Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?

While sensory loss in leprosy skin is the consequence of invasion by M. lep rae of Schwann cells related to unmyelinated fibres, early loss of cutaneou s pain sensation, even in the presence of nerve fibres and inflammation is a hallmark of leprosy, and requires explanation. In normal skin, nerve grow th factor (NGF) is produced by basal keratinocytes, and acts via its high a ffinity receptor (trk A) on nociceptor nerve fibres to increase their sensi tivity, particularly in inflammation. We have therefore studied NGF- and tr k A-like immunoreactivity in affected skin and mirror-site clinically-unaff ected 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- posi tive nerve fibres were reduced only in affected leprosy skin, with fewer fi bres contacting keratinocytes. However, NGF-immunoreactivity in basal kerat inocytes, and intra-epidermal PGP 9.5-positive nerve fibres, were reduced i n both sites compared to non-leprosy controls, as were nerve fibres positiv e for the sensory neurone specific sodium channel SNS/PN3, which is regulat ed by NGF, and may mediate inflammation-induced hypersensitivity. Keratinoc yte trk A expression (which mediates an autocrine role for NGF) was increas ed in clinically affected and unaffected skin, suggesting a compensatory me chanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF- and SNS/PN3-immunoreactivity, and loss of intra-epidermal in nervation, may be found without sensory loss on quantitative testing in cli nically-unaffected skin in leprosy; this appears to be a sub-clinical chang e, and may explain the lack of cutaneous pain with inflammation. Sensory lo ss occurred with reduced sub-epidermal nerve fibres in affected skin, but t hese still showed trk A-staining, suggesting NGF treatment may restore pain sensation. (C) 2000 International Association for the Study of Pain. Publi shed by Elsevier Science B.V. All rights reserved.