The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles

Abstract

The mechanisms of chronic neuropathic pain are not well understood. Postherpetic neuralgia (PHN), which occurs in some patients after shingles (herpes zoster), was used to investigate the neural determinants of chronic pain. Skin biopsies were obtained from 38 adults with or without PHN at least 3 months after healing of shingles on the torso. Vertical sections were immunolabeled against PGP9.5, a pan-axonal marker, to measure the density of remaining nerve endings in skin previously affected by shingles. All axons that end in the epidermis are nociceptors, neurons that transmit pain messages. The densities ranged between 2 and 3976 neurites/mm² skin surface, but the overlap between subjects and without PHN was small. Of 19 subjects without PHN, 17 had more than 670 neurites/mm² skin surface area (mean±SEM=1569±230), and 18 of 19 subjects with PHN had 640 or fewer neurites/mm² (mean±SEM=367±92). PHN may be a ‘phantom-skin’ pain associated with loss of nociceptors. This threshold of approximately 650 neurites/mm² skin surface was not detected in previous studies that used summary statistics. It implies that the absence of pain after shingles may require the preservation of a minimum density of primary nociceptive neurons, and that the density of epidermal innervation may provide an objective correlate for the presence or absence of PHN pain.