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Dissecting the precise nature of itch-evoked scratching.

ABSTRACT: Itch is a discrete and irritating sensation tightly coupled to a drive to scratch. Acute scratching developed evolutionarily as an adaptive defense against skin irritants, pathogens, or parasites. In contrast, the itch-scratch cycle in chronic itch is harmful, inducing escalating itch and skin damage. Clinically and preclinically, scratching incidence is currently evaluated as a unidimensional motor parameter and believed to reflect itch severity. We propose that scratching, when appreciated as a complex, multidimensional motor behavior, will yield greater insight into the nature of itch and the organization of neural circuits driving repetitive motor patterns. We outline the limitations of standard measurements of scratching in rodent models and present new approaches to observe and quantify itch-evoked scratching. We argue that accurate quantitative measurements of scratching are critical for dissecting the molecular, cellular, and circuit mechanisms underlying itch and for preclinical development of therapeutic interventions for acute and chronic itch disorders.

SUBMITTER: Wimalasena NK

PROVIDER: S-EPMC8497439 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE: Recently, we reported that 12(S)-HPETE (12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)-HPETE might act as an agonist of the low-affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)-HPETE-induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4'-[[pentanoyl (phenyl) amino]methyl]-1,1'-biphenyl-2-carboxylic acid) and 12(S)-HETE (12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid). EXPERIMENTAL APPROACH: A video recording was used to determine whether the BLT2 receptor agonists caused itch-associated scratching in ICR mice. Selective antagonists and several chemicals were used. KEY RESULTS: Both 12(S)-HETE and compound A dose dependently induced scratching in the ICR mice. The dose-response curve for compound A showed peaks at around 0.005-0.015 nmol per site. Compound A- and 12(S)-HETE-induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6-[6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl]-1,5-hexanediol, the BLT1 receptor antagonist) and LY255283 (1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone, the BLT2 receptor antagonist) on the BLT2 agonist-induced scratching. LY255283 suppressed compound A- and 12(S)-HETE-induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A-induced scratching than it did to suppress the 12(S)-HETE-induced scratching. One of the BLT(2) receptor agonists, 12(R)-HETE (12(R)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid), also induced scratching in the ICR mice. CONCLUSIONS AND IMPLICATIONS: Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)-lipoxygenase-product-induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.

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Dissecting the precise nature of itch-evoked scratching.

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