A Small Molecule Angiotensin II Type 2 Receptor (AT(2)R) Antagonist Produces Analgesia in a Rat Model of Neuropathic Pain by Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) and p44/p42 MAPK Activation in the Dorsal Root Ganglia

作者：Smith Maree T^*; Woodruff Trent M; Wyse Bruce D; Muralidharan Arjun; Walther Thomas

来源：Pain Medicine, 2013, 14(10): 1557-1568.

DOI：10.1111/pme.12157

• Angiotensin II Type 2 Receptor (AT(2)R)
• Neuropathic Pain
• Analgesia
• p38 Mitogen Activated Protein Kinase (MAPK)
• p44
• p42 MAPK
• Angiotensin II
• Dorsal Root Ganglia

ObjectiveThere is an unmet clinical need for novel analgesics for neuropathic pain. This study was designed to elucidate the mechanism through which EMA300, a small molecule antagonist of the angiotensin II type 2 receptor (AT(2)R) with %26gt;1,000-fold selectivity over the angiotensin II type 1 receptor, produces analgesia in a rodent model of neuropathic pain. %26lt;br%26gt;Design and MethodsGroups of AT(2)R knockout, hemizygotes, and wild-type mice with a chronic constriction injury (CCI) of the sciatic nerve received single intraperitoneal (i.p.) bolus doses of EMA300 (100 or 300mg/kg), and analgesic efficacy was assessed. Groups of control, sham-operated, and CCI rats were euthanized and perfusion fixed. Lumbar dorsal root ganglia (DRGs) were removed for investigation of the mechanism through which EMA300 alleviates neuropathic pain. %26lt;br%26gt;ResultsEMA300 analgesia was abolished in AT(2)R knockout CCI mice with intermediate responses in the hemizygotes, affirming the AT(2)R as the target mediating EMA300 analgesia. In CCI rats, DRG immunofluorescence (IF) levels for angiotensin II, the main endogenous ligand of the AT(2)R, were increased approximate to 1.5-2.0-fold (P%26lt;0.05) cf. sham-controls. Mean DRG IF levels for activated p38 (pp38) and activated p44/p42 (pp44/pp42) MAPK were also increased approximate to 1.5-2.0-fold (P%26lt;0.05) cf. sham-controls. At the time of peak EMA300 analgesia in CCI rats, mean DRG levels of pp38 MAPK and pp44/pp42 MAPK (but not angiotensin II) were reduced to match the respective levels in sham-controls. %26lt;br%26gt;ConclusionAugmented angiotensin II/AT(2)R signaling in the DRGs of CCI rats is attenuated by EMA300 to block p38 MAPK and p44/p42 MAPK activation, a mechanism with clinical validity for alleviating neuropathic pain.

• 出版日期2013-10