title: Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine.
abstract: We hypothesized that the up-regulated expression of one or more members of the regulator of G protein signaling (RGS) family can cause an attenuation of signaling via Gi/Go-coupled opioid receptors, and thereby play a role in the development of hyperalgesia and accompanying insensitivity to morphine observed in animal models of neuropathic pain. Accordingly, we examined the mRNA expression of several RGS genes in a rat model of chronic neuropathic pain induced by partial ligation of the sciatic nerve. During the development of hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased significantly (up to 230%) in the lumbar spinal cord. In situ hybridization studies confirmed that RGS4 is present in the dorsal horn of the spinal cord where mu-opioid receptors (MORs) are also expressed. Overexpression of RGS4 in human embryonic kidney 293 cells stably expressing mu-opioid receptors predictably attenuated opioid agonist-induced inhibition of adenylyl cyclase. This inhibitory effect was overcome partially at high agonist concentrations, supporting the view that morphine insensitivity is promoted by RGS4 overexpression. These studies provide evidence that the up-regulation of RGS4 expression may contribute to changes in pain signal processing that lead to the development of hyperalgesia, and further affect its modulation by morphine.
authors.affiliation: Department of Neurobiology Research, GlaxoSmithKline Pharmaceuticals, Milan, Italy.
authors.forename: Martine
authors.initials: M
authors.lastname: Garnier
authors.forename: Paola F
authors.initials: PF
authors.lastname: Zaratin
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ficalora
authors.forename: Maurizio
authors.initials: M
authors.lastname: Valente
authors.forename: Laura
authors.initials: L
authors.lastname: Fontanella
authors.forename: Man-Hee
authors.initials: MH
authors.lastname: Rhee
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Scheideler
mesh_terms: D000818:Animals; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009020:Morphine; D010146:Pain / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020710:RGS Proteins; D017450:Receptors, Opioid, mu; C098799:RGS4 protein; D009020:Morphine