Neurotrophin-3 (NT-3), a member of the neurotrophin family, has been shown to be necessary for the development of muscle spindle and Merkel cell aVerent nerve fibres in animal models.The presence of NT-3 in the suprabasal epidermis, where many unmyelinated sensory fibres terminate, has been shown for the first time. As these fibres are aVected in early diabetic neuropathy and a clinical trial of recombinant human NT-3 in diabetic neuropathy is in progress, the concentrations of endogenous NT-3 in skin of 24 patients at diVerent stages of diabetic polyneuropathy have been investigated. NT-3 concentrations, measured with a specific immunoassay, were significantly higher in aVected skin biopsies from patients with diabetic neuropathy than matched control skin (diabetic skin 6.32 (1.18) pg/mg v control skin 1.28 (0.05) (mean (SEM)); p<0.004, Mann-Whitney U test), particularly in the later stages. The optical density of NT-3-immunostaining was also significantly greater in the epidermis in diabetic patients (diabetic epidermis 0.30 (0.06) v controls 0.24 (0.01); p<0.02). No correlation was found between individual quantitative sensory tests and the increase of NT-3 concentration. The increase of NT-3 seems to reflect the degree of skin denervation in diabetic neuropathy, and may represent a compensatory mechanism. The concentrations of NT-3 in other peripheral targets deserve study in diabetic neuropathy. (J Neurol Neurosurg Psychiatry 1998;65:393-395)
Glial cell line-derived neurotrophic factor (GDNF) is trophic to motor and sensory neurones in animal models. GDNF mRNA is up-regulated in Schwann cells after peripheral nerve injury in rats. We have quantified and localized GDNF and its receptor component Ret, for the first time in any species, in injured human peripheral nerves and dorsal root ganglia (DRG) avulsed from the spinal cord. Significantly higher levels of GDNF were found in nerve distal to the site of the injury than in proximal or intact nerve, and in avulsed DRG than in post-mortem control DRG. GDNF immunostaining was seen in Schwann cells and in DRG neurones, especially of small and medium size, with significantly increased numbers of medium sized sensory neurones immunoreactive for GDNF after avulsion. Ret immunoreactivity was restricted to DRG neurones and axons, with no significant changes in numbers of positive DRG cells after injury. Our findings suggest that GDNF may play a role in injured human nerves and sensory ganglia, particularly in medium sized sensory neurones.
The peptidergic sensory innervation of cranial blood vessels may play an important part in vascular head pain. The neuropeptides calcitonin gene-related peptide (CGRP) and substance P in sensory fibres are dependent on nerve growth factor (NGF) produced by the blood vessels, and when released from nerve terminals mediate neurogenic inflammation. NGF is increased in inflamed tissues, and acts via its high aYnity receptor trk A on nociceptor fibres to produce hyperalgesia. CGRP and trk A immunoreactive nerve fibres have therefore been studied, for the first time, in inflamed (n=7) and non-inflamed (n=10) temporal arteries biopsied from patients with headache and suspected giant cell arteritis. CGRP immunoreactivity was markedly decreased to absent in adventitial nerve fibres in inflamed regions of vessels, which may reflect secretion from nerve terminals, as CGRP immunoreactivity could still be seen in nerve trunks in periadventitial tissue. Trk A immunoreactive nerve fibres were found in a similar distribution to CGRP containing nerve fibres in non-inflamed vessels, and the trk A immunoreactivity was virtually unchanged in inflamed vessels. The evidence supports a role for NGF related mechanisms in inflammatory vascular head pain. Anti-NGF or anti-trk A agents may represent novel analgesics in this condition. (J Neurol Neurosurg Psychiatry 1999;66:390-392)
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