Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Jul;97(3):835–842. doi: 10.1111/j.1476-5381.1989.tb12023.x

Mode of antinociceptive action of flupirtine in the rat.

I Szelenyi 1, B Nickel 1, H O Borbe 1, K Brune 1
PMCID: PMC1854566  PMID: 2569346

Abstract

1. Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail-flick test. 2. The selective destruction of noradrenergic pathways by 6-hydroxydopamine considerably reduced the flupirtine-induced inhibition of nociceptive responses but not the clonidine-induced antinociception which was significantly enhanced. Depletion of spinal 5-hydroxytryptaminergic pathways by pretreatment with 5,7-dihydroxytryptamine failed to affect the action of flupirtine and clonidine. 3. The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine-induced inhibition of nociceptive responses remained unchanged. 4. Inhibition of the synthesis of noradrenaline by alpha-methyl-L-p-tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5-hydroxytryptamine by (+/-)-6-fluorotryptophan did not influence the antinociceptive activity of flupirtine. 5. Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine-induced antinociception. 6. Selective antagonists at alpha-adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin. 7. The 5-hydroxytryptamine (5-HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional alpha 1-adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin. 8. Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine-induced antinociception also remained unchanged after pretreatment with haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
835

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Archer T., Jonsson G., Minor B. G., Post C. Noradrenergic-serotonergic interactions and nociception in the rat. Eur J Pharmacol. 1986 Jan 29;120(3):295–307. doi: 10.1016/0014-2999(86)90470-x. [DOI] [PubMed] [Google Scholar]
  2. Borbe H. O., Zierenberg O. Amitriptylinoxide: receptor-binding profile compared with other antidepressant drugs. Pharmacopsychiatry. 1985 Sep;18(5):314–319. doi: 10.1055/s-2007-1017388. [DOI] [PubMed] [Google Scholar]
  3. Bromm B., Ganzel R., Herrmann W. M., Meier W., Scharein E. The analgesic efficacy of flupirtine in comparison to pentazocine and placebo assessed by EEG and subjective pain ratings. Postgrad Med J. 1987;63 (Suppl 3):109–112. [PubMed] [Google Scholar]
  4. Carlsson K. H., Jurna I. Depression by flupirtine, a novel analgesic agent, of motor and sensory responses of the nociceptive system in the rat spinal cord. Eur J Pharmacol. 1987 Nov 3;143(1):89–99. doi: 10.1016/0014-2999(87)90738-2. [DOI] [PubMed] [Google Scholar]
  5. Engel J. Flupirtine--a new centrally acting analgesic with unique chemical structure. Postgrad Med J. 1987;63 (Suppl 3):15–17. [PubMed] [Google Scholar]
  6. Hayes A. G., Skingle M., Tyers M. B. Alpha-adrenoceptor-mediated antinociception and sedation in the rat and dog. Neuropharmacology. 1986 Apr;25(4):391–396. doi: 10.1016/0028-3908(86)90233-9. [DOI] [PubMed] [Google Scholar]
  7. Hayes A. G., Skingle M., Tyers M. B. Antagonism of alpha-adrenoceptor agonist-induced antinociception in the rat. Neuropharmacology. 1986 Apr;25(4):397–402. doi: 10.1016/0028-3908(86)90234-0. [DOI] [PubMed] [Google Scholar]
  8. Howe J. R., Yaksh T. L. Changes in sensitivity to intrathecal norepinephrine and serotonin after 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) or repeated monoamine administration. J Pharmacol Exp Ther. 1982 Feb;220(2):311–321. [PubMed] [Google Scholar]
  9. Hoyer D., Vos P., Closse A., Palacios J. M., Engel G., Davies H. [3H]ketanserin labels serotonin 5-HT2 and alpha 1-adrenergic receptors in human brain cortex. J Cardiovasc Pharmacol. 1987;10 (Suppl 3):S48–S50. [PubMed] [Google Scholar]
  10. Ikeda K., Takata M., Tomoda F., Mikawa M., Iida H., Sasayama S. Differences in vasodilating action between ketanserin, a 5-HT2-serotonergic receptor antagonist, and terazosin, an alpha 1-adrenoceptor antagonist, in anesthetized rabbits. J Cardiovasc Pharmacol. 1987;10 (Suppl 3):S69–S72. [PubMed] [Google Scholar]
  11. Juan H., Lembeck F. Action of peptides and other algesic agents on paravascular pain receptors of the isolated perfused rabbit ear. Naunyn Schmiedebergs Arch Pharmacol. 1974;283(2):151–164. doi: 10.1007/BF00501142. [DOI] [PubMed] [Google Scholar]
  12. Kobal G., Hummel T. Effects of flupirtine on the pain-related evoked potential and the spontaneous EEG. Agents Actions. 1988 Feb;23(1-2):117–119. doi: 10.1007/BF01967210. [DOI] [PubMed] [Google Scholar]
  13. Kulkarni S. K., Robert R. K. Reversal by serotonergic agents of reserpine-induced hyperalgesia in rats. Eur J Pharmacol. 1982 Sep 24;83(3-4):325–328. doi: 10.1016/0014-2999(82)90271-0. [DOI] [PubMed] [Google Scholar]
  14. McMahon F. G., Arndt W. F., Jr, Newton J. J., Montgomery P. A., Perhach J. L. Clinical experience with flupirtine in the U.S. Postgrad Med J. 1987;63 (Suppl 3):81–85. [PubMed] [Google Scholar]
  15. Molinero M. T., Del Rio J. Substance P, nicotinic acetylcholine receptors and antinociception in the rat. Neuropharmacology. 1987 Dec;26(12):1715–1720. doi: 10.1016/0028-3908(87)90122-5. [DOI] [PubMed] [Google Scholar]
  16. Nickel B., Engel J., Szelenyi I. Possible involvement of noradrenergic descending pain-modulating pathways in the mode of antinociceptive action of flupirtine, a novel non-opioid analgesic. Agents Actions. 1988 Feb;23(1-2):112–116. doi: 10.1007/BF01967209. [DOI] [PubMed] [Google Scholar]
  17. Nickel B., Herz A., Jakovlev V., Tibes U. Untersuchungen zum Wirkmechanismus des Analgetikums Flupirtin. Arzneimittelforschung. 1985;35(9):1402–1409. [PubMed] [Google Scholar]
  18. Nickel B., Zerrahn H. Pharmaco-electroencephalography in the rat as a method for characterization of different types of analgesics. Postgrad Med J. 1987;63 (Suppl 3):45–47. [PubMed] [Google Scholar]
  19. Nishimura J., Kanaide H., Shogakiuchi Y., Nakamura M. Ketanserin blocks alpha 1-adrenoceptors of porcine vascular smooth muscle cells. Eur J Pharmacol. 1987 Jan 13;133(2):235–238. doi: 10.1016/0014-2999(87)90155-5. [DOI] [PubMed] [Google Scholar]
  20. Riethmüller-Winzen H. Flupirtine in the treatment of post-operative pain. Postgrad Med J. 1987;63 (Suppl 3):61–65. [PubMed] [Google Scholar]
  21. Sinanović O., Chiba S. Different antagonistic effects of bunazosin and ketanserin on the norepinephrine-induced vasoconstriction in isolated, perfused canine and simian skeletal muscle arteries. Jpn J Pharmacol. 1988 Feb;46(2):200–203. doi: 10.1254/jjp.46.200. [DOI] [PubMed] [Google Scholar]
  22. Szelenyi I., Nickel B. Putative site(s) and mechanism(s) of action of flupirtine, a novel analgesic compound. Postgrad Med J. 1987;63 (Suppl 3):57–60. [PubMed] [Google Scholar]
  23. U'Prichard D. C., Bechtel W. D., Rouot B. M., Snyder S. H. Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol Pharmacol. 1979 Jul;16(1):47–60. [PubMed] [Google Scholar]
  24. Watanabe Y., Lai R. T., Maeda H., Yoshida H. Reserpine and sympathetic denervation cause an increase of postsynaptic alpha 2-adrenoceptors. Eur J Pharmacol. 1982 May 7;80(1):105–108. doi: 10.1016/0014-2999(82)90183-2. [DOI] [PubMed] [Google Scholar]
  25. Zemlan F. P., Corrigan S. A., Pfaff D. W. Noradrenergic and serotonergic mediation of spinal analgesia mechanisms. Eur J Pharmacol. 1980 Jan 25;61(2):111–124. doi: 10.1016/0014-2999(80)90154-5. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES