The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB2 receptor activation

• Published in: Neuropharmacology 2025-02, Vol.264, p.110216, Article 110216
• Main Authors: Reck, Antonio Matt, Siderovski, David P., Kinsey, Steven G.
• Format: Article
• Language: English
• Subjects: Antipruritic agent; Cannabinoid receptor; Endocannabinoid system; Pruritus; WIN 55,212-2; β-caryophyllene; Δ8-tetrahydrocannabinol
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.110216

Pruritus (i.e., the experience that evokes a desire to scratch) is an adaptive process that can become maladaptive, leading to a persistent scratch-itch cycle that potentiates pruritus and increases the risk of infection. Cannabinoid drugs have been reported to decrease pruritus, but often at doses that also decrease locomotor activity, which confounds assessments of utility. To determine the utility of cannabinoids in treating pruritus without undesirable adverse effects, the current preclinical study investigated a range of doses of the synthetic cannabinoid agonist, WIN 55,212-2, and two minor Cannabis phytoconstituents, Δ8-tetrahydrocannabinol and β-caryophyllene, in experimentally induced pruritus in male and female C57BL/6J adult mice. WIN 55,212-2 reduced compound 48/80-induced scratching, and this antipruritic effect was prevented by either chemically blocking (via SR144528 antagonism) or genetically deleting the CB2 cannabinoid receptor. The CB2 receptor selective agonist, JWH-133, also attenuated compound 48/80-induced scratching, while the CB1 positive allosteric modulator, ZCZ011, had no effect. Similarly, the minor phytocannabinoid Δ8-tetrahydrocannabinol reduced scratching at doses that did not affect locomotor activity. In contrast, the sesquiterpene cannabis constituent β-caryophyllene induced scratching, acting as a pruritogen. These preclinical data support the continuing investigation of cannabinoid receptor modulation as a potential therapeutic strategy for pruritus. •WIN 55,212-2 reduces compound 48/80-induced pruritus without locomotor deficits.•WIN 55,212-2 antipruritus is blocked by CB2 receptor antagonism or genetic deletion.•Δ8-tetrahydrocannabinol reduces compound 48/80-induced pruritus despite injection site.•β-caryophyllene fails to reduce 5-HT-induced pruritus; causes scratching itself.