Related Experiment Video

Updated: Mar 7, 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

Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo

Cherkaouia Kibaly1, Hong-Yiou Lin2, Horace H Loh1

  • 1Department of Pharmacology and Basic Research Center on Molecular and Cell Biology of Drug Addiction, University of Minnesota, Minneapolis, MN 55455, USA.

Pharmacological Research
|February 10, 2017
PubMed

Insights

Morphine tolerance mechanisms remain unclear. This study found that μ-opioid receptor (MOR) C-terminus phosphorylation is not critical for morphine tolerance, unlike fentanyl tolerance, suggesting different pathways for these analgesics.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Development of tolerance to morphine, a potent analgesic, presents a significant clinical challenge in chronic pain management.
  • Mechanisms underlying opioid tolerance, particularly concerning the μ-opioid receptor (MOR), are not fully understood.
  • G-protein-coupled receptor (GPCR) phosphorylation and subsequent desensitization are implicated in tolerance, but specific roles for different agonists vary.

Purpose of the Study:

  • To investigate the contribution of μ-opioid receptor (MOR) C-terminus phosphorylation to the development of antinociceptive tolerance.
  • To compare the roles of MOR C-terminus phosphorylation in tolerance to morphine (partial agonist) versus fentanyl (full agonist) in vivo.
  • To elucidate the differential mechanisms of tolerance for various MOR agonists.

Main Methods:

  • Utilized MOR knockout (MORKO) mice and lentiviral gene delivery to express wild-type MOR (WTMOR) or phosphorylation-deficient MOR (Cterm(-S/T)MOR) in key pain pathways (vlPAG and SC).
  • Assessed and compared analgesic efficacy (ED50) and tolerance development after morphine or fentanyl administration in modified MORKO mice.
  • Examined the impact of MOR C-terminus phosphorylation status on antinociceptive tolerance in vivo.

Main Results:

  • Morphine-induced antinociception was partially restored in MORKO mice expressing either WTMOR or Cterm(-S/T)MOR.
  • Fentanyl-induced antinociception was observed only when transgenes were expressed in the spinal cord (SC).
  • Crucially, morphine antinociceptive tolerance was unaffected by the expression of the phosphorylation-deficient Cterm(-S/T)MOR in either the vlPAG or SC.
  • Fentanyl induced greater tolerance than morphine in MORKO mice expressing WTMOR or Cterm(-S/T)MOR.

Conclusions:

  • μ-opioid receptor (MOR) C-terminus phosphorylation does not appear to be a critical factor in the development of morphine-induced antinociceptive tolerance in vivo.
  • Differential mechanisms may underlie tolerance to morphine and fentanyl, highlighting the complexity of opioid analgesia and tolerance.
  • Findings suggest that targeting MOR C-terminus phosphorylation may not be effective for mitigating morphine tolerance.
Keywords:
C-terminus phosphorylationFentanylFentanyl hydrochloride: CID: 83932Formaldehyde − Paraformaldehyde: CID: 712Isoflurane: CID: 3763Ketamine: CID: 3821MorphineMorphine sulfate: CID: 16051935Pentobarbital sodium: CID: 23676152ToleranceXylazine hydrochloride: CID: 68554mu-opioid receptor (MOR)

More Related Videos

3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache10:39

3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache

Published on: June 2, 2014

18.8K
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

47.9K

Related Concept Videos

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,...
5.7K
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...
2.5K
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
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
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
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