Abstract
The influence of morphine on different pain reactions integrated at different levels of the central nervous system was studied in rats together with the determination of the turnover rate of noradrenaline and dopamine in discrete areas of the brain.
Morphine was found to increase the thresholds for vocalisation and vocalisation afterdischarge leaving the threshold for motor response unaffected. The effect of morphine on the threshold for vocalisation was found to be antagonized by naloxone and yohimbine and increased by α-methyl-p-tyrosine, FLA 63, phenoxybenzamine, chlorpromazine and pimozide. The effects on the threshold for vocalisation afterdischarge were antagonized by naloxone, and reduced by α-methyl-p-tyrosine, pimozide and chlorpromazine and were enhanced by phenoxybenzamine and yohimbine. Atropine did not change the morphine effect on either threshold. Morphine (5 mg/kg s.c.) was found to increase the turnover rate of dopamine in the telencephalic cortex and the diencephalons-mesencephalon-striatum and that of noradrenaline in the medulla oblongata-pons region. Both increases were antagonized by naloxone.
The ability of morphine to increase the threshold for vocalisation afterdischarge (proposed to reflect the emotional component of pain reactions) is suggested to be closely related to the increased turnover of dopamine in limbic structures of the brain, most probably by an increased release of this transmitter. The effect of morphine on the threshold for vocalisation remains to be evaluated but a decreased activity of noradrenaline and dopamine neurotransmission was found to increase the morphine effect on this threshold.
Similar content being viewed by others
References
Andén, N.-E., Butcher, S. G., Corrdoi, H., Fuxe, K., Ungerstedt, U.: Recptor activity and turnover of dopamine and noradrenaline after neuroleptics. Europ. J. Pharmacol. 11, 303–314 (1970)
Andén, N.-E., Corrodi, H., Dahlström, A., Fuxe, K., Hökfelt, T.: Effects of tyrosine hydroxylase inhibition on the amine levels of central monoamine neurons. Life Sci. 5, 561–568 (1966)
Andén, N.-E., Strömbom, U.: Adrenergic receptor blocking agents: Effects on central noradrenaline and dopamine receptors and on motor activity. Psychopharmacologia (Berl.) 38, 91–103 (1974)
Anderson, C., Stone, T. W.: On the mechanism of action of clonidine: Effects on single central neurones. Brit. J. Pharmacol. 51, 359–365 (1974)
Ayhan, I. H.: Effect of 6-hydroxydopamine on morphine analgesia. Psychopharmacologia (Berl.) 25, 183–188 (1972)
Beecher, H. K.: In: The measurement of subjective responses: quantitative effects of drugs. New York: Oxford University Press 1959
Bhargava, H. N., Afifi, A. H., Way, E. L.: Effect of chemical sympathectomy on morphine antinociception and tolerance development in the rat. Biochem. Pharmacol. 22, 2769–2772 (1973)
Bhargava, H. N., Way, E. L.: Effect of 1-phenyl-3-(2-thiazalyl)-2-thiourea, a dopamine Β-hydroxylase inhibitor, on morphine analgesia, tolerance and physical dependence. J. Pharmacol. exp. Ther. 190, 165–175 (1974)
BlÄsig, J., Reinhold, K., Herz, A.: Effect of 6-hydroxydopamine, 5,6-dihdroxytryptamine and raphe lesions on the antinociceptive actions of morphine in rats. Psychopharmacologia (Berl.) 31, 111–119 (1973)
Bolme, P., Corrodi, H., Fuxe, K., Hökfelt, T., Lidbrink, P., Goldstein, M.: Possible involvement of central adrenaline neurons in vasomotor and respiratory control. Studies with clonidine and its interactions with piperoxane and yohimbine. Europ. J. Pharmacol. 28, 89–94 (1974)
Brodie, B. B., Costa, E., Dlabac, A., Neff, N. H., Smookler, H. H.: Application of Steady State Kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J. Pharmacol. exp. Ther. 154, 493–498 (1966)
Buxbaum, D. M., Yarbrough, G. G., Carter, M. E.: Biogenic amines and narcotic effects. 1. Modification of morphine-induced analgesia and motor activity after alteration of cerebral amine levels. J. Pharmacol. exp. Ther. 185, 317–327 (1973)
Cahn, J., Herold, M.: Pain and psychotropic drugs. In: Pain. A. Soulairac, J. Cahn and J. Charpentier, eds., pp. 335–371. London-New York: Academic Press 1968
Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4-α-dimethyl-metatyramine. Europ. J. Pharmacol. 5, 367–373 (1969)
Carlsson, A., Lindqvist, M.: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and nor-metanephrine in mouse brain. Acta pharmacol. (Kbh.) 20, 140–144 (1963)
Carrol, M. N., Lim, R. K. S.: Observations on the neuropharmacology of morphine and morphine-like analgesia. Arch. int. Pharmacodyn. 125, 383–403 (1960)
Cicero, T. J., Meyer, E. R., Smithloff, B. R.: Alpha adrenergic blocking agents: antinociceptive activity and enhancement of morphine-induced analgesia. J. Pharmacol. exp. Ther. 189, 72–82 (1974)
Clouet, D. H., Ratner, M.: Catecholamine biosynthesis in brains of rats treated with morphine. Science 168, 854–856 (1970)
Elchisak, M. A., Rosecrans, J. A.: Effect of central catecholamine depletions by 6-hydroxydopamine on morphine antinociception in rats. Res. Comm. Chem. Path. Pharm. 6, 349–352 (1973)
Ernst, A. M.: Mode of action of apomorphine and dexamphetamine on gnawing compulsions in rats. Psychopharmacologia (Berl.) 10, 316–326 (1967)
Fennessy, M. R., Lee, J. R.: Comparison of the dose-response effects of morphine on brain amines, analgesia and activity in mice. Brit. J. Pharmacol. 45, 240–248 (1972)
Fischer, E., Heller, B., Lumbreras, N.: Influence of anticholinergic-antiparkinsonian agents on the effects of narcoanalgesic drugs in the rat. Experientia (Basel) 29, 188–189 (1973)
Fukui, K., Takagi, H.: Effect of morphine on the cerebral contents of metabolites of dopamine in normal and tolerant mice: its possible relation to analgesic action. Brit. J. Pharmacol. 44, 45–51 (1972)
Gunne, L. M.: Noradrenaline and adrenaline in the rat brain during acute and chronic morphine administration and during withdrawal. Nature (Lond.) 184, 1950–1951 (1959)
Görlitz, B.-D., Frey, H.-H.: Central monoamines and antinociceptive drug action. Europ. J. Pharmacol. 20, 171–180 (1972)
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
Hoffmeister, F., Kroneberg, G.: Experimental studies in animals on the differentiation of analgesic activity. In: Methods in drug evaluation. P. Mantegazza and F. Piccinini, eds., pp. 270–277. Amsterdam: North Holland Publ. Co. 1966
Korf, J., Bunney, B. S., Aghajanian, G. K.: Noradrenergic neurons: morphine inhibition of spontaneous activity. Europ. J. Pharmacol. 25, 165–169 (1974)
Kuschinsky, K., Hornykiewicz, O.: Morphine catalepsy in the rat: Relation to striatal dopamine metabolism. Europ. J. Pharmacol. 19, 119–122 (1972)
Kuschinsky, K., Hornykiewicz, O.: Effects of morphine on striatal dopamine metabolism: possible mechanism of its opposite effect on locomotor activity in rats and mice. Europ. J. Pharmacol. 26, 41–50 (1974)
Major, C. T., Pleuvry, B. J.: Effects of α-methyl-p-tyrosine, p-chlorophenylalanine, 1-Β(3,4-dihydroxyphenyl) alanine, 5-hydroxytryptophan and diethyldithiocarbamate on the analgesic activity of morphine and methylamphetamine in the mouse. Brit. J. Pharmacol. 42, 512–521 (1971)
Nakamura, K., Kuntzman, R., Maggio, A. C., Augulis, V., Conney, A. H.: Influence of 6-hydroxydopamine on the effect of morphine on the tail-flick latency. Psychopharmacologia (Berl.) 31, 177–189 (1973)
Nickerson, M., Hollenberg, N. K.: Blockade of α-adrenergic receptors. In: Physiological pharmacology, vol. IV, W. S. Root and F. G. Hofmann, eds., pp. 243–305. New York-London: Academic Press 1967
Paalzow, L.: Studies on the relationship between the analgesic activity of salicylic acid and the brain catecholamines in mice. Acta pharmacol. (Kbh.) 32, 11–21 (1973)
Paalzow, L.: Analgesia produced by clonidine in mice and rats. J. Pharm. Pharmacol. 26, 361–363 (1974)
Paalzow, L., Paalzow, G.: Studies on the relationship between morphine analgesia and the brain catecholamines in mice. Acta pharmacol. (Kbh.) 30, 104–114 (1971)
Paalzow, G., Paalzow, L.: The effects of caffeine and theophylline on nociceptive stimulation in the rat. Acta pharmacol. (Kbh.) 32, 22–32 (1973)
Paalzow, G., Paalzow, L., Stalby, B.: Pentazocine analgesia and regional rat brain catecholamines. Europ. J. Pharmacol. 27, 78–88 (1974)
Reinhold, K., BlÄsig, J., Herz, A.: Changes in brain concentration of biogenic amines and the antinociceptive effect of morphine in rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 278, 69–80 (1973)
Saarnivara, L.: Analgesic activity of some sympathetic drugs and their effect on morphine analgesia in rabbits. Ann. Med. exp. Fenn. 47, 180–190 (1969)
Samanin, R., Bernasconi, S.: Effects of intraventricularly injected 6-OH dopamine on midbrain raphe lesion on morphine analgesia. Psychopharmacologia (Berl.) 25, 175–182 (1972)
Schellenberger, M. K., Gordon, J. H.: A rapid, simplified procedure for simultaneous assay of norepinephrine, dopamine and 5-hydroxytryptamine from discrete brain areas. Analyt. Biochem. 39, 356–372 (1971)
Schmitt, H., Le Douarec, J.-C, Petillot, N.: Antagonism of the antinociceptive action of xylazine, an α-sympathomimetic agent, by adrenoceptor and cholinoceptor blocking agents. Neuropharmacology 13, 295–303 (1974)
Smith, C. B., Villarreal, J. E., Bednarczyk, J. H., Scheldon, M. I.: Tolerance to morphine induced increases in 14C catecholamine synthesis in mouse brain. Science 170, 1106–1108 (1970)
Sokal, R. R., Rohlf, F. J.: Biometry. San Francisco: Freeman 1969
Starke, K.: Regulation of catecholamine release: α-Receptor mediated feed-back control in peripheral and central neurones. In: Frontiers in catecholamine research. E. Usdin and S. S. Snyder, eds., pp. 561–565. New York-Toronto-Oxford-Sydney-Braunschweig: Pergamon Press 1973
Watanabe, K., Matsui, Y., Iwata, H.: Enhancement of the analgesic effect of morphine by sodium diethyldithiocarbamate in rats. Experientia (Basel) 25, 950–951 (1969)
Vedernikov, Y. P., Afrikanov, J. J.: On the role of adrenergic mechanism in morphine analgesic action. J. Pharm. Pharmacol. 21, 845–847 (1969)
Verri, R. A., Graeff, F. G., Corrado, A. P.: Effect of reserpine and alphamethyltyrosine on morphine analgesia. Int. J. Neuropharmacol. 7, 283–292 (1968)
Vogt, M.: The concentration of sympathin in different parts of the central nervous system under normal conditions and after the administration of drugs. J. Physiol. (Lond.) 123, 451–481 (1954)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Paalzow, G., Paalzow, L. Morphine-induced inhibition of different pain responses in relation to the regional turnover of rat brain noradrenaline and dopamine. Psychopharmacologia 45, 9–20 (1975). https://doi.org/10.1007/BF00426204
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00426204