Peripheral Opioids

The sensation of itch is difficult to define but is generally accepted as an unpleasant cutaneous sensation, leading to the desire to scratch. It has clear survival value as it has been conserved across many mammalian species through different evolutionary pathways. There are many different manifestations of itch or other related sensations, such as tingling, crawling, or irritation. Some of these more diffuse sensations are initiated in the central nervous system (CNS), but most originate from the periphery, in particular, the skin. Cutaneous itch has many different causes and triggers, and it is crucial to understand that the interactions between the periph eral nonmyelinated, sensory C-fibers and different skin cells is the initial step for the initiation of the itch sensation in skin. Numerous skin cells are involved in this nerveskin interaction, ranging from keratinocytes, melanocytes, Merkel cells, Langerhans cells to various dermal cells such as mastocytes, endothelial cells, fibroblasts, and cells in skin appendages. In previous publications we proposed the existence of a keratinocyte-nerve “unit, " consisting of very fine and superficial nerve fibers in the epidermis connecting to keratinocytes that may be specialized in function. These keratinocytes could act as sensors and send signals either to other keratinocytes or to the epidermal C-fibers. The interaction between different cell systems in the epidermis might be crucial for the initiation of various peripheral sensations such as pain, itching, burning, tickling, and tingling. All these sensations have very distinct functions, but most of these sensation qualities do not require an immediate reflex mechanical withdrawal reaction such as the stimulation of dermal myelinated A-delta fibers with conduction of deep, well-defined injuries. Sensations such as itching, not well localized pain burning, tickling or tingling are danger signals that do not require an immediate withdrawal action but rather notify of a danger that needs to be removed by swiping or scratching. This clearly implies that the skin has very sophisticated mechanisms to sense different levels of danger and to react in different ways.