Animal Models of Opiate Dependence

  • Rafael Maldonado
  • Luis Stinus
  • George F. Koob
Part of the Neuroscience Intelligence Unit book series (NIU.LANDES)

Abstract

Endogenous opioid peptides exert a wide range of central and peripheral effects. It was thought that tolerance to opiates could be assessed for any of its measurable actions. However, tolerance develops to many different effects of morphine, to different degrees and at different rates. Moreover, some effects seem to be unchanged while others increase after repeated opiate administration. Thus, these adaptive mechanisms, which develop for each morphine effect, must not have absolute common bases. They must depend upon the interaction between the overstimulation of opioid receptors by opiates and the complex neuronal circuitries responsible for the physiological effects. It is important to emphasize that these adaptive processes are mediated through physiological feedback mechanisms. Following the repeated exposure to the drug, their activities will increase out of the physiological range, and this situation will become progressively permanent and will establish a new artificial homeostatic equilibrium of the “milieu interieur,” in which the opiate will exert a controlling role in the sense that the permanent stimulation of opiate receptors is now needed. In opiate-addicted subjects, abstinence of the drug will disrupt this artificial homeostatic state triggering physiological, behavioral and psychological effects. Together, these symptoms will define opiate dependence. Thus, one must consider that when a subject is tolerant or sensitized to a given drug effect, the subject is dependent on the drug as a whole.

Keywords

Placebo Dioxide Magnesium Dopamine Cage 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Van der Laan JW, de Groot G. Changes in locomotor activity patterns as a measure of spontaneous morphine withdrawal: No effect of clonidine. Drug Alcohol Depend 1988; 22: 133–140.CrossRefGoogle Scholar
  2. 2.
    Van der Laan JW, Land CJ, Loeber JG et al. Validation of spontaneous morphine withdrawal symptoms in rats. Arch Int Pharmacodyn Ther 1991; 311: 42–45.Google Scholar
  3. 3.
    Gellert VF, Holtzman SG. Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions. J Pharmacol Exp Ther 1978; 205: 536–546.PubMedGoogle Scholar
  4. 4.
    Auriacombe M, Tignol J, Le Moal M et al. Transcutaneous electrical stimulation with limoge current potentiates morphine analgesia and attenuates opiate abstinence syndrome. Biol Psychiatry 1990; 28: 650–656.PubMedCrossRefGoogle Scholar
  5. 5.
    Meltzer LT, Moreton JE, Khazan N. Electroencephalographic and behavioral tolerance and cross-tolerance to morphine and methadone in the rat. Toxicol Appl Pharmacol 1978; 45: 837–844.PubMedCrossRefGoogle Scholar
  6. 6.
    Weeks JR. Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 1962; 138: 143–144.PubMedCrossRefGoogle Scholar
  7. 7.
    Gold LH, Stinus L, Inturrisi CE et al. Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat. Eur J Pharmacol 1994; 253: 45–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Yoburn BC, Chen T, Huang T et al. Pharmacokinetic and pharmacodynamics of subcutaneous morphine pellets in the rat. J Pharmacol Exp Ther 1985; 235: 282–286.PubMedGoogle Scholar
  9. 9.
    Bläsig J, Herz A, Reinhold K et al. Development of physical dependence on morphine with respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 1973; 33: 19–38.PubMedCrossRefGoogle Scholar
  10. 10.
    Cerletti C, Keinath SH, Reidenberg MM et al. Chronic morphine administration: Plasma levels and withdrawal syndrome in rats. Pharmacol Biochem Behav 1976; 4: 323–327.PubMedCrossRefGoogle Scholar
  11. 11.
    Maldonado R, Feger J, Fournié-Zaluski MC et al. Differences in physical dependence induced by selective mu or delta opioid agonists and by endogenous enkephalins protected by peptidase inhibitors. Brain Res 1990; 520: 247–254.PubMedCrossRefGoogle Scholar
  12. 12.
    Wei E, Loh HH, Way EL. Quantitative aspects of precipitated abstinence in morphine-dependent rats. J Pharmacol Exp Ther 1973; 184: 398–403.PubMedGoogle Scholar
  13. 13.
    Schulteis G, Markou A, Gold L et al. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: A quantitative dose-response analysis. J Pharmacol Exp Ther 1994; 271: 1391–1398.PubMedGoogle Scholar
  14. 14.
    Stinus L, Allard M, Gold L et al. Changes in CNS neuropeptide FF-like material, pain sensitivity and opiate dependence following chronic morphine treatment. Peptides 1995; 16: 1235–1241.PubMedCrossRefGoogle Scholar
  15. 15.
    Espejo EF, Cador M, Stinus L. Ethopharmacological analysis of naloxone-precipitated morphine withdrawal syndrome in rats: A newly developed “etho-score”. Psychopharmacology 1995; 122: 122–130.CrossRefGoogle Scholar
  16. 16.
    Jaffe JH. Drug addiction and drug abuse. In: Gilman AG, Goodman LS, Rall TW, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 7th ed. New York: MacMillan Publishing Co., 1990: 522–573.Google Scholar
  17. 17.
    Henningfield JE, Johnson RE, Jasinski DR. Clinical procedures for the assessment of abuse potential. In: Bozarth MA, ed. Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer-Verlag, 1987: 573–590.CrossRefGoogle Scholar
  18. 18.
    Jasinski DR, Johnson RE, Kocher TR. Clonidine in morphine withdrawal: Differential effects of signs and symptoms. Arch Gen Psychiatry 1985; 42: 1063–1066.PubMedCrossRefGoogle Scholar
  19. 19.
    Stinus L. Neurobiological aspects of opiate dependence. In: Stefanis C, Hippius H, eds. Psychiatry in Progress: Research in Addiction, Vol. 2. Seattle: Hogrefe and Huber Publishing, 1995: 1–21.Google Scholar
  20. 20.
    Martin WR, Wikler A, Eades CG et al. Tolerance to and physical dependence on morphine in rats. Psychopharmacologia 1963; 4: 247–260.PubMedCrossRefGoogle Scholar
  21. 21.
    Sala M, Braida D, Leone MP et al. Chronic morphine affects working memory during treatment and withdrawal in rats: Possible residual long-term impairment. Behav Pharmacol 1994; 5: 570–580.PubMedCrossRefGoogle Scholar
  22. 22.
    Babbini M, Gaiardi M, Bartoletti M. Persistence of chronic mor-phine effects upon activity in rats 8 months after ceasing the treatment. Neuropharmacology 1975; 14: 611–614.PubMedCrossRefGoogle Scholar
  23. 23.
    Brady L, Holtzman SG. Locomotor activity in morphine-dependent and post-dependent rats. Pharmacol Biochem Behav 1981; 14: 361–370.PubMedCrossRefGoogle Scholar
  24. 24.
    Koob GF, Wall TL, Bloom FE. Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal. Psychopharmacology (Berlin) 1989; 98: 530–534.CrossRefGoogle Scholar
  25. 25.
    Markou A, Koob GF. Post-cocaine anhedonia. An animal model of cocaine withdrawal. Neuropharmacology 1991; 4: 17–26.Google Scholar
  26. 26.
    Negus SS, Pasternak GW, Koob GF et al. Antagonist effect of 13funaltrexamine and naloxonazine on alfentanil-induced antinociception and muscle rigidity in the rat. J Pharmacol Exp Ther 1993; 264: 739–745.PubMedGoogle Scholar
  27. 27.
    Kornetsky C, Esposito RU. Euphorigenic drugs: Effects on reward pathways of the brain. Fed Proc 1979; 38: 2473–2476.PubMedGoogle Scholar
  28. 28.
    Perry W, Esposito RU, Kornetsky C. Effects of chronic naloxone treatment on brain stimulation reward. Pharmacol Biochem Behav 1981; 14: 247–249.PubMedCrossRefGoogle Scholar
  29. 29.
    Oswald I, Evans JI, Lewis SA. Addictive drugs cause suppression of paradoxical sleep with withdrawal rebound. In: Steinberg H, ed. Scientific Basis of Drug Dependence. London: J and A Churchill, 1969: 243–257.Google Scholar
  30. 30.
    Khazan N. EEG correlates of morphine dependence and withdrawal in the rat. In: Singh JM, Miller LH, Al H, eds. Experimental Pharmacology. New York: Futura Publishing House, 1972: 159–172.Google Scholar
  31. 31.
    Colasanti B, Kirchman A, Khazan N. Changes in the electroencephalogram and REM sleep time during morphine abstinence in pellet-implanted rats. Res Commun Chem Pathol Pharmacol 1975; 12: 163–172.PubMedGoogle Scholar
  32. 32.
    Khazan N, Colasanti B. EEG correlates of morphine challenge in post-addict rats. Psychopharmacologia 1971; 22: 56–63.PubMedCrossRefGoogle Scholar
  33. 33.
    O’Brien C. Experimental analysis of conditioning factors in human narcotic addiction. Pharmacol Rev 1975; 27: 533–543.PubMedGoogle Scholar
  34. 34.
    O’Brien C, Childress A, McLellan A et al. Learning factors in substance abuse, Ray BA (ed). NIDA Res Monogr 1988; 84: 44–61.PubMedGoogle Scholar
  35. 35.
    Higgins GA, Nguyen P, Joharchi N et al. Effects of 5-HT3 receptor antagonists on behavioral measures of naloxone-precipitated opioid withdrawal. Psychopharmacology 1991; 105: 322–328.PubMedCrossRefGoogle Scholar
  36. 36.
    Mucha RF. Is the motivational effect of opiate withdrawal reflected by common somatic indices of precipitated withdrawal? Brain Res 1987; 418: 214–220.PubMedCrossRefGoogle Scholar
  37. 37.
    Stinus L, Le Moal M, Koob GF. The nucleus accumbens and amygdala as possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience 1990; 37: 767–773.PubMedCrossRefGoogle Scholar
  38. 38.
    Hand TH, Koob GF, Stinus L et al. Aversive properties of opiate receptor blockade are centrally mediated and are potentiated by previous exposure to opiates. Brain Res 1988; 474: 364–368.PubMedCrossRefGoogle Scholar
  39. 39.
    Hand TH, Stinus L, Le Moal M. Differential mechanisms in the acquisition and expression of heroin-induced place preference. Psychopharmacology 1989; 98: 61–67.PubMedCrossRefGoogle Scholar
  40. 40.
    Baldwin HA, Koob GF. Rapid induction of conditioned opiate withdrawal. Neuropsychopharmacology 1993; 8: 15–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Heishman SJ, Stitzer ML, Bigelow GE et al. Acute opioid physical dependence in humans: Effect of varying the morphine-naloxone interval. J Pharmacol Exp Ther 1989; 250: 485–491.PubMedGoogle Scholar
  42. 42.
    Azorlosa JL, Stitzer ML, Greenwald MK. Opioid physical dependence development: Effects of single versus repeated morphine pre-treatments and of subjects’ opioid exposure history. Psychopharmacology 1994; 114: 71–80.CrossRefGoogle Scholar
  43. 43.
    Kim DH, Fields HL, Barbaro NM. Morphine analgesia and acute physical dependence: Rapid onset of two opposing dose-related processes. Brain Res 1990; 516: 37–40.PubMedCrossRefGoogle Scholar
  44. 44.
    Hendrie CA. Naloxone-sensitive hyperalgesia follows analgesia induced by morphine and environmental stimulation. Pharmacol Biochem Behav 1989; 32: 961–966.PubMedCrossRefGoogle Scholar
  45. 45.
    Kanof PD, Aronson MJ, Ness R et al. Levels of opioid physical dependence in heroin addicts. Drug Alcohol Depend 1991; 27: 253–262.PubMedCrossRefGoogle Scholar
  46. 46.
    Babbini M, Davis WM. Time-dose relationship for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 1972; 46: 213–224.PubMedCrossRefGoogle Scholar
  47. 47.
    Young GA, Khazan N. Differential protracted effects of morphine and ethylketocylazocine challenges on EEG and behavior in the rat. Eur J Pharmacol 1986; 125: 265–271.PubMedCrossRefGoogle Scholar
  48. 48.
    Gianutsos G, Hynes MD, Drawbauch RB et al. Morphine withdrawal aggression during protracted abstinence: Role of latent dopaminergic supersensitivity. Pharmacologist 1973; 15: 348.Google Scholar
  49. 49.
    Gianutsos G, Hynes MD, Puri SK et al. Effect of apomorphine and nigrostriatal lesions on aggression and striatal dopamine turnover during morphine withdrawal: Evidence for dopaminergic supersentivitiy in protracted abstinence. Psychopharmacologia 1974; 34: 37–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Spain JW, Newsom GC. Chronic opioids impair acquisition of both radial maze and Y-maze choice escape. Psychopharmacology 1991; 105: 101–106.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • Rafael Maldonado
    • 1
  • Luis Stinus
    • 2
  • George F. Koob
    • 3
  1. 1.Pharmacochimie Moléculaire et StructuraleParisFrance
  2. 2.Université de Bordeaux IIBordeaux CédexFrance
  3. 3.The Scripps Research InstituteLa JollaUSA

Personalised recommendations