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Naloxone antagonizes theophylline-induced potentiation of morphine inhibition of a nociceptive reaction in rats

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In the rat, theophylline has been shown to potentiate the effect of morphine on the threshold for vocalisation after withdrawal of stimulation. This response to painful stimulation is considered to be integrated at the level of the thalamus-hypothalamus-rhinencephalon. Naloxone antagonized the effect of the combined treatment with morphine and theophylline, suggesting pharmacological specificity for morphine. Moreover, the theophylline-induced enhancement of this pharmacological response to morphine was attenuated after pimozide pretreatment, indicating an underlying dopaminergic mechanism.

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  1. Akil, H., Liebeskind, J. C.: Monoaminergic mechanisms of stimulation-produced analgesia. Brain Res. 94, 279–296 (1975)

  2. Andén, N.-E., Rubenson, A., Fuxe, K., Hökfelt, T.: Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol. 19, 627–629 (1967)

  3. Andén, N.-E., Butcher, S. G., Corrodi, H., Fuxe, K., Ungerstedt, U.: Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol. 11, 303–314 (1970)

  4. Andén, N.-E., Jackson, D. M.: Locomotor activity stimulation in rats produced by dopamine in the nucleus accumbens: potentiation by caffeine. J. Pharm. Pharmacol. 27, 666–670 (1975)

  5. Bergmann, F., Chaimovitz, M., Pasternak, V., Ramu, A.: Compulsive gnawing in rats after implantation of drugs into the ventral thalamus. A contribution to the mechanism of morphine action. Br. J. Pharmacol. 51, 197–205 (1974)

  6. Carrol, M. N., Lim, R. K. S.: Observations on the neuropharmacology of morphine and morphine-like analgesia. Arch. Int. Pharmacodyn. Ther. 125, 383–403 (1960)

  7. Charpentier, J.: Analysis and measurement of pain in animals. A new conception of pain. In: Pain, A. Soulairac, J. Cahn, and J. Charpentier, eds., pp. 171–200. London, New York: Academic Press 1968

  8. Dunai-Kovács, Z., Székely, J. I.: Effect of apomorphine on the antinociceptive activity of morphine. Psychopharmacology 53, 65–72 (1977)

  9. Fuxe, K., Ungerstedt, U.: Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with dopa and dopamine receptor agonists. Med. Biol. 52, 48–54 (1974)

  10. Glick, S. D., Morihisa, J. M.: Changes in sensitivity of morphine-induced circling behaviour after chronic treatment and persistence after withdrawal in rats. Nature 260, 159–161 (1976)

  11. Hoffmeister, F.: On the possible relations between post-ganglionic adrenergic and cholinergic neurone blockade demonstrable in the peripheral autonomous nervous system and central analgesia. In: Pain, A. Soulairac, J. Cahn, and J. Charpentier, eds., pp. 281–296. London, New York: Academic Press 1968

  12. Horn, A. S., Cuello, A. C., Miller, R. J.: Dopamine in the mesolimbic system of the rat brain: endogenous levels and the effects of drugs on the uptake mechanism and stimulation of adenylate cyclase activity. J. Neurochem. 22, 265–270 (1974)

  13. Iwatsubo, K., Clouet, D. H.: Dopamine-sensitive adenylate cyclase of the caudate nucleus of rats treated with morphine of haloperidol. Biochem. Pharmacol. 24, 1499–1503 (1975)

  14. Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the “dopamine receptor.” Proc. Natl. Acad. Sci. U.S.A. 69, 2145–2149 (1972)

  15. Klawans, H. L., Moses, H., Beaulieu, D. M.: The influence of caffeine on d-amphetamine and apomorphine induced stereotyped behavior. Life Sci. 14, 1493–1500 (1974)

  16. Klee, W. A., Lampert, A., Nirenberg, M.: Dual regulation of adenylate cyclase by endogenous opiate peptides. In: Opiates and endogenous opioid peptides, H. W. Kosterlitz, ed., pp. 153–159. Amsterdam, New York, Oxford: North Holland 1976

  17. Kuschinsky, K., Hornykiewicz, O.: Morphine catalepsy in the rat: relation to striatal dopamine metabolism. Eur. J. Pharmacol. 19, 119–122 (1972)

  18. Lal, H.: Minireview: narcotic dependence, narcotic action and dopamine receptors. Life Sci. 17, 483–496 (1975)

  19. Lee, C. M., Wong, P. C. L., Chan, S. H. H.: The involvement of dopaminergic neurotransmission in the inhibitory effect of morphine on caudate neurone activities. Neuropharmacology 16, 571–576 (1977)

  20. Myers, P. R., Livengood, D. R., Shain, W.: Effect of morphine on a depolarising dopamine response. Nature 257, 238–239 (1975)

  21. Nakamura, K., Kuntzman, R., Maggio, A., Conney, A. H.: Decrease in morphine's analgesic action and increase in its cataleptic action by 6-hydroxydopamine injected bilaterally into caudate and putamen areas; partial restoration by L-dopa plus decarboxylase inhibition. Neuropharmacology 12, 1153–1160 (1973)

  22. Paalzow, G., Paalzow, L.: The effects of caffeine and theophylline on nociceptive stimulation in the rat. Acta Pharmacol. Toxicol. (Kbh.) 32, 22–32 (1973)

  23. Paalzow, G., Paalzow, L.: Theophylline increased sensitivity to nociceptive stimulation and regional turnover of rat brain 5-HT, noradrenaline and dopamine. Acta Pharmacol. Toxicol. (Kbh.) 34, 157–173 (1974)

  24. Paalzow, G., Paalzow, L.: Morphine induced inhibition of different pain responses in relation to the regional turnover of rat brain noradrenaline and dopamine. Psychopharmacologia (Berl.) 45, 9–20 (1975a)

  25. Paalzow, G., Paalzow, L.: Enhancement of apomorphine-induced inhibition of vocalisation afterdischarge response by theophylline. Life Sci. 17, 1145–1152 (1975b)

  26. Paalzow, G.: The potential role of catecholamines in drug induced changes of central pain responses, with special emphasis on morphine effects in the rat. Ph. D. Dissertation. Acta Universitatis Upsaliensis 9 (1976)

  27. Paalzow, G., Paalzow, L.: Involvement of both pre- and postsynaptic catecholaminergic receptors in the mediation of analgesic activity-possibel implications for morphine. In: Opiates and endogenous opioid peptides, H. W. Kosterlitz, ed., pp. 427–430. Amsterdam, New York, Oxford: North Holland 1976

  28. Price, M. T. C., Fibiger, H. C.: Ascending catecholamine systems and morphine analgesia. Brain Res. 99, 189–193 (1975)

  29. Puri, S. K., Cochin, J., Volicer, L.: Effect of morphine sulfate on adenylate cyclase and phosphodiesterase activities in rat corpus striatum. Life Sci. 16, 759–768 (1975)

  30. Schechter, M. D.: Caffeine potentiation of amphetamine: implications for hyperkinesis therapy. Pharmacol. Biochem. Behav. 6, 359–361 (1977)

  31. Scheel-Krüger, J., Golembiowska, K., Mogilnicka, E.: Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with mophine. Psychopharmacology 53, 55–63 (1977)

  32. Sokal, R. R., Rohlf, F. J.: Biometry. San Francisco: Freeman 1969

  33. Strömberg, U., Waldeck, B.: Further studies on the behavioural and biochemical interaction between caffeine and L-dopa. J. Neural Transmission 34, 241–252 (1973)

  34. Waldeck, B.: Effect of caffeine on locomotor activity and central catecholamine mechanisms: a study with special reference to drug interaction. Acta Pharmacol. Toxicol. (Kbh.) 36, 1–23 (1975)

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Paalzow, G. Naloxone antagonizes theophylline-induced potentiation of morphine inhibition of a nociceptive reaction in rats. Psychopharmacology 62, 235–239 (1979). https://doi.org/10.1007/BF00431953

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Key words

  • Theophylline
  • Morphine
  • Drug interactions
  • Dopamine
  • Cyclic AMP
  • Analgesia