Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain

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Abstract

Background

Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood.

Methods

Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF).

Results

TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] – no pain group, n = 8, 0.69 [0–1.27]; pain group, n = 10, 2.15 [0.77–4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] – no pain group, n = 6, 0.75 [0–2]; pain group, n = 11, 2 [ 1- 3], p = 0.008; TRPV4, median [range] – no pain group, n = 6, [0–1]; pain group, n = 11, 1 [0.5–2], p = 0.014).

Conclusion

Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study.

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Most cited references 20

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TRPV3 is a temperature-sensitive vanilloid receptor-like protein.

G D Smith, M J Gunthorpe, R E Kelsell … (2002)

Vanilloid receptor-1 (VR1, also known as TRPV1) is a thermosensitive, nonselective cation channel that is expressed by capsaicin-sensitive sensory afferents and is activated by noxious heat, acidic pH and the alkaloid irritant capsaicin. Although VR1 gene disruption results in a loss of capsaicin responses, it has minimal effects on thermal nociception. This and other experiments--such as those showing the existence of capsaicin-insensitive heat sensors in sensory neurons--suggest the existence of thermosensitive receptors distinct from VR1. Here we identify a member of the vanilloid receptor/TRP gene family, vanilloid receptor-like protein 3 (VRL3, also known as TRPV3), which is heat-sensitive but capsaicin-insensitive. VRL3 is coded for by a 2,370-base-pair open reading frame, transcribed from a gene adjacent to VR1, and is structurally homologous to VR1. VRL3 responds to noxious heat with a threshold of about 39 degrees C and is co-expressed in dorsal root ganglion neurons with VR1. Furthermore, when heterologously expressed, VRL3 is able to associate with VR1 and may modulate its responses. Hence, not only is VRL3 a thermosensitive ion channel but it may represent an additional vanilloid receptor subunit involved in the formation of heteromeric vanilloid receptor channels.

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Pain after breast surgery: a survey of 282 women.

M Dobke, Brian J. Lee, B. A. Wallace (1996)

Breast surgery is a common procedure performed in women. Many women who undergo breast surgery suffer from ill-defined pain syndromes. Although there exists a few reports on the incidence of post mastectomy pain, there are no published reports on chronic pain after breast reconstruction. This investigation attempts to characterize the pain after four types of breast surgery: (1) mastectomy, (2) mastectomy with reconstruction, (3) cosmetic augmentation, and (4) breast reduction. A questionnaire was mailed to 479 women who underwent breast surgery at the University of California, San Diego Medical Center between January 1988 and December 1992. A second mailing was sent to women who did not respond to the first mailing. Women were divided into four groups; mastectomy, mastectomy with reconstruction, cosmetic augmentation, and breast reduction. In the mastectomy and mastectomy with reconstruction groups, only women who had a lumpectomy with axillary dissection, a modified radical mastectomy, or a radical mastectomy were used in the study. 59% of the women responded. The incidence of pain occurring at least one year after surgery in the mastectomy + reconstruction group (49%) was significantly higher than the mastectomy (31%) and breast reduction (22%) groups. Thirty-eight percent of the women with breast augmentation complained of pain. Women who had reconstruction using breast implants had a higher incidence of pain (53%) than those without (30%). The pain incidence in women who had reconstruction without implants was identical to women who had a mastectomy without reconstruction. There was no relationship between the use of silicone or saline implants and pain (22% and 33% respectively). However, the submuscular placement of the implants resulted in a significantly higher incidence of pain (50%) than the subglandular placement (21%). Of the women that reported pain, arm pain was significantly higher in the mastectomy and mastectomy + reconstruction group (56% and 42%, respectively) as compared to the breast reduction group (0%). Most patients reported intermittent pain in all groups. Of the women that reported pain, the mastectomy and mastectomy + reconstruction group had higher pain related to movement (41% and 42%, respectively) than the augmentation and breast reduction groups (15% and 9%, respectively). The peak pain intensity was significantly higher in the augmentation group as compared to the mastectomy group. Our incidence of post mastectomy pain is higher than most reports. The incidence of breast pain is highest in the mastectomy + reconstruction and augmentation groups which is assumed to be secondary to breast implants. Every effort should be made to achieve the best cosmetic result in breast reconstruction which in many cases justifies the use of breast implants. However, these women should be counseled on the possibility of developing chronic pain.

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Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency.

C L H Chan, P Facer, J Davis … (2003)

Faecal urgency and incontinence with rectal hypersensitivity is a distressing, unexplained disorder that is inadequately treated. We aimed to determine whether expression of the heat and capsaicin receptor vanilloid receptor 1 (TRPV1 or VR1) was changed in rectal sensory fibres, and to correlate nerve fibre density with sensory abnormalities. We compared full-thickness rectal biopsy samples from nine patients with physiologically characterised rectal hypersensitivity with tissue samples from 12 controls. Sensory thresholds to rectal balloon distension and heating the rectal mucosa were measured before biopsy. We assessed specimens with immunohistochemistry and image analysis using specific antibodies to TRPV1; nerve growth factor (NGF) receptor tyrosine kinase A; glial cell line-derived neurotrophic factor (GDNF); neuropeptides calcitonin gene-related peptide (CGRP) and substance P; the related vanilloid receptor-like protein (VRL) 2; glial markers S-100 and glial fibrillary acid protein (GFAP); and the nerve structural marker peripherin. In rectal hypersensitivity, nerve fibres immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers: in the mucosal layer, the median% area positive was 0.44 (range 0.30-0.59) in patients who were hypersensitive and 0.11 (0.00-0.21) in controls (p=0.0005). The numbers of peripherin-positive fibres also increased in the mucosal layer (hypersensitive 3.00 [1.80-6.50], controls 1.20 [0.39-2.10]: (p=0.0002). The increase in TRVP1 correlated significantly with the decrease in rectal heat (p=0.03) and the distension (p=0.02) sensory thresholds. The thresholds for heat and distension were also significantly correlated (p=0.0028). Expression of nerve fibres positive for GDNF (p=0.001) and tyrosine kinase A (p=0.002) was also increased, as were cell bodies of the submucosal ganglia immunoreactive to CGRP (p=0.0009). Faecal urgency and rectal hypersensitivity could result from increased numbers of polymodal sensory nerve fibres expressing TRPV1. The triggering factor or factors remain uncertain, but drugs that target nerve terminals that express this receptor, such as topical resiniferatoxin, deserve consideration.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Womens Health

Title: BMC Women's Health

Publisher: BioMed Central (London )

ISSN (Electronic): 1472-6874

Publication date Collection: 2005

Publication date (Electronic): 8 March 2005

Volume: 5

Page: 2

Affiliations

[1 ]Peripheral Neuropathy Unit, Hammersmith Hospital, Faculty of Medicine, Imperial College London, London, UK

[2 ]Department of Anaesthesia, Chelsea and Westminster Hospital, Faculty of Medicine, Imperial College London, London, UK

[3 ]Neurology CEDD, GlaxoSmithKline, Harlow, UK

Article

Publisher ID: 1472-6874-5-2

DOI: 10.1186/1472-6874-5-2

PMC ID: 554997

PubMed ID: 15755319

SO-VID: f8007fa3-e9b6-4582-9746-7410301506c1

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain

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Abstract

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Conclusion

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Most cited references 20

TRPV3 is a temperature-sensitive vanilloid receptor-like protein.

Pain after breast surgery: a survey of 282 women.

Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency.

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