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C Chavkin

Publications and source records attributed to C Chavkin.

99 records · Page 6Linked to original sources
PubMed1981

Specific receptor for the opioid peptide dynorphin: structure--activity relationships.

The structural features responsible for the high potency and opiate receptor specificity of the opioid peptide dynorphin in the guinea pig ileum myenteric plexus were examined. Successive removal of COOH-terminal amino acids from dynorphin-(1--13) demonstrated important contributions of lysine-13, lysine-11, and arginine-7 to the potency. Removal of the NH2-terminal tyrosine abolished the biologic activity. Several other structural modifications were shown to affect potency: substitution of D-alanine for glycine-2 reduced the potencies of dynorphin-(1--13) amide, -(1--11), and -(1--10); and methyl esterification of the COOH terminus enhanced the potencies of dynorphin-(1--12), -(1--10), -(1--9), -(1--8), and -(1--7). Within the dynorphin sequence, lysine-11 and arginine-7 were found to be important for selectivity of interaction with the dynorphin receptor, which is distinguishable from the mu receptor in this tissue.

Animals↗
PubMedDate not supplied

Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea.

Spare opiate receptors in the guinea pig ileum have been detected by the use of the opiate receptor alkylating agent beta-chlornaltrexamine (CNA). Treatment of the guinea pig ileum longitudinal muscle in vitro with low concentrations (less than 10nM) of CNA resulted in an irreversible parallel shift to the right of the normorphine log concentration response curve. With increasing concentration of the reagent, the agonist EC50 becomes progressively greater. Finally a point is reached at which the maximal agonist effect decreases, so that parallelism is no longer seen. The maximal parallel shift provides a measure from which one can estimate the spare receptor fraction that is present in untreated tissue. In ilea from normal guinea pigs, roughly 80-90% of the opiate receptors for normorphine were found to be spare. Even after the largest parallel shifts that could be achieved, the naloxone Ke value for antagonism was unchanged, indicating that normorphine acts through spare mu receptors. Ilea from guinea pigs made tolerant by chronic morphine pellet implantation were found to be more sensitive to the effects of CNA treatment; there was a reduction in the number of spare receptors for normorphine. It is suggested that the opiate spare receptor fraction is physiologically modulated to control neuronal sensitivity to opioid effect.

Animals↗
PubMedDate not supplied

The hypothesis that antagonism of fentanyl analgesia by 2-chloroprocaine is mediated by direct action on opioid receptors.

BACKGROUND AND OBJECTIVES: Although 2-chloroprocaine continues to be a useful drug for epidural anesthesia in obstetrics, it has the anomalous action of decreasing the analgesic effectiveness of subsequently administered epidural fentanyl. Some investigators have suggested that 2-chloroprocaine may act at an opioid receptor site to antagonize the effects of fentanyl. The purpose of our studies was to investigate this hypothesis. METHODS: Radioligand binding assays using the mu and kappa opioid receptor-selective radioligands [3H]-DAMGO and [3H]-U69,593, respectively, were performed to determine the potencies of lidocaine, 2-chloroprocaine, and 2-chloroprocaine metabolites at the mu and kappa opioid receptor sites. Electrophysiologic experiments in in vitro hippocampal slice preparations were then used to examine the effects of 2-chloroprocaine at these opioid receptor subtypes. RESULTS: Lidocaine caused a partial reduction of [3H]-DAMGO binding, which was dose-limited owing to the solubility of lidocaine. 2-Chloroprocaine caused complete displacement of [3H]-DAMGO binding, with a median effective concentration of 1.44 +/- 0.36 mM. The EC50 values for [3H]-U69,593 displacement were 177 +/- 47 microM for 2-chloroprocaine and 2.53 +/- 0.48 mM for lidocaine. Assuming a competitive interaction between anesthetic and opioid, the Ki value for 2-chloroprocaine was 435 microM at mu receptors and 49 microM at kappa receptors. In the mu activity bioassay, 2-chloroprocaine reversed the increased neuronal excitability caused by fentanyl, but this effect was further reduced by naloxone. In addition, 2-chloroprocaine did not reverse the after depolarization caused by fentanyl. In the kappa activity bioassay, 2-chloroprocaine produced effects similar to the kappa agonist U69, 593, but these were not antagonized by naloxone. CONCLUSIONS: Although 2-chloroprocaine has binding affinity at mu and kappa opioid receptor sites, it does not appear to act through an opioid receptor to antagonize the physiologic effects of fentanyl.

Analgesics↗