Table 2.
Selective, small molecule, angiotensin II type 2 recptor antagonists alleviate pain-like behavior in rodent models of neuropathic and chronic inflammatory pain.
| Pain type | Rodent model and pain-like behavioral end points | AT2R antagonist(s) evaluated and dosing regimen | ED50 (95%CI) (mg/kg) | Ref | ||
|---|---|---|---|---|---|---|
| EMA200 | EMA300 | EMA400/EMA401 or analogue | ||||
| Neuropathic | CCI of the sciatic nerve in the rat; mechanical allodynia | Single i.p. bolus doses; EMA200 1-10 mg/kg; EMA300 1-10 mg/kg; EMA400 0.003-0.03 mg/kg | 3.22 (2.02-5.14) | 0.78 (0.08-7.68) | 0.013 (0.008-0.021) | 103 |
| Single oral dose; EMA401 (30 mg/kg) | NA | NA |
|
30 | ||
| Single oral dose; compound 15 (EMA401 analogue) | NA | NA |
|
30 | ||
| ddC-induced ATN in the rat; mechanical allodynia (single doses); mechanical hyperalgesia (repeat doses) | Single i.p. bolus doses; EMA200 at 0.3–10 mg/kg | 3.2 (1.43-7.0) | NA | NA | 105 | |
| Twice-daily i.p. doses; EMA300 at 1, 10, and 30 mg/kg for 3 days | NA |
|
NA | 105 | ||
| SNI of sciatic nerve in mice; mechanical and cold allodynia | Single i.p. dose; EMA200 at 10 mg/kg |
|
NA | NA | ||
| Single perisciatic dose of EMA200 (30 nmol) |
|
NA | NA | 96 | ||
| Single intrathecal dose of EMA200 (30 nmol) | Inactive | NA | NA | 96 | ||
| Acute paclitaxel neuropathic pain in mice; mechanical and cold allodynia | Single i.v. doses as prevention protocol; i.v. EMA200 at 20 mg/kg |
|
NA |
|
123 | |
| Oral EMA401 at 10 ng/kg | ||||||
| Inflammatory | Unilateral i.pl. FCA-induced inflammatory pain in the rat; mechanical and thermal hyperalgesia | Single i.p. dose of EMA200 at 10 mg/kg on day 7; chronic i.p. dosing of EMA200 at 5 mg/kg/d for 7 consecutive days as a prevention protocol |
|
NA | NA | 97 |
|
||||||
| Unilateral i.pl. FCA-induced inflammatory pain in the rat | Single i.p. dose of EMA200 at 10 mg/kg on day 2, day 4, or day 7 | X | 96 | |||
| FCA-induced monoarthritic pain in the rat knee joint | Single i.p. bolus doses of EMA300 and EMA400 at 0.1-10 mg/kg. | NA |
|
|
102 | |
| FCA-induced vestibulodynia in the rat; perivaginal mechanical allodynia | Chronic i.p. doses of EMA200 at 5 mg/kg/d) for 7 consecutive days as a prevention protocol |
|
NA | NA | 14 | |
| Inflammatory and neuropathic | Prostate cancer–induced bone pain in the rat; mechanical allodynia and thermal hyperalgesia in ipsilateral and contralateral hind paws | Single i.v. doses of EMA200 at 0.3–10 mg/kg | 0.8 (0.61-1.03) ipsi; 1.8 (1.2-2.8) contra; | NA | NA | 70 |
| 3.9 (3.0-5.2) ipsi; 5.5 (3.9-7.7) contra | ||||||
| Acute pain | i.pl. or intrathecal Ang II in noninjured mice; mechanical allodynia | Single i.pl. dose of EMA200 (10 pmol) |
|
NA | NA | 97 |
| Single intrathecal dose of EMA200 (10 pmol) | X | |||||
Ang II, angiotensin II; AT2, angiotensin II type 2; ATN, antiretroviral neuropathy; CCI, chronic constriction injury; CI, confidence interval; contra, contralateral; ddC, dideoxycytidine; FCA, Freund complete adjuvant; i.p., intraperitoneal; ipsi, ipsilateral; i.v., intravenous; NA, not assessed; SNI, spared nerve injury.