The role of the skin in peripheral neuropathic pain

In addition to homeostatic and immunologic barrier functions, the skin acts as a complex sensory organ. Traditionally, the sensory modality of pain was thought to be transduced exclusively by primary afferent neurons, but the concept of a neuro-immuno-cutaneous system (NICS) is becoming more recognized. This system involves signals between both neuronal and non-neuronal skin cells. The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor plays an important role in the NICS. It is highly expressed on nociceptive sensory nerves, as well as on non-neuronal skin cells, especially keratinocytes. Keratinocytes, which account for 85% of the cells of the dermis, have a close anatomic relationship with peripheral nerves and have TRPV1 receptors on their surface. TRPV1 receptors have also been reported on Langerhans cells, sebocytes and sweat gland epithelium, although due to different staining techniques there is controversy about the actual amount. TRPV1 receptors are activated by capsaicin and the topical application of a high-concentration capsaicin patch has been shown to significantly reduce pain in patients with post-herpetic neuralgia or HIV-associated neuropathy. Given the emerging picture of the role played by cutaneous cells in pain transmission, this review will discuss the critical interplay between cutaneous cells and nociceptors, and how their interactions contribute to the pathophysiology of peripheral neuropathic pain.