Opioids II pp 573-596 | Cite as

Opioid Tolerance and Physical Dependence and Their Relationship

  • E. L. Way
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 2)


Two well-known consequences of frequent and repeated administration of opioids are tolerance and physical dependence. Tolerance is demonstrable by a gradual loss of effectiveness of an agonist after repeated administration, and proportionately higher doses of the compound become necessary to elicit the same response. In the tolerant state, physical dependence also can usually be demonstrated, as evidenced by the need to continue administering the compound to avoid physical discomfort. Its discontinuance results in a constellation of signs and symptoms that are generally opposite to those observed after acute administration and are immediately reversible by readministration of the agonist.


Adenylate Cyclase Physical Dependence Opiate Receptor Locus Ceruleus Chronic Morphine 
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  1. Abood ME, Law PY, Loh HH (1985) Pertussis toxin treatment modifies opiate action in the rat brain striatum. Biochem Biophys Res Commun 127:477–483PubMedCrossRefGoogle Scholar
  2. Aghajanian GK (1978) Tolerance of locus coeruleus neurone to morphine and suppression of withdrawal response by clonidine. Nature 267:186–188CrossRefGoogle Scholar
  3. Baram D, Simantov R (1983) Enkephalins and opiate agonists control calmodulin distribution in neuroblastoma-glioma cells. J Neurochem 40:55–63PubMedCrossRefGoogle Scholar
  4. Berridge MJ, Irvine RF (1989) Inositol triphosphate and cell signaling. Nature 341:197–205PubMedCrossRefGoogle Scholar
  5. Blanchard SG, Chang K-J, Cuatrecasas P (1983) Characterization of the association of tritiated enkephalin with neuroblastoma cells under conditions optimal for receptor down-regulation. J Bioi Chern 258:1092–1097Google Scholar
  6. Bläsig J, Herz A, Reinhold K, Zieglgänsberger W (1973) Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 33:19–38PubMedCrossRefGoogle Scholar
  7. Brady JV, Lukas SF (eds) (1984) Testing drugs for physical dependence potential and abuse liability. NIDA Res Monogr 52:153Google Scholar
  8. Brase DA, Iwamoto ET, Loh HH, Way E, Leong H (1976) Reinitiation of sensitivity to naloxone by a single narcotic injection in postaddict mice. J Pharmacol Exp Ther 197:317–325PubMedGoogle Scholar
  9. Chapman DB, Way EL (1980) Metal ion interactions with opiates. Annu Rev Pharmacol Toxicol 20:553–579PubMedCrossRefGoogle Scholar
  10. Christie MJ, Williams JT, North RA (1987) Cellular mechanisms in opioid tolerance: studies in single brain neurons. Mol Pharmcol 32:633–638Google Scholar
  11. Cochin J, Kometsky C (1964) Development and loss of tolerance in the rat after simple and multiple injections. J Pharmacol Exp Ther 145:1–10PubMedGoogle Scholar
  12. Collier HOJ (1965) A general theory of the genesis of drug dependence by induction of receptors. Nature 205:181–182PubMedCrossRefGoogle Scholar
  13. Collier HOJ (1980) Cellular site of opiate dependence. Nature 283:625–629PubMedCrossRefGoogle Scholar
  14. Collier HOJ, Francis DL (1975) Morphine abstinence is associated with increased brain cyclic AMP. Nature 255:159–162PubMedCrossRefGoogle Scholar
  15. Collier HOJ, Roy AC (1974) Morphine-like drugs inhibit the stimulation by E prostaglandins of cyclic AMP formation by rat brain homogenate. Nature 248:24–27PubMedCrossRefGoogle Scholar
  16. Collier HOJ, Tucker JF (1984) Sites and mechanisms of dependence in the myenteric plexus of the guinea pig ileum. In: Sharo C (ed) Mechanisms of tolerance and dependence. US Govt Printing Office, Washington DC, pp 81–94Google Scholar
  17. Collier HOJ, Cuthbert NJ, Francis DL (1981) Model of opiate dependence in the guinea-pig isolated ileum. Br J Pharmacol 73:921–932PubMedGoogle Scholar
  18. Costa T, Aktories G, Schulz G, Wuster M (1983) Pertussis toxin decreases opiate receptor binding and adenylate cyclase inhibition in a neuroblastoma × glioma hybrid cell line. Life Sci 33 [Suppl I]:219–222PubMedCrossRefGoogle Scholar
  19. Cox BM, Osman OH (1970) Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis. Br J Pharmacol 38: 157 -170PubMedGoogle Scholar
  20. Crain S, Crain B, Peterson E (1986) Cyclic AMP or forskolin rapidly attenuates the depressant effect of opioids on sensory-evoked dorsal-horn responses in mouse spinal cord-ganglion explants. Brain Res 370:61–72PubMedCrossRefGoogle Scholar
  21. Crain S, Shen KF, Chalazonitis A (1988) Opioids excite rather than inhibit sensory neurons after chronic opioid exposure of spinal cord ganglion cultures. Brain Res 455:61–72CrossRefGoogle Scholar
  22. Crain SM (1988) Regulation of excitatory opioid responsivity of dorsal root ganglion neurons. In: Illes P, Farsang C (eds) Regulatory roles of opioid peptides. VCH, Weinheim, pp 186–201Google Scholar
  23. Dingledine R, Valentino RJ, Bostock E, King ME, Chang K-J (1983) Down regulation of delta but not mu opioid receptors in the hippocampal slice associated with loss of physiological response. Life Sci 33 [Suppl I]:333–336PubMedCrossRefGoogle Scholar
  24. Ehrenpreis S, Light I, Schonbuch GH (1972) Use of the electrically stimulated guinea pig ileum to study potent analgesics. In: Singh JM, Millar LH, Lal H (eds) Drug addiction experimental pharmacology. Futura, New York, pp 319–342Google Scholar
  25. Fry JP, Herz A, Zieglgänsberger W (1980) A demonstration of naloxoneprecipitated withdrawal on single neurons in the morphine-tolerant/dependent rat brain. Br J Pharmacol 68:585–592PubMedGoogle Scholar
  26. Gillan MGC, Kosteriltz HW, Robson LE, Waterfield AA (1979) The inhibitory effects of presynaptic alpha-adreno-ceptor agonists on contractions of guinea pig ileum and mouse vas deferens in the morphine-dependent and withdrawn states produced in vitro. Br J Pharmacol 66:601–608PubMedGoogle Scholar
  27. Goldstein A, Goldstein DB (1968) Enzyme expansion theory of drug tolerance and physical dependence. Res Publ Assoc Ment Dis 46:265–267Google Scholar
  28. Griffin MT, Law PY, Loh HH (1983) Modulation of adenylate cyclase activity by a cytosolic factor following chronic opiate exposure in neuroblastoma × glioma NG108–15 hybrid cells. Life Sci 33:365–369PubMedCrossRefGoogle Scholar
  29. Griffin MT, Law PY, Loh HH (1985) Involvement of both inhibitory and stimulatory guanine nucleotide binding proteins in the expression of chronic opiate regulation of adenylate cyclase activity in NG108–15 Cells. J Neurochem 45:1585–1589PubMedCrossRefGoogle Scholar
  30. Griffin MT, Law PY, Loh HH (1986) Effects of phospholipases on chronic opiate action in neuroblastoma × glioma NG108–15 hybrid cells. J Neurochem 47:1098–1105PubMedCrossRefGoogle Scholar
  31. Guerrero-Munoz F, Guerrero M, Way EL (1979) Effect of morphine on calcium uptake by lysed synaptosomes. J Pharmacol Exp Ther 211:370–374PubMedGoogle Scholar
  32. Guitart X, Nestler EJ (1989) Identification of morphine and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of rat brain; regulation by acute and chronic morphine. J Neurosci 9(12):4371–4387PubMedGoogle Scholar
  33. Hazum E, Chang K-J, Cuatrecases P (1979) Opiate (enkephalin) receptors of neuroblastoma cells: occurrence in clusters on the cell surface. Science 206:1077–1079PubMedCrossRefGoogle Scholar
  34. Henderson G, Hughes J (1976) The effect of morphine on the release of noradrenaline from the mouse vas deferens. Br J Pharmacol 57:571–576Google Scholar
  35. Himmelsbach CK (1942) Clinical studies of drug addiction: physical dependence, withdrawal and recovery. Arch Intern Med 69:766–772CrossRefGoogle Scholar
  36. Ho IK, Loh HH, Way EL (1973a) Cyclic AMP antagonism of morphine analgesia. J Pharmacol Exp Ther 185:340–346Google Scholar
  37. Ho IK, Loh HH, Way EL (1973b) Effects of cyclic 3′,5 ′-adenosine monophosphate on morphine tolerance and physical dependence. J Pharmacol Exp Ther 185:347–357PubMedGoogle Scholar
  38. Ho IK, Loh H, Bharghava HN, Way EL (1975) Effect of cyclic nucleotides and phosphodiesterase inhibition on morphine tolerance and physical dependence. Life Sci 16:1895PubMedCrossRefGoogle Scholar
  39. Huidobro-Toro JP, Foree B, Way EL (1978) Single dose tolerance and cross tolerance studies with the endorphins in isolated guinea pig ileum. Proc West Pharmacol Soc 21:381–386PubMedGoogle Scholar
  40. Jacob JJC, Barthelemy CD, Tremblay EC, Colombel ML (1974) Potential usefulness of single-dose acute physical dependence on and tolerance to morphine for the evaluation of narcotic antagonists. Adv Biochem Psychopharmacol 8:299–318Google Scholar
  41. Jaffee JH, Sharpless SK (1968) Pharmacological denervation supersensitivity in the central nervous system: a theory of physical dependence. In: Wilker A (eds) The addiction states. Williams and Wilkins, Baltimore, pp 226–246Google Scholar
  42. Jasinski, DS (1977) Assessment of the abuse potentiality of morphinelike drugs (methods used in man). In: Martin WR (eds) Drug addiction. Springer, Berlin Heidelberg New York, pp 197–258 (Handbook of experimental pharmacology, vol 45/1)Google Scholar
  43. Johnson SM, Fleming WW (1978) Sensitivities of the isolated ilea longitudinal muscle myenteric plexus and hypogastric nerve-vas deferens of the guinea pig after chronic morphine implantation. J Pharmacol 204:54–66Google Scholar
  44. Johnson SM, Fleming WW (1989) Mechanisms of cellular adaptive sensitivity changes. Applications to opioid tolerance and dependence. Pharmacol Rev 41(4):435–488PubMedGoogle Scholar
  45. Klee WA, Nirenberg M (1974) A neuroblastoma and glioma hybrid cell line with morphine receptors. Proc Natl Acad Sci USA 71:3474–3477PubMedCrossRefGoogle Scholar
  46. Kolb L, Himmelsbach CK (1938) Clinical studies of drug addiction. A critical review of the withdrawal treatment with method of evaluating abstinence syndromes. J Psychiatr 94:759–797Google Scholar
  47. Kosersky DA, Harris RA, Harris LS (1974) Naloxone-precipitated jumping activity in mice following the acute administration of morphine. Eur J Pharmacol 26:122–124PubMedCrossRefGoogle Scholar
  48. Koski G, Klee WA (1981) Opiates inhibit adenylate cyclase by stimulating GTP hydrolysis. Proc Natl Acad Sci USA 78:4185–4189PubMedCrossRefGoogle Scholar
  49. Law PY, Hom DS, Loh HH (1983a) Opiate receptor down-regulation and desensitization in neuroblastoma × glioma NG108–15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol 25:413–424Google Scholar
  50. Law PY, Hom DS, Loh HH (1983b) Opiate regulation of adenosine 3′, 5′-cyclic monophosphate level in neuroblastoma × glioma NG108–15 hybrid cells. Mol Pharmacol 23:23–35Google Scholar
  51. Law PY, Hom DS, Loh HH (1984) Down-regulation of opiate receptor in neuroblastoma × glioma NG108–15 hybrid cells: chloroquine promotes accumulation of tritiated enkephalin in the lysomes. J BioI Chern 259:4096–4104Google Scholar
  52. Law PY, Hom DS, Loh HH (1985a) Multiple affinity states of opiate receptor in neuroblastoma × glioma NG108–15 hybrid cells. J BioI Chern 260:3561–3569Google Scholar
  53. Law PY, Louie AK, Loh HH (1985b) Effect of pertussis toxin treatment of downregulation of opiate receptors in neuroblastoma × glioma NG108–15 hybrid cells. J BioI Chern 260:14818–14823Google Scholar
  54. Law PY, Griffin MT, Loh HH (1986) Mechanisms of multiple cellular adaptation processes in clonal cell lines during chronic opiate treatmentGoogle Scholar
  55. Lin SC, Way EL (1984) Calcium transport in and out brain nerve ending in vitro - the role of synaptosomal plasma membrane Ca2+ ATPase in Ca2+ extrusion. Brain Res 298:225–234PubMedCrossRefGoogle Scholar
  56. Loh HH, Shen EH, Way EL (1969) Inhibition of morphine tolerance, and physical dependence development and brain serotonin synthesis by cycloheximide. Biochem Pharmacol 18:2711–2721PubMedCrossRefGoogle Scholar
  57. Louie AK, Way EL (1991) Overview of opiate tolerance and physical dependence. In: Almeida OF, Shippenberg TS (eds) Neurobiology of opioids. Springer, Berlin Heidelberg New YorkGoogle Scholar
  58. Louie AK, Law PY, Loh HH (1986) Cell free desensitization of opiate inhibition of adenylate cyclase in neuroblastoma × glioma NG108–15 hybrid cell membranes. J Neurochem 47:733–737PubMedCrossRefGoogle Scholar
  59. Lux B, Schulz R (1983) Cholera toxin selectively affects the expression of opioid dependence in the tolerant myenteric plexus of the guinea-pig. Eur J Pharmacol 96:175–176PubMedCrossRefGoogle Scholar
  60. Lux B, Schulz R (1986) Effects of cholera toxin and pertussis toxin on opioid tolerance and dependence in the guinea pig myenteric plexus. J Pharmacol Exp Ther 237:995–100PubMedGoogle Scholar
  61. Martin WR (1968) A homeostatic and redundancy theory of tolerance to and physical dependence on narcotic analgesics. In: Wilker A (ed) The addictive states. Williams and Wilkins, Baltimore, pp 206–225Google Scholar
  62. Martin WR, Wikler A, Eades CG, Pescor FT (1963) Tolerance to and physical dependence on morphine in rats. Psychopharmacologia 4:247–260PubMedCrossRefGoogle Scholar
  63. Martin WR, Laskinki DR, Haertzen CA, Kay CD, Jones BE, Mansky PA, and Carpenter RW (1973) Methadone: a reevaluation. Arch Gen Psychiatry 28:286–295PubMedCrossRefGoogle Scholar
  64. Mudge A W, Leeman SE, Fischbach GS (1979) Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc Natl Acad Sci USA 76:526–530PubMedCrossRefGoogle Scholar
  65. Murayama T, Ui M (1983) Loss of the inhibitory function of the guanine nucleotide regulatory components of adenylate cyclase due its ADP ribosylation by isletactivating protein pertussis toxin in adipocyte membranes. J BioI Chem 258:319–326Google Scholar
  66. Nehmed R, Nadler U, Simantov R (1982) Effects of acute and chronic morphine treatment on calmodulin activity of rat brain. Mol Pharmacol 22:389–394Google Scholar
  67. Nestler E, Erdos JJ, Terwilliger R, Duman RS, Tallman IF (1989) Regulation of G proteins by chronic morphine in the rat coeruleus. Brain Res 476:230–239PubMedCrossRefGoogle Scholar
  68. Nicoll R (1988) The coupling of neurotransmitter receptors to ion channels in the brain. Science 241:540–551CrossRefGoogle Scholar
  69. North RA, Vitek L (1980) The effect of chronic morphine treatment on excitatory junction potentials in the mouse vas deferens. Br J Pharmacol 68:399–406PubMedGoogle Scholar
  70. O’Callaghan IP, Williams N, Clouet D (1979) The effect of morphine on the endogenous phosphorylation of synaptic plasma membrane proteins of rat striatum. J Pharmacol Exp Ther 208:96–105PubMedGoogle Scholar
  71. Opmeer FA, van Ree JM (1978) Tolerance and dependence in vitro. In: Van Ree JM, Terenius L (eds) Characteristics and functions of opioid. Elsevier/North Holland, Amsterdam, pp 63–64Google Scholar
  72. Quock C, Cheng J, Chan SC, Way EL (1968) The abstinence syndrome in long-term high dosage narcotic addiction. Br J Addict 63:261–270CrossRefGoogle Scholar
  73. Rasmussen K, Beitner-Johnson DB, Krystal IH, Aghajanian GS, Nestler EJ (1990) Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J Neurosci 10(7):2308–2317PubMedGoogle Scholar
  74. Rezvani A, Way EL (1983) Hypersensitivity of the opioid-tolerant guinea pig ileum to electrical stimulation after abrupt agonist withdrawal. Life Sci 33:349–352PubMedCrossRefGoogle Scholar
  75. Rezvani A, Huidobro-Toro J, Hu J, Way EL (1983) A rapid and simple method for quantitative determination of tolerance development in the guinea pig ileum in vitro. J Pharmacol Exp Ther 225:251–255PubMedGoogle Scholar
  76. Rezvani A, Hwang F, Song ZH, Lin ET, Way EL (1990) Supersensitivity to electrical stimulation for assessing physical dependence on opioids on isolated tissue. J Pharmacol Exp Ther 254:52–57PubMedGoogle Scholar
  77. Salter RS, Krink MU, Klee CB, Neer BS (1981) Calmodulin activates the isolated catalytic unit of brain adenylate cyclase. J BioI Chem 256:9830–9833Google Scholar
  78. Satoh M, Zieglgänsberger W, Herz A (1976) Actions of opiates upon single unit activity in the cortex of naive and tolerant rats. Brain Res 115:99–110PubMedCrossRefGoogle Scholar
  79. Schmidt WK, Way EL (1980) Effect of a calcium chelator on morphine tolerance development. Eur J Pharmacol 63:243–250PubMedCrossRefGoogle Scholar
  80. Schulz R, Wüster B, Herz A (1981) Differentation of opiate receptors in the brain by the selective development of tolerance. Pharmacol Biochem Behav 14:75–79PubMedCrossRefGoogle Scholar
  81. Schuster L (1961) Repression and de-repression of enzyme synthesis as a possible explanation of some aspects of drug action. Nature 189:314–315CrossRefGoogle Scholar
  82. Sharma SK, Klee W A, Nirenberg M (1977) Opiate-dependent modulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci USA 72:3092–3096CrossRefGoogle Scholar
  83. Smits SE (1975) Quantitation of physical dependence in mice by naloxoneprecipitated jumping after a single dose of morphine. Res Commun Chern Pathol Pharmacol 10:651–661Google Scholar
  84. Takemori AE, Oka T, Nishiyama N (1973) Alteration of analgesic-antagonist interaction induced by morphine. J Pharmacol Exp Ther 186:261–265PubMedCrossRefGoogle Scholar
  85. Tang A, Collins R (1978) Enhanced analgesic effects of morphine after chronic administration of naloxone in the rat. Eur J Pharmacol 47:473–474PubMedCrossRefGoogle Scholar
  86. Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87PubMedCrossRefGoogle Scholar
  87. Tsou K, Louie B, Way EL (1982) Manifestation of gut opiate withdrawal contracture and its blockade by capsaicin. Eur J Pharmacol 81:377–385PubMedCrossRefGoogle Scholar
  88. Tsou K, Wu SH, Lu YA, Way EL (1985) Blockade of the hyoscine-resistant opiate withdrawal contracture of ileum by a new substance P antagonist [D-Arg 1, D-Phe 5, D-Trp 7,9, Leu II] substance P. Eur J Pharmacol 110:155–156PubMedCrossRefGoogle Scholar
  89. Tulunay FC, Takemori AE (1974) The increased efficacy of narcotic antagonists induced by various narcotic analgesics. J Pharmacol Exp Ther 190:395–400PubMedGoogle Scholar
  90. Way EL, Mo BP, Quock CP, Yap PM, Ou G, Chan SC, Cheng J (1966) Evaulation of the nalorphine pupil diagnostic test for narcotic usage in long-term heroin and opium addicts. Clin Pharmacol Ther 7:300–311PubMedGoogle Scholar
  91. Way EL, Loh HH, Shen FH (1969) Simultaneous quantitative assessment of morphine tolerance and physical dependence. J Pharmacol Exp Ther 167:1–8PubMedGoogle Scholar
  92. Wei E, Way EL (1975) Application of the pellet implantation technique for the assessment of tolerance and physical dependence in the rodent. In: Ehrenpreis S, Neidle A (eds) Methods in narcotics research, vol 5. Dekker, New York, pp 241–259Google Scholar
  93. Wikler A, Frazer HF, Isbell H (1953) N-Allylnormorphine: effects of single doses and precipitation of acute “abstinence syndromes” during addiction to morphine methadone or heroin in man (postaddicts). J Pharmacol Exp Ther 109:8–20PubMedGoogle Scholar
  94. Wüster M, Costa T (1984) The opioid-induced desensitization (tolerance) in neuroblastoma × glioma NG108–15 hybrid cells: results from receptor uncoupling. In: Sharo C (ed) Mechanisms of tolerance and dependence. US Govt Printing Office (ADM84–1330), Washington DC, pp 136–145Google Scholar
  95. Yamamato H, Harris RA, Loh HH, Way EL (1978) Effects of acute and chronic morphine treatments on calcium localization and binding in brain. J Pharmacol Exp Ther 205:255–264Google Scholar
  96. Yamasaki Y, Way EL (1985) Inhibition of Ca++-ATPase of rat erythrocyte membranes by κ-appa-opioid agonists. Neuropeptides 5:359–362PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1993

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  • E. L. Way

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