Pamoic acid-induced peripheral GPR35 activation improves pruritus and dermatitis

Background and Purpose: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here, we propose a novel pharmacological modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35, and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here, we investigated its effects on dermatitic pathology. Experimental Approach: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus. Key Results: Local PA application mitigated acute non-histaminergic itch and, consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene and psoriasis models were also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the 1-chloro-2,4-dinitrobenzene and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology. Conclusion and Implications: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.