title: Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB1 receptor signalling.
abstract: OBJECTIVE
  Regulators of G protein signalling (RGS) are major determinants of metabotropic receptor activity, reducing the lifespan of the GTP-bound state of G proteins. 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.
  
  
  METHODS
  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 CB1 receptors and conditional expression of RGS4 were used to correlate cAMP production and ERK phosphorylation with receptor activation and RGS4 action.
  
  
  RESULTS
  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 CB1 receptors was unaffected, HU210-induced CB1 receptor signalling was inhibited in PSNL rats and restored after intrathecal CCG 63802. In transfected HEK cells expressing CB1 receptors and RGS4, inhibition of cAMP production, a downstream effect of CB1 receptor signalling, was blunted after RGS4 overexpression. RGS4 expression also attenuated the CB1 receptor-controlled activation of ERK1/2.
  
  
  CONCLUSIONS
  Inhibition of spinal RGS4 restored endogenous analgesic signalling pathways and mitigated neuropathic pain. Signalling through CB1 receptors may be involved in this beneficial effect.
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bosier
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Doyen
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Amandine
authors.initials: A
authors.lastname: Brolet
authors.affiliation: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.|Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Eman
authors.initials: E
authors.lastname: Ahmed
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desmet
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hermans
authors.affiliation: Neuropharmacology Group, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: Deumens
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism*; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D010812:Physical Stimulation; D020710:RGS Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D012584:Sciatic Nerve / Q000601:surgery; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D020710:RGS Proteins; D043884:Receptor, Cannabinoid, CB1; C098799:RGS4 protein; D000242:Cyclic AMP