The evaluation of antipruritic effect of paracetamol and its metabolite AM404 in an acute allergenic mice model.

Ahmet Dogrul1, Fatih Ilkaya1, Melik Seyrek1, Ozgur Yesilyurt1, Ahmet Akar2. 1Gulhane Military Medical Faculty, Medical Pharmacology, Turkey, 2Gulhane Military Medical Faculty, Dermatology, Turkey

Recent studies have identified the role of endocannabinoid and endovanilloid system in the mechanism of pruritus, representing CB1 and TRPV1 receptors as a potential target in the treatment of itching. Although pain and itching appear to be different sensations, there is a close interaction between two sensory systems. Paracetamol undergoes a metabolic transformation in the brain to form N-arachydonylphenolamine (AM404), which is a potent activator of TRPV1, a ligand of CB1 receptor and an inhibitor of anandamide uptake. In this study, we investigated antipruritic effect of paracetamol and its metabolite AM404 in comparison with their effects on nociception.
Antipruritic effect was evaluated by using mast cell degralunator compound 48/80 induced scratching behavior model in male Balb-C mice. Compound 48-80 (100 µg) injected intradermally in a volume of 50 µl into the rostral part of skin on the back of mice and the frequency of scratching around injected site by the hind paw were counted throughout the 30-min observation period. Antinociception was evaluated by hot plate test. Paracetamol and AM404 were given intraperitoneally (i.p.) 30 min prior to compound 48-80 administration and hot plate test. Data was expressed as mean ± S.E.M. and each group included 8 mice. The significance of any differences in scratching and hot plate response were assessed by using ANOVA followed by Dunnet test. The differences were considered significant at P<0.05.
Compound 48-80 elicited a strong scratching response which was found to be 131.4 ± 7.3. A significant inhibition of scratching response was observed at the dose of 200 and 300 mg/kg of paracetamol (79.4 ± 10.2 and 6.8 ± 1.2, respectively), while 100 mg/kg was ineffective (126.7 ± 9.2). AM404 (1, 5 and 10 mg/kg, i.p.) did not alter scratching response (138.5 ± 11.2, 129.3 ± 7.3 and 143 ± 6.5, respectively). Paracetamol produced antinociceptive effect at 200 and 300 mg/kg, while 100 mg/kg was ineffective in the hot plate test. AM404 (1, 5 and 10 mg/kg, i.p.) did not elicit antinociceptive effect. The present findings suggest that paracetamol-induced antipruritic effect appears to be independent of cannabinoid and TRPV1 since AM404 did not mediate antipruritic effect. Nevertheless, antipruritic effect of paracetamol is corresponding to its antinociceptive doses and thus, false positive results of compound 48-80 induced pruritus model remain to be clarified.
Our study indicates that paracetamol induces antipruritic effect in acute allergenic pruritus model which is independent of its metabolite AM404.