, Volume 87, Issue 4, pp 425–429 | Cite as

Effects of single and repeated daily injections of morphine, clonidine, and l-nantradol on avoidance responding of rats

  • James B. Smith
Original Investigations


Interruption of a photobeam by rats was maintained under a continuous shock avoidance schedule, and moderate response rates were maintained at low shock frequencies. Responding decreased, and shock frequency increased, in a dose-dependent manner after acute injections of the narcotic morphine, the antihypertensive l-nantradol clonidine, and the cannabinoid l-nantradol. Clonidine and l-nantradol were about 100 times more potent than morphine for decreasing overall responding, and l-nantradol was about 3 times more potent than clonidine for decreasing escape responding. When drugs were given repeatedly prior to daily experimental sessions, tolerance developed to response rate decreases of morphine and l-nantradol within seven to ten sessions, but tolerance did not develop to rate decreases of clonidine for up to 30 sessions. Continued decreased responding by clonidine was antagonized by yohimbine, but not by prazosin or naltrexone. These results extend observations for the acute effects of l-nantradol and clonidine to operant responding under a schedule of continuous shock avoidance. Different potencies for drugs in the present and previous experiments suggest important effects of response topography on dose effects.

Key words

Morphine Clonidine l-Nantradol Tolerance Shock avoidance Rat 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Benowitz NL, Rosenberg J, Rogers W, Bachman J, Jones RT (1979) Cardiovascular effects of delta-9-tetrahydrocannabinol: Autonomic nervous mechanisms. Clin Pharmacol Ther 25:440–446Google Scholar
  2. Bloom AS, Dewey WL (1978) A comparison of some pharmacological actions of morphine and delta-9-tetrahydrocannabinol in the mouse. Psychopharmacology 57:243–248Google Scholar
  3. Brunk SF, Noyes R Jr, Avery DH, Canter A (1975) The analgesic effects of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15:554Google Scholar
  4. Buxbaum GB (1972) Analgesic activity of delta-9-tetrahydrocannabinol in the rat and mouse. Psychopharmacology 25:272–280Google Scholar
  5. Colleli B, Meyer DR, Sparber SB (1976) Clonidine antagonizes disruption of fixed-ratio operant behavior in morphine pelleted rats given caloxone. Pharmacologist 18:236Google Scholar
  6. Conrad DG, Elsmore TFT, Sodetz FJ (1972) Delta-9-tetrahydrocannabinol: Dose-related effects on timing behavior in the chimpanzee. Science 175:547–550Google Scholar
  7. Creese I, Snyder SH (1975) Receptor binding and pharmacological activity of opiates in the guinea pig intestine. J Pharmacol Exp Ther 194:205–219Google Scholar
  8. Dallemagne G (1971) Proloned treatment with morphine in rats: Drug-behavior interactions under aversive control. Psychopharmacology 20:77–84Google Scholar
  9. Delini-Stula A (1973) Suppression of conditioned avoidance behavior and the development of tolerance to delta-8-tetrahydrocannabinol and demethylheptylpyran in rats. Pharmakopsychiatry 6:189–197Google Scholar
  10. Dykstra LA (1981) Effects of morphine, levonantradol, and n-methyllevonantradol on shock intensity discrimination. J Clin Pharmacol 21:341S-347SGoogle Scholar
  11. Dykstra LA (1983) Electric shock titration in Squirrel monkeys following administration of nantradol, levonantradol or n-methyl-levonantradol. Psychopharmacology 79:322–324Google Scholar
  12. Eckenhoff JE, Oech SR (1960) The effects of narcotics and antagonists upon respiration and circulation in man. Clin Pharmacol Ther 1:483–524Google Scholar
  13. Fielding S, Lal H (1981) Clonidine: New research in psychotropic drug pharmacology. Med Res Rev 1:97–123Google Scholar
  14. Fielding S, Wikler J, Hynes M, Szewczak M, Novick WJ Jr, Lal H (1977) Antinociceptive and antiwithdrawal actions of clonidine: A comparison with morphine. Fed Proc 36:1024Google Scholar
  15. Fielding S, Wikler J, Hynes M, Szewczak M, Novick WJ Jr, Lal H (1978) A comparison of clonidine with morphine for antinociceptive and antiwithdrawal actions. J Pharmacol Exp Ther 207:899–905Google Scholar
  16. Gilbert PE (1981) A comparison of delta-9-tetra-hydrocannabinol, nantradol, nabilone, and morphine in the chronic spinal dog. J Clin Pharmacol 21:311–319Google Scholar
  17. Grisham MG, Ferraro DP (1972) Biphasic effects of delta-9-tetrahydrocannabinol on variable-interval schedule performance in rats. Psychopharmacology 27:163–169Google Scholar
  18. Harris RA, Snell D, Loh HH, Way EL (1977) Behavioral interactions between naloxone and dopamine agonists. Eur J Pharmacol 43:243–246Google Scholar
  19. Heifetz SA, McMillan DE (1971) Development of behavioral tolerance to morphine and methadone using the schedule-controlled behavior of the pigeon. Psychopharmacology 19:40–52Google Scholar
  20. Henriksson B, Jarbe T (1971) The effect of two tetrahydrocannabinols (delta-9-THC and delta-8-THC) on conditioned avoidance learning in rats and its transfer to normal state conditions. Psychopharmacology 22:23–30Google Scholar
  21. Hine B, Friedman E, Torrelio M, Gerson S (1975) Morphine dependent rats. Blockade of precipitated abstinence by tetrahydrocannabinol. Science 187:443–445Google Scholar
  22. Holtzman SG, Jewett RE (1972) Shock intensity as a determinant of the behavioral effects of morphine in the rat. Life Sci 11:1085–1091Google Scholar
  23. Holtzman SG (1976) Effects of morphine and narcotic antagonists on avoidance behavior of the squirrel monkey. J Pharmacol Exp Ther 196:145–155Google Scholar
  24. Jacob JJ, Ramabadran K, Campso-Medeiros M (1981) A pharmacological analysis of levonantradol antinociception in mice. J Clin Pharmacol 21:327S-333SGoogle Scholar
  25. Jaffe JH, Martin WR (1980) Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics, 4th Edition. pp 494–534Google Scholar
  26. Jain AK, Ryan JR, McMahon F, Smith G (1981) Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 21:320S-326SGoogle Scholar
  27. Jarbe TUC, Henriksson BG (1973) Acute effects of two tetrahydrocannabinols (delta-9-THC and delta-8-THC) on water intake in deprived rats: Implications for behavioral studies of marihuana compounds. Psychopharmacology 30:315–322Google Scholar
  28. Johnson MR, Melvin LS, Althuis TH, Bindra JS, Harbert CA, Milne GM, Weissman A (1981) Selective and potent analgetics derived from cannabinoids. J Clin Pharmacol 21:271S-282SGoogle Scholar
  29. Lal H, Bennett DA, Shearman GT, McCarten MD, Murphy R, Angeja A (1981) Effectiveness of nantradol in blocking narcotic withdrawal signs through non-narcotic mechanisms. J Clin Pharmacol 21:361S-366SGoogle Scholar
  30. Lal H, Sherman GT (1981) Psychotropic actions of clonidine. In: Lal H, Fielding S (eds) Psychopharmacology of clonidine. Alan R Liss, New York, pp 99–145Google Scholar
  31. Laverty R, Taylor KM (1969) Behavioral and biochemical effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) on the central nervous system. Br J Pharmacol 35:253–264Google Scholar
  32. McCleary PE, Leander JD (1981) Clonidine analgesia and suppression of operaant responding: Dissociation of mechanism. Eur J Pharmacol 69:63–69Google Scholar
  33. McKearney JW (1983) Effects of clonidine on operant behavior and electric shock titration in the squirrel monkey: Effects of alpha-2-adrenoreceptor antagonism. Neuropharmacology 22:775–779Google Scholar
  34. McMillan DE, Dewey WL, Harris LS (1971) Characteristics of tetrahydrocannabinol tolerance. Ann NY Acad Sci 191:83–99Google Scholar
  35. Meyer DR, El-azhary R, Bierer DW, Hanson SK, Robbins MS, Sparber SB (1977) Tolerance and dependence after chronic administration of clonidine to the rat. Pharmacol Biochem Behav 7:227–231Google Scholar
  36. Milne GM, Koe BK, Johnson MR (1979) Stereospecific and potent analgetic activity for nantradol — a structurally novel, cannabinoid-related analgetic. In: Harris LS (ed) Problems of drug dependence. NIDA Research Monograph 27. Rockville, Maryland, pp 84–92Google Scholar
  37. Milne GM, McIlhenny HM, Johnson MR, Koe BK, Weissman A (1980) One-way cross tolerance from morphine to nantradol — a potent, non-opioid analgetic. In: Leong WE (ed) Endogenous and exogenous opiate agonists and antagonists. Pergamon Press, New York, pp 367–370Google Scholar
  38. Milne GM, Johnson MR (1981) Levonantradol — A role for central prostanoid mechanisms? J Clin Pharmacol 21:367S-374SGoogle Scholar
  39. Ng J, Phelan EL, McGregor DD, Laverty R, Taylor KM, Smirk H (1967) Properties of Catapres, a new hypotensive drug: A preliminary report. N Z Med J 66:864–870Google Scholar
  40. Paalzow G, Paalzow L (1976) Clonidine antinociceptive activity: effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat. Naunyn-Schmiedebergs Arch Pharmacol 292:119–126Google Scholar
  41. Parker RB (1974) Mouse locomotor activity: Effect of morphine, narcotic antagonists, and the interaction of morphine and narcotic antagonists. Psychopharmacology 38:15–23Google Scholar
  42. Pert CB, Snyder SH (1973) Opiate receptor: demonstration in nervous tissue. Science 179:1011–1014Google Scholar
  43. Scheckel CL, Boff E, Dahlen P, Smart T (1968) Behavioral effects in monkeys of racemates of two biologically active marijuana constituents. Science 160:1467–1469Google Scholar
  44. Sidman M (1953) Two temporal parameters of the maintenance of avoidance behavior by the white rat. J Comp Physiol Psychol 46:253–261Google Scholar
  45. Smith JB (1980) Effects of morphine and two cannabinoidrelated analgesics on responding under schedules of electric shock titration. Fed Proc 39:761Google Scholar
  46. Smith JB (1985) Effects of single and repeated daily injections of morphine, clonidine, and l-nantradol on responding of squirrel monkeys under escape titration. J Pharmacol Exp Ther 234:94–99Google Scholar
  47. Tilson HA, Chamberlain JH, Gylys JA, Buynishi JP (1977) Behavioral suppressant effects of clonidine in strains of normotensive and hypertensive rats. Eur J Pharmacol 43:99–105Google Scholar
  48. Vasko MR, Domino EF (1978) Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat. J Pharmacol Exp Ther 207:848–858Google Scholar
  49. Yaksh TL (1981) The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat. J Clin Pharmacol 21:334S-340SGoogle Scholar
  50. Young AM, Katz JL, Woods JH (1981) Behavioral effects of levonantradol and nantradol in the rhesus monkey. J Clin Pharmacol 21:348S-360SGoogle Scholar
  51. Zaluzny SG, Chesher GB, Jackson DM, Malor R (1979) The attenuation by delta-9-tetrahydrocannabinol and morphine of the quasi-morphine withdrawal syndrome in rats. Psychopharmacology 61:207–216Google Scholar
  52. Zelis R, Flaim SF, Eisele JH (1977) Effects of morphine on reflex arteriolar constriction induced in man by hypercapnia. Clin Pharmacol Ther 22:172–178Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • James B. Smith
    • 1
  1. 1.Worcester Foundation for Experimental BiologyShrewsburyUSA

Personalised recommendations