Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 173, Issue 5, Pages 937-950Publisher
WILEY
DOI: 10.1111/bph.13413
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Funding
- National Basic Research Program of China [2013CB835100, 2011CB504100]
- National Key Technology RD Program [2013BAI04B04]
- NSFC [81171049, 31500854]
- Twelfth Five-Year project [AWS12J004]
- Social Development Project of Shaanxi Province [2015SF003]
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Background and PurposeThe Rho GTPase, Rac1, is involved in the pathogenesis of neuropathic pain induced by malformation of dendritic spines in the spinal dorsal horn (sDH) neurons. In the present study, the contribution of spinal Rac1 to peripheral inflammatory pain was studied. Experimental ApproachEffects of s.c. bee venom (BV) injection on cellular localization of Rac1 in the rat sDH was determined with double labelling immunofluorescence. Activation of Rac1 and its downstream effector p21-activated kinase (PAK), ERKs and p38 MAPK in inflammatory pain states was evaluated with a pull-down assay and Western blotting. The preventive and therapeutic analgesic effects of intrathecal administration of NSC23766, a selective inhibitor of Rac1, on BV-induced spontaneous nociception and pain hypersensitivity were investigated. Key ResultsRac1 labelling was mainly localized within neurons in both the superficial and deep layers of the sDH in rats of naive, vehicle-treated and inflamed (BV injected) groups. GTP-Rac1-PAK and ERKs/p38 were activated following s.c. BV injection. Post-treatment with intrathecal NSC23766 significantly inhibited GTP-Rac1 activity and phosphorylation of Rac1-PAK, ERKs and p38 MAPK in the sDH. Both pre-treatment and post-treatment with intrathecal NSC23766 dose-dependently attenuated the paw flinches, primary thermal and mechanical hyperalgesia and the mirror-image thermal hyperalgesia induced by BV injection, but without affecting the baseline pain sensitivity and motor coordination. Conclusions and ImplicationsThe spinal GTP-Rac1-PAK-ERK/p38MAPK signalling pathway is involved in both the development and maintenance of peripheral inflammatory pain and can be used as a potential molecular target for developing a novel therapeutic strategy for clinical pain.
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