dynorphins and ketazocine

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Choice Behavior; Cyclazocine; Diuresis; Drinking; Dynorphins; Eating; Endorphins; Ethylketocyclazocine; Humans; Morphine; Narcotic Antagonists; Phenazocine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Satiety Response

There is ample evidence from studies of peripheral isolated organs, binding of opiate receptor ligands to brain membranes and behavioural experiments that opiate receptors are not homogeneous but consist of different types such as the mu- (= morphine), delta- (= enkephalin), kappa- (= ketocyclazocine) and the epsilon- (= beta-endorphin) receptors. In addition, there are indications for subtypes within the particular classes of receptors, at least in the case of mu- and kappa-receptors. In one organ or particular brain structure, several types of receptors can be present-though big differences in the relative concentrations between various brain areas exist. The precise nature of the relationship between the multiplicity of opiate receptors and the multiplicity of endogenous opioids is not clear. The enkephalins and dynorphin appear to be, however, related to, respectively, delta- and kappa-receptors. According to our present knowledge, there is no strict relationship between certain physiological functions (or pharmacological actions) and the activation of a particular receptor type; for example, mu-, delta- and kappa-receptors are involved in pain modulation.

Topics: Animals; beta-Endorphin; Brain; Cyclazocine; Dynorphins; Endorphins; Enkephalins; Ethylketocyclazocine; Morphine; Receptors, Opioid; Tissue Distribution

Topics: Animals; beta-Endorphin; Brain; Cyclazocine; Dogs; Drug Tolerance; Dynorphins; Endorphins; Ethylketocyclazocine; Male; Mice; Morphine; Naloxone; Neuromuscular Junction; Phenazocine; Rabbits; Radioligand Assay; Rats; Receptors, Opioid; Synaptic Transmission

Gastric function was evaluated in rhesus monkeys during a continuous, s.c. infusion of three kappa agonists; dynorphin-(1-13), (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate hydrate) (U50,488H) and ketocyclazocine (KETO). A dye dilution technique was used to determine gastric fractional emptying rate, hydrogen ion, sodium ion and fluid secretion after the intragastric administration of a water meal. All agonists significantly inhibited fractional emptying rate after the water meal. The kappa receptor antagonist, (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, prevented the inhibitory response to dynorphin-(1-13) and partially blocked the effect of KETO, but, at the dose used in the present study, was completely ineffective against the specific kappa agonist, U50,488H. This suggests that dynorphin-(1-13) and U50,488H may not bind to the same kappa receptor isotype. The partial antagonism of KETO by both naloxone and (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate is consistent with a kappa/mu effect of this compound. Naloxone, at the dose used in these studies, did not modify the response to U50,488H. In contrast to their inhibitory action on gastric emptying, the kappa agonists, dynorphin-(1-13) and U50,488H, did not alter acid secretion. The suppressive action of KETO on acid secretion may be due to activation of mu receptors. The inhibitory effect of dynorphin-(1-13) on sodium output was blocked by (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, suggesting a role for kappa agonists in the control of nonparietal secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Cyclazocine; Dynorphins; Ethylketocyclazocine; Gastric Acid; Gastric Emptying; Macaca mulatta; Male; Narcotics; Peptide Fragments; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Sodium

The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The kappa-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other kappa-agonists Dynorphin-A (1-13) amide, and its protected analog D[Ala]2-dynorphin-A (1-13) amide also produced a significant increase in the formation of [3H]-IP's, whereas the mu-selective agonists [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin and morphine and the delta-selective agonist [D-Pen2,5]-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the kappa-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medulla. The results indicate that brain kappa- but neither mu- nor delta-receptors are coupled to the PI turnover response.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Brain; Cyclazocine; Dynorphins; Enkephalins; Ethylketocyclazocine; Male; Phosphatidylinositols; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Rats implanted with the Walker-256 (W-256) tumor exhibit marked anorexia that is most apparent at night. In this model, the hypothalamic kappa opioid system was examined for deficits that might contribute to this tumor-induced anorexia. In anorexic tumor-bearing rats (TBR), nocturnal levels of ir-DYN-8 were significantly reduced in the hypothalamus, but ir-DYN-17 levels were not. Accumulation of 3H-etorphine or 3H-ethylketocyclazocine, a putative ligand for the kappa receptor subtype, was not increased in the hypothalamus of the TBR, as might have been expected if there were less endogenous dynorphin to occupy the opioid receptors in this region. In vitro binding assays with 3H-ethylketocyclazocine indicated that dynorphin depletion in the TBR was not sufficient to increase the numbers of kappa opioid receptors in the hypothalamus. Also, the sensitivity of kappa opioid receptors involved in feeding was not altered in the TBR as indicated by an intact feeding response to ketocyclazocine. In summary, the marginal deficits of hypothalamic dynorphin in W-256 tumor-bearing rats that coincide with the phase of tumor-induced anorexia may contribute to the reduction in food intake.

Topics: Animals; Anorexia; Carcinoma 256, Walker; Circadian Rhythm; Cyclazocine; Dynorphins; Eating; Ethylketocyclazocine; Feeding and Eating Disorders; Hypothalamus; Male; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Dynorphin is one of the most potent appetite stimulants among the endogenous opioids. In this study, we describe the anorexic effects of 5 days of forced 2% NaCl drinking in rats, a regimen which depletes vasopressin as well as dynorphin in the neurohypophysis. Feeding induced by direct activation of kappa-opioid receptors with ketocyclazocine was unaffected by the NaCl regimen. However, 2% NaCl imbibition reduced 2-deoxy-D-glucose (2-DG) induced feeding by 65% and spontaneous nocturnal feeding by 38%. Feeding subsequent to 24 hour food deprivation was not decreased. Naloxone-resistant hyperphagia induced by insulin and spontaneous daytime feeding were also not reduced. The combination of naloxone (3.0 mg/kg) and the NaCl regimen produced an additional 50% reduction in 2-DG induced feeding and an extra 40% decrease in nocturnal feeding. Naloxone, given with 2% NaCl to food deprived animals, retained its appetite suppressing activity, indicating that the NaCl regimen did not deplete the endogenous opioid which mediates food deprivation hyperphagia. These results demonstrate that 2% NaCl imbibition suppresses certain opioid mediated hyperphagias. However, the failure of 2% NaCl to affect all of the naloxone-sensitive types of feeding and the independence of naloxone-sensitive and NaCl-sensitive components suggests that NaCl drinking does not deplete dynorphin in the brain areas which mediate opiate-sensitive hyperphagias.

Topics: Animals; Cyclazocine; Deoxyglucose; Dynorphins; Ethylketocyclazocine; Feeding Behavior; Insulin; Male; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Receptors, Opioid; Sodium Chloride; Time Factors

Nanomolar concentrations of neurotensin caused a dose-dependent contraction of the longitudinal muscle layer of the guinea-pig ileum. The contractile activity of neurotensin was partially blocked by tetrodotoxin or atropine, indicating that a component of the neurotensin-mediated contraction is indirect in nature and likely involves the release of endogenous acetylcholine from nervous terminals in the myenteric plexus. Dynorphin and related peptide fragments also blocked in part the neurotensin contraction; the potency of this opioid peptide was about the same as that of atropine. Other peptides and alkaloids tested for ability to block the neurotensin contractures included the enkephalins, beta-endorphin, normorphine and the ketocyclazocines; all these opioids inhibited in a dose-dependent fashion the neuronal component of the excitatory effect of neurotensin. The potency of these compounds to reduce the contractions of neurotensin showed good correlation with the potency of these agents to depress by 50% the electrically evoked neuromuscular twitches in the same tissue (r = 0.99); in these tests dynorphin was found to be the most potent of the endogenous opioid-like peptides. The dynorphin blockade was selective to the excitatory effect of neurotensin because the opioid peptide did not antagonize the contractile action of acetylcholine, histamine, substance P, angiotensin II, bradykinin, Ba++ or K+ ions. In addition, somatostatin, vasointestinal peptide, gastrin or adenosine did not modify the potency of neurotensin whereas thyrotropin releasing hormone and epinephrine caused a modest doubling of the neurotensin EC50. The inhibitory action of dynorphin was reduced in the presence of naloxone, suggesting that the interaction involved opiate receptors. Morphine tolerance was not extended to the inhibitory action of dynorphin as evidenced by the finding that the potency of dynorphin-(1-13) to block the neurotensin responses was increased after chronic morphine exposure. In contrast, the potency of dynorphin-(1-13) was significantly reduced in tissues rendered tolerant to the action of ketocyclazocine or ethylketocyclazocine, suggesting that the action of dynorphin could be partially mediated via occupation of K-opiate receptors. Thus, a cholinergic-neuronal component activated by neurotensin on the myenteric plexus appears to be under the inhibitory influence of opiate receptors, suggesting that dynorphin may play a role in the modulation of cholinergic sy

Topics: Animals; Atropine; Cyclazocine; Dose-Response Relationship, Drug; Drug Tolerance; Dynorphins; Endorphins; Ethylketocyclazocine; Guinea Pigs; Ileum; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Naloxone; Nerve Tissue Proteins; Neurotensin; Peptide Fragments; Receptors, Opioid; Tetrodotoxin

A number of lines of evidence have suggested that alterations in gonadal steroids may modulate opioid function. We report here the effects of manipulation of female gonadal steroids on the opioid feeding system. Naloxone produced a depression of feeding in all groups. Although the group X dosage interaction was not significant, an internally consistent tendency effect of naloxone among the different treatment groups was observed. Estradiol treated rats were 20 times less sensitive to naloxone's suppressive effects of feeding than ovariectomized animals. Sham operated controls and animals treated with estradiol and progesterone had sensitivities to naloxone which were intermediate to those seen in estradiol treated and ovariectomized animals. A significant drug X dosage interaction was present for the ketocyclazocine effects at 4 hours. Overall, ovariectomized animals were resistant to feeding induced by ketocyclazocine compared to the other groups. Ovariectomy significantly decreased ir-dynorphin levels in the cortex and these values were restored towards normal by a combination of estrogen and progesterone treatment. These studies add to the growing literature suggesting a role for the peripheral endocrine system in the modulation of opioid feeding system.

Topics: Animals; Appetite Regulation; Brain; Castration; Cyclazocine; Dynorphins; Eating; Estradiol; Ethylketocyclazocine; Female; Naloxone; Progesterone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Topics: Animals; Cyclazocine; Drug Interactions; Drug Tolerance; Dynorphins; Endorphins; Ethylketocyclazocine; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Naloxone; Peptide Fragments; Receptors, Opioid; Receptors, Opioid, kappa

Topics: Animals; Cyclazocine; Drug Tolerance; Dynorphins; Electric Stimulation; Endorphins; Enkephalin, Leucine; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Narcotics; Receptors, Opioid; Receptors, Opioid, kappa

Topics: Animals; Cyclazocine; Dynorphins; Electric Stimulation; Endorphins; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Receptors, Opioid; Receptors, Opioid, kappa