title: 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.
abstract: 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 (AT2 R) antagonists with >1,000-fold selectivity over the angiotensin II type 1 receptor produced dose-dependent analgesia in a rat model of neuropathic pain. Here, we assessed the analgesic efficacy and mode of action of the AT2 R antagonist, EMA200, in a rat model of PCIBP.
  
  
  METHODS
  At 14-21 days after unilateral intratibial injection of AT3B PCa cells, rats exhibiting hindpaw hypersensitivity received single intravenous bolus doses of EMA200 (0.3-10 mg/kg) or vehicle, and analgesic efficacy was assessed. The mode of action was investigated using immunohistochemical, Western blot, and/or molecular biological methods in lumbar dorsal root ganglia (DRGs) removed from drug-naïve and EMA200-treated PCIBP rats relative to sham-control rats.
  
  
  RESULTS
  Intravenous bolus doses of EMA200 produced dose-dependent analgesia in PCIBP rats. Lumbar DRG levels of angiotensin II, nerve growth factor (NGF), tyrosine kinase A (TrkA), phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p44/p42 MAPK, but not the AT2 R, were increased significantly (P < 0.05) in PCIBP rats, c.f. the corresponding levels for sham controls. EMA200 produced analgesia in PCIBP rats by reducing elevated angiotensin II levels in the lumbar DRGs to attenuate augmented angiotensin II/AT2 R signaling. This in turn reduced augmented NGF/TrkA signaling in the lumbar DRGs. The net result was inhibition of p38 MAPK and p44/p42 MAPK activation.
  
  
  CONCLUSIONS
  Small molecule AT2 R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Queensland, Australia; The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Arjun
authors.initials: A
authors.lastname: Muralidharan
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wyse
authors.forename: Maree T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary*; D045744:Cell Line, Tumor / Q000637:transplantation; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000737:chemistry / Q000473:pathology; D006930:Hyperalgesia / Q000209:etiology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008161:Lumbosacral Region; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D020932:Nerve Growth Factor / Q000032:analysis; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011471:Prostatic Neoplasms / Q000150:complications*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011984:Sensory Receptor Cells / Q000502:physiology
chemical_list: D000700:Analgesics; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D009363:Neoplasm Proteins; D011725:Pyridines; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; C073402:PD 123319; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases
keywords: Angiotensin II; Angiotensin II Type 2 Receptor (AT2R); Nerve Growth Factor (NGF); Phospho-p38 Mitogen-Activated Protein Kinase (MAPK); Phospho-p44/p42 MAPK; Prostate Cancer-Induced Bone Pain (PCIBP)