03322nas a2200529   4500000000100000008004100001260001300042653001000055653000900065653001000074653001100084653002000095653001100115653002500126653002600151653001800177653001200195653000900207653001600216653002500232653001600257653000900273653001900282653002500301653003800326653001100364653000900375653002000384653002600404653002800430653001700458100001200475700001100487700001300498700001300511700001500524700001400539700001200553700001800565700001500583700001200598245010200610300001000712490000700722520204900729022001402778       2000                            d  c2000 Mar10aAdult10aAged10aAxons10aFemale10aHot Temperature10aHumans10aImmunohistochemistry10aIn Situ Hybridization10aKeratinocytes10aleprosy10aMale10aMiddle Aged10aNerve Growth Factors10aNociceptors10aPain10aPain Threshold10aPhysical Stimulation10aReceptor Protein-Tyrosine Kinases10aReflex10aSkin10aSodium Channels10aThiolester Hydrolases10aUbiquitin Thiolesterase10aVasodilation1 aFacer P1 aMann D1 aMathur R1 aPandya S1 aLadiwala U1 aSinghal B1 aHongo J1 aSinicropi D V1 aTerenghi G1 aAnand P00aDo nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?  a231-80 v853 a<p>While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation, is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its high affinity receptor (trk A) on nociceptor nerve fibres to increase their sensitivity, particularly in inflammation. We have therefore studied NGF- and trk A-like immunoreactivity in affected skin and mirror-site clinically-unaffected skin from patients with leprosy, and compared these with non-leprosy, control skin, following quantitative sensory testing at each site. Sensory tests were within normal limits in clinically-unaffected leprosy skin, but markedly abnormal in affected skin. Sub-epidermal PGP 9.5- and trk A- positive nerve fibres were reduced only in affected leprosy skin, with fewer fibres contacting keratinocytes. However, NGF-immunoreactivity in basal keratinocytes, and intra-epidermal PGP 9.5-positive nerve fibres, were reduced in both sites compared to non-leprosy controls, as were nerve fibres positive for the sensory neurone specific sodium channel SNS/PN3, which is regulated by NGF, and may mediate inflammation-induced hypersensitivity. Keratinocyte trk A expression (which mediates an autocrine role for NGF) was increased in clinically affected and unaffected skin, suggesting a compensatory mechanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF- and SNS/PN3-immunoreactivity, and loss of intra-epidermal innervation, may be found without sensory loss on quantitative testing in clinically-unaffected skin in leprosy; this appears to be a sub-clinical change, and may explain the lack of cutaneous pain with inflammation. Sensory loss occurred with reduced sub-epidermal nerve fibres in affected skin, but these still showed trk A-staining, suggesting NGF treatment may restore pain sensation.</p>  a0304-3959