FIGURE 4.

Itch and pain pathway interaction. Pruritogens (A) initiate itch sensation via pruriceptors (blue line) activation present in cutaneous sensory neurons. (B) In addition, other cell types are involved in itch signaling, such as keratinocytes, or innate immune cells that release pruritogens (yellow dots) such as histamine and IL-31, leading to the activation of pruriceptors and induction of peripheral sensitization. (C) The intraspinal terminals of pruriceptors (blue line in insert) release gastrin releasing peptide (GRP) (blue dots) and/or substance P (SP) (green dots) as neuropeptide transmitters to excite post-synaptic neurons expressing GRP and/or NK-1 receptors. (D) Scratching the skin presumably activates mechanically sensitive C-fiber polymodal nociceptors with primary afferent projections to the superficial dorsal horn of the spinal cord (red line). These afferents release glutamate to excite inhibitory interneurons in the superficial dorsal horn resulting in inhibition of the itch pathway (E). The inhibitory interneurons use glycine and GABA as neurotransmitters to inhibit pruritogen-responsive neurons (orange dots).