sb-334867-a and Neuralgia

To date several circuities in supraspinal site of the central nervous system have been known to engage in pain modulation. Lateral hypothalamus (LH) is known as part of the circuit of pain modulation among supraspinal sites. Its role in several animal pain models has been well defined. In this study, we examined the role of spinal orexin receptors in antinociceptive response elicited by the LH stimulation in an animal model of neuropathic pain. Male Wistar rats were unilaterally implanted with a cannula into the LH and a catheter into the L4-L5 segments of the spinal cord followed by chronic constriction injury (CCI) surgery. Intra-LH microinjection of carbachol (500 nM; 0.5 μL) was done 5 min after intrathecal administration of the orexin receptor antagonists, SB-334867 or TCS OX2 29; control animals received DMSO. Mechanical allodynia and thermal hyperalgesia were evaluated using von Frey filaments and a thermal stimulus. The results showed that carbachol induces antiallodynic and anti-thermal hyperalgesic effects in a dose-dependent manner. The antiallodynic and anti-thermal hyperalgesic effects induced by intra-LH injection of carbachol were reversed by intrathecal administration of 10 μL-100 nM solutions of SB-334867 or TCS OX2 in neuropathic rats. However, solely intrathecal administration of both antagonists had no effect in neuropathic rats. There appears to be a neural pathway from the LH to the spinal cord, which potentially contributes to the modulation of neuropathic pain. The implications are that there may be novel therapeutic approaches for the treatment of people suffered from chronic neuropathic pain in clinic.

Topics: Animals; Benzoxazoles; Carbachol; Disease Models, Animal; Dose-Response Relationship, Drug; Hot Temperature; Hyperalgesia; Hypothalamic Area, Lateral; Isoquinolines; Naphthyridines; Neuralgia; Orexin Receptor Antagonists; Orexin Receptors; Pain Management; Pain Threshold; Pyridines; Rats; Rats, Wistar; Spinal Cord; Urea

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Benzoxazoles; Brain; Brain Ischemia; Hyperalgesia; Isoquinolines; Male; Mice; Mitochondrial Proteins; Naphthyridines; Neuralgia; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Piperazines; Pyridines; Serotonin Antagonists; Signal Transduction; Urea; Yohimbine

No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p < .05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p < .05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

Topics: Analgesics, Non-Narcotic; Animals; Benzoxazoles; Carbachol; Female; Hyperalgesia; Hypothalamic Area, Lateral; Naphthyridines; Neuralgia; Orexins; Pain Management; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn; Urea