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.