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Haematologica. 2015 Dec;100(12):1517-25. doi: 10.3324/haematol.2015.128736. Epub 2015 Aug 20.

Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice.

Author information

1
Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
2
Astraea Therapeutics, Mountain View, CA, USA.
3
Astraea Therapeutics, Mountain View, CA, USA gupta014@umn.edu nurulain@astraeatherapeutics.com.
4
Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA gupta014@umn.edu nurulain@astraeatherapeutics.com.

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.

PMID:
26294734
PMCID:
PMC4666327
DOI:
10.3324/haematol.2015.128736
[Indexed for MEDLINE]
Free PMC Article

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