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. 1994 Dec;113(4):1487–1493. doi: 10.1111/j.1476-5381.1994.tb17164.x

Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity.

N M Rupniak 1, S Patel 1, R Marwood 1, J Webb 1, J R Traynor 1, J Elliott 1, S B Freedman 1, S R Fletcher 1, R G Hill 1
PMCID: PMC1510487  PMID: 7889306

Abstract

1. Epibatidine is an analgesic substance, isolated from the skin of the poisonous frog Epipedobates tricolor, for which the mechanism of action was previously unknown. 2. The IC50 of synthetic (+)-epibatidine oxalate (the naturally occurring isomer) for [3H]-nicotine binding to rat whole-brain membranes was 0.1 nM. The (-)-isomer also exhibited high affinity (IC50 = 0.2 nM). 3. (+)- and (-)-Epibatidine exhibited much lower affinity for displacement of the muscarinic ligand [3H]-N-methylscopolamine binding to rat cortical membranes (Kapp = 6.9 microM and 16.0 microM respectively). The (+)-enantiomer of epibatidine had an antagonist/agonist (NMS/oxo-M) binding ratio of 4.2 This is consistent with a muscarinic antagonist profile. 4. (+)-Epibatidine oxalate (10 microM) did not cause significant (> 30%) displacement of radioligand binding to opioid, excitatory amino acid, benzodiazepine, 5-HT, dopamine, adrenaline or peptide receptors. 5. (+)- and (-)-Epibatidine (5-20 micrograms kg-1 s.c.) doubled response latency in the mouse hot-plate test. Antinociception and behavioural depression induced by (+)-epibatidine (5 micrograms kg-1) was fully blocked by the nicotinic antagonists mecamylamine (2 mg kg-1 s.c.) or dihydro-beta-erythroidine (2 mg kg-1 s.c.). The muscarinic antagonist scopolamine (0.4 and 10 mg kg-1 s.c.) caused partial reversal of antinociception induced by (+)-epibatidine in mice, but not in rats. 6. These findings demonstrate that (+)-epibatidine oxalate salt is a highly selective and potent nicotinic analgesic agent.

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Selected References

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  1. Badio B., Daly J. W. Epibatidine, a potent analgetic and nicotinic agonist. Mol Pharmacol. 1994 Apr;45(4):563–569. [PubMed] [Google Scholar]
  2. Brodie M. S., Proudfit H. K. Hypoalgesia induced by the local injection of carbachol into the nucleus raphe magnus. Brain Res. 1984 Jan 23;291(2):337–342. doi: 10.1016/0006-8993(84)91266-6. [DOI] [PubMed] [Google Scholar]
  3. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  4. Daly J. W., Brown G. B., Mensah-Dwumah M., Myers C. W. Classification of skin alkaloids from neotropical poison-dart frogs (Dendrobatidae). Toxicon. 1978;16(2):163–188. doi: 10.1016/0041-0101(78)90036-3. [DOI] [PubMed] [Google Scholar]
  5. Damaj M. I., Welch S. P., Martin B. R. Involvement of calcium and L-type channels in nicotine-induced antinociception. J Pharmacol Exp Ther. 1993 Sep;266(3):1330–1338. [PubMed] [Google Scholar]
  6. EDDY N. B., LEIMBACH D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 1953 Mar;107(3):385–393. [PubMed] [Google Scholar]
  7. Freedman S. B., Dawson G. R., Iversen L. L., Baker R., Hargreaves R. J. The design of novel muscarinic partial agonists that have functional selectivity in pharmacological preparations in vitro and reduced side-effect profile in vivo. Life Sci. 1993;52(5-6):489–495. doi: 10.1016/0024-3205(93)90306-n. [DOI] [PubMed] [Google Scholar]
  8. Freedman S. B., Harley E. A., Iversen L. L. Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo-M ratio as an index of efficacy at cortical muscarinic receptors. Br J Pharmacol. 1988 Feb;93(2):437–445. doi: 10.1111/j.1476-5381.1988.tb11451.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jarvik M. E. Beneficial effects of nicotine. Br J Addict. 1991 May;86(5):571–575. doi: 10.1111/j.1360-0443.1991.tb01810.x. [DOI] [PubMed] [Google Scholar]
  10. Miranda H. F., Bustamante D., Kramer V., Pelissier T., Saavedra H., Paeile C., Fernandez E., Pinardi G. Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol. 1992 Jul 7;217(2-3):137–141. doi: 10.1016/0014-2999(92)90833-p. [DOI] [PubMed] [Google Scholar]
  11. Qian C., Li T., Shen T. Y., Libertine-Garahan L., Eckman J., Biftu T., Ip S. Epibatidine is a nicotinic analgesic. Eur J Pharmacol. 1993 Dec 21;250(3):R13–R14. doi: 10.1016/0014-2999(93)90043-h. [DOI] [PubMed] [Google Scholar]
  12. Romano C., Goldstein A. Stereospecific nicotine receptors on rat brain membranes. Science. 1980 Nov 7;210(4470):647–650. doi: 10.1126/science.7433991. [DOI] [PubMed] [Google Scholar]
  13. Traynor J. R., Hunter J. C., Rodriguez R. E., Hill R. G., Hughes J. Delta-opioid receptor binding sites in rodent spinal cord. Br J Pharmacol. 1990 Jun;100(2):319–323. doi: 10.1111/j.1476-5381.1990.tb15802.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Tripathi H. L., Martin B. R., Aceto M. D. Nicotine-induced antinociception in rats and mice: correlation with nicotine brain levels. J Pharmacol Exp Ther. 1982 Apr;221(1):91–96. [PubMed] [Google Scholar]
  15. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983 Jun;16(2):109–110. doi: 10.1016/0304-3959(83)90201-4. [DOI] [PubMed] [Google Scholar]

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