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Updated: Aug 23, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice
1Department of Anesthesiology, Stanford University and Veterans Affairs Palo Alto Health Care System, 112A, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. Djclark@stanford.edu
Abstract:
The chronic administration of morphine and related opioid drugs results in tolerance and dependence which reduces the clinical utility of these agents. The CO/NO-cGMP signal transduction cascade plays an important role in morphine tolerance. Principal components of this pathway include heme oxygenase (HO), nitric oxide synthase (NOS), soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (cGK). We measured and compared the spinal gene expression patterns of these key components using real-time PCR and Western blot analysis after chronic morphine treatment in mice. Our findings indicate that the CO/NO-cGMP signaling pathway is upregulated at multiple points after morphine exposure demonstrating a coordinated molecular and biochemical response. These findings underscore the importance of this signaling pathway in the neuroplastic events occurring during chronic opioid exposure and the value of analyzing the participation of multiple components of a signaling pathway simultaneously rather than individual members in isolation.
Insights
Chronic morphine use causes tolerance by upregulating the carbon monoxide/nitric oxide-cyclic guanosine monophosphate (CO/NO-cGMP) pathway in the spinal cord. This coordinated response highlights the pathway's role in opioid dependence.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic opioid administration, such as morphine, leads to tolerance and dependence, limiting their therapeutic use.
- The carbon monoxide/nitric oxide-cyclic guanosine monophosphate (CO/NO-cGMP) signaling cascade is implicated in the development of morphine tolerance.
Purpose of the Study:
- To investigate the spinal gene expression patterns of key CO/NO-cGMP pathway components after chronic morphine treatment in mice.
- To understand the coordinated molecular response within this pathway during opioid exposure.
Main Methods:
- Utilized real-time PCR and Western blot analysis to measure gene and protein expression.
- Examined key components: heme oxygenase (HO), nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), and cyclic GMP-dependent protein kinase (cGK).
- Administered chronic morphine to a mouse model.
Main Results:
- Chronic morphine treatment resulted in the upregulation of the CO/NO-cGMP signaling pathway at multiple points in the spinal cord.
- Demonstrated a coordinated molecular and biochemical response to morphine exposure.
- Observed significant changes in the expression of HO, NOS, sGC, and cGK.
Conclusions:
- The CO/NO-cGMP signaling pathway plays a crucial role in the neuroplastic changes associated with chronic opioid exposure.
- Simultaneous analysis of multiple pathway components is valuable for understanding complex signaling events in opioid tolerance.
- Findings support targeting this pathway for potential therapeutic interventions against opioid tolerance and dependence.
