Opioid receptors have been pharmacologically classified as µ, δ, κ and ε. We have recently reported that the antinociceptive effect of morphine (a µ-opioid receptor agonist), but not that of β-endorphin (a novel µ/ε-opioid receptor agonist), is attenuated by whole body irradiation (WBI). It is unclear at present whether WBI has differential effects on the antinociceptive effects of µ-, δ-, κ- and ε-opioid receptor agonists. In our current experiments, male ICR mice were exposed to WBI (5Gy) from a 60 Co gamma-source and the antinociceptive effects of opioid receptor agonists were assessed two hours later using the hot water (52℃) tail-immersion test. Morphine and D-Ala2,N-Me-Phe4,Gly-ol-enkephalin (DAMGO), [D-Pen2-D-Pen5]enkephalin (DPDPE), trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]¬benzeneacetamide (U50,488H), and β-endorphin were tested as agonists for µ, δ, κ, and ε-opioid receptors, respectively. WBI significantly attenuated the antinociceptive effects of morphine and DAMGO, but increased those of β-endorphin. The antinociceptive effects of DPDPE and U50,488H were not affected by WBI. In addition, to more preciously understand the differential effects of WBI on µ- and ε¬opioid receptor agonists, we assessed pretreatment effects of β-funaltrexamine (β-FNA, a µ-opioid receptor antagonist) or β-endorphin1-27 (β-EP1-27, an ε-opioid receptor antagonist), and found that pretreatment with β-FNA significantly attenuated the antinociceptive effects of morphine and β endorphin by WBI. significantly reversed the β-EP1-27 attenuation of morphine by WBI and significantly attenuated the increased effects of β-endorphin by WBI. The results demonstrate differential sensitivities of opioid receptors to WBI, especially for µ- and ε-opioid receptors.

Whole-body y-irradiation(WBI), which produces an oxidative stress, is reported to attenuate the acute antinociceptive action of morphine (aμ-opioid receptor agonist), but not DPLPE (að-opioid receptor agonist), in mice. Recently, we also reported that antinociceptive effect of morphine, but not β-endorphin (a novel ε-opioid receptor agonist), was attenuated by oxidative stress. These findings prompted us to investigate the effect of WBI on the antinociception of morphine and β-endorphin in mice. Mice were exposed to WBI (5 Gy) from a 60Co gamma-source and tested 2 hours later for antinociception produced by intracerebroventricular administration of morphine or β-endorphin using the hot water tail-immersion and the writhing tests. WBI significantly attenuated the antinociception produced by morphine only in the hot water tail-immersion test, whereas the antinociception of -endorphin was significantly potentiated by WBI in both tests. These results demonstrate a differential sensitivity of μ- and ε-opioid receptors to WBI, and support the hypothesis that morphine and β-endorphin administered supraspinally produce antinociception by different neuronal mechanisms.

Background : This study aimed to identify the mechanisms of the antinociceptive effects of PG in the fibromyalgia (FM)-like animal model. Methods and Results : To assess the possible effect of PG on FM symptoms, we constructed a FM animal model induced by intermittent cold stress with slight modification. All mice underwent nociceptive assays using electronic von Frey anesthesiometer and Hargreaves equipment. To assess the relation between PG and the expression levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and phosphorylated CREB (p-CREB), western blotting and immunohistochemistry analyses were performed. In behavioral analysis, nociception tests showed that the pain threshold was significantly decreased in the FM group compared to control group. Western blot and immunohistochemical analyses of the medial prefrontal cortex and hippocampus showed downregulation of BDNF and p-CREB proteins in the FM group compared to control group. PG recovered these changes at behavioral tests and protein level. These results provide evidence that the effects of PG extract in the FM model may be related to its modulating effect on the BDNF signaling pathway in the hippocampus and medial prefrontal cortex. Conclusion : Our animal model may be involved in the mechanism by which PG extract is effective as a therapeutic agent for FM.

In the present study, the antinociceptive profiles of Viola tricolor L. (V. tricolor L.) extract were examined in ICR mice. V. tricolor L. extract administered orally (200mg/kg) showed an antinociceptive effect as measured by the tail-flick and hot-plate tests. In addition, V. tricolor L. extract attenuated the writhing numbers in the acetic acid-induced writhing test. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of substance P (0.7 μg) was diminished by V. tricolor L. extract. Intraperitoneal (i.p.) pretreatment with yohimbine (α2-adrenergic receptor antagonist) attenuated antinociceptive effect induced by V. tricolor L. extract in the writhing test. However, naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by V. tricolor L. extract in the writhing test. Our results suggest that V. tricolor L. extract shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of V. tricolor L. extract may be mediated by α2-adrenergic receptor, but not opioidergic and serotonergic receptors.