Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1978 Sep;64(1):75–82. doi: 10.1111/j.1476-5381.1978.tb08643.x

Effects of narcotic analgesics on the uptake and release of 5-hydroxytryptamine in rat synaptosomal preparations

Tiziana Mennini, R Pataccini, R Samanin
PMCID: PMC1668261  PMID: 29686

Abstract

1 The effects of various narcotic analgesics on the uptake and release of labelled 5-hydroxytryptamine (5-HT) in brain and spinal cord synaptosomes were investigated.

2 Methadone was most active in inhibiting 5-HT uptake (IC50 2.5 × 10-7 M). Levorphanol also inhibited 5-HT uptake to a large extent (IC50 8.8 × 10-7 M) while dextrophan, pethidine and pentazocine showed much less activity. Etorphine and morphine had virtually no such activity, with IC50S higher than 10-4 and 10-3 M respectively.

3 The same order of potency as `5-HT releasers' was found when radioactivity was measured in [3H]-5-HT preloaded synaptosomal pellets incubated for 20 min with the various narcotics. Methadone, like chlorimipramine, showed a significant effect at a concentration of 10-7 M while morphine, at a concentration of 10-4 M, had no effect.

4 When 5-HT release was studied by a perfusion technique, which largely prevents reuptake of the released amine, only fenfluramine, an anorectic agent proposed as a 5-HT releaser, significantly increased spontaneous 5-HT release. These data suggest that the apparent 5-HT release induced by various narcotics in traditional incubation techniques may largely depend on their ability to interfere with neurotransmitter reuptake mechanisms.

5 The effects of the various narcotics on 5-HT uptake have no relationship to their relative potency as analgesics in the rat. In the light of their poor effectiveness as 5-HT releasers, it can be concluded that mechanisms other than 5-HT uptake inhibition and release are probably involved in the analgesic effects of these compounds in intact animals.

Full text

PDF
75

Selected References

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

  1. Belin M. F., Kouyoumdjian J. C., Bardakdjian J., Gonnard P. Effets de la 5-6 dihydroxytryptamine sur les mecanismes de transport de divers neurotransmetteurs ou de leurs precurseurs au niveau des synaptosomes du mesencephale de rat. Biochem Pharmacol. 1975 Nov 15;24(22):2117–2120. doi: 10.1016/0006-2952(75)90115-x. [DOI] [PubMed] [Google Scholar]
  2. Blane G. F., Boura A. L., Fitzgerald A. E., Lister R. E. Actions of etorphine hydrochloride, (M99): a potent morphine-like agent. Br J Pharmacol Chemother. 1967 May;30(1):11–22. doi: 10.1111/j.1476-5381.1967.tb02108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bowers M. B., Jr, Kleber H. D. Methadone increases mouse brain 5-hydroxyindoleacetic acid. Nature. 1971 Jan 8;229(5280):134–135. doi: 10.1038/229134a0. [DOI] [PubMed] [Google Scholar]
  4. Buxbaum D. M., Yarbrough G. G., Carter M. E. Biogenic amines and narcotic effects. I. Modification of morphine-induced analgesia and motor activity after alteration of cerebral amine levels. J Pharmacol Exp Ther. 1973 May;185(2):317–327. [PubMed] [Google Scholar]
  5. Cahill A. L., Medzihradsky F. Interaction of central nervous system drugs with synaptosomal transport processes. Biochem Pharmacol. 1976 Oct 15;25(20):2257–2264. doi: 10.1016/0006-2952(76)90007-1. [DOI] [PubMed] [Google Scholar]
  6. Carlsson A., Corrodi H., Fuxe K., Hökfelt T. Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethyl-meta-tyramine. Eur J Pharmacol. 1969 Mar;5(4):357–366. doi: 10.1016/0014-2999(69)90113-7. [DOI] [PubMed] [Google Scholar]
  7. Carlsson A., Jonason J., Lindqvist M. On the mechanism of 5-hydroxytryptamine release by thymoleptics. J Pharm Pharmacol. 1969 Nov;21(11):769–773. doi: 10.1111/j.2042-7158.1969.tb08167.x. [DOI] [PubMed] [Google Scholar]
  8. Carlsson A., Lindqvist M. Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines. J Pharm Pharmacol. 1969 Jul;21(7):460–464. doi: 10.1111/j.2042-7158.1969.tb08287.x. [DOI] [PubMed] [Google Scholar]
  9. Ciofalo F. R. Methadone inhibition of 3H-5-hydroxytryptamine uptake by synaptosomes. J Pharmacol Exp Ther. 1974 Apr;189(1):83–89. [PubMed] [Google Scholar]
  10. Flórez J., Delgado G., Armijo J. A. Adrenergic and serotonergic mechanisms in morphine-induced respiratory depression. Psychopharmacologia. 1972;24(2):258–274. doi: 10.1007/BF00403646. [DOI] [PubMed] [Google Scholar]
  11. GRAY E. G., WHITTAKER V. P. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat. 1962 Jan;96:79–88. [PMC free article] [PubMed] [Google Scholar]
  12. Garattini S., Buczko W., Jori A., Samanin R. The mechanism of action of fenfluramine. Postgrad Med J. 1975;51 (Suppl 1):27–35. [PubMed] [Google Scholar]
  13. Garau L., Mulas M. L., Pepeu G. The influence of raphe lesions on the effect of morphine on nociception and cortical ACh output. Neuropharmacology. 1975 Apr;14(4):259–263. doi: 10.1016/0028-3908(75)90071-4. [DOI] [PubMed] [Google Scholar]
  14. Genovese E., Zonta N., Mantegazza P. Decreased antinociceptive activity of morphine in rats pretreated intraventricularly with 5,6-dihydroxytryptamine, a long-lasting selective depletor of brain serotonin. Psychopharmacologia. 1973 Oct 15;32(4):359–364. doi: 10.1007/BF00429472. [DOI] [PubMed] [Google Scholar]
  15. Goldstein A., Sheehan P. Tolerance to opioid narcotics. I. Tolerance to the "running fit" caused by levorphanol in the mouse. J Pharmacol Exp Ther. 1969 Oct;169(2):175–184. [PubMed] [Google Scholar]
  16. Goodlet I., Sugrue M. F. Effect of acutely administered analgesic drugs on rat brain serotonin turnover. Eur J Pharmacol. 1974 Dec;29(2):241–248. doi: 10.1016/0014-2999(74)90022-3. [DOI] [PubMed] [Google Scholar]
  17. Görlitz B. D., Frey H. H. Central monoamines and antinociceptive drug action. Eur J Pharmacol. 1972 Nov;20(2):171–180. doi: 10.1016/0014-2999(72)90146-x. [DOI] [PubMed] [Google Scholar]
  18. Haubrich D. R., Blake D. E. Modification of serotonin metabolism in rat brain after acute or chronic administration of morphine. Biochem Pharmacol. 1973 Nov 1;22(21):2753–2759. doi: 10.1016/0006-2952(73)90135-4. [DOI] [PubMed] [Google Scholar]
  19. JOHNSON M. K. The intracellular distribution of glycolytic and other enzymes in rat-brain homogenates and mitochondrial preparations. Biochem J. 1960 Dec;77:610–618. doi: 10.1042/bj0770610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Johnson K. M., Ho B. T., Dewey W. L. Effects of delta9-tetrahydrocannabinol on neurotransmitter accumulation and release mechanisms in rat forebrain synaptosomes. Life Sci. 1976 Aug 1;19(3):347–356. doi: 10.1016/0024-3205(76)90038-2. [DOI] [PubMed] [Google Scholar]
  21. Kamat U. G., Sheth U. K. The role of central monoamines in decapitation convulsions of mice. Neuropharmacology. 1971 Sep;10(5):571–579. doi: 10.1016/0028-3908(71)90023-2. [DOI] [PubMed] [Google Scholar]
  22. Keller K. J., Elliott G. R., Holman R. B., Vernikos-Danellis J., Barchas J. D. Tryptoline inhibition of serotonin uptake in rat forebrain homogenates. J Pharmacol Exp Ther. 1976 Sep;198(3):619–625. [PubMed] [Google Scholar]
  23. Knapp S., Mandell A. J. Parachlorophenylalanine--its three phase sequence of interactions with the two forms of brain tryptophan hydroxylase. Life Sci I. 1972 Aug 15;11(16):761–771. doi: 10.1016/0024-3205(72)90210-x. [DOI] [PubMed] [Google Scholar]
  24. Krajl M. A rapid microfluorimetric determination of monoamine oxidase. Biochem Pharmacol. 1965 Nov;14(11):1684–1686. doi: 10.1016/0006-2952(65)90025-0. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Lorens S. A., Yunger L. M. Morphine analgesia, two-way avoidance, and consummatory behavior following lesions in the midbrain raphe nuclei of the rat. Pharmacol Biochem Behav. 1974 Mar-Apr;2(2):215–221. doi: 10.1016/0091-3057(74)90055-0. [DOI] [PubMed] [Google Scholar]
  27. Major C. T., Pleuvry B. J. Effects of alpha-methyl-p-tyrosine, p-chlorophenylalanine, l-beta-(3,4-dihydroxyphenyl)alanine, 5-hydroxytryptophan and diethyldithiocarbamate on the analgesic activity of morphine and methylamphetamine in the mouse. Br J Pharmacol. 1971 Aug;42(4):512–521. doi: 10.1111/j.1476-5381.1971.tb07137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Moffat J. A., Jhamandas K. Effects of acute and chronic methadone treatment of the uptake of 3H-5-hydroxytryptamine in rat hypothalamus slices. Eur J Pharmacol. 1976 Apr;36(2):289–297. doi: 10.1016/0014-2999(76)90082-0. [DOI] [PubMed] [Google Scholar]
  29. Papeschi R., Theiss P., Herz A. Effects of morphine on the turnover of brain catecholamines and serotonin in rats-acute morphine administration. Eur J Pharmacol. 1975 Dec;34(2):253–261. doi: 10.1016/0014-2999(75)90250-2. [DOI] [PubMed] [Google Scholar]
  30. Proudfit H. K., Anderson E. G. Morphine analgesia: blockade by raphe magnus lesions. Brain Res. 1975 Nov 21;98(3):612–618. doi: 10.1016/0006-8993(75)90380-7. [DOI] [PubMed] [Google Scholar]
  31. Pérez-Cruet J., Thoa N. B., Ng L. K. Acute effects of heroin and morphine on newly synthesized serotonin in rat brain. Life Sci. 1975 Aug 1;17(3):349–362. doi: 10.1016/0024-3205(75)90484-1. [DOI] [PubMed] [Google Scholar]
  32. Raiteri M., Angelini F., Levi G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur J Pharmacol. 1974 Mar;25(3):411–414. doi: 10.1016/0014-2999(74)90272-6. [DOI] [PubMed] [Google Scholar]
  33. Reinhold K., Bläsig J., Herz A. Changes in brain concentration of biogenic amines and the antinociceptive effect of morphine in rats. Naunyn Schmiedebergs Arch Pharmacol. 1973;278(1):69–80. doi: 10.1007/BF00501864. [DOI] [PubMed] [Google Scholar]
  34. Samanin R., Gumulka W., Valzelli L. Reduced effect of morphine in midbrain raphe lesioned rats. Eur J Pharmacol. 1970;10(3):339–343. doi: 10.1016/0014-2999(70)90205-0. [DOI] [PubMed] [Google Scholar]
  35. Samanin R., Valzelli L. Increase of morphine-induced analgesia by stimulation of the nucleus raphe dorsalis. Eur J Pharmacol. 1971 Nov-Dec;16(3):298–302. doi: 10.1016/0014-2999(71)90030-6. [DOI] [PubMed] [Google Scholar]
  36. Sawa A., Oka T. Effects of narcotic analgesics on serotonin metabolism in brain of rats and mice. Jpn J Pharmacol. 1976 Oct;26(5):599–605. doi: 10.1254/jjp.26.599. [DOI] [PubMed] [Google Scholar]
  37. Sewell R. D., Spencer P. S. Anti-nociceptive activity of narcotic agonists and partial agonists in mice given biogenic amines by intracerebroventricular injection. Psychopharmacologia. 1975 Apr 30;42(1):67–71. doi: 10.1007/BF00428828. [DOI] [PubMed] [Google Scholar]
  38. Tenen S. S. Antagonism of the analgesic effect of morphine and other drugs by p-chlorophenylalanine, a serotonin depletor. Psychopharmacologia. 1968;12(4):278–285. doi: 10.1007/BF00401407. [DOI] [PubMed] [Google Scholar]
  39. Vogt M. The effect of lowering the 5-hydroxytryptamine content of the rat spinal cord on analgesia produced by morphine. J Physiol. 1974 Jan;236(2):483–498. doi: 10.1113/jphysiol.1974.sp010448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Warwick R. O., Schnell R. C. Studies relating morphine hypothermia with serotonin reuptake in the rat hypothalamus. Eur J Pharmacol. 1976 Aug;38(2):329–335. doi: 10.1016/0014-2999(76)90336-8. [DOI] [PubMed] [Google Scholar]
  41. Yarbrough G. G., Buxbaum D. M., Sanders-Bush E. Biogenic amines and narcotic effects. II. Serotonin turnover in the rat after acute and chronic morphine administration. J Pharmacol Exp Ther. 1973 May;185(2):328–335. [PubMed] [Google Scholar]

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

RESOURCES