Related Experiment Video

Updated: Mar 14, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

34.3K

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Catherine M Cahill1, Wendy Walwyn2, Anna M W Taylor2

  • 1Department of Anesthesiology and Perioperative Care, University of California, Irvine, 837 Health Sciences Road, Irvine, CA 92697, USA.

Trends in Pharmacological Sciences
|September 28, 2016
PubMed

Insights

Opioid tolerance involves cellular adaptations (cellular allostasis) and downstream effects (pass-forward allostasis) impacting brain circuitry. Neurons and microglia interact to drive tolerance to opioid drugs.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cellular Biology

Background:

  • Opioid tolerance mechanisms traditionally focus on cellular adaptations within opioid receptor-containing cells.
  • These adaptations, termed cellular allostasis, primarily involve regulating the opioid receptor signalosome.
  • Additional regulatory and opponent processes also contribute to behavioral tolerance.

Purpose of the Study:

  • To review mechanisms of opioid tolerance, including cellular and behavioral aspects.
  • To explore mechanistic differences between opioid receptor agonists (agonist bias) and between mu- and delta-opioid receptors.
  • To introduce and define 'pass-forward allostasis' as a key mechanism in opioid tolerance.

Main Methods:

  • Literature review and synthesis of existing research on opioid tolerance.
  • Analysis of cellular and systems-level adaptations to opioid exposure.
  • Examination of the roles of neurons and microglia in opioid tolerance.

Main Results:

  • Opioid tolerance involves both direct cellular adaptations (cellular allostasis) and indirect effects on downstream circuitry (pass-forward allostasis).
  • Pass-forward allostasis occurs because opioid-modified cells alter connected circuitry, broadly affecting the brain.
  • Neurons and microglia are identified as key interactive cellular contributors to cumulative allostatic processes.

Conclusions:

  • Opioid tolerance is a complex process involving multiple layers of allostasis, from the cellular signalosome to downstream neural networks.
  • Pass-forward allostasis highlights the widespread impact of opioid action throughout the brain.
  • Understanding these cumulative allostatic processes, involving neurons and microglia, is crucial for addressing analgesic and hedonic tolerance to opioids.
Keywords:
arrestinbias signalingdopaminemicrogliaopponent processesrewardμ opioid receptor

More Related Videos

Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis07:48

Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis

Published on: July 3, 2015

9.3K
Use of the Operant Orofacial Pain Assessment Device OPAD to Measure Changes in Nociceptive Behavior12:20

Use of the Operant Orofacial Pain Assessment Device OPAD to Measure Changes in Nociceptive Behavior

Published on: June 10, 2013

22.0K

Related Concept Videos

Analgesia and Pain Management01:25

Analgesia and Pain Management

Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
2.7K
Opioid Receptors: Overview01:22

Opioid Receptors: Overview

Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2,...
6.0K
Opioid Analgesics: Synthetic and Semisynthetic Opioids01:15

Opioid Analgesics: Synthetic and Semisynthetic Opioids

Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
1.3K
Desensitization and Tachyphylaxis01:20

Desensitization and Tachyphylaxis

Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
3.3K
Opioid Analgesics: Morphine and Other Natural Cogeners01:20

Opioid Analgesics: Morphine and Other Natural Cogeners

Opioids are a class of drugs that mimic endogenous opioid peptides and act on opioid receptors, and help in pain relief. These compounds are classified as natural, synthetic, or semi-synthetic. Natural opioids, like morphine, codeine, and thebaine, are derived from the opium poppy plant (Papaver somniferum or Papaver album) and are termed opiates. Synthetic opioids are artificial, while semi-synthetic opioids combine natural and synthetic compounds. Morphine, a prototypical opioid, possesses a...
1.3K
Drug Abuse and Addiction: Pharmacological Phenomena01:15

Drug Abuse and Addiction: Pharmacological Phenomena

Drug dependence, abuse, and addiction are complex phenomena that can precipitate various abnormal states. Physical dependence refers to a state of pharmacological adaptation to a drug. This adaptation often results in tolerance—a reduced response to the drug after repeated administrations. When the drug use is abruptly stopped, withdrawal symptoms occur due to the body's need to readjust from the pharmacologically induced imbalance. However, tolerance and withdrawal symptoms do not...
1.4K