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

Authors

  • Arjun Muralidharan PhD,

    1. Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Queensland, Australia
    2. The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia
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  • Bruce D. Wyse PhD,

    1. Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Queensland, Australia
    2. The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia
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  • Maree T. Smith PhD

    Corresponding author
    1. Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Queensland, Australia
    2. The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia
    • Reprint requests to: Maree T. Smith, PhD, Centre for Integrated Preclinical Drug Development, Level 3, Steele Building, St Lucia Campus, Brisbane, QLD 4072, Australia. Tel: +61-7-33652554; Fax: +61-7-33467391; E-mail: maree.smith@uq.edu.au.

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  • Disclosures: Arjun Muralidharan was supported by an International PhD Scholarship funded by The University of Queensland, and this project was supported by research funds from The University of Queensland. This work utilized facilities funded by the Queensland Government Smart State Research Facilities Fund. MTS and BDW are named inventors on a UQ patent for the use of AT2R antagonists in neuropathic pain, and MTS is a named inventor on a UQ patent for the use of AT2R antagonists in inflammatory pain. This technology is being commercialized by the UQ spin-out company, Spinifex Pharmaceuticals Pty Ltd. UQ owns shares in Spinifex Pharmaceuticals Pty Ltd, and according to UQ policy, inventors will receive a portion of any net income received by UQ in the event of successful commercialization.

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 (AT2R) 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 AT2R 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 AT2R, 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/AT2R 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.

Conclusion

Small molecule AT2R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.

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