Central, but not peripheral, nervous system ERK2 is essential for itch signals in murine allergic skin inflammation.

Abstract

Itch is a common cutaneous symptom in a variety of dermatological diseases, but detailed neuropathological mechanisms remain to be fully elucidated. This study aimed to assess in vivo ERK2 functions in the nervous system for itch responses. We generated conditional knockout mice deficient in ERK2 of the central nervous system (CNS) or peripheral nervous system (PNS), respectively, and assessed chemical and mechanical itch responses in vivo. Chemical itch responses to histamine, but not to BAM8-22, were alleviated in CNS Erk2-deficient mice. In contrast, both histamine- and BAM8-22-induced mechanical itch (alloknesis) were alleviated in CNS Erk2-deficient mice. Neither chemical itch nor mechanical itch induced by these pruritogens was affected by PNS ERK2 deficiency. Spontaneous scratching behaviors during acute and chronic contact hypersensitivity were impaired in CNS Erk2-deficient mice, but not PNS Erk2-deficient mice. In addition, CNS ERK2 deficiency attenuated mechanical itch responses during chronic contact hypersensitivity. Again, PNS Erk2-deficient mice showed comparable responses of mechanical itch to control mice. In addition, alleviated mechanical itch in CNS Erk2-deficient mice was observed in IgE-mediated prurigo-like allergic skin inflammation. Mechanical itch induced by IL-31 was also alleviated by CNS ERK2 deficiency. Phosphorylated ERK1/2 was detected in neurokinin B-expressing cells of the spinal dorsal horn of control mice; these cells accumulated during the induction of chronic contact hypersensitivity. Notably, phosphorylated ERK1/2 was also localized in spinal urocortin3-expressing neurons that are known to transmit mechanical itch. Spinal cord ERK2 could be a potential therapeutic target for intractable itch in pruritic skin diseases.