Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy

Paul Facer,Graham D Smith,Praveen Anand,Christopher D Benham,Marco Sinisi,Chas Bountra,Iain P Chessell,Rolfe Birch,Maria A Casula

doi:10.1186/1471-2377-7-11

Paul Facer, Graham D Smith + Show 7 more

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https://doi.org/10.1186/1471-2377-7-11

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Abstract

BackgroundTransient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol, have been characterised in pre-clinical models. However, the role of TRPs in common clinical sensory neuropathies needs to be established.MethodsWe have studied TRPV1, TRPV3, TRPV4, and TRPM8 in nerves (n = 14) and skin from patients with nerve injury, avulsed dorsal root ganglia (DRG) (n = 11), injured spinal nerve roots (n = 9), diabetic neuropathy skin (n = 8), non-diabetic neuropathic nerve biopsies (n = 6), their respective control tissues, and human post mortem spinal cord, using immunohistological methods.ResultsTRPV1 and TRPV3 were significantly increased in injured brachial plexus nerves, and TRPV1 in hypersensitive skin after nerve repair, whilst TRPV4 was unchanged. TRPM8 was detected in a few medium diameter DRG neurons, and was unchanged in DRG after avulsion injury, but was reduced in axons and myelin in injured nerves. In diabetic neuropathy skin, TRPV1 expressing sub- and intra-epidermal fibres were decreased, as was expression in surviving fibres. TRPV1 was also decreased in non-diabetic neuropathic nerves. Immunoreactivity for TRPV3 was detected in basal keratinocytes, with a significant decrease of TRPV3 in diabetic skin. TRPV1-immunoreactive nerves were present in injured dorsal spinal roots and dorsal horn of control spinal cord, but not in ventral roots, while TRPV3 and TRPV4 were detected in spinal cord motor neurons.ConclusionThe accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. Reduction of TRPV1 levels in nerve fibres in diabetic neuropathy skin may result from the known decrease of nerve growth factor (NGF) levels. The role of TRPs in keratinocytes is unknown, but a relationship to changes in NGF levels, which is produced by keratinocytes, deserves investigation. TRPV1 represents a more selective therapeutic target than other TRPs for pain and hypersensitivity, particularly in post-traumatic neuropathy.

Highlights

Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology
Thermal sensations and pain are detected via sub-sets of neurons which are activated within distinct temperature ranges, from cool (27°C – 38°C – TRPV3[4,5] and TRPV4 [6,7] to noxious/painful heat (>43°C – 52°C – TRPV2 [8] and TRPV1[1,2]) and cold (
Searches of the GenBank nucleotide databank revealed an unfinished human sequence homologous to TRPV1, which has since been identified as a temperature-sensitive but capsaicin and pH insensitive, vanilloid receptor-like protein nominated as TRPV3 [4,5]

Summary

Introduction

Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. TRPV1 is a non-selective, cation channel activated by capsaicin and heat (42°C or greater), and is a member of the transient receptor potential (TRP) family of temperature sensitive ion channels. Studies of TRPV1 in animal models have revealed its role in heat and pain mechanisms [11,12]. Searches of the GenBank nucleotide databank revealed an unfinished human sequence homologous to TRPV1, which has since been identified as a temperature-sensitive but capsaicin and pH insensitive, vanilloid receptor-like protein nominated as TRPV3 [4,5]. In the Seltzer model, where undamaged afferents may be identified by retrograde labelling, the expression of the neuropeptides substance P and galanin, both known nociceptive mediators, as well as mRNA for the sodium channel SNS, increased in the somata of undamaged fibres [21,22,23]

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