Analgesic effect of intrathecally administered orexin‐A in the rat formalin test and in the rat hot plate test

Orexin‐A and orexin‐B (also known as hypocretin‐1 and hypocretin‐2) are hypothalamic peptides and regulate feeding behaviour, energy metabolism and the sleep‐wake cycle. Orexin‐A binds equally to both orexin‐1 and orexin‐2 receptors, while orexin‐B has a preferential affinity for orexin‐2 receptors. Orexins are also known to be concentrated in superficial laminae of the spinal dorsal horn, and orexin‐A and orexin‐1 receptors are found in the dorsal root ganglion cells. In the present study, the authors examined the effect of intrathecal injection of either orexin‐A or orexin‐B in the rat formalin test (a model of inflammatory pain) and in the rat hot plate test. The paw formalin injection induces biphasic flinching (phase 1: 0–6 min; phase 2: 10–60 min) of the injected paw. Intrathecal injection of orexin‐A, but not orexin‐B, decreased the sum of flinches in phases 1 and 2 in the formalin test and increased the hot plate latency. These effects of orexin‐A were completely antagonized by pre‐treatment with SB‐334867, a selective orexin‐1 receptor antagonist. Intrathecal injection of SB‐334867 alone had no effect in the formalin test or in the hot plate test. Intrathecal injection of orexin‐A suppressed the expression of Fos‐like immunoreactivity (Fos‐LI), induced by paw formalin injection, in laminae I‐II of L4–5 of the spinal cord. These data suggest that the spinal orexin‐1 receptor is involved in the nociceptive transmission and that the activation of the spinal orexin‐1 receptor produces analgesic effects in the rat formalin test and in the rat hot plate test.British Journal of Pharmacology (2002) 137 , 170–176. doi: 10.1038/sj.bjp.0704851