Drug tolerance

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Addiction and dependence glossary[1][2][3]
addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
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Drug tolerance is a pharmacology concept where a subject's reaction to a specific drug and concentration of the drug is reduced followed repeated use, requiring an increase in concentration to achieve the desired effect.[4]

The following are characteristics of drug tolerance: it is reversible, the rate depends on the particular drug, dosage and frequency of use, differential development occurs for different effects of the same drug.[medical citation needed]


Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.

Pharmacodynamic tolerance[edit]

Pharmacodynamic tolerance occurs when the cellular response to a substance is reduced with repeated use. This may be caused by a reduced receptor response to receptor agonists (receptor desensitization), a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate.[5] Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.

Pharmacodynamic tolerance to morphine[edit]

See also: morphine

Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization),[6] mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.[7]) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol.

Significant involvement of the intracellular beta-arrestin-2 protein expression in the agonist-mediated desensitization of G protein-coupled receptors, such as the μ-opioid receptor (MOR), has been elucidated.[8]

It was reported that VTA dopamine neurons in rats remain increased for at least 3 days after a single morphine exposure. Within this limited window of time, the VTA dopamine neurons failed to respond to additional morphine challenge. Indicating a transient morphine tolerance in VTA DA neuron activity in rats was developed with a single dose of morphine treatment. It further demonstrated that this acute morphine tolerance was associated with impairment of opiate receptor-G protein coupling, indicating that down regulation of G-protein activation may contribute to acute morphine tolerance.[9]

Pharmacokinetic (metabolic) tolerance[edit]

Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs. All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action.

Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol.

This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug’s effect. However, it is only one of several mechanisms of tolerance

Behavioral tolerance[edit]

Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use; it may occur through drug-independent learning or as a form of pharmacodynamics tolerance in the brain; the latter mechanism of behavioral tolerance occurs when people learn how to actively overcome drug-induced impairments through practice. Behavioral sensitization describes the opposite phenomenon.

See also[edit]


  1. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. 
  2. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. 
  3. ^ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015. 
  4. ^ Drug Tolerance at the US National Library of Medicine Medical Subject Headings (MeSH)
  5. ^ Klaassen, Curtis D. (2001-07-27). Casarett & Doull's Toxicology: The Basic Science of Poisons (6th ed.). McGraw-Hill Professional. p. 17. ISBN 0-07-134721-6. 
  6. ^ Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR (2009). "Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone". Epilepsy Res. 83 (2–3): 261–4. doi:10.1016/j.eplepsyres.2008.10.011. PMID 19059761. 
  7. ^ Koch T, Höllt V (2008). "Role of receptor internalization in opioid tolerance and dependence". Pharmacol. Ther. 117 (2): 199–206. doi:10.1016/j.pharmthera.2007.10.003. PMID 18076994. 
  8. ^ Li, Y; Liu, X; Liu, C; Kang, J; Yang, J; Pei, G; Wu, C (2009). "Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter". International Journal of Molecular Sciences 10 (3): 954–963. doi:10.3390/ijms10030954. PMC 2672012. PMID 19399231. 
  9. ^ Zhang, Die; Zhang, Hai; Jin, Guo-Zhang; Zhang, Kehong; Zhen, Xuechu (2008). "Single dose of morphine produced a prolonged effect on dopamine neuron activities". Molecular Pain 4: 57. doi:10.1186/1744-8069-4-57. PMC 2603002. PMID 19014677.