Analgesic Efficacy and Mode of Action of a Selective Small Molecule Angiotensin II Type 2 Receptor Antagonist in a Rat Model of Prostate Cancer‐Induced Bone Pain

摘要: Objective The pathobiology of prostate cancer (PCa)-induced bone pain (PCIBP) has both inflammatory and neuropathic components. Previously, we showed that small molecule angiotensin II type 2 receptor (AT2R) antagonists with >1,000-fold selectivity over the 1 produced dose-dependent analgesia in a rat model pain. Here, assessed analgesic efficacy mode action AT2R antagonist, EMA200, PCIBP. Methods At 14–21 days after unilateral intratibial injection AT3B PCa cells, rats exhibiting hindpaw hypersensitivity received single intravenous bolus doses EMA200 (0.3–10 mg/kg) or vehicle, was assessed. investigated using immunohistochemical, Western blot, and/or molecular biological methods lumbar dorsal root ganglia (DRGs) removed from drug-naive EMA200-treated PCIBP relative to sham-control rats. Results Intravenous rats. Lumbar DRG levels II, nerve growth factor (NGF), tyrosine kinase A (TrkA), phospho-p38 mitogen-activated protein (MAPK), phospho-p44/p42 MAPK, but not AT2R, were increased significantly ( P < 0.05) rats, c.f. corresponding for sham controls. by reducing elevated DRGs attenuate augmented II/AT2R signaling. This turn reduced NGF/TrkA signaling DRGs. net result inhibition p38 MAPK p44/p42 activation. Conclusion Small are worthy further investigation as novel analgesics relief intractable other types where hyperalgesia worsens symptoms.