title: Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice.
abstract: Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia.
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors: Derek
authors: D
authors: Vang
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors: Jinny A
authors: JA
authors: Paul
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors: Julia
authors: J
authors: Nguyen
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors: Huy
authors: H
authors: Tran
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors: Lucile
authors: L
authors: Vincent
authors: Astraea Therapeutics, Mountain View, CA, USA.
authors: Dennis
authors: D
authors: Yasuda
authors: Astraea Therapeutics, Mountain View, CA, USA gupta014@umn.edu nurulain@astraeatherapeutics.com.
authors: Nurulain T
authors: NT
authors: Zaveri
authors: Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA gupta014@umn.edu nurulain@astraeatherapeutics.com.
authors: Kalpna
authors: K
authors: Gupta
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003508:Cycloheptanes / Q000737:chemistry / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D000094942:Nociceptin Receptor
chemical_list: D003508:Cycloheptanes; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse