mild - to - severe 
 pruritus accompanies numerous inflammatory skin disorders including atopic 
 dermatitis , eczema , psoriasis , or lichen planus .
psoriasis is one of the most common chronic inflammatory skin diseases with a complex , multifactorial , and 
 still not fully understood etiopathogenesis .
the main factors contributing to the development of psoriatic lesions are genetic predispositions and immunological 
 disturbances [ 1 , 2 ] .
however , the exacerbation of psoriasis can also be provoked by numerous exogenous factors including stress , smoking , infections , and some 
 drugs .
pruritus is observed in about 
 70 to 90% of patients with psoriasis [ 39 ] , and many of them ( at least 30% ) had 
 generalized itching [ 5 , 6 ] .
the mean intensity of this symptom assessed 
 according to 10 point visual analogue scale ranged between 3.76.4 points 
 [ 5,7 , 1012 ] .
this is less than the intensity of pruritus observed in atopic dermatitis or uremic pruritus [ 13 , 14 ] .
however , despite less intensive , 
 pruritus was mentioned by many psoriatic patients as the most bothersome 
 symptom of psoriasis   and it was clearly documented that pruritus intensity 
 significantly correlated in psoriatics with degree of quality of life 
 impairment , level of stigmatization , as well as the presence and severity of depressive symptoms .
it seems that patients with pruritus suffer from more 
 severe psoriasis [ 4 , 6 , 8 ] although some authors did not find a significant relationship 
 between pruritus intensity and psoriasis severity .
the presence and 
 intensity of itching were independent on age , 
 gender , marital status , family history of psoriasis or atopy , type of 
 psoriasis , alcohol or smoking habits , duration of the disease , as well as 
 duration of the last outbreak of psoriasis [ 5 , 6 , 8 ] . despite the high frequency 
 of this symptom ,
here , we reviewed the available literature data on this symptom in order to 
 summarize our current knowledge of the origin of pruritus in psoriasis .
histamine , one of the major mediators of 
 pruritus , does not seem to be involved in its development in psoriasis .
there 
 was no correlation between pruritus intensity and histamine plasma level in psoriasis , as well as no difference was observed in histamine plasma levels between pruritics and nonpruritics patients with psoriasis . in addition , less than 20% of psoriatic subjects 
 claimed that oral antihistaminics were effective in reducing pruritus 
 .
it 
 seems that only sedating antihistaminics should be tried in pruritic psoriatics 
 as they sometimes could be effective due to evoked sedation .
it is 
 generally accepted that the histamine blockade does not prevent pruritus in 
 psoriasis .
the most often discussed theory on pruritus in 
 psoriasis mentioned the importance of impaired innervation and neuropeptides 
 imbalance in psoriatic skin . interactions between nerves , neuropeptides , and 
 mast cells , leading to neurogenic inflammation , have also been implicated in 
 another chronic itchy immunodermatosis : atopic dermatitis [ 16 , 17 ] .
several 
 studies demonstrated altered expression and/or distribution of several 
 neuropeptides and their receptors within various layers of psoriatic skin , 
 including substance p ( sp ) , calcitonin gene - related peptide ( cgrp ) , vasoactive 
 intestinal peptide ( vip ) , somatostatin , -endorphin , or pituitary adenylate 
 cyclase activating polypeptide ( pacap ) [ 1726 ] . neuropeptides degranulate 
 mastocytes , activate dendritic cells , lymphocytes , macrophages , and 
 neutrophils , and produce vascular changes in the skin by inducing angiogenesis , 
 dilatation of vessels , and stimulation of synthesis of nitric oxide .
they 
 also stimulate synthesis and release of many proinflammatory cytokines from mast 
 cells , lymphocytes , dendritic cells , fibroblasts , and keratinocytes , induce 
 expression of vascular adhesion molecules on endothelium , and exert hyperproliferative 
 effect on keratinocytes .
neuropeptides in the skin may be released from 
 dermal nerve endings , but they can also be directly produced by several cell 
 types , for example , mastocytes .
nakamura et al .   observed that pruritic psoriatic skin 
 demonstrated significantly increased number of nerve growth factor- ( ngf- ) immunoreactive 
 keratinocytes , elevated ngf content in the lesional skin , and enhanced 
 expression of high - affinity receptor for ngf ( trk - a ) in the epidermis and 
 dermal nerve fibres .
moreover , pruritic skin showed increased number of protein 
 gene product ( pgp ) 9.5-immunoreactive nerve fibers in the epidermis and in the 
 upper dermal areas , increased number of sp - containing nerves in the 
 perivascular areas , as well as decreased expression of neutral endopeptidase 
 ( nep ) in the epidermal basal layer and in the endothelia of blood vessels . 
 the pruritus intensity correlated with the number of pgp 9.5-immunoreactive 
 intraepidermal nerve fibers , the number of ngf - immunoreactive keratinocytes and 
 the expression level of trka in the epidermis .
nakamura et al .   also found an increased number of mast cells in the papillary 
 dermis of pruritic psoriatic skin among the various cellular components 
 examined , including resident cells and infiltrating cells in the skin lesions . 

ultrastructural examination showed that these mast cells possessed 
 degranulating specific granules indicating that mast cells in pruritic 
 psoriatic skin are activated .
the particularly characteristic finding of mast 
 cells in lesional skin from patients with pruritus was the presence of free 
 mast cell granules in close apposition to the perineurium surrounding 
 unmyelinated nerve fibers .
did not find any differences between pruritic and nonpruritic psoriatics 
 regarding the skin expression of brain - derived neurotrophic factor , 
 neurotrophin-3 , vip , neuropeptides y ( npy ) , somatostatin , low - affinity receptor 
 for ngf , and angiotensin - converting enzyme . in another study ,
a 
 hyperproliferation of small cutaneous nerves was found in the lesional skin of 
 pruritic psoriatic subjects compared to nonpruritic ones .
keratinocytes in the 
 psoriatic plaques of patients with pruritus also showed consistently increased 
 expression of sp receptor , trka and cgrp receptor , but the immunoreactivity for 
 sp , cgrp , vip , and pacap 
 was independent on the occurrence of pruritus .
the expression of ngf , 
 neurotrophin-4 , low - affinity receptor for ngf , pacap receptor expression , as 
 well as nep activity did not differ between pruritus and nonpruritus group . 

interestingly , remrd et al .   did not find any relationship between sp - positive 
 fibers nor cells and the degree of pruritus , but the analyzed group of patients 
 in this study was very small .
in addition , the npy plasma level was 
 significantly decreased in patients with pruritus compared to patients without 
 pruritus .
plasma levels of sp , cgrp , and vip did not differ significantly 
 between pruritics and nonpruritics , however , a tendency to lower sp and vip 
 plasma levels in patients with pruritus was noted .
moreover , significant , negative 
 correlations between pruritus severity and sp as well as vip plasma levels were 
 found .
it seems probable , that increased expression of neuropeptides in the 
 pruritic skin might activate the neuropeptides degrading enzymes like nep or angiotensin - converting 
 enzyme in a regulatory mechanism .
this hypothesis could be supported by 
 the observations that the proportion between chymase- and tryptase - positive 
 mast cells was shown to be disturbed in lesional psoriatic skin   as well as patients with psoriasis 
 were characterized by higher serum activity of angiotensin - converting enzyme 
 which was normalized after effective antipsoriatic treatment . in the study by our group  
it was noted that 
 cgrp plasma level was significantly elevated in pruritic psoriatic patients 
 compared to healthy subjects , a difference that was not found between nonpruritic 
 psoriatics and healthy volunteers , and that cgrp plasma level correlated with 
 itching intensity in some subgroups of psoriatics
. the important role of 
 altered innervations and neuropeptide imbalance in pruritus accompanying 
 psoriasis may also be supported by the observations that topically applied capsaicin , a 
 potent sp depletory , effectively treated pruritus in psoriatics [ 30 , 31 ] . 

finally , it was documented that stress - exacerbated pruritus in psoriasis   and neuropeptides 
 seem to be good candidates for linking nervous system and skin .
it could 
 be hypothesized that increased innervations in the skin of psoriatic patients 
 with pruritus may lead to a lower threshold for pruritic stimuli compared to 
 patients without pruritus .
additionally , 
 pruritus might be evoked by the release of selected neuropeptides from dermal 
 nerve endings and cells during stress , but this hypothesis still requires 
 further investigations ( table 1 ) .
concerning the 
 role of cytokines in pruritus in psoriasis , nakamura et al .   found an 
 increased number of interleukin ( il)-2 immunoreactive cells in pruritic versus 
 nonpruritic lesions of psoriasis ( table 1 ) .
there were no significant 
 differences in the expression of other cytokines ( interferon ( inf)- , tumor 
 necrosis factor ( tnf)- , il-1 , il-1 , il-4 , il-5 , il-6 , il-8 , il-10 , and il-12 ) 
 .
recently , a novel cytokine , il-31 , was suggested to play an important 
 role in pruritus in atopic dermatitis , as il-31 caused the itch - associated 
 scratching behavior in conventional nc / nga mice , an experimental animal model 
 for atopic dermatitis . 

it seems that changes of dermal vasculature may be 
 important in the pathogenesis of pruritus in psoriasis ( table 1 ) .
a marked 
 increase of the density of e - selectin - positive 
 venules was found in psoriatic patients with pruritus compared to nonpruritic 
 subjects .
however , there was no statistical difference in the number of 
 vessels immunoreactive for intercellular cell adhesion molecule ( icam)-1 , 
 vascular cell adhesion molecule ( vcam)-1 , or platelet endothelial cell adhesion 
 molecule ( pecam)-1 in the upper dermis or in the expression of icam-1 in the 
 epidermis .
however , significant correlation was observed between the 
 itching intensity and the density of e - selectin - immunoreactive vessels .
in addition , madej et 
 al .   found an increased serum concentration of soluble vascular adhesion 
 protein ( vap)-1 in psoriatic subjects with pruritus compared to patient free of 
 this symptom .
despite the lack of solid laboratory data , 
 other mediators may also play a role in the pathogenesis of pruritus in 
 psoriasis ( table 1 ) .
they were found to be important in several pruritic 
 conditions , but have not been investigated in psoriasis yet . it could be speculated that neuropeptides in psoriatic skin may induce expression 
 and/or activity of dermal proteases , and these enzymes acting via protease - activated receptors 
 ( par ) might be responsible for prurtius . 

recent findings suggested that proteases are not only degrading enzymes , 
 but rather represent a group of mediators communicating with nerves , and 
 thereby modulating inflammation , pain , and pruritus [ 43 , 44 ] .
tryptase 
 and microbial proteases induced itch by the par-2-mediated neurogenic mechanism 
 [ 43 , 45 ] .
activation of par-2 evoked itching both in mice and in human [ 4346 ] . 
 because par-2 is irreversibly activated by proteases
it is believed that activation of 
 -opioid receptors induces while activation of -opioid receptors alleviates 
 pruritus . a significantly altered - and
-opioid receptor expression was 
 observed in the epidermis of patients with atopic dermatitis , showing mainly 
 downregulation of -opioid system [ 35 , 36 ] .
puva treatment , a frequently applied 
 and effective therapy of atopic dermatitis , was shown to reconstitute the 
 altered opioid receptor distribution in epidermis of these patients . 

it was shown 
 that intrathecal administration of morphine elicits pruritus and both naloxone 
 and naltrexone , the potent -opioid receptor antagonists , reduces histamine - induced 
 pruritus in atopic dermatitis subjects to greater extend than antihistaminic 
 drugs [ 37 , 38 ] .
on the other hand , nalfurafine , a -opioid receptor agonist , led 
 to significant reduction of itching in patients with uremic or cholestatic 
 pruritus [ 39 , 40 ] .
prostanoids , 
 mainly prostaglandin d2 [ 41 , 42 ] and tromboxane a2   or 
 serotonin , could be further candidates as mediators of pruritus in 
 psoriasis .
the importance of the latter one might be 
 supported by the observations that mirtazapine , an 
 antihistaminic drug acting also via noradrenergenic 2-receptors and 5ht2 and 5ht3 serotonin receptors , 
 relieved psoriatic itch even in cases of severe pruritus associated with 
 erythrodermic psoriasis .
pruritus causes the 
 desire to scratch the skin and is experienced as a sensation arising in the 
 skin .
however , like all other skin sensations , itch is a product of 
 central nervous system activities .
the itch - selective spinal neurons form 
 a distinct pathway projecting from lamina i of the spinal cord to the 
 ventrocaudal part of the nucleus medialis , which projects to the anterior 
 cingulated and dorsal insular cortex .
recent studies characterized the 
 supraspinal processing of itch in humans by different imaging techniques .
intradermal 
 injection of histamine in healthy volunteers led to activation of anterior 
 cingulate cortex , supplementary motor area , premotor area , and inferior 
 parietal lobe [ 50 , 51 ] .
prolonged itch stimuli activated a superior frontal 
 gyrus and the gyrus rectus in both hemispheres as well as in a small area of 
 the left anterior cingulated gyrus .
further activation was located in the 
 left temporal pole and some parts of the left cerebellum .
repetitive scratching 
 induced bilateral activation of the secondary somatosensory cortex , insular 
 cortex , inferior parietal lobe , and cerebellum while anterior and posterior 
 cingulated cortices were deactivated .
the main limitation of these studies 
 is the observations of healthy subjects . as it was demonstrated by ishiuji et 
 al .
, the brain processing of itch in chronic skin conditions like in 
 atopic dermatitis is significantly different than in healthy individuals . 

therefore , further data are needed to identify the brain areas responsible for 
 pruritus in patients with chronic itch , including those having psoriasis .
summarizing , pruritus is an important symptom 
 of psoriasis . despite the fact that several studies have been undertaken to 
 investigate the pathogenesis of pruritus in psoriasis ,
therefore , the pathogenesis of this symptoms is far 
 to be well understood and , as a consequence , the therapy of pruritic psoriatic 
 patients still remains a big challange for clinicians .
we hope that in the near 
 future new studies will be conducted to better characterize and understand this 
 symptom in psoriasis .
we do believe that this progress may facilitate the 
 development of new effective antipruritic treatment modalities .
 the pathogenesis of pruritus in psoriasis remains unclear . 
 many possible mediators were implicated to transmit or modulate this sensation in psoriasis , but none has been clearly proven to be a causative agent of itching . the most often discussed theory mentioned the importance of impaired innervations and neuropeptides imbalance in psoriatic skin . 
 other possible causes of itching might be increased expression of interleukin 2 or vascular abnormalities . 
 recent data indicated that pruritus could be also evoked by opioid system , prostanoids , interleukin 31 , serotonin , or proteases . 
 whether these mechanisms are also involved in pruritus accompanying psoriasis requires further investigation . 
 limited knowledge of pruritus origin in psoriasis is responsible for the lack of the effective antipruritic treatments for psoriatics . here , 
 we summarize the current knowledge about the pathogenesis of pruritus in psoriasis and point out possible directions of future studies aiming the pathogenesis of this symptom in psoriasis . 
1. INTRODUCTION
2. HISTAMINE
3. NEUROPEPTIDES AND ALTERED CUTANEOUS  INNERVATIONS
4. CYTOKINES
5. VESSELS AND ADHESION MOLECULES
6. OTHER POSSIBLE MEDIATORS
7. THE ROLE OF CENTRAL NERVOUS SYSTEM
8. CONCLUSIONS