AngiotensinIItype 2 receptor (AT2R) localization and antagonist‐mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons

AbstractBackgroundThe angiotensinII(AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration.MethodsWe used immunostaining with characterized antibodies to study the localization ofAT2Rin cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects ofAngIIandAT2RantagonistEMA401on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density withGap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence.ResultsAT2Rexpression was localized in small‐/medium‐sized cultured neurons of human and ratDRG. Treatment with theAT2RantagonistEMA401resulted in dose‐related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8‐bromo‐cAMP, and reduced neurite length and density;AngIItreatment significantly enhanced capsaicin responses,cAMPlevels and neurite outgrowth. TheAT1Rantagonist losartan had no effect on capsaicin responses.AT2Rwas localized in sensory neurons of humanDRG, 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 humanDRG; some very small neurons appeared to be intensely immunoreactive, withTRPV1co‐localization. WhileAT2Rlevels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas.ConclusionsAT2Rantagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.