Chronic pruritus: still a challenge but new directions of development have been indicated
Department of Dermatology, Venereology and Allergology, Wrocław Medical University
Head of Department: prof. Eugeniusz Baran, MD, PhD
Pruritus is defined as a subjective sensation which provokes a desire to scratch. It could be acute (lasting less than 6 weeks) or chronic (with a 6 week duration or longer) (1). An acute pruritus may be considered as a defensive mechanism, that should protect our body from being hurt by insects or other parasites. On the other hand, a chronic itching represents a significant medical problem, responsible often for marked morbidity, quality of life impairment, and, in some patient population, even for increased mortality (2, 3). Pruritus seems to be a quite frequent symptom, as 8 to nearly 30% of participants of population based studies declared, that they have suffered from itching at least sometimes (4-7). This sensation can accompany not only a long list of skin diseases, but also a number of systemic, neurological or psychiatric conditions. Based on the newest itch classification proposed by the International Forum for the Study of Itch, pruritus could be divided into three major groups according to clinical manifestation: pruritus on primarily diseased, inflamed skin (group I), pruritus on primarily normal, non-inflamed skin (group II) and pruritus with chronic secondary scratch lesions (group III) (8). Furthermore, six categories of pruritus reflecting its pathogenesis have been defined, namely dermatologic, systemic, neurological, psychogenic, mixed and other type of pruritus (8). The new pruritus classification has unified previous attempts of itch categorization and, in addition, included clinical manifestation as an important prerequisite of patient assignment. Therefore, it seems, that it is well fitted both for clinical, as well as for scientific purposes.
Despite a high prevalence of pruritus in general population, treatment of patients with chronic itch remains a challenge. It is related to a complex and multifactorial pathogenesis of this ailment. Antihistamines, the classic antipruritic drugs, are only effective in selected diseases, like urticaria or mastocytosis (i.e. in histaminergic itch), while in other pruritus forms they provide only partial relief or are not satisfactory at all (i.e. in non-histaminergic itch). However, recent decade has brought a number of crucial discoveries in itch knowledge which give a hope for the development of new effective therapeutic strategies in the near future.
The exact pathomechanism of chronic pruritus is still not exactly known. For a long time, pruritus was considered as a subliminal pain, however, currently it is handled as a distinct sensation that admittedly shares some similarities and cross-linking with pain feeling, but possesses separate neurons dedicated solely for itch transmission (9-11). This hypothesis has been supported by a rapidly growing evidence arising over last years. In 2007 Sun et al. (12, 13) identified gastrin-releasing peptide (GRP)-positive dorsal root ganglion neurons, that were itch-specific. Expression of GPR receptors was restricted to lamina I of the dorsal spinal cord. Blockade of these receptors by direct spinal cerebrospinal fluid injection of a GRP receptor antagonist significantly inhibited scratching behavior in three independent itch models, while pain sensation evoked by various stimuli remained unchanged (12, 13). Similar effect was noticed by selective ablation of GRP-positive neurons (13). It was also shown, that these neurons are important to both histamine dependent and histamine independent pathways of itch, however, it seems that they mediated more non-histaminergic itch stimuli (14). Recently, attempts have been made to develop antagonists of these receptors that might be used as a potent antiprutic therapy in the future (15). Interestingly, transmission of itch stimuli by GRP-positive neurons was regulated by Toll-like receptors 3 (TLR-3), which represent other potential target for new antiprutic molecules to be developed (16). In addition, TLR-7, which is activated by imiquimod, has also been shown to mediate pruritus transmission in primary sensory neurons (17, 18).
Central transmission of itch is also modulated by endogenous opioid system. Central activation of μ-opioid receptors (MOR) (e.g. by opiates like morphine) produces pruritus, while activation of κ-opioid receptors (KOR) alleviates itch (19). A relief of itch or decrease of pruritus intensity may be expected during the blockade of MOR by naloxone or naltrexone (MOR antagonists) or by the stimulation of KOR by its agonists like nalfurafine or butorphanol (20-23). Unfortunately, central acting drugs may also produce a number of side effects, like nausea and vominiting, sleeping difficulty, fatigue and reversal of analgesia, which limits their wider use as antipruritic medications (19, 22). However, recent data showed that opioid receptors are also present on peripheral sensory neurons and partake in itch perception (24). As in central nervous system, activation of peripheral MOR produced itching, that could be effectively diminished by subsequent selective activation of peripheral KOR (24). A decrease of pruritus was also noticed after treatment with naloxone (a MOR antagonist) as well as naloxone methiodide (a peripherally restricted MOR antagonist) (24). Furthermore, Nelson et al. (25) reported that endogenous opioid-mediated antinociception in cholestatic mice is peripherally and not centrally mediated, again underlying the importance of peripheral opioid system in itch perception. In addition, Tominaga et al. (26) demonstrated that PUVA therapy diminished MOR immunoreactivity in the skin of patients with atopic dermatitis, and the degree of this decrease significantly correlated with pruritus improvement. It was also suggested, that pruritus in patients with psoriasis may be related to the imbalance of peripheral opioid system, as psoriatic patients with pruritus showed decreased expression of KOR and dynorphin A (the endogenous KOR agonist) within the epidermis in comparison to healthy controls, while the expression of MOR and β-endorphin (the endogenous MOR agonist) was similar in both groups (27). Thus, it seems, that higher MOR tone in the skin may be responsible for pruritus at least in some dermatological diseases. On the other hand, potentiating peripheral KOR activity via KOR selective ligands or inhibiting peripheral MOR would offer a new possibility of itch controlling (28).
A variety of other mediators released by skin cells (e.g. mast cells) were shown to be able to induce or modulate itch by activating approximately 5-20% of primary afferent itch-sensitive C-fibers, which can be divided into multiple subgroups based on pruritogen-sensitivity. A study on chloroquine-induced itch enabled to identify new pruritus receptors on C-fibers, namely Mrgprs, a family of G protein-coupled receptors that are expressed exclusively in peripheral sensory neurons (Mrgprs stays for Mas-related G protein-coupled receptors) (29, 30). These receptors may be activated by endogenous peptides, e.g. BAM8-22 (bovine adrenal medulla 8-22 peptide) and by exogenous substances (e.g. chloroquine) (29). Mice lacking a cluster of Mrgpr genes displayed significant deficits in itch induced by chloroquine but not by histamine. It seems, that Mrgprs are even more important for non-histaminergic itch, than PAR (protease activated receptors), that were also linked with chronic itch sensation (31, 32).
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