ALT Figure 1. Non-neuronal–neuron communication in the skin. (1) Non-neuronal cells and extracellular matrix in the skin. (2) When in ammatory events such as IL-6, ATP, and protease production from injury or infection are introduced, it causes an activation of cells, a disruption in extracellular matrix, and damage to sensory neurons. (3) During in ammatory cascades, injured or sensitized neurons potentiate pain and the development of a chronic pain state.

ALT Figure 2. Cell–cell interactions in joint pain. Numerous pathogenic changes occur within the OA joint and other musculoskeletal conditions that can contribute to pain, including cartilage degradation, synovitis, and bone remodeling (1). Within the joint evidence has established the role of some key non-neuronal cell types that contribute to pain (2) and some of the signaling nociceptor activation and sensitization mechanisms involved (3). There is also growing evidence for cell–cell interactions within the DRG that contribute to pain (4). See text for more details.

ALT Figure 3. Keratinocytes contribute to normal touch and chemotherapy-induced mechanical sensitivity through PIEZO1. Keratinocytes in the most super cial layer of the skin respond to mechanical forces via their expression of PIEZO1 channels and activated keratinocytes release ATP which signals to P2X4 channels on cutaneous sensory nerve endings. After a patient is treated with the chemotherapeutic paclitaxel, keratinocyte PIEZO1 is sensitized; the keratinocytes release more ATP and additional mediators, resulting in greater action potential signaling in sensory neurons that is sent to the spinal cord and brain through touch and pain pathways.