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Angiotensin II receptor antagonist EMA401 used for sciatic nerve constriction‐induced neuropathic pain in rats: behavior assessment and analgesic mechanisms

BACKGROUND: Chronic pain is characterized as high morbidity, long course and poor curative efficacy, and the underlying mechanism still remains unclear. The research on analgesics and analgesic mechanisms is an issue of concern. OBJECTIVE: To explore the effect of angiotensin II receptor antagonists EMA401 on the mechanical withdrawal threshold in a rat model of sciatic nerve constriction-induced neuropathic pain and the underlying mechanisms. METHODS: Sprague-Dawley rats were randomized into five groups: the rat sciatic nerve was exposed without ligation (sham group), and NaCl solution was given via gastric lavage; the model of sciatic nerve constriction was established in the remaining rats, followed by treatment with 2, 5 and 10 mg/kg EMA401, and NaCl solutions (model group) via gastric lavage, respectively. As a behavioral indicator, mechanical withdrawal threshold was detected at 1 preoperative day, 3, 7 and 14 postoperative days. Subsequently, the spinal dorsal root ganglion was removed, and the expression levels of glial fibrillary acidic protein, brain-derived neurotrophic factor and activating transcription factor 3 were detected by western blot assay. RESULTS AND CONCLUSION: Compared with the model group, EMA401 significantly improved the mechanical withdrawal threshold of the rats with sciatic nerve constriction (P < 0.05). Moreover, EMA401 significantly upregulated the expression levels of glial fibrillary acidic protein, brain-derived neurotrophic factor and activating transcription factor 3 in the dorsal root ganglion (P < 0.05); the expression levels in the 5 and 10 mg/kg EMA401 groups were significantly lower than those in the 2 mg/kg EMA401 group at 3, 7 and 14 days postoperatively (P < 0.05). These findings implicate that EMA401 exerts obvious analgesic effect on the rat model of sciatic nerve constriction, which may be via inhibiting astrocyte activation in the spinal dorsal root ganglion, downregulating the expression level of brain-derived neurotrophic factor, and further inhibiting the dorsal root ganglion neuron activation that appears with an increase in activated transcription factor 3 expression. Subject headings: Angiotensin Receptor Antagonists; Pain; Brain-Derived Neurotrophic Factor; Glial Fibrillary Acidic Protein; Tissue Engineering Funding: the Project of Science and Technology Planning Bureau of Mudanjiang, No. Z2016S0034; the Project of Mudanjiang Medical University, No. zs201621; the Project of Health and Family Planning Commission of Heilongjiang Province, No. 2017-336