Commentary 4

Itch is related to pain. Just like in pain research, it is important to distinguish different kinds of pruritus. The causes and consequent therapeutic strategy for acute itching will not be the same as in chronic itching. An acute itching in urticaria seems to be histamine dependent. However, a chronic itching in atopic dermatitis or prurigo will involve several different inflammatory molecules and neuropeptides, such as opioids. We will look into some of the controversies on opioids. Opioid receptor antagonists have successfully been used to treat several different pruritic conditions such as atopic dermatitis (1), cutaneous lymphoma, dry skin dermatitis, amyloidosis, psoriasis, prurigo nodularis (2), and hepatogenic pruritus (3). Some authors suggest that the opiate receptor system is more important in induction of chronic itch in atopic dermatitis than the histamine system (4). However, there are two major controversies involving opioids and itching. Can opioids induce itching independently from histamine? Some groups suggested that the opioid-induced itching in the periphery is only due to opioid-induced histamine release from mast cells in the dermis. However, in a placebo-controlled, double-blind study on histamine-induced focal itch and alloknesis with healthy subjects using the opioid receptor antagonist naltrexone and the H1-blocking agent cetirizine, naltrexone was found to reduce significantly both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon involved in chronic itch in atopic dermatitis (5). In a dry skin mouse model for chronic itching, there was no apparent difference of spontaneous scratching between mast cell-deficient mice and normal littermates. Subcutaneously administered opioid antagonists significantly suppressed spontaneous scratching in the dry skin model mice. These results could explain why non-sedative, second and third generation H1-antagonists have very limited effects on chronic itch and support the hypothesis that there is indeed an important histamine-independent opioid-induced pruritus. Do opioids induce itching only in the central nervous system (CNS) or are the nerve endings in skin involved as well? Although several authors describe an important role of opioids in the induction of itch, most of them believe that this effect is limited to the CNS. However, methylnaltrexone significantly decreases opioid-induced pruritus without affecting analgesia (6). Methylnaltrexone is a novel quaternary deriative of naltrexone that does not cross the blood–brain barrier and acts as a selective peripheral opioid receptor antagonist. Our own studies strongly suggest that epidermal opioid receptors are involved in chronic itching in atopic dermatitis and prurigo. We discovered a functional active opioid receptor system in human skin, including peripheral nerve endings and keratinocytes (7,8). Additionally, we observed an internalization of the µ-opiate receptors on keratinocytes in atopic dermatitis. The free opioid receptor ligands bind to the receptors on the thin and stretched peripheral nerve endings in hypertrophic epidermis in chronic dermatitis. This could lead to a strong itch signal to the CNS, where it will be further processed (8). We performed clinical studies using topically applied opioid receptor antagonists to treat chronic pruritus. The results show an increase of µ-opiate receptor expression in keratinocytes and a change of the nerve quality in the epidermis after local treatment. These changes correlated with the clinical response to the topically applied drug (unpublished data). Just recently we postulated the ‘Layer Hypothesis’ as our working hypothesis. This hypothesis is a result of the above-described observations in chronic pruritus in patients and mice. The ‘Layer Hypothesis’ suggests that ‘itch’ is elicited in the epidermal unmyelinated nerve C-fibers and ‘pain’ in unmyelinated nerve fibers in the dermis (9). This theory combines elements from the neurophysiological ‘Pattern’ and ‘Intensity’ hypothesis and is supported by the observation that the removal of epidermis eliminates itch but not pain (10). Maybe these epidermal nerve fibers are the low electrical threshold and histamine-insensitive C-fibers described recently by Ikoma et al. (11). The stronger stimulation which causes pain will activate mostly the dermal nerve endings. The ‘Layer Hypothesis’ can open a new discussion in itch research and will raise again some controversies in this field. The physiological mechanisms of itching remain to be elucidated and tested in a reliable, comprehensive experimental model, which should cover different itch elicitor and different kinds of itching. Likewise, future treatments of itching should not be only restricted to the use of antihistaminics. To understand the involvement of different cytokines and neuropeptides in the different forms of itching will not only solve the ‘itching’ puzzle but also help to find new strategies to treat this very common, but sometimes devastating symptom. Our patients will be grateful.