Evaluation of itch and pain induced by bovine adrenal medulla (<scp>BAM</scp>)8–22, a new human model of non‐histaminergic itch

Aliotta, Giulia Erica; Vecchio, Silvia Lo; Elberling, Jesper; Arendt‐Nielsen, Lars

doi:10.1111/exd.14611

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…Superficial blood perfusion was significantly enhanced when skin temperature was increased by 7°C for serotoninergic itch, while for cowhage-evoked itch it was increased both at +4 and +7°C above the resting skin temperature. This line of evidence confirm, what previously observed, that neurogenic inflammation is not necessary for the development of itch sensation because the first was increased exactly when the latter was not different from the control condition 49,80,92,189,190 . A very captivating explanation could be that increased superficial blood perfusion leads to increased tissue clearance and therefore this would counteract what would be an increased itch intensity, but this study does not provide enough data to make such an assumption.…”

Section: Enhanced Superficial Blood Perfusion Due To Innocuous Skin H...supporting

confidence: 91%

“…Other itch models rely on the application of various pruritogens. Bovine adrenal medulla 8-22 (BAM8-22) can be applied to the skin to evoke an itch sensation similar to the one achieved with cowhage spicules 52,[90][91][92] . BAM8-22 is a direct agonist of MRGPRX1 and can be introduced by the use of intradermal injection or inactivated cowhage spicules soaked in a solution of this compound 90 .…”

Section: Itch Human Modelsmentioning

confidence: 99%

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Heat stimulation as a modulatory tool for the histaminergic and non-histaminergic itch

Riccio¹

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Section: Enhanced Superficial Blood Perfusion Due To Innocuous Skin H...supporting

confidence: 91%

Section: Itch Human Modelsmentioning

confidence: 99%

Heat stimulation as a modulatory tool for the histaminergic and non-histaminergic itch

Riccio¹

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“…This may reflect the spatial contrast between strongly-activated fibers and non-activated fibers innervating the same site, causing a mismatched signal that is interpreted centrally as an itch [ 41 ]. Also previous studies of other groups showed that application of BAM 8-22 via spicules caused more itch then pain [ 42 , 43 ]. Another less focal application via 25 pricks evoked more pain and less itch [ 43 ].…”

Section: Discussionmentioning

confidence: 90%

Peripheral signaling pathways contributing to non-histaminergic itch in humans

Fiebig,

Leibl,

Oostendorf

et al. 2023

J Transl Med

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Background Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. Results The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A “slow bursting discharge pattern” was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Conclusion Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade.

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“…Thus, antihistamines are frequently used for the treatment of itch in the clinic. The Mrgprs family, as the well-characterized histamine-independent itch receptors, can be activated by many endogenous and exogenous pruritogens, such as chloroquine, substance P and bovine adrenal medulla (BAM) 8-22 (Klein et al, 2021;Aliotta et al, 2022). Notably, the majority of chronic itches are insensitive to antihistamine treatment, thus suggesting the existence of histamine-independent mechanisms and distinct pruritogens that have yet to be discovered.…”

Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channel 3 is required for agmatine-induced histamine-independent itch in mice

Zhou

Xu²,

Lü³

et al. 2023

Front. Mol. Neurosci.

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IntroductionItch is a common symptom of many skin and systemic diseases. Identifying novel endogenous itch mediators and the downstream signaling pathways involved will contribute to the development of new strategies for the treatment of chronic itch. In the present study, we adopted behavioral testing, patch clamp recording and metabonomics analysis to investigate the role of agmatine in itch and the underlying mechanism.MethodsBehavioral analysis was used to evaluate the establishing of acute and chronic itch mice model, and to test the effects of different drugs or agents on mice itch behavior. Western blotting analysis was used to test the effect of agmatine on phosphorylation of ERK (p-ERK) expression in the spinal cord. Patch clamp recording was used to determine the effect agmatine on the excitability of DRG neurons and the role of ASIC3. Finally, the metabonomics analysis was performed to detect the concentration of agmatine in the affected skin under atopic dermatitis or psoriasis conditions.ResultsWe fused a mouse model and found that an intradermal injection of agmatine (an endogenous polyamine) into the nape of the neck or cheek induced histamine-independent scratching behavior in a dose-dependent manner. In addition, the ablation of nociceptive C-fibers by resiniferatoxin (RTX) abolished agmatine-induced scratching behavior. However, agmatine-induced itch was not affected by the pharmacological inhibition of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1); similar results were obtained from TRPV1−/− or TRPA1−/− mice. Furthermore, agmatine-induced itch was significantly suppressed by the administration of acid-sensing ion channel 3 (ASIC3) inhibitors, APETx2 or amiloride. Agmatine also induced the upregulation of p-ERK in the spinal cord; this effect was inhibited by amiloride. Current clamp recording showed that the acute perfusion of agmatine reduced the rheobase and increased the number of evoked action potentials in acute dissociated dorsal root ganglion (DRG) neurons while amiloride reversed agmatine-induced neuronal hyperexcitability. Finally, we identified significantly higher levels of agmatine in the affected skin of a mouse model of atopic dermatitis (AD) when compared to controls, and the scratching behavior of AD mice was significantly attenuated by blocking ASIC3.DiscussionCollectively, these results provide evidence that agmatine is a novel mediator of itch and induces itch via the activation of ASIC3. Targeting neuronal ASIC3 signaling may represent a novel strategy for the treatment of itch.

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Evaluation of itch and pain induced by bovine adrenal medulla (BAM)8–22, a new human model of non‐histaminergic itch

Cited by 9 publications

References 41 publications

Heat stimulation as a modulatory tool for the histaminergic and non-histaminergic itch

Heat stimulation as a modulatory tool for the histaminergic and non-histaminergic itch

Peripheral signaling pathways contributing to non-histaminergic itch in humans

Acid-sensing ion channel 3 is required for agmatine-induced histamine-independent itch in mice

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