Antiallodynic Effects of Intrathecal Orexins in a Rat Model of Postoperative Pain

Abstract

Orexin A and B (hypocretin 1 and 2) are the endogenous ligands of orexin receptors, a G-protein-coupled orphan receptor family containing orexin 1 (OX 1 ) and orexin 2 (OX 2 ) types. Orexin A induces analgesia in acute and inflammatory pain models. We further elucidated the possible antiallodynic effect of intrathecal orexins in a rat model of postoperative pain. Mechanical allodynia was induced by incising the rat hind paw and evaluated with the withdrawal threshold to von Frey filament stimulation. Intrathecal orexin A (0.03-1 nmol) and orexin B (0.1-3 nmol) dose dependently attenuated the incision-induced allodynia. Orexin A (ED 50 ϭ 0.06 nmol) is more potent than orexin B. The effects of orexin A and B were abolished by their respective antibodies, but not by naloxone, and were attenuated by suramin and strychnine, the P 2X purinergic and glycine receptor antagonists, respectively. SB-334867, an OX 1 receptor antagonist, at 30 nmol completely blocked the effect of orexin A but, even at 100 nmol, only partially antagonized the effect of orexin B. Orexin A antibody, SB-334867, suramin, strychnine, or naloxone enhanced the incision-induced allodynic response. It is concluded that intrathecal orexins reduce incision-induced allodynia through OX 1 receptors. Glycine and P 2X purinergic receptors, but not opioid receptors, might be involved in the antiallodynic effects of orexins. Endogenous orexin might be released after incision injury to activate the spinal OX 1 receptors as an endogenous analgesic protector.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…In a few instances, administration of SB-334867 alone enhanced sensitivity in the in vivo models, supporting the idea of enhanced or tonic OX 1 receptor-mediated inhibitory tone during pain (Bingham et al, 2001;Cheng et al, 2003;Jeong and Holden, 2009). Consistent with this hypothesis of orexin-mediated inhibitory tone, orexin peptide knockout mice show enhanced thermal hypersensitivity in an inflammatory pain model (Watanabe et al, 2005).…”

“…OX-B may elicit its effect by facilitating glycine release presynaptically. Behavioral studies support these electrophysiological findings, because intrathecal administration of OX-A and, to a lesser extent, OX-B inhibits withdrawal responses and spontaneous nociceptive behaviors in acute, chemical, inflammatory, neuropathic, and postsurgical pain models (Yamamoto et al, , 2003aCheng et al, 2003;Kajiyama et al, 2005;Mobarakeh et al, 2005a;Jeong and Holden, 2009). The antinociceptive effects of the orexins are blocked by intrathecally administered SB-334867, once again suggesting that pain modulation may be mediated through OX 1 receptors.…”

Changes in Biochemical Markers of Pain Perception and Stress Response After Spinal Manipulation

“…14,23 Our data indicate an increase in neurotensin plasmatic concentration after an SM, suggesting that the mechanical stimulus provided by SM is enough to modulate the liberation of this neuropeptide. In this sense, neurotensin has long been known to include analgesia among its actions.…”

Orexin 1 Receptor Activation Attenuates Neurogenic Dural Vasodilation in an Animal Model of Trigeminovascular Nociception

“…Peripherally, orexin fibers and receptors have been localized to the pituitary, adrenal glands, gut, and testis (Blanco et al, 2001;Johren et al, 2001). The broad projections of the orexinergic system have led to its implication in a variety of functions, including feeding, sleep wake cycle, cardiovascular function, hormone secretion (Ferguson and Samson, 2003;Siegel, 2004;Sakurai, 2005;Samson et al, 2005) and more recently the modulation of nociceptive processing (Bingham et al, 2001;Cheng et al, 2003;Yamamoto et al, 2003;Kajiyama et al, 2005).…”