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Angiotensin II type 2 receptor ( AT 2 R ) localization and antagonist‐mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons
Author(s) -
Anand U.,
Facer P.,
Yiangou Y.,
Sinisi M.,
Fox M.,
McCarthy T.,
Bountra C.,
Korchev Y.E.,
Anand P.
Publication year - 2013
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/j.1532-2149.2012.00269.x
Subject(s) - dorsal root ganglion , neurite , capsaicin , trpv1 , endocrinology , medicine , immunostaining , chemistry , antagonist , nociception , agonist , receptor , biology , sensory system , neuroscience , immunohistochemistry , in vitro , transient receptor potential channel , biochemistry
Background The angiotensin II ( AngII ) receptor subtype 2 ( AT 2 R ) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. Methods We used immunostaining with characterized antibodies to study the localization of AT 2 R in cultured human and rat dorsal root ganglion ( DRG ) neurons and a range of human tissues. The effects of AngII and AT 2 R antagonist EMA401 on capsaicin responses in cultured human and rat ( DRG ) neurons were measured with calcium imaging, on neurite length and density with G ap43 immunostaining, and on cyclic adenosine monophosphate ( cAMP ) expression using immunofluorescence. Results AT 2 R expression was localized in small‐/medium‐sized cultured neurons of human and rat DRG . Treatment with the AT 2 R antagonist EMA401 resulted in dose‐related functional inhibition of capsaicin responses ( IC 50 = 10 nmol/ L ), which was reversed by 8‐bromo‐ cAMP , and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT 1 R antagonist losartan had no effect on capsaicin responses. AT 2 R was localized in sensory neurons of human DRG , and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub‐population (60%) of small‐/medium‐diameter neuronal cells were immunopositive in both control post‐mortem and avulsion‐injured human DRG ; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co‐localization. While AT 2 R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas. Conclusions AT 2 R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.