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Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days. [ABSTRACT FROM AUTHOR]

Using an animal model of inflammatory itch and pain produced by allergic contact dermatitis, Qu et al. reveal hyperexcitability in two distinct populations of pruriceptive cutaneous nociceptors, due in part to enhanced sodium currents. Similar mechanisms may contribute to spontaneous itch and pain in human allergic and inflammatory diseases.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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

• Contact hypersensitivity (CHS) upregulated CCL2/MCP-1 and CCR2 in nociceptors. • CCL2 injected into CHS site evoked site-directed itch- and pain-like behaviors. • CCL2 activated nociceptive dorsal root ganglion neurons innervating CHS site. • A CCR2 antagonist decreased these behavioral and neuronal responses. • Targeting CCL2/CCR2 signaling might treat allergic itch and pain in humans. Spontaneous itch and pain are the most common symptoms in various skin diseases, including allergic contact dermatitis (ACD). The chemokine (C-C motif) ligand 2 (CCL2, also referred to as monocyte chemoattractant protein 1 (MCP-1)) and its receptor CCR2 are involved in the pathophysiology of ACD, but little is known of the role of CCL2/CCR2 for the itch- and pain-behaviors accompanying the murine model of this disorder, termed contact hypersensitivity (CHS). C57BL/6 mice previously sensitized to the hapten, squaric acid dibutyl ester, applied to the abdomen were subsequently challenged twice with the hapten delivered to either the cheek or to the hairy skin of the hind paw resulting in CHS at that site. By 24 h after the 2nd challenge to the hind paw CCL2 and CCR2 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion (DRG). Calcium imaging and whole-cell current-clamp recordings revealed that CCL2 directly acted on its neuronal receptor, CCR2 to activate a subset of small-diameter, nociceptive-like DRG neurons retrogradely labeled from the CHS site. Intradermal injection of CCL2 into the site of CHS on the cheek evoked site-directed itch- and pain-like behaviors which could be attenuated by prior delivery of an antagonist of CCR2. In contrast, CCL2 failed to elicit either type of behavior in control mice. Results are consistent with the hypothesis that CHS upregulates CCL2/CCR2 signaling in a subpopulation of cutaneous small diameter DRG neurons and that CCL2 can activate these neurons through neuronal CCR2 to elicit itch- and pain-behavior. Targeting the CCL2/CCR2 signaling might be beneficial for the treatment of the itch and pain sensations accompanying ACD in humans. [ABSTRACT FROM AUTHOR]