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

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.

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

“…5). 28 These data together with previous in vitro work by others showing EMA200 had no significant effect on NGF-induced neurite outgrowth in cultured adult rat DRG neurons 7 suggest that in the adult rat lumbar DRGs, augmented Ang II/AT 2 receptor signaling is upstream of the augmented NGF/TrkA signaling cascade (Fig. 5).…”

“…28 However, lumbar DRG expression levels of the AT 2 receptor did not differ between PCIBP rats and sham rats. 28 At the time of peak pain relief (0.5 hours) after an intravenous dose of EMA200 at 10 mg/kg in PCIBP rats, augmented Ang II/AT 2 receptor signaling in the lumbar DRGs was reduced. This was underpinned by a decrease in the elevated lumbar DRG levels of Ang II together with AT 2 receptor blockade (Fig.…”

“…2 Blockade of Ang II-mediated sensitization and also p38 MAPK and ERK activation by EMA401 2 is aligned with ex vivo findings of the analgesic mechanism of action of AT 2 receptor antagonists in the lumbar DRGs from rat models of neuropathic pain. 28,40 Injury and inflammation may increase local expression levels of Ang II that contribute to the sensitization of nociceptors, particularly in sprouting nerve fibers, as shown in a rodent model of inflammatory hypersensitivity. 8 AT 2 receptor antagonists including EMA401 may thus act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in Ang II/NGF/TRPV1-convergent pathways (Fig.…”

“…28 In PCIBP-rats, the corresponding mean ED 50 s for relief of thermal February 2016 · Volume 157 · Number 2 · Supplement 1 www.painjournalonline.com S35 hyperalgesia in the ipsilateral and contralateral hindpaws were 3.9 mg/kg and 5.5 mg/kg, respectively. 28 5.6. Prostate cancer-induced bone pain-rats: ex vivo mode of action in the peripheral somatosensory system…”

“…27,28 The mean ED 50 s for antiallodynia in the ipsilateral and contralateral hindpaws were 0.8 mg/kg and 1.8 mg/kg, respectively. 28 In PCIBP-rats, the corresponding mean ED 50 s for relief of thermal February 2016 · Volume 157 · Number 2 · Supplement 1 www.painjournalonline.com S35 hyperalgesia in the ipsilateral and contralateral hindpaws were 3.9 mg/kg and 5.5 mg/kg, respectively. 28 5.6.…”