title: Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112.
abstract: Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, National Institute of Neuroscience, University of Ferrara, 44100 Ferrara, Italy Department of Pharmaceutical Sciences, Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy Department of Psychology, Institute of Neuroscience, National Cheng-Chi University, Taipei 11605, Taiwan.
authors: Eric
authors: E
authors: Hu
authors: Girolamo
authors: G
authors: Calò
authors: Remo
authors: R
authors: Guerrini
authors: Mei-Chuan
authors: MC
authors: Ko
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002211:Capsaicin / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007278:Injections, Spinal / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D009271:Naltrexone / Q000494:pharmacology; D018847:Opioid Peptides / Q000819:agonists* / Q000627:therapeutic use*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D002211:Capsaicin; D009020:Morphine; D009271:Naltrexone; D018847:Opioid Peptides; D010880:Piperidines; D000097629:Nociceptin; C402921:J 113397; C525846:nociceptin-amide, Nphe(1)-(pF)Phe(4)-Aib(7)-Arg(14)-Lys(15)-