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Differential effect of chronic morphine on mRNA encoding adenylyl cyclase isoforms: relevance to physiological
1Department of Biochemistry, State University of New York, Health Sciences Center, Brooklyn 11203, USA.
Abstract:
In opiate naive longitudinal muscle myenteric plexus tissue, facilitation (GS-mediated) and inhibition (Gi-mediated) of adenylyl cyclase (AC) activity is observed in response to low (nM) and high (microM) concentrations of sufentanil, respectively. Following chronic in vivo exposure to morphine, previously inhibitory concentrations produce excitatory effects. The present study was undertaken to explore the potential relevance of AC isoform-specific regulation to the qualitative change in opioid responsiveness following chronic morphine. Following persistent activation of opiate receptors, levels of AC I mRNA remain unchanged but that of AC IV is significantly augmented (approximately 37%, P < 0.05). AC I and IV are differentially regulated by G alpha i and G beta gamma. The former is inhibited by G alpha i and G beta gamma whereas the latter is relatively insensitive to G alpha i and is stimulated by G beta gamma. Thus, an increase in AC IV mRNA could represent a shift from inhibitory to stimulatory opiate receptor-G protein signalling, as has been observed following chronic morphine. These results indicate that persistent activation of opiate receptors can induce selective changes in the abundance (activity) of AC isoforms. This could explain, in part, some of the adaptations that occur following chronic in vivo morphine exposure.
Insights
Chronic morphine exposure alters opioid receptor signaling by changing adenylyl cyclase (AC) isoform levels. This shift from inhibitory to stimulatory signaling helps explain adaptations to long-term opioid use.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid receptors modulate adenylyl cyclase (AC) activity via G proteins.
- Chronic opioid exposure can lead to altered cellular responses and tolerance.
- The specific molecular mechanisms underlying these changes in AC regulation are not fully understood.
Purpose of the Study:
- To investigate the role of adenylyl cyclase (AC) isoform regulation in altered opioid responsiveness after chronic morphine exposure.
- To explore how chronic morphine affects the expression of specific AC isoforms in the myenteric plexus.
- To determine the differential regulation of AC isoforms by G protein subunits.
Main Methods:
- Measurement of adenylyl cyclase (AC) I and AC IV mRNA levels in myenteric plexus tissue.
- Analysis of AC isoform regulation by G alpha i and G beta gamma subunits.
- Comparison of AC activity in opiate-naive versus chronically morphine-exposed tissues.
Main Results:
- Chronic morphine exposure significantly increased the mRNA levels of adenylyl cyclase (AC) IV by approximately 37%.
- AC I mRNA levels remained unchanged following chronic morphine exposure.
- AC IV demonstrated relative insensitivity to G alpha i inhibition and stimulation by G beta gamma, contrasting with AC I.
Conclusions:
- Persistent activation of opioid receptors by chronic morphine induces selective changes in adenylyl cyclase (AC) isoform abundance.
- Increased AC IV mRNA levels may contribute to a shift from inhibitory to stimulatory opioid receptor-G protein signaling.
- These findings provide a molecular explanation for adaptations observed following chronic in vivo morphine exposure.