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@article{Anand:2015:10.1186/s12990-015-0038-x,
author = {Anand, U and Yiangou, Y and Sinisi, M and Fox, M and MacQuillan, A and Quick, T and Korchev, YE and Bountra, C and McCarthy, T and Anand, P},
doi = {10.1186/s12990-015-0038-x},
journal = {Molecular Pain},
title = {Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT(2)R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies},
url = {http://dx.doi.org/10.1186/s12990-015-0038-x},
volume = {11},
year = {2015}
}

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TY  - JOUR
AB  - Background: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherallyrestrictedanalgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2Ris expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRGneurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, andtheir signalling pathways, require investigation. We have immunostained AngII, AT2R and the capsaicin receptor TRPV1in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons.AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT2R agonist C21, and Nervegrowth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 andp42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calciumimaging.Results: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control(n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised withAT2R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference betweencontrol (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves(4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g,n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths weresignificantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGFsignificantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitizationof capsaicin responses was not obs
AU  - Anand,U
AU  - Yiangou,Y
AU  - Sinisi,M
AU  - Fox,M
AU  - MacQuillan,A
AU  - Quick,T
AU  - Korchev,YE
AU  - Bountra,C
AU  - McCarthy,T
AU  - Anand,P
DO  - 10.1186/s12990-015-0038-x
PY  - 2015///
SN  - 1744-8069
TI  - Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT(2)R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies
T2  - Molecular Pain
UR  - http://dx.doi.org/10.1186/s12990-015-0038-x
UR  - http://hdl.handle.net/10044/1/28307
VL  - 11
ER  -

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