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. Issue 1 (30th October 2013)

• Record Type: Journal Article
• Authors: Muralidharan, Arjun; Wyse, Bruce D.; Smith, Maree T.
• Is Part Of: Pain medicine. Volume 15:Issue 1(2014)
• Page Start: 93
• Page End: 110
• Publication Date: 2013-10-30
• Subjects: Pain -- Periodicals; Pain -- Treatment -- Periodicals; Analgesics -- Periodicals; Pain -- Periodicals; Pain Management -- Periodicals; Douleur -- Périodiques; Douleur -- Traitement -- Périodiques; Analgésiques -- Périodiques; Analgésique; Soulagement de la douleur; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.047205
• DOI: 10.1111/pme.12258
• Languages: English
• ISSNs: 1526-2375

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="pme12258-sec-0001" sec-type="section"> <title>Objective</title> <p>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 (AT<sub>2</sub>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 AT<sub>2</sub>R antagonist, EMA200, in a rat model of PCIBP.</p> </sec> <sec id="pme12258-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="pme12258-sec-0003" sec-type="section"> <title>Results</title> <p>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 AT<sub>2</sub>R, were increased significantly (<italic>P</italic> < 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/AT<sub>2</sub>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.</p> </sec> <sec id="pme12258-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Small molecule AT<sub>2</sub>R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.</p> </sec> </abstract>