Peripheral Opioids

Excerpt

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 peripheral 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 nerve–skin 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.

The brain provides a conscious realization that there is a sensation of itch, after which we will react by rubbing or scratching to remove the noxious stimulus. The itch signal from the periphery will be modulated during its journey through the peripheral nerves, dorsal root ganglia and spinal cord to the higher centers in the brain. Inflammation of the skin as well as constant stimulation of the peripheral nerve system will modify signals emanating from the skin and in transmission of these signals to the CNS; indeed, the threshold and the irritability of the nerve fibers will change under the influence of various cytokines, growth factors, neuropeptides, and neurotransmitters. The different perceptions of itch and pain seem to have very distinct pathways in the CNS. The removal of pain is not a prerequisite for induction of itch (Liu et al. 2011). It is very difficult to separate the peripheral events in itch and pain from the processes in the CNS, but it is clear that these various sensations can be modulated at every level of transduction (Sun and Chen 2007). The events in the periphery appear to be equally important as mechanisms occurring in the CNS, and this is especially true for the involvement of the opioid receptor system in modulation of sensory function both in the periphery and CNS. While the opioid system, and in particular its influence on pain, has been well studied in the CNS, very little is known about the role of opioid receptors in skin, and in addition we are at the infancy of understanding the nerve systems in the skin.

The goal of this chapter is to describe the role of the opioid receptor system in the induction and regulation of the peripheral components of pain and itching mechanisms, with strong focus on itch. Also discussed are possibilities of treating very cumbersome sensations (itch, pain, and tingling) that have been peripherally induced by topical applications of opioids, with the intention of limiting the side effects generated by opioidergic activity within the CNS.