed to the site on the cheek of the CHS elicited by a subsequent challenge with the same hapten. In comparison with responses of control mice, CHS mice exhibited a significant increase in the scratching evoked by bovine adrenal medulla 8-22, a peptide that elicits a histamine-independent itch, but did not alter the scratching to histamine. Bradykinin, an algogen that elicited only wiping in control mice, additionally evoked significant scratching in CHS mice. Thus, within an area of CHS, histamine-independent itch is enhanced and chemically evoked pain is accompanied by itch.
    Neuroscience Letters 04/2014; 579. DOI:10.1016/j.neulet.2014.03.062 · 2.03 Impact Factor
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    • "Spontaneously ongoing activity in C-pruriceptors was also identified in patients with chronic itch (Ikoma et al., 2004). Indeed, peripheral sensitization of pruriceptive primary sensory afferents has been suggested as a mechanism underlying the chronic itch of atopic dermatitis (Schmelz et al., 2003). "
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    ABSTRACT: Itch is a common symptom of diseases of the skin but can also accompany diseases of other tissues including the nervous system. Acute itch from chemicals experimentally applied to the skin is initiated and maintained by action potential activity in a subset of nociceptive neurons. But whether these pruriceptive neurons are active or might become intrinsically more excitable under the pathological conditions that produce persistent itch and nociceptive sensations in humans is largely unexplored. Recently, two distinct types of cutaneous nociceptive dorsal root ganglion neurons were identified as responding to pruritic chemicals and playing a role in itch sensation. One expressed the mas-related G-coupled protein receptor MRGPRA3 and the other MRGPRD (MRGPRA3(+) and MRGPRD(+) neurons, respectively). Here we tested whether these two distinct pruriceptive nociceptors exhibited an enhanced excitability after the development of contact hypersensitivity, an animal model of allergic contact dermatitis, a common pruritic disorder in humans. The characteristics of increased excitability of pruriceptive neurons during this disorder may also pertain to the same types of neurons active in other pruritic diseases or pathologies that affect the nervous system and other tissues or organs. We found that challenging the skin of the calf of the hind paw or the cheek of previously sensitized mice with the hapten, squaric acid dibutyl ester, produced symptoms of contact hypersensitivity including an increase in skin thickness and site-directed spontaneous pain-like (licking or wiping) and itch-like (biting or scratching) behaviours. Ablation of MRGPRA3(+) neurons led to a significant reduction in spontaneous scratching of the hapten-challenged nape of the neck of previously sensitized mice. In vivo, electrophysiological recordings revealed that MRGPRA3(+) and MRGPRD(+) neurons innervating the hapten-challenged skin exhibited a greater incidence of spontaneous activity and/or abnormal after-discharges in response to mechanical and heat stimuli applied to their receptive fields compared with neurons from the vehicle-treated control animals. Whole-cell recordings in vitro showed that both MRGPRA3(+) and MRGPRD(+) neurons from hapten-challenged mice displayed a significantly more depolarized resting membrane potential, decreased rheobase, and greater number of action potentials at twice rheobase compared with neurons from vehicle controls. These signs of neuronal hyperexcitability were associated with a significant increase in the peak amplitude of tetrodotoxin-sensitive and resistant sodium currents. Thus, the hyperexcitability of MRGPRA3(+) and MRGPRD(+) neurons, brought about in part by enhanced sodium currents, may contribute to the spontaneous itch- and pain-related behaviours accompanying contact hypersensitivity and/or other inflammatory diseases in humans.
    Brain 02/2014; 137(4). DOI:10.1093/brain/awu007 · 9.20 Impact Factor
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