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. 1992 Jan;105(1):147–151. doi: 10.1111/j.1476-5381.1992.tb14226.x

Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.

B Driessen 1, W Reimann 1
PMCID: PMC1908625  PMID: 1596676

Abstract

1. Tramadol is a centrally acting analgesic with low opioid receptor affinity and therefore presumably other mechanisms of analgesic action. Tramadol inhibits noradrenaline uptake but since 5-hydroxytryptamine (5-HT) is also involved in the modulation of pain perception, we tested the effects of tramadol on 5-HT uptake and release in vitro. 2. Tramadol inhibited the uptake of [3H]-5-HT into purified rat frontal cortex synaptosomes with an IC50 of 3.1 microM. The (+)-enantiomer was about four times more potent than the (-)-enantiomer; the main metabolite of tramadol, O-desmethyltramadol, was about ten times less potent. 3. Rat frontal cortex slices were preincubated with [3H]-5-HT, then superfused and stimulated electrically. Tramadol facilitated the basal outflow of [3H]-5-HT, at concentrations greater than 1 microM, while the uptake inhibitor 5-nitroquipazine enhanced both basal and stimulation-evoked overflow. Effects of the (+)-enantiomer were more potent than either the racemate, the (-)-enantiomer or the principal metabolite. 4. The effects of tramadol on the basal outflow of [3H]-5-HT were almost completely abolished when the superfusion medium contained a high concentration of the selective 5-HT uptake blocker, 6-nitroquipazine. 5. The results provide evidence for an interaction of tramadol with the neuronal 5-HT transporter. An intact uptake system is necessary for the enhancement of extraneuronal 5-HT concentrations by tramadol indicating an intraneuronal site of action.

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Selected References

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  1. Bauman P. A., Maitre L. Is drug inhibition of dopamine uptake a misinterpretation of in vitro experiments? Nature. 1976 Dec 23;264(5588):789–790. doi: 10.1038/264789a0. [DOI] [PubMed] [Google Scholar]
  2. Baumann P. A., Waldmeier P. C. Further evidence for negative feedback control of serotonin release in the central nervous system. Naunyn Schmiedebergs Arch Pharmacol. 1981 Aug;317(1):36–43. doi: 10.1007/BF00506254. [DOI] [PubMed] [Google Scholar]
  3. Besson J. M., Chaouch A. Descending serotoninergic systems. Pain Headache. 1987;9:64–100. [PubMed] [Google Scholar]
  4. Cerrito F., Raiteri M. Serotonin release is modulated by presynaptic autoreceptors. Eur J Pharmacol. 1979 Aug 15;57(4):427–430. doi: 10.1016/0014-2999(79)90506-5. [DOI] [PubMed] [Google Scholar]
  5. Dodd P. R., Hardy J. A., Oakley A. E., Edwardson J. A., Perry E. K., Delaunoy J. P. A rapid method for preparing synaptosomes: comparison, with alternative procedures. Brain Res. 1981 Dec 7;226(1-2):107–118. doi: 10.1016/0006-8993(81)91086-6. [DOI] [PubMed] [Google Scholar]
  6. Friderichs E., Felgenhauer F., Jongschaap P., Osterloh G. Pharmakologische Untersuchungen zur Analgesie, Abhängigkeits- und Toleranzentwicklung von Tramadol, einem stark wirkenden Analgetikum. Arzneimittelforschung. 1978;28(1A):122–134. [PubMed] [Google Scholar]
  7. Galzin A. M., Moret C., Verzier B., Langer S. Z. Interaction between tricyclic and nontricyclic 5-hydroxytryptamine uptake inhibitors and the presynaptic 5-hydroxytryptamine inhibitory autoreceptors in the rat hypothalamus. J Pharmacol Exp Ther. 1985 Oct;235(1):200–211. [PubMed] [Google Scholar]
  8. Glowinski J., Iversen L. L. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem. 1966 Aug;13(8):655–669. doi: 10.1111/j.1471-4159.1966.tb09873.x. [DOI] [PubMed] [Google Scholar]
  9. Göthert M., Schlicker E., Köstermann F. Relationship between transmitter uptake inhibition and effects of alpha-adrenoceptor agonists on serotonin and noradrenaline release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1983 Mar;322(2):121–128. doi: 10.1007/BF00512384. [DOI] [PubMed] [Google Scholar]
  10. Göthert M. Serotonin-receptor-mediated modulation of Ca2+-dependent 5-hydroxytryptamine release from neurones of the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1980 Nov;314(3):223–230. doi: 10.1007/BF00498543. [DOI] [PubMed] [Google Scholar]
  11. Göthert M., Weinheimer G. Extracellular 5-hydroxytryptamine inhibits 5-hydroxytryptamine release from rat brain cortex slices. Naunyn Schmiedebergs Arch Pharmacol. 1979 Dec;310(1):93–96. doi: 10.1007/BF00499879. [DOI] [PubMed] [Google Scholar]
  12. Hashimoto K., Goromaru T. High-affinity [3H]6-nitroquipazine binding sites in rat brain. Eur J Pharmacol. 1990 May 16;180(2-3):273–281. doi: 10.1016/0014-2999(90)90310-3. [DOI] [PubMed] [Google Scholar]
  13. Hennies H. H., Friderichs E., Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung. 1988 Jul;38(7):877–880. [PubMed] [Google Scholar]
  14. Hennies H. H., Friderichs E., Wilsmann K., Floh e L. Effect of the opioid analgesic tramadol on inactivation of norepinephrine and serotonin. Biochem Pharmacol. 1982 Apr 15;31(8):1654–1655. doi: 10.1016/0006-2952(82)90398-7. [DOI] [PubMed] [Google Scholar]
  15. Iversen L. L. Uptake mechanisms for neurotransmitter amines. Biochem Pharmacol. 1974 Jul 15;23(14):1927–1935. doi: 10.1016/0006-2952(74)90250-0. [DOI] [PubMed] [Google Scholar]
  16. Kellstein D. E., Malseed R. T., Ossipov M. H., Goldstein F. J. Effect of chronic treatment with tricyclic antidepressants upon antinociception induced by intrathecal injection of morphine and monoamines. Neuropharmacology. 1988 Jan;27(1):1–14. doi: 10.1016/0028-3908(88)90194-3. [DOI] [PubMed] [Google Scholar]
  17. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  18. Reimann W., Steinhauer H. B., Hedler L., Starke K., Hertting G. Effect of prostaglandins D2, E2 and F2alpha on catecholamine release from slices of rat and rabbit brain. Eur J Pharmacol. 1981 Feb 19;69(4):421–427. doi: 10.1016/0014-2999(81)90445-3. [DOI] [PubMed] [Google Scholar]
  19. Richelson E., Pfenning M. Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol. 1984 Sep 17;104(3-4):277–286. doi: 10.1016/0014-2999(84)90403-5. [DOI] [PubMed] [Google Scholar]
  20. Roberts M. H. 5-Hydroxytryptamine and antinociception. Neuropharmacology. 1984 Dec;23(12B):1529–1536. doi: 10.1016/0028-3908(84)90097-2. [DOI] [PubMed] [Google Scholar]
  21. Ross S. B., Ogren S. O., Renyi A. L. (Z)-dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl) propene (h 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake. Acta Pharmacol Toxicol (Copenh) 1976 Aug;39(2):152–166. doi: 10.1111/j.1600-0773.1976.tb03166.x. [DOI] [PubMed] [Google Scholar]
  22. Ross S. B., Renyi A. L. Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)- and (E)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl) allylamines and their secondary analogues. Neuropharmacology. 1977 Jan;16(1):57–63. doi: 10.1016/0028-3908(77)90048-x. [DOI] [PubMed] [Google Scholar]
  23. Schmauss C., Hammond D. L., Ochi J. W., Yaksh T. L. Pharmacological antagonism of the antinociceptive effects of serotonin in the rat spinal cord. Eur J Pharmacol. 1983 Jun 17;90(4):349–357. doi: 10.1016/0014-2999(83)90556-3. [DOI] [PubMed] [Google Scholar]
  24. Smith D. F. The stereoselectivity of serotonin uptake in brain tissue and blood platelets: the topography of the serotonin uptake area. Neurosci Biobehav Rev. 1986 Spring;10(1):37–46. doi: 10.1016/0149-7634(86)90031-x. [DOI] [PubMed] [Google Scholar]
  25. Solomon R. E., Gebhart G. F. Mechanisms of effects of intrathecal serotonin on nociception and blood pressure in rats. J Pharmacol Exp Ther. 1988 Jun;245(3):905–912. [PubMed] [Google Scholar]
  26. Vaatstra W. J., Deiman-Van Aalst W. M., Eigeman L. Du 24565, a quipazine derivative, a potent selective serotonin uptake inhibitor. Eur J Pharmacol. 1981 Mar 12;70(2):195–202. doi: 10.1016/0014-2999(81)90214-4. [DOI] [PubMed] [Google Scholar]
  27. Yaksh T. L. CNS mechanisms of pain and analgesia. Cancer Surv. 1988;7(1):5–28. [PubMed] [Google Scholar]
  28. Yaksh T. L., Wilson P. R. Spinal serotonin terminal system mediates antinociception. J Pharmacol Exp Ther. 1979 Mar;208(3):446–453. [PubMed] [Google Scholar]

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