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Bremazocine differentially antagonizes responses to selective mu and delta opioid receptor agonists in rat
Abstract:
The effects of mu, delta and kappa opioid receptor agonists were examined on evoked field potentials in brain slices prepared from rat hippocampus. The effects of the mu-selective opioid peptide [D-Ala2, NMe-Phe4, Met(O)5ol]enkephalin (FK 33-824) and the delta-selective peptide [D-Pen2, D-Pen5]enkephalin (DPDPE) were qualitatively and quantitatively similar. Both increased the amplitude of evoked population spike responses when perfused in low nanomolar concentrations in a fashion consistent with what has been previously reported for other opiate agonists such as morphine. The kappa-selective agonists bremazocine and U-50, 488H were without effect upon evoked responses at concentrations as high as 10 microM. Bremazocine, but not U-50, 488H, proved to be an extremely potent antagonist of responses to both mu- and delta- selective agonists. Moreover, bremazocine was considerably more potent in antagonizing responses to FK 33-824 than DPDPE, which supports the hypothesis that FK 33-824 and DPDPE act via different receptors. Thus, although bremazocine is an agonist at kappa receptors, it appears to act as an antagonist at other opioid receptor sites.
Insights
Mu and delta opioid receptor agonists, FK 33-824 and DPDPE, enhanced hippocampal responses. Kappa agonists bremazocine and U-50,488H were ineffective, but bremazocine antagonized mu and delta effects, suggesting distinct receptor actions.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid receptors (mu, delta, kappa) modulate neuronal activity.
- Understanding receptor-specific effects is crucial for drug development.
Purpose of the Study:
- To investigate the effects of mu, delta, and kappa opioid receptor agonists on hippocampal evoked potentials.
- To characterize the antagonistic properties of kappa agonists.
Main Methods:
- Electrophysiological recordings of evoked field potentials in rat hippocampal slices.
- Application of selective mu (FK 33-824), delta (DPDPE), and kappa (bremazocine, U-50,488H) opioid receptor agonists and antagonists.
Main Results:
- Mu and delta agonists (FK 33-824, DPDPE) increased evoked population spike amplitude.
- Kappa agonists (bremazocine, U-50,488H) had no effect at high concentrations.
- Bremazocine potently antagonized mu and delta agonist effects, with greater potency against FK 33-824 than DPDPE.
Conclusions:
- Mu and delta opioid receptor activation enhances hippocampal excitability.
- Bremazocine acts as a kappa agonist but an antagonist at mu and delta receptors.
- FK 33-824 and DPDPE likely act via distinct mu and delta receptor subtypes.