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Cholera toxin and pertussis toxin on opioid- and alpha 2-mediated supraspinal analgesia in mice
1Neuropharmacology Unit, Cajal Institute, C.S.I.C., Madrid, Spain.
Abstract:
Cholera toxin, an agent that impairs the function of Gs transducer proteins, was injected (0.5 microgram/mouse, icv) and the antinociceptive activity of opioids and clonidine was studied 24h later in the tail-flick test. In these animals, an enhancement of the analgesic potency of morphine, beta-endorphin and clonidine could be observed. Cholera toxin did not modify the antinociception evoked by the enkephalin derivatives DAGO and DADLE. Pertussis toxin that catalyses the ADP ribosylation of alpha subunits of Gi/Go regulatory proteins was given icv (0.5 microgram/mouse). This treatment reduced the analgesic effect of opioids and clonidine. However, while the analgesia elicited by DAGO, DADLE and clonidine was greatly decreased, the effect of morphine and beta-endorphin was reduced to a moderate extent. It is concluded that Gi/Go regulatory proteins functionally coupled to opioid and alpha 2 receptors are implicated in the efficacy displayed by opioids and clonidine to produce supraspinal analgesia. Moreover, these two receptors are susceptible to regulation by a process that might involve a Gs protein.
Insights
Cholera toxin enhances opioid and clonidine analgesia by affecting Gs proteins. Pertussis toxin impairs opioid and clonidine pain relief by impacting Gi/Go proteins, indicating their role in supraspinal analgesia.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid and alpha-2 adrenergic agonists are key analgesics.
- The roles of Gs and Gi/Go proteins in mediating supraspinal analgesia are not fully understood.
Purpose of the Study:
- To investigate the involvement of Gs and Gi/Go proteins in the analgesic effects of opioids and clonidine.
- To elucidate the regulatory mechanisms of opioid and alpha-2 receptors.
Main Methods:
- Administration of cholera toxin (inhibits Gs) or pertussis toxin (inhibits Gi/Go) intracerebroventricularly in mice.
- Assessment of antinociceptive activity using the tail-flick test.
- Evaluation of the effects on analgesia induced by morphine, beta-endorphin, and enkephalin derivatives (DAGO, DADLE), and clonidine.
Main Results:
- Cholera toxin pretreatment enhanced the analgesic potency of morphine, beta-endorphin, and clonidine, but not DAGO or DADLE.
- Pertussis toxin pretreatment reduced the analgesic effects of all tested opioids and clonidine.
- The reduction in analgesia was more pronounced for DAGO, DADLE, and clonidine compared to morphine and beta-endorphin.
Conclusions:
- Gi/Go regulatory proteins are crucial for supraspinal analgesia mediated by opioid and alpha-2 receptors.
- Opioid and alpha-2 receptors may be regulated by a process involving Gs proteins.