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Updated: Aug 18, 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

Inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance in rats

María Teresa Santamarta1, Isabel Ulibarri, Joseba Pineda

  • 1Department of Pharmacology, Faculty of Medicine, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain.

Synapse (New York, N.Y.)
|April 29, 2005
PubMed

Insights

Nitric oxide synthase inhibition prevents morphine tolerance in rats. This study shows that blocking neuronal nitric oxide synthase with 7-nitroindazole attenuates opioid receptor desensitization and analgesic tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pain Research

Background:

  • Nitric oxide (NO) is implicated in acute opioid receptor desensitization.
  • Morphine tolerance, a decrease in drug efficacy with repeated use, is a significant clinical challenge.

Purpose of the Study:

  • To investigate the in vivo effect of neuronal nitric oxide synthase (NOS) inhibition on morphine-induced mu-opioid receptor tolerance.
  • To determine if blocking NO production can prevent the development of cellular and analgesic tolerance to opioids.

Main Methods:

  • Rats were treated with morphine to induce tolerance.
  • Neuronal NOS was inhibited using 7-nitroindazole (7-NI).
  • Mu-opioid receptor function was assessed via Met5-enkephalin's effect on locus coeruleus neuron firing rates and morphine's antinociceptive effects using tail-flick tests.

Main Results:

  • Morphine treatment induced a 5-fold rightward shift in Met5-enkephalin concentration-effect curves, indicating tolerance.
  • Co-administration of 7-NI fully prevented tolerance to Met5-enkephalin in the locus coeruleus.
  • 7-NI partially prevented the reduction in morphine's antinociceptive effect, indicating partial prevention of analgesic tolerance.

Conclusions:

  • Subchronic inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance.
  • Targeting neuronal nitric oxide synthase may offer a strategy to manage opioid tolerance.

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