Antinociceptive profiles and mechanisms of centrally administered oxyntomodulin in various mouse pain models

In the present study, the antinociceptive profiles of oxyntomodulin were examined in ICR mice. Oxyntomodulin administered intrathecally (i.t.) and intracerebroventricularly (i.c.v.) (from 1 to 5 mu g/5 mu l) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Moreover, cumulative response time of nociceptive behaviors induced by intraplantar formalin injection was reduced by i.t. or i.c.v. treatment with oxyntomodulin during the second, but not the first phase. In addition, the cumulative nociceptive response time after i.t. injection with substance P (0.7 mu g), glutamate (20 mu g), and pro-inflammatory cytokines such as TNF-alpha, IL-beta or IFN-gamma (100 pg/5 mu l) was diminished by spinally or supraspinally administered oxyntomodulin. However, i.t. and i.c.v. treatment with oxyntomodulin did not affect latencies of the tail-flick and hot-plate paw-licking responses. Furthermore, the i.t. pretreatment with yohimbine (adrenergic receptor antagonist), but not naloxone (an opioid receptor antagonist) or methysergide (a serotonergic receptor antagonist), attenuated antinociceptive effect induced by oxyntomodulin administered i.c.v. in the writhing test. The i.c.v. or i.t. pretreatment with oxyntomodulin attenuated formalin-induced increase of phosphorlated ERK (p-ERK) expression in the spinal cord. Our results suggest that centrally administered oxyntomodulin shows an antinociceptive property in various pain models except for thermal-induced nociception. Furthermore, supraspinally administered oxyntomodulin-induced antinociception may be mediated by spinal adrenergic receptors, but not serotonergic and opioidergic receptors. Furthermore, the antinociception induced by oxyntomodulin appears to be mediated by reduced formalin-induced p-ERK expression in the spinal cord.