Pharmacological evaluation of orexin receptor antagonists in preclinical animal models of pain.
Orexin signaling, known to modulate arousal and vigilance, is also involved in nociception as orexin neurons project to regions of the brain and spinal cord involved in pain processing, and the administration of orexin peptides can alter pain response in a wide range of preclinical models. Pharmacological treatment with the potent, selective and structurally distinct dual orexin receptor antagonists (ORAs) DORA-12 and DORA-2 significantly reduced pain responses during both phases I and II of the mouse formalin pain model and significantly reversed hyperalgesia in the rat complete Freund's adjuvant pain model, respectively. Significant antinociceptive effects of DORA-12 in the formalin model were also observed in orexin 1 receptor (OX1R) knockout mice, but not orexin 2 receptor (OX2R) or OX1R/OX2R double knockout mice. Mechanical hypersensitivity was significantly reduced with a series of structurally distinct, potent and highly selective ORAs (DORA-2, DORA-12 and DORA-22) in the rat spinal nerve ligation (SNL) injury model of neuropathic pain. Selective pharmacological targeting of OX2R with 2-SORA-7 also reduced pain responses in acute inflammatory (complete Freund's adjuvant) and neuropathic (SNL) rat pain models. Performance on the rotarod test of psychomotor performance and baseline thermal sensitivity were not affected in OX1R/OX2R knockout mice or ORA-treated mice, indicating that the observed pain-reducing effects were not due to sedation or motor deficits. These findings indicate that ORAs have pain-reducing effects across a number of acute and chronic neuropathic preclinical mouse and rat pain models. Further studies on the potential pain-relieving effects of orexin receptor antagonism are warranted.
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Terrence
T
McDonald
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Hongyu A
HA
Liang
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Raul
R
Sanoja
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Anthony L
AL
Gotter
b Department of Medicinal Chemistry , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Scott D
SD
Kuduk
b Department of Medicinal Chemistry , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Paul J
PJ
Coleman
c Department of In Vivo Pharmacology , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA.
Karen M
KM
Smith
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
Christopher J
CJ
Winrow
a Department of Neuroscience , Merck Research Laboratories, Merck & Co., Inc. , Kenilworth , NJ , USA ;
John J
JJ
Renger
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000503:physiopathology; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000068796:Orexin Receptor Antagonists
Antinociception; formalin pain model; knockout mice; neuropathic pain; orexin; orexin receptor antagonist