beta-funaltrexamine and dynorphin-(1-8)

Stimulation of the perforant path, a major input to the hippocampal formation, produced significant decreases in the hippocampal levels of methionine enkephalin, dynorphin A(1-8) and an increase in the hippocampal level of gamma-aminobutyric acid. In addition, it was also observed that both mu and delta opioid receptor antagonists reduce wet dog shakes elicited by perforant path stimulation. The antagonists did not affect the changes in hippocampal levels of methionine enkephalin, dynorphin A(1-8) or gamma-aminobutyric acid. The results demonstrate that endogenous opioids are involved in the wet dog shakes elicited by perforant path stimulation. Since electrographic seizure activity occurs in the hippocampus in conjunction with perforant path stimulation-induced wet dog shakes, these data provide further evidence that endogenous opioid peptides play an important role in regulation of limbic system epileptogenic phenomena.

Topics: Animals; Dynorphins; Electric Stimulation; Enkephalin, Leucine; Enkephalin, Methionine; gamma-Aminobutyric Acid; Hippocampus; Male; Naltrexone; Peptide Fragments; Rats; Rats, Inbred F344; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Stereotyped Behavior

1. The agonist action of the opioid peptide dynorphin A(1-8) on the myenteric plexus-longitudinal muscle of the guinea-pig ileum has been characterized. 2. The endogenous opioid peptide dynorphin A(1-8) was rapidly degraded by slices of myenteric plexus-longitudinal muscle of the guinea-pig ileum. 3. A product of the degradation was the delta-receptor preferring [Leu5]enkephalin. Levels of [Leu5]enkephalin were markedly increased in the presence of the peptidase inhibitors bestatin, thiorphan and captopril. 4. In the myenteric plexus dynorphin A(1-8) acted as a kappa-receptor agonist. In the presence of bestatin, thiorphan and captopril a mu-receptor agonist effect was observed. This mu-agonist action was lost in the presence of N-[1-(RS)-carboxy-2-phenylethyl]Ala-Ala-Phe-p-aminobenzoate, an inhibitor of the endopeptidase enzyme EC 3.4.24.15. 5. The results suggest that formation of [Leu5]enkephalin from dynorphin A(1-8) may be an important conversion process. The enzyme responsible may be the Zn2(+)-metalloendopeptidase, EC 3.4.24.15.

Topics: Animals; Dynorphins; Enkephalin, Leucine; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle Contraction; Myenteric Plexus; Naltrexone; Narcotic Antagonists; Peptide Fragments; Receptors, Opioid

The opioid receptor preference of dynorphin A fragments, particularly of dynorphin A-(1-8) (DYN 8), has been evaluated in the mouse vas deferens by means of cross-tolerance studies, by their sensitivity to naloxone antagonism and by the use of the irreversible narcotic antagonist beta-funaltrexamine. The tolerance studies revealed kappa receptor activity for the longer fragments and delta activity for the shorter fragments. DYN 8 displayed kappa as well as delta activity, whereas no interaction with mu receptors was observed. The naloxone sensitivity of dynorphin A and its fragments was low with the exception of DYN 8, that displayed an intermediate sensitivity. There was no indication that this intermediate value for DYN 8 was due to an interaction with mu receptors. This conclusion was strengthened in experiments using beta-funaltrexamine. The kappa and delta activity of DYN 8 does not explain the intermediate sensitivity to naloxone. It is proposed that DYN 8 may interact in the mouse vas deferens with a different opioid receptor than the classical mu, kappa- and delta-type.

Topics: Animals; Drug Tolerance; Dynorphins; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Fentanyl; Male; Mice; Naloxone; Naltrexone; Peptide Fragments; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vas Deferens