Differential Effect of Chronic Morphine on MRNA Encoding Adenylyl Cyclase Isoforms: Relevance to Physiological Sequela of Tolerance/dependence

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.