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Paper text:
in this issue of jid , dr . bigliardi s team presents evidence that dors are 
 expressed in the suprabasal layers of the epidermis and that they are phenotypically active 
 ( neumann et al . , 2014 ) . 

specifically , ligand activation of dors can stimulate the erk 1/2 mapk pathway with 
 attendant effects on keratinocyte proliferation and differentiation programs .
the authors 
 conclude that dors activity in human keratinocytes can profoundly affect epidermal 
 morphogenesis and homeostasis with implications in skin physiology and pathology .
interestingly , dors are expressed predominantly in the suprabasal differentiated 
 layers of human epidermis , with expression patterns that are almost identical to those of 
 proenkephalin ( penk ) and met- and leu - enkephalin antigens ( slominski et al . , 2011 ) . because enkephalins serve as ligands for 
 dors , both findings ( neumann et al . , 
 2014 ; slominski et al . , 
 2011 )
identify a novel opioid system composed of endogenously produced enkephalins 
 that would act in para- or autocrine fashion to regulate epidermal homeostasis . because the epidermis , serving as a physical and biological barrier ( feingold and elias , 2014 ) , senses and reacts to 
 environmental factors to regulate epidermal and skin homeostasis ( slominski and wortsman , 2000 ; slominski 
 et al . ,
2012 ) , the local endogenous opioidogenic system should 
 also be regulated by environmental factors in order to play a significant role in the 
 regulation of local homeostasis . in agreement with this concept , expression of penk and 
 penk - derived neuropeptides
is regulated by tlr4 ( lps ) and tlr2 ( pam3csk4 ) agonists as well 
 as by ultraviolet b ( uvb ) radiation ( slominski et 
 al . , 2011 ) , indicating that production of penk - derived neuropeptides can 
 be stimulated by biological and physical insults .
however , it still remains to be determined 
 whether similar biological and physical insults regulate dor expression in a fashion similar 
 to the regulation of melanocortin receptors , which are widely expressed in human skin ( bohm et al .
in addition , the proposed role 
 of dors in wound healing ( neumann et al . , 
 2014 ) would require determining whether physical disruption of the skin barrier 
 also enhances the expression of penk as a part of skin wound healing processes ; this could 
 be similar to the mechanisms of skin responses to stress that rely on complex neuropeptides 
 action ( mclaughlin and zagon , 2012 ; slominski et al .
( neumann et 
 al . , 2014 ) , in conjunction with regulated production of penk - derive 
 peptides ( slominski et al . , 2011 ) 
 and the complex role of opioids in regulating cell proliferation and the function of 
 epithelia ( mclaughlin and zagon , 2012 ) , the local 
 opioid system would include opioid growth factor ( ogf )  ogf receptors ( ogfr ) axis , 
 acting as a homeostatic regulator of the epidermis as proposed by ( mclaughlin and zagon , 2012 ) .
additional functions of local opioid activity would be secondary to a 
 well - documented immunomodulatory role of penk - derived peptides that include stimulation of 
 innate immunity , which is conserved across many species ( metz - boutigue et al . , 2003 ;
these functions were discussed 
 previously in the context of regulating local skin immunity and antimicrobial activities 
 ( slominski et al . , 2011 ) .
the 
 stimulation of the innate immune activity by opioids could be crucial in regulating wound 
 healing and restoration of epidermal integrity , in particular when the latter is disrupted 
 by uvb radiation ( slominski et al .
consistent with the above is deregulated expression of penk antigens in 
 pathological skin , including psoriasis , inflammatory dermatoses and neoplastic processes 
 ( slominski et al . , 2011 ) .
the 
 above pattern of penk expression nicely complements the hypothesis that dor s 
 activity is spatially and temporally controlled in human skin , affecting skin physiology and 
 pathology ( neumann et al . , 2014 ) , 
 with implications in dermatopharmacology , as also proposed by ( mclaughlin and zagon , 2012 ;
it must be noted that skin cells and cutaneous nerve endings also express : 1 ) other 
 opioid receptors , including  -and -or ( mclaughlin and zagon , 2012 ; neumann et 
 al . , 2014 ; slominski et 
 al . , 2012 ) ,
2 ) proopiomelanocortin ( pomc ) together with a molecular 
 system regulating its processing towards - endorphins , 3 ) melanocortin peptides that 
 include pc1 and pc2 convertases , and 4 ) a crh signalling system regulating pomc processing 
 in a context dependent manner ( slominski et 
 al . , 2000 ; slominski et 
 al . , 2013 )
pc1 and pc2 convertases process both penk and pomc 
 precursors towards final regulatory neuropeptides in a regulated fashion .
thus , the extended 
 local opioid system ( mclaughlin and zagon , 2012 ; neumann et al . , 2014 ; slominski et al . , 2000
; slominski et al . , 2011 ) can be 
 integrated into the function of the broader skin neuroendocrine system regulating 
 homeostasis on local and systemic levels , including sending signals to the brain ( slominski and wortsman , 2000 ; slominski et al . , 2012 ) .
in this context , the extended opioid cutaneous system is highly organized , encoding 
 mediators and receptors coupled differentially to signal transduction systems and endowed 
 with stress - neutralizing activities .
this system helps to maintain skin integrity and to 
 restrict stress - dependent disruptions of internal homeostasis . from the evolutionary point 
 of view ,
such a system could develop in the integument , as proposed for the hpa axis ( slominski , 2007 ) , in order to protect the integrity of the 
 integument . during evolution
the dor system would adapt as an efficient regulator of central 
 and systemic homeostasis .
the presence of functional opioid receptors on epidermal keratinocytes , with 
 attendant regulation of keratinocyte proliferation and differentiation , indicate their 
 novel role in maintaining epidermal homeostasis . 
 expression of proenkephalin precursors 
 and neuropeptide products in the same compartment opens an opportunity to study the role 
 of this endogenous opioid circuitry , with its regulators , in modulating epidermal barrier 
 function .