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Determination of receptors that mediate opiate side effects in the mouse
Abstract:
The effects of mu and kappa-opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side-effects in man. These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion. The mu-receptor agonists tested produced opiate side-effects in the mouse at doses between 2.4 and 34 times higher than their antinociceptive doses in the abdominal constriction test. Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency. In contrast, the kappa-receptor agonists only produced opiate side-effects at doses between 29 and greater than 2500 times higher than their antinociceptive doses. There was no correlation between the potency ratios in these tests and in the abdominal constriction test. It is concluded that mu-receptor agonists may produce both their antinociceptive effects and opiate side-effects by interacting with the mu-receptor. The kappa-receptor agonists have previously been shown to produce antinociception via the kappa-receptor, but the opiate-like side-effects which appear with some of the drugs at much higher doses are probably due either to interaction with the mu-receptor or to some other non-specific action.
Insights
Mu- and kappa-opiate receptor agonists were tested for side effects in mice. Mu-receptor agonists caused side effects at lower doses than kappa-receptor agonists, suggesting different mechanisms for pain relief and side effects.
Area of Science:
- Pharmacology
- Neuroscience
- Opiate Receptor Research
Background:
- Opiate receptor agonists are used for pain relief but can cause side effects.
- Understanding the distinct roles of mu and kappa opiate receptors is crucial for developing safer analgesics.
Purpose of the Study:
- To investigate and compare the side effect profiles of mu- and kappa-opiate receptor agonists in mice.
- To determine the dose-response relationship between antinociception and side effects for both receptor types.
Main Methods:
- Administered mu- and kappa-opiate receptor agonists to mice.
- Assessed various physiological effects corresponding to clinical side effects (sedation, respiratory rate, etc.).
- Compared doses required for antinociception (abdominal constriction test) versus side effect induction.
Main Results:
- Mu-receptor agonists produced side effects at doses only 2.4–34 times higher than antinociceptive doses.
- Kappa-receptor agonists required much higher doses (29–>2500 times) for side effects compared to antinociception.
- Potency rankings for side effects closely mirrored antinociceptive potency for mu-agonists, but not for kappa-agonists.
Conclusions:
- Mu-receptor agonists likely mediate both antinociception and side effects via mu-receptor interaction.
- Kappa-receptor agonists' antinociception is via kappa-receptors, but high-dose side effects may involve mu-receptor interaction or non-specific actions.