Skip to main content
Log in

Clonidine antinociceptive activity: Effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Clonidine is able to increase the threshold for vocalisation during stimulation and the threshold for vocalisation after withdrawal of stimulus (vocalisation afterdischarge). These effects of clonidine were investigated after treatment of rats with drugs influencing central monoaminergic and cholinergic mechanisms.

Chlorpromazine, atropine and p-chlorophenyl-alanine increased the activity of clonidine at both thresholds while phenoxybenzamine and reserpine pretreatment increased the activity at the threshold for vocalisation only.

Yohimbine decreased clonidine activity at both thresholds while 5-HTP and α-methyl-p-tyrosine decreased the effects at the threshold for vocalisation afterdischarge. Naloxone did not change the activity of clonidine at either pain response studied.

It is concluded from the present findings that influence from several neuronal systems modulate the antinociceptive action of clonidine.

The inhibition of the medullary nociceptive response after clonidine might be connected to a decreased activity of noradrenergic neurons. Endogenous noradrenaline seems to be of minor importance in mediating this effect. It is moreover shown that decreased cholinergic receptor activity enhances clonidine antinociceptive action on both medullary and diencephalic-rhinencephalic pain responses. The possible involvement of serotonin in these functional responses after clonidine is also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Aghajanian, G. K., Kuhar, M. J., Roth, R. H.: Serotonin-containing neuronal perikarya and terminals: Differential effects of p-chlorophenylalanine Brain Res. 54, 85–101 (1973)

    Google Scholar 

  • 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)

    Google Scholar 

  • Andén, N.-E., Corrodi, H., Fuxe, K., Hökfelt, B., Hökfelt, T., Rydin, C., Svensson, T.: Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sci. 9, 513–523 (1970)

    Google Scholar 

  • Andén, N.-E., Corrodi, H., Fuxe, K., Hökflt, T.: Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamine. Brit. J. Pharmacol. 34, 1–7 (1968)

    Google Scholar 

  • 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)

    Google Scholar 

  • Anderson, C., Stone, T. W.: On the mechanism of action of clonidine: Effects on single central neurons. Brit. J. Pharmacol. 51, 359–365 (1974)

    Google Scholar 

  • 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)

    Google Scholar 

  • Carlsson, A.: Pharmacological depletion of catecholamine stores. Pharmacol. Rev. 18, 541–549 (1966)

    Google Scholar 

  • Carlsson, A., Lindqvist, M.: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta pharmacol. (Kbh.) 20, 140–144 (1963)

    Google Scholar 

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

    Google Scholar 

  • Cheney, D. L., Trabucchi, M., Racagni, G., Wang, C., Costa, E.: Effects of acute and chronic morphine on regional rat brain acetylcholine turnover rate. Life Sci. 15, 1977–1990 (1974)

    Google Scholar 

  • Corrodi, H., Fuxe, K., Hamberger, B., Ljungdahl, Å.: Studies on central and peripheral noradrenaline neurons using a new dopamine-β-hydroxylase inhibitor. Europ. J. Pharmacol. 12, 145–155 (1970)

    Google Scholar 

  • Deck, R., Oberdorf, A., Kroneberg, G.: Die Wirkung von 2-(2,6-Dichlorphenylamino)-2-imidazolin-Hydrochlorid (Clonidin) auf die Kontraktion und die Acetylcholin-Freisetzung am isolierten, koaxial elektrisch gereizten Meerschweinchenileum. Arzneimittel-Forsch. 21, 1580–1584 (1971)

    Google Scholar 

  • Delbarre, B., Schmitt, H.: Effects of clonidine and some α-adrenoreceptor blocking agents on avoidance conditioned reflexes in rats: Their interactions and antagonism by atropine. Psychopharmacologia (Berl.) 35, 195–202 (1974)

    Google Scholar 

  • Fuxe, K., Lidbrink, P., Hökfelt, T., Bolme, P., Goldstein, M.: Effects of piperoxane on sleep and waking in the rat. Evidence for increased waking by blocking inhibitory adrenaline receptors on the locus coeruleus. Acta physiol. scand. 91, 566–567 (1974)

    Google Scholar 

  • Geller, I., Blum, K.: The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior. Europ. J. Pharmacol. 9, 319–324 (1970)

    Google Scholar 

  • Gey, K. F., Pletscher, A.: Influence of chlorpromazine and chlorprothixene on the cerebral metabolism of 5-hydroxytryptamine, norepinephrine and dopamine J. Pharmacol. exp. Ther. 133, 18–24 (1961)

    Google Scholar 

  • Haigler, H. J., Aghajanian, G. K.: Lysergic acid diethylamide and serotonin: a comparison of effects on serotonergic neurones and neurons receiving a serotonergic input. J. Pharmacol. exp. Ther. 188, 688–699 (1974)

    Google Scholar 

  • Harris, L. S., Dewey, W. L., Howes, J. F., Kennedy, J. S., Pars, H.: Narcotic-antagonist analgesics: interactions with cholinergic systems. J. Pharmacol. exp. Ther. 169, 17–22 (1969)

    Google Scholar 

  • Harvey, J. A., Schlosberg, A. J., Yunger, L. M.: Effect of p-chlorophenylalanine and brain lesions on pain sensitivity and morphine analgesia in the rat. In: Advances in biochemical psychopharmacology (E. Costa, G. L. Gessa, and M. Sandler, eds.), vol. 10, pp. 233–245. New York: Raven Press 1974

    Google Scholar 

  • Herold, M., Cahn, J.: The possible role of serotonin in pain. In: Pain (A. Soulairac, J. Cahn, and J. Charpentier, eds.), pp. 251–280. London-New York: Academic Press 1968

    Google Scholar 

  • Herz, A., Metyš, J.: Inhibition of nociceptive responses by substances acting central cholinoceptive systems. In: Pain (A. Soulairac, J. Cahn, and J. Charpentier, eds.), pp. 321–334. London-New York: Academic Press 1968

    Google Scholar 

  • Hoefke, W., Kobinger, W.: Pharmakologische Wirkungen des 2-(2,6-Dichlorphenylamino)-2-imidazolin-Hydrochlorids, einer neuen, antihypertensiven Substanz. Arzneimittel-Forsch. 16, 1038–1058 (1966)

    Google Scholar 

  • Hoffmeister, F.: On the possible relations between postganglionic 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 1968a

    Google Scholar 

  • Hoffmeister, F.: Effects of psychotropic drugs on pain In: Pain (A. Soulairac, J. Cahn, and J. Charpentier, eds.), pp. 309–319. London-New York: Academic Press 1968b

    Google Scholar 

  • 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

    Google Scholar 

  • Holman, R. B., Shillito, E. E., Vogt, M.: Sleep produced by clonidine (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride). Brit. J. Pharmacol. 43 685–695 (1971)

    Google Scholar 

  • Hökfelt, T., Fuxe, K., Goldstein, M., Johansson, O.: Evidence for adrenaline neurons in the rat brain. Acta physiol. scand. 89, 286–288 (1973)

    Google Scholar 

  • Hökfelt, T., Fuxe, K., Goldstein, M., Johansson, O.: Immunohistochemical evidence for the existence of adrenaline neurons in the rat brain. Brain Res. 66, 235–251 (1974)

    Google Scholar 

  • Jenden, D. J.: Effects of chlorpromazine on acetylcholine turnover in vivo. In: Phenothiazines and structurally related drugs (I. S. Forrest, C. J. Carr, and E. Usdin, eds.), pp. 769–777. New York: Raven Press 1974

    Google Scholar 

  • Koslow, S. H., Schlumpf, M.: Quantitation of adrenaline in rat brain nuclei and areas by mass fragmentography. Nature (Lond.) 251, 530–531 (1974)

    Google Scholar 

  • Kroneberg, G., Oberdorf, A., Hoffmeister, F., Wirth, W.: Zur Pharmakologie von 2-(2,6-Diphenylamino)4H-5,6-dihydro-1,3-thiazin (Bayer 1470), eines Hemmstoffes adrenergischer und cholinergischer Neurone. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 256, 257–280 (1967)

    Google Scholar 

  • Maj, J., Baran, L., Grabowska, M., Sowińska, H.: Effect of clonidine on the 5-hydroxytryptamine and 5-hydroxyindoleacetic acid brain levels. Biochem. Pharmacol. 22, 2679–2683 (1973)

    Google Scholar 

  • Nickerson, M., Hollenberg, N. K.: Blockade of α-adrenergic receptors. In: Physiological pharmacology (W. S. Root and F. G. Hofmann, eds.), pp. 243–305. New York-London: Academic Press 1967

    Google Scholar 

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

    Google Scholar 

  • Paalzow, G., Paalzow, L.: Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT. Europ. J. Pharmacol. 31, 261–272 (1975a)

    Google Scholar 

  • 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.) (in press, 1975b)

  • Paalzow, G., Paalzow, L., Stalby, B.: Pentazocine analgesia and regional rat brain catecholamines. Europ. J. Pharmacol. 27, 78–88 (1974)

    Google Scholar 

  • 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)

    Google Scholar 

  • Paalzow L.: Analgesia produced by clonidine in mice and rats. J. Pharm. Pharmacol. 26, 361–363 (1974)

    Google Scholar 

  • Papeschi, R., Sourkes, T. L., Youdim, M. B. H.: The effect of yohimbine on brain serotonin metabolism, motor behavior and body temperature of the rat. Europ. J. Pharmacol. 15, 318–326 (1971)

    Google Scholar 

  • 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)

    Google Scholar 

  • Robichaud, R. C., Sledge, K. L.: The effects of p-chlorophenylalanine on experimentally induced conflict in the rat. Life Sci. 8, 965–969 (1969)

    Google Scholar 

  • Samanin, R., Ghezzi, D., Mauron, C., Valzelli, L.: Effect of midbrain raphe lesion on the antinociceptive action of morphine and other analgesics in rats. Psychopharmacologia (Berl.) 33, 365–368 (1973)

    Google Scholar 

  • Schmitt, H., Le Douarec, J.-C., Petillot, N.: Antinociceptive effects of some α-sympathomimetic agents. Neuropharmacology 13, 389–394 (1974a)

    Google Scholar 

  • 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 (1974b)

    Google Scholar 

  • Schmitt, H., Schmitt, H.: Localization of the hypotensive effect of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155, Catapresan). Europ. J. Pharmacol. 6, 8–12 (1969)

    Google Scholar 

  • Schuberth, J., Sundwall, A., Sparf, B.: A technique for the study of acetylcholine turnover in mouse brain in vivo. J. Neurochem. 16, 695–700 (1969)

    Google Scholar 

  • Shiomi, H., Takagi, H.: Morphine analgesia and the bulbospinal noradrenergic system: increase in the concentration of normetanephrine in the spinal cord of the rat caused by analgesics. Brit. J. Pharmacol. 52, 519–526 (1974)

    Google Scholar 

  • Sokal, R. R., Rohlf, F. J.: Biometry. San Francisco: W. H. Freeman and Comp. 1969

    Google Scholar 

  • 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

    Google Scholar 

  • Svensson, T. H., Bunney, B. S., Aghajanian, G. K.: Inhibition of both noradrenergic and serotonergic neurons in brain by the α-adrenergic agonist clonidine. Brain Res. 92, 291–306 (1975)

    Google Scholar 

  • Tagliamonte, A., Tagliamonte, P., Gessa, G. L., Brodie, B. B.: Compulsive sexual activity induced by p-chlorophenylalanine in normal and pinealectomized male rats. Science 166, 1433–1435 (1969)

    Google Scholar 

  • Tenen, S. S.: The effects of p-chlorophenylalanine, a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychopharmacologia (Berl.) 10, 204–219 (1967)

    Google Scholar 

  • Tenen, S. S.: Antagonism of the analgesic effect of morphine and other drugs by p-chlorophenylalanine, a serotonin depletor. Psychopharmacologia (Berl.) 12, 278–285 (1968)

    Google Scholar 

  • Way, E. L., Shen, F.-H.: Catecholamines and 5-hydroxytryptamine. In: Narcotic drugs biochemical pharmacology (D. H. Clouet, ed.), pp. 229–253. New York-London: Plenum Press 1971

    Google Scholar 

  • Werner, U., Starke, K., Schümann, H. J.: Actions of clonidine and 2-(2-methyl-6-ethyl-cyclohexylamino)-2-oxazoline on postganglionic autonomic nerves. Arch. int. Pharmacodyn. 195, 282–290 (1972)

    Google Scholar 

  • Wilson, A. E., Domino, E. F.: Verification of rat brain acetylcholine antidepletion by morphine using gas chromatography. Biochem. Pharmacol. 22, 1943–1944 (1973)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paalzow, G., Paalzow, L. Clonidine antinociceptive activity: Effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 292, 119–126 (1976). https://doi.org/10.1007/BF00498581

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00498581

Key words

Navigation