Prostaglandin D2 improves IL-31-induced alloknesis: itch-stimulation becomes pain-stimulation in mouse skin

We examined the effect of prostaglandin D2 (PGD2) on IL-31-induced alloknesis in mice. We investigated itch-associated scratching behavior (long-lasting scratching: LLS) as an indicator of itching. Topically applied PGD2 and dexamethasone each significantly suppressed IL-31 (acute or repeated administration)-induced LLS. However, neither PGD2 nor dexamethasone suppressed the IL-31 (repeated administration)-induced increase in IL-31 receptor A mRNA expression in dorsal root ganglia. Next, we investigated the scratching behavior induced by pruritogens (histamine, serotonin and compound 48/80) or algogens (acetylcholine, bradykinin and capsaicin) in IL-31-induced itchy-skin mice. In naïve mice, these irritants caused many counts of short-lasting scratching (SLS) and a few counts of LLS for 60 min. In contrast, IL-31-induced itchy-skin mice showed significant increases in LLS counts compared with naïve mice. Topical application of PGD2 significantly suppressed LLS counts induced by these pruritogens or algogens in IL-31-induced itchy-skin mice. The anti-pruritic efficacy of PGD2 may be related to its ability to reverse the hyperkinesis of primary afferents; thus, PGD2 improves IL-31-induced alloknesis. In a hot-plate test, topical application of PGs (PGD2, PGE2 and PGI2) caused a decrease in the nociceptive threshold in naïve mice, indicating that PGs enhance pain. These results suggest that PGs (especially PGD2) can change itch-stimulation into pain-stimulation in itchy-skin mice caused by pretreatment with IL-31. Therefore, it is possible that IL-31 and PGs may play a role in the regulation of a primary sensory nerves for the sensation of itch and pain.