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Because the reduced potency of analgesic agents in neuropathic pain may reflect alterations in RGS, we assessed the effects of CCG 63802, a specific RGS4 inhibitor, on pain hypersensitivity and signalling through cannabinoid receptors, in a model of neuropathic pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The partial sciatic nerve ligation (PSNL) model in male Sprague Dawley rats was used to measure paw withdrawal thresholds to mechanical (von Frey hairs) or thermal (Hargreaves method) stimuli, during and after intrathecal injection of CCG 63802. HEK293 cells expressing CB<jats:sub>1<\/jats:sub> receptors and conditional expression of RGS4 were used to correlate cAMP production and ERK phosphorylation with receptor activation and RGS4 action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Treatment of PSNL rats with CCG 63802, twice daily for 7 days after nerve injury, attenuated thermal hyperalgesia during treatment. Spinal levels of anandamide were higher in PSNL animals, irrespective of the treatment. Although expression of CB<jats:sub>1<\/jats:sub> receptors was unaffected, HU210\u2010induced CB<jats:sub>1<\/jats:sub> receptor signalling was inhibited in PSNL rats and restored after intrathecal CCG 63802. In transfected HEK cells expressing CB<jats:sub>1<\/jats:sub> receptors and RGS4, inhibition of cAMP production, a downstream effect of CB<jats:sub>1<\/jats:sub> receptor signalling, was blunted after RGS4 overexpression. RGS4 expression also attenuated the CB<jats:sub>1<\/jats:sub> receptor\u2010controlled activation of ERK1\/2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Inhibition of spinal RGS4 restored endogenous analgesic signalling pathways and mitigated neuropathic pain. Signalling through CB<jats:sub>1<\/jats:sub> receptors may be involved in this beneficial effect<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13324","type":"journal-article","created":{"date-parts":[[2015,9,11]],"date-time":"2015-09-11T11:37:20Z","timestamp":1441971440000},"page":"5333-5346","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB<sub>1<\/sub> receptor signalling"],"prefix":"10.1111","volume":"172","author":[{"given":"Barbara","family":"Bosier","sequence":"first","affiliation":[{"name":"Neuropharmacology Group, Institute of Neuroscience Universit\u00e9 catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre J.","family":"Doyen","sequence":"additional","affiliation":[{"name":"Neuropharmacology Group, Institute of 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