Related Experiment Video

Updated: Jun 10, 2025

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

33.3K

Targeting exosomal double-stranded RNA-TLR3 signaling pathway attenuates morphine tolerance and hyperalgesia

Bing Wang1, Dong-Sheng Le2, Li Liu2

  • 1Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.

Cell Reports. Medicine
|October 16, 2024
PubMed

Insights

Long-term morphine use causes pain hypersensitivity by increasing spinal cord double-stranded RNA (dsRNA). Reducing dsRNA via ADAR1 or blocking its release prevents this, offering new pain management strategies.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Long-term morphine use in chronic pain patients leads to tolerance and hyperalgesia.
  • Neuroinflammation is implicated, but its mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of double-stranded RNA (dsRNA) in morphine tolerance and hyperalgesia.
  • To identify therapeutic targets for mitigating these morphine-induced side effects.

Main Methods:

  • Administered intrathecal morphine injections in a preclinical model.
  • Manipulated adenosine deaminase RNA specific 1 (ADAR1) expression using lentivirus.
  • Investigated dsRNA release via exosomes (Exos).
  • Utilized TLR3 signaling inhibitors and GW4869 to block exosome release.

Main Results:

  • Repeated morphine increased spinal neuron dsRNA by downregulating ADAR1.
  • Elevating ADAR1 reduced dsRNA levels and attenuated morphine tolerance/hyperalgesia.
  • Morphine-induced dsRNA is released via exosomes and activates microglia through TLR3-TRIF-IL-6 signaling.
  • Blocking exosome release or TLR3 signaling prevented morphine tolerance and hyperalgesia.
  • TLR3 inhibition alone provided analgesia in neuropathic pain and enhanced morphine's effects.

Conclusions:

  • Morphine tolerance and hyperalgesia involve increased dsRNA production and subsequent neuroinflammation.
  • Targeting the dsRNA-TLR3 signaling pathway presents a potential therapeutic strategy for managing morphine tolerance.
Keywords:
ADAR1TLR3double-stranded RNAmicrogliamorphine

More Related Videos

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence09:54

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence

Published on: March 8, 2020

5.2K
In Vivo SiRNA Transfection and Gene Knockdown in Spinal Cord via Rapid Noninvasive Lumbar Intrathecal Injections in Mice05:24

In Vivo SiRNA Transfection and Gene Knockdown in Spinal Cord via Rapid Noninvasive Lumbar Intrathecal Injections in Mice

Published on: March 22, 2014

46.5K

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...
540
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,...
555
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...
237
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...
188
Nociception01:44

Nociception

Nociception—the ability to feel pain—is essential for an organism’s survival and overall well-being. Noxious stimuli such as piercing pain from a sharp object, heat from an open flame, or contact with corrosive chemicals are first detected by sensory receptors, called nociceptors, located on nerve endings. Nociceptors express ion channels that convert noxious stimuli into electrical signals. When these signals reach the brain via sensory neurons, they are perceived as pain.
27.7K
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.
1.6K