Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in...

Area of Science:

• Neuroscience
• Dermatology
• Pharmacology

Background:

• Lysophosphatidic acids (LPAs) are implicated in nociception and itch.
• Hydroxychloroquine (HCQ) induces itch, increasing LPAs peripherally and centrally.
• The specific signaling pathways for HCQ-evoked pruritus remain unclear.

Purpose of the Study:

• To investigate the signaling pathways involved in hydroxychloroquine-induced itch.
• To determine the roles of specific lysophosphatidic acid receptors (LPARs) and related genes in itch.
• To explore the potential of targeting LPAR5 for itch treatment.

Main Methods:

• Utilized knockout mouse models for LPAR5, LPAR2, autotaxin/ENPP2, and plasticity-related genes (Prg1, Prg2).
• Assessed hydroxychloroquine-evoked scratching behavior and nociception.
• Employed LacZ reporter studies and RNAscope for gene localization; measured calcium fluxes in sensory neurons.

Main Results:

• LPAR5 was localized in sensory neurons and keratinocytes; LPAR2 in central neurons; Prg1 in the dorsal horn and thalamus.
• HCQ-induced scratching was reduced in LPAR5-deficient mice but increased in LPAR2 and Prg1 deficient mice.
• Peripheral LPAR5 activation was critical for HCQ-itch, evidenced by reduced scratching with LPAR5 antagonist and autotaxin inhibitor.

Conclusions:

• Hydroxychloroquine-mediated itch primarily involves peripheral LPAR5 activation.
• Central LPAR2 and Prg1 signaling appear to modulate itch.
• Targeting peripheral LPAR5 with topical agents may offer a novel strategy for non-histaminergic itch.