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Altered mu-opiate receptor-G protein signal transduction following chronic morphine exposure
1Department of Biochemistry, State University of New York, Health Science Center at Brooklyn 11203, USA.
Abstract:
This laboratory has demonstrated that the longitudinal muscle/myenteric plexus (LMMP) preparation manifests pleiotropic responses to opioid agonists. For example, the mu-selective opiate receptor agonist sufentanil can produce a naloxone-reversible increase or decrease in the electrically stimulated formation of cyclic AMP, depending on its concentration. The present study demonstrates that the sufentanil facilitation and inhibition of stimulated cyclic AMP formation are mediated via Gs- and Gi-like G proteins, respectively. Inactivation of Gi (via pertussis toxin) not only abolishes sufentanil inhibition of cyclic AMP formation but also unmasks a facilitory effect. The latter response is eliminated following treatment with cholera toxin. In tolerant/dependent LMMP tissue, previously inhibitory concentrations of sufentanil produce a facilitation of cyclic AMP formation. However, this unmasked facilitory effect is resistant to cholera toxin. Thus, although inactivation of the inhibitory signal transduction pathway (via pertussis toxin) is sufficient to unmask excitatory sufentanil effects in opiate naive preparations, this mechanism cannot explain the reversal of sufentanil inhibition to facilitation that is observed in tolerant/dependent tissue. Instead, the chronic morphine-induced emergence of a mu-opiate receptor-coupled facilitory pathway that is either not expressed or not fully manifest in opiate naive LMMP tissue is suggested.
Insights
Opioid agonists like sufentanil have complex effects on cyclic AMP formation in the longitudinal muscle/myenteric plexus. Tolerance to opioids reveals a new facilitory pathway, suggesting distinct signaling mechanisms in opioid-naive versus tolerant tissues.
Area of Science:
- Pharmacology
- Neuroscience
- Gastrointestinal Physiology
Background:
- Opioid agonists exhibit diverse effects on cyclic AMP (cAMP) formation in the longitudinal muscle/myenteric plexus (LMMP) preparation.
- Sufentanil, a mu-selective opioid agonist, can either increase or decrease cAMP levels reversibly, depending on concentration.
- The underlying signaling pathways for these pleiotropic responses are not fully elucidated.
Purpose of the Study:
- To investigate the G protein-mediated signaling pathways responsible for sufentanil's dual effects on cAMP formation in LMMP.
- To explore the mechanisms behind the altered sufentanil response observed in opioid-tolerant/dependent LMMP tissue.
Main Methods:
- Utilized pertussis toxin and cholera toxin to selectively inactivate Gi-like and Gs-like G proteins, respectively.
- Measured electrically stimulated cAMP formation in LMMP preparations from opioid-naive and tolerant/dependent rats.
- Administered sufentanil at varying concentrations to assess its effects on cAMP levels under different experimental conditions.
Main Results:
- Sufentanil's inhibition of cAMP formation is mediated by Gi-like G proteins, while facilitation involves Gs-like G proteins.
- Inactivation of Gi-like proteins with pertussis toxin unmasked a facilitory effect, which was abolished by cholera toxin.
- In tolerant/dependent LMMP, previously inhibitory sufentanil concentrations induced facilitation, a response resistant to cholera toxin.
Conclusions:
- Sufentanil's dual effects on cAMP are mediated by distinct Gs- and Gi-like G protein pathways.
- While Gi inactivation unmasks facilitation in naive tissue, it doesn't explain the reversal of inhibition to facilitation in tolerant tissue.
- Chronic morphine exposure likely induces a novel mu-opiate receptor-coupled facilitory pathway in tolerant LMMP.