Antinociceptive Mechanisms of Platycodin D Administered Intracerebroventricularly in the Mouse

Abstract

Platycodin D administered intracerebroventricularly (i. c. v.) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick assay. The antinociception induced by platycodin D was maintained at least 1 h. MK-801 [(±)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], a competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a non-NMDA receptor antagonist, muscimol (a GABA_A receptor agonist), or baclofen (a GABA_B receptor antagonist), or sulfated cholecystokinin (CCK-8 s; CCK_A receptor agonist), injected i. c. v. significantly reduced the inhibition of the tail-flick response induced by platycodin D administered i. c. v. Additionally, intrathecal (i. t.) pretreatment with yohimbine (an α₂-adrenergic receptor antagonist) or methysergide (a serotonin receptor antagonist) dose-dependently attenuated inhibition of the tail-flick response induced by i. c. v. administered platycodin D. However, naloxone (an opioid receptor antagonist) did not affect the inhibition of the tail-flick response induced by platycodin D. Our results suggest that platycodin D has an antinociceptive effect when it is administered supraspinally, and supraspinal GABA_A, GABA_B, NMDA and non-NMDA receptors are involved in platycodin D-induced antinociception. Furthermore, platycodin D administered supraspinally produces antinociception by stimulating descending noradrenergic and serotonergic, but not opioidergic, pathways.

Key words

Platycodin D - Platycodon grandiflorum - Campanulaceae - antinociception - glutamate receptor - GABA receptor - CCK receptor - descending pain inhibitory system

References

• 1 Takagi K, Lee E B. Pharmacological studies on Platycodon grandiflorum A. DC. 3. Activities of crude platycodin on respiratory and circulatory systems and its other pharmacological activities. Yakugaku Zasshi.  J Pharm Soc Japan. 1972;  92 969-73
• 2 Tada A, Kaneiwa Y, Shoji J, Shibata S. Studies on the saponins of the root of Platycodon grandiflorum A. De Candolle. I. Isolation and the structure of platycodin-D.  Chem Pharm Bull (Tokyo). 1975;  23 2965-72
• 3 Kim T -J, Lee S -I, Lee T -H, Ko J -S. Isolation and determination of platycodin D from platycodi radix.  Anal Sci Tech, J Kor Soc Anal Sci. 1990;  3 399-404
• 4 Arai I, Komatsu Y, Hirai Y, Shingu K, Ida Y, Yamaura H, Yamamoto T, Kuroiwa Y, Sasaki K, Taguchi S. Stimulative effects of saponin from kikyo-to, a Japanese herbal medicine, on pancreatic exocrine secretion of conscious rats.  Planta Med. 1997;  63 419-24
• 5 Suh H H, Tseng L F. Different types of opioid receptors mediating analgesia induced by morphine, DAMGO, DPDPE, DADLE and beta-endorphin in mice.  Naunyn-Schmiedeberg"s Arch of Pharmacol. 1990;  342 67-71
• 6 Suh H W, Song D K, Kim Y H, Yoo J S, Tseng L F. Differential antagonism by MK-801 against antinociception induced by opioid receptor agonists administered supraspinally in mice.  Eur J Pharmacol. 1994;  263 217-21
• 7 Suh H W, Choi Y S, Yoo J S, Song D K, Kim Y H, Tseng L F. Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not beta-endorphin, D-Pen2-D-Pen5-enkephalin, and U50, 488H administered intracerebroventricularly in mice.  Neuropeptides. 1995;  28 125-9
• 8 Mantegazza P, Tammiso R, Vicentini L, Zambotti F, Zonta N. Muscimol antagonism of morphine analgesia in rats.  Br J Pharmacol. 1979;  67 103-7
• 9 Jensen T S, Yaksh T L. Spinal monoamine and opiate systems partly mediate the antinociceptive effects produced by glutamate at brainstem sites.  Brain Res. 1984;  321 287-97
• 10 Jones S L, Gebhart G F. Inhibition of spinal nociceptive transmission from the midbrain, pons and medulla in the rat: activation of descending inhibition by morphine, glutamate and electrical stimulation.  Brain Res. 1988;  460 281-96
• 11 Suh H H, Fujimoto J M, Tseng L L. Differential mechanisms mediating beta-endorphin- and morphine-induced analgesia in mice.  Eur J of Pharmacol. 1989;  168 61-70
• 12 D'Amour F E, Smith D L. A method for determining loss of pain sensation.  J Pharmacol Exp Ther. 1941;  72 74-9
• 13 Hylden J L, Wilcox G L. Intrathecal morphine in mice: a new technique.  Eur J Pharmacol. 1980;  67 313-6
• 14 Haley T, McCormick W G. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse.  Br J Pharmacol. 1957;  12 12-5
• 15 Zambotti F, Zonta N, Parenti M, Tommasi R, Vicentini L, Conci F, Mantegazza P. Periaqueductal gray matter involvement in the muscimol-induced decrease of morphine antinociception.  Naunyn-Schmiedeberg's Arch Pharmacol. 1982;  318 368-9
• 16 Itoh S, Katsuura G, Maeda Y. Caerulein and cholecystokinin suppress beta-endorphin-induced analgesia in the rat.  Eur J Pharmacol. 1982;  80 421-5
• 17 Faris P L, Komisaruk B R, Watkins L R, Mayer D J. Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.  Science. 1983;  219 310-2
• 18 Watkins L R, Kinscheck I B, Mayer D J. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.  Science. 1984;  224 395-6
• 19 Li Y, Han J S. Cholecystokinin-octapeptide antagonizes morphine analgesia in periaqueductal gray of the rat.  Brain Res. 1989;  480 105-10
• 20 Suh H H, Collins K A, Tseng L F. Intrathecal cholecystokinin octapeptide attenuates the antinociception and release of immunoreactive Met-enkephalin induced by intraventricular beta-endorphin in the rat.  Neuropeptides. 1992;  21 131-7