mr-2266 and alpha-neoendorphin

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arthritis; Arthritis, Experimental; Benzomorphans; beta-Endorphin; Dynorphins; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Morphine; Naloxone; Nociceptors; Pain; Pituitary Gland, Anterior; Protein Precursors; Pyrrolidines; Rats; Receptors, Opioid; Sensory Thresholds; Spinal Cord; Thalamus

Magnocellular neurons synthesize vasopressin (VP) or oxytocin (OT) and release these hormones preferentially from the neural lobe during physiological stimulation. In the rat, VP is secreted preferentially during dehydration and hemorrhage, whereas OT is released without VP by suckling, parturition, stress, and nausea. Vasopressinergic neurons also synthesize and release dynorphin-related peptides--alpha- and beta-neoendorphin, dynorphin A (1-8) or (1-17), dynorphin B--which are agonists selective for kappa opiate receptors in the neural lobe. We proposed that one mechanism for preferential secretion of neurohypophysial hormones is that a dynorphin-related peptide(s) coreleased with VP inhibits selectively OT secretion from magnocellular neurons. We tested this hypothesis in conscious adult male Sprague-Dawley rats which were stimulated by either hypertonic saline administered intraperitoneally (2.5%, 20 ml/kg) or subcutaneously (1 M, 15 ml/kg) or by 24 h of water deprivation. Two approaches were used: (1) dynorphin-related peptides (0.02-20.4 mM) were injected intracerebroventricularly 1 min before decapitating the animal, and (2) the action of endogenous opioid peptides was blocked by injecting subcutaneously or intracerebroventricularly either naloxone or a selective kappa receptor antagonist, Mr 2266 or nor-binaltorphimine. VP and OT were measured by radioimmunoassay. After 24 h of water deprivation, the elevation in plasma [OT] but not [VP] was attenuated (p less than 0.05) by alpha-neoendorphin. Dynorphin A (1-8) also inhibited the release of OT and not VP after intraperitoneal administration of hypertonic saline. Blocking the action of endogenous opioid peptides at kappa receptors with Mr 2266 given peripherally (s.c.) elevated plasma [OT] but not [VP] after stimulation with hypertonic saline administered intraperitoneally or subcutaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzomorphans; Dehydration; Dynorphins; Endorphins; Hypertonic Solutions; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neurons; Osmolar Concentration; Oxytocin; Peptide Fragments; Pituitary Gland, Posterior; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Vasopressins

Methionine enkephalin, leucine enkephalin, [D-Ala2, D-Leu5] enkephalin, alpha-neoendorphin, beta-endorphin, dynorphin (1-13) and ethylketocyclazocine inhibited the contractions of rabbit ear artery ring segments elicited by transmural nerve stimulation at 8 Hz. Ethylketocyclazocine, dynorphin (1-13) and leucine enkephalin produced partial inhibition, their apparent intrinsic activities (alpha) being 0.57, 0.75 and 0.66, respectively. Morphine and normorphine, which are agonists at mu-receptors, did not inhibit the response of the artery. Naloxone antagonized the actions of opioids and ethylketocyclazocine, and was more effective against methionine enkephalin, leucine enkephalin and [D-Ala2, D-Leu5] enkephalin than against alpha-neoendorphin, ethylketocyclazocine and dynorphin (1-13). The pA2 values of naloxone against so-called delta-agonists were approx. 8.5, and against so-called kappa-agonists were approx. 7.7. The supposed kappa-antagonist, Mr2266, was more effective than naloxone in antagonizing the actions of alpha-neoendorphin, and the kappa-agonists dynorphin (1-13) and ethylketocyclazocine. The pA2 values of Mr2266 against kappa-agonists were 8.5-9.0, and against delta-agonists were 7.8 or less. The opioid peptides and opioids tested did not cause dilatation of the artery previously contracted with histamine. These results suggest that the opioid peptides and ethylketocyclazocine acted on opioid receptors at adrenergic nerve terminals in the ear artery. The opioid receptors appear to be of the delta- and kappa-types, not the mu-type.

Topics: Animals; Arteries; Benzomorphans; Ear; Electric Stimulation; Endorphins; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Naloxone; Narcotic Antagonists; Nerve Endings; Protein Precursors; Rabbits; Receptors, Opioid; Sympathetic Nervous System; Vasoconstriction

The choice of opiate receptor subtype by alpha- and beta-neo-endorphin was studied in isolated preparations. Neo-endorphins had significant inhibitory actions on the electrically evoked contractions of guinea-pig ileum, mouse vas deferens and rabbit ileum as well as on the rabbit vas deferens which had been shown to contain kappa-receptors exclusively. Mr 2266, a relatively specific kappa-receptor antagonist, was more effective than naloxone, a relatively mu-receptor antagonist, to antagonize the agonist actions of neo-endorphins in either the guinea-pig and rabbit ileum or in the rabbit vas deferens. By contrast, in the mouse vas deferens, the effectiveness of Mr 2266 to antagonize the agonist actions of neo-endorphins was low and similar to that of naloxone. The potencies of neo-endorphins relative to that of ethylketocyclazocine, a representative kappa-receptor agonist, in the guinea-pig ileum were similar to those in the rabbit ileum but were significant different from those in the mouse vas deferens. The data indicate that neo-endorphins act as kappa-receptor agonists in either the guinea-pig and rabbit ileum or in the rabbit vas deferens while in the mouse vas deferens they act on opiate receptor subtypes other than kappa- and mu-receptors.

Topics: Animals; Benzomorphans; beta-Endorphin; Cyclazocine; Drug Interactions; Endorphins; Enkephalins; Ethylketocyclazocine; Guinea Pigs; Ileum; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Naloxone; Protein Precursors; Rabbits; Receptors, Opioid