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PubMed1983

The binding to rat brain homogenates of Mr2034, a universal opiate.

Mr2034 has been proposed as a kappa opiate. While Mr2034 inhibited the binding of the kappa opiate 3H-ethylketocyclazocine better than unlabeled ethylketocyclazocine, it also displaced the binding of 3H-dihydromorphine and 3H-SKF 10047 more potently than morphine and SKF 10047, respectively. 3H-D-ala2-D-leu5-enkephalin was displaced equally well by Mr2034 and D-ala2-D-leu5-enkephalin. Saturation studies of 3H-Mr2034 binding demonstrated curvilinear Scatchard plots which could be dissected into two components by computer: KD1 0.06 nM, Bmax1 2.49 fmoles/mg tissue; and KD2 2.4 nM, Bmax2 6.57 fmoles/mg tissue. A portion of the higher affinity (KD 0.06 nM) component was inhibited by naloxonazine treatment in vitro (50 nM), suggesting that 3H-Mr2034 bound with very high affinity to mu1 sites. Displacement of 3H-Mr2034 binding by opioids was multiphasic, again implying that 3H-Mr2034 was binding to more than one class, of site. In view of its similar potency in inhibiting mu (3H-dihydromorphine), kappa (3H-ethylketocycla-zocine), sigma (3H-SKF 10047) and delta (3H-D-ala2-D-leu5-enkephalin) opioids Mr2034 might be considered a universal opiate.

Animals↗
PubMed1984

Bremazocine induces antinociception, but prevents opioid-induced constipation and catatonia in rats and precipitates withdrawal in morphine-dependent rats.

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.

Analgesics↗
PubMed1985

Multiple opiate receptors may be involved in suppressing gamma-aminobutyrate release in substantia nigra.

Slices of rat substantia nigra were preloaded with tritiated gamma-aminobutyrate (GABA) or dopamine (DA) and perfused with Krebs solution containing 5 microM aminooxyacetic acid or 10 microM nialamide to inhibit the catabolism of GABA and DA respectively. Repeated brief exposures to high potassium medium (+ 30 mM K+ for 1 min) evoked a consistent pattern of calcium-dependent 3H efflux against which the effects of opiates (10-400 microM) were assessed. Opiate agonists inhibited K+-induced 3H-GABA efflux in the following decreasing order of potency: bremazocine greater than D-Ala2-Met5-enkephalinamide (ENK) greater than SKF 10047 much greater than morphine, consistent with the participation of kappa, delta, sigma and to a lesser extent mu opiate receptors respectively. Naloxone (1 microM) partially antagonised the response to morphine and ENK, while ICI 154129 attenuated ENK only. Save for a GABA-releasing action of SKF 10047 at high doses, none of the compounds altered basal outflow of 3H-GABA. Naloxone, in the dose range 10-400 microM, also significantly inhibited depolarisation-induced release of 3H-GABA. In parallel experiments none of the compounds tested were found to influence 3H-DA release in concentrations up to 40 microM, but thereafter suppressed K+-induced 3H-DA outflow indiscriminately. The results are discussed with reference to the possible mechanism(s) via which injected and endogenous opiates may affect motor performance by attenuating GABA transmission in the nigra.

Aminooxyacetic Acid↗
PubMed1985

Selective presence of opiate receptors on intestinal circular muscle cells.

Smooth muscle cells isolated separately from the longitudinal and circular muscle layers of guinea pig and human intestine exhibited a unique pattern of response to derivatives of proenkephalin and prodynorphin present in the myenteric plexus. Receptors for other myenteric transmitters (acetylcholine, the octapeptide of cholecystokinin and substance P) capable of mediating contraction, were present on both circular and longitudinal muscle cells, whereas opiate receptors were present on circular muscle cells and selectively absent from longitudinal muscle cells in both species. The opiate myoreceptors belonged to the three main subclasses (kappa, delta and mu) and exhibited a rank order of sensitivity similar to that of opiate neuroreceptors. The distribution of these receptors parallels the distribution of opioid nerve fibers and appears to reflect the role of opioids in the regulation of neuromuscular activity.

Acetylcholine↗
PubMed1985

TENA, a selective kappa opioid receptor antagonist.

A number of opioid antagonists (TENA, naloxone, Mr 2266, WIN 44441) were evaluated for their selectivity in antagonizing the effect of mu, kappa, and delta agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Among these four antagonists, TENA was the most potent and the only ligand which was selective for kappa receptors. In this regard TENA was approximately 27-times more effective in antagonizing the kappa agonist, U-50488H, relative to the mu agonist, morphine, and it was about 5-times more effective against ethylketazocine (EK) relative to morphine. At the same concentration (20 nM) TENA did not significantly antagonize the delta agonist, [D-Ala2,D-Ala5]enkephalin (DADLE), in the MVD. Also, TENA was more effective than naloxone, EK, or U-50488H in protecting kappa receptors from irreversible blockage by beta-CNA. The results of this study indicate that TENA is the most selective kappa antagonist yet reported.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

A dose-ratio comparison of mu and kappa agonists in formalin and thermal pain.

The effects of putative mu and kappa agonists, with and without naloxone, were compared in the formalin and tail flick tests in rats. The mu agonist sufentanil was more potent in the tail flick test than the formalin test while the opposite was true for the kappa agonist ethylketocyclazocine (EKC). MR2034 was equipotent in the two tests and in the tail flick test, analgesia decreased at high doses. The naloxone (0.1 mg/kg) dose-ratios (DR) for sufentanil and EKC were 3 to 7 times larger for the tail flick test than the formalin test. From this and other DR studies it is argued that in thermal pain tests, opioid analgesia is mediated primarily by mu receptors while in non thermal tests kappa effects predominate.

Analgesia↗
PubMed1986

Opioid receptors of human placental villi modulate acetylcholine release.

The human placental villous tissue contains components of the cholinergic system and opioid receptors of the kappa type. In vitro stimulation of the villous tissue releases acetylcholine in organ baths. A selective kappa agonist, ethylketocyclazocine, inhibits the release of acetylcholine. This inhibition is reversed by the antagonist Mr 2266. The antagonist alone stimulates the release of acetylcholine 18-fold over control. These results demonstrate an interaction between the placental opioid receptors and the cholinergic system in a non-neural tissue. The modulation of acetylcholine release by endogenous opioid peptides could be one of the in vivo functions of placental opioid receptors.

Acetylcholine↗
PubMed1987

Opioid control of oxytocin secretion: evidence of distinct regulatory actions of two opiate receptor types.

Stress induced oxytocin (OT) secretion was measured in female rats following treatment with various opiate antagonists selective for different types of opiate receptor. Naloxone (mu selective) and MR2266 BS (kappa selective) potentiated the OT response to an emotional stress (1 min. immobilization) whereas the delta selective antagonist ICI 154129 was without effect. Similarly, naloxone and MR2266 BS, but not ICI 154129, potentiated the response to a physical stress (i.p. hypertonic saline). A dose response comparison of the actions of naloxone and MR2266 BS revealed that naloxone was most effective in potentiating the immobilization response whereas MR2266 BS elicited greater responses than naloxone when administered prior to hypertonic saline. The results indicate that the opioid regulation of stress induced OT secretion is primarily mediated via mu and kappa opiate receptor types, the two types differentially regulating the OT response to two different stressors.

Animals↗
PubMed1987

Reversal of the actions of morphine on mesocortical dopamine metabolism in the rat by the kappa agonist MR-2034: tentative mu-2 opioid control of mesocortical dopaminergic projections.

Morphine was shown to enhance dopamine metabolism, as assessed by increased dihydroxyphenylacetic acid measurements, in the mesocortical dopaminergic projections of the rat (cingulate, pyriform and prefrontal cortices). In contrast, the kappa agonist MR-2034 did not alter dopamine metabolism but did antagonize the actions of morphine. Similar antagonism of the actions of morphine were noted in the striatum and olfactory tubercle. These data suggest that the mesolimbic and mesocortical dopaminergic projections may possess a mu-2 opioid receptor regulation as previously defined for the nigrostriatal pathway.

Animals↗
PubMed1988

Regulation of feeding behaviour in monosodium glutamate (MSG) treated mice.

Regulation of food intake was studied in mice treated neonatally with MSG. A diurnal pattern of food intake with a significantly greater nocturnal intake was observed. In response to restricted food availability (4 hours/day). MSG mice increased intake progressively although less efficiently than control mice. The opioid kappa receptor agonist ketocyclazocine enhanced food intake. It is concluded that in MSG treated mice opioid kappa receptor mechanisms involved with regulation of food intake are basically intact.

Animals↗
PubMed1988

Characterization of opioid receptors on isolated canine gallbladder smooth muscle cells.

Smooth muscle cells were isolated from the fundus of the canine gallbladder and examined for the presence of opioid receptors. The cells contracted in a concentration-dependent manner in response to three opioid peptides (Met-enkephalin, dynorphin1-13 and Leu-enkephalin), which are known derivatives of opioid precursors present in myenteric neurons of the gut. The order of potency was Met-enkephalin greater than dynorphin1-13 greater than Leu-enkephalin. The contractile response to opioid agonists was selectively inhibited by opioid antagonists (naloxone and Mr2266) but not by muscarinic, CCK/gastrin or tachykinin antagonists. Equivalent responses to the three opioid peptides exhibited differential sensitivity to preferential antagonists of mu (naloxone) and kappa (Mr2266) opioid receptors consistent with the presence of the three main types of opioid receptors (mu, delta and kappa) on canine gallbladder muscle cells.

Animals↗
PubMed1988

Effect of opioid agonist-antagonist interaction on morphine dependence in rats.

Morphine dependence was induced by treatment with morphine-admixed food (0.25mg/g of food) for 7 days. Withdrawal was precipitated by injecting naloxone (0.5mg/kg, s.c.). Rats treated with morphine exhibited body weight loss upon the naloxone injection. When morphine-dependent rats were injected subcutaneously with morphine, codeine, meperidine and pentazocine 30 min before the naloxone injection, these drugs significantly suppressed the naloxone-precipitated loss of body weight in a dose-dependent manner. However, body weight loss induced through coadministration of naloxone and Mr-2266 BS were not suppressed by morphine pretreatment. These results suggest that opioids protect against naloxone-precipitated loss of body weight, and that mu and kappa opiate receptors play an important role in the protection against naloxone-precipitated withdrawal.

Animals↗
PubMed1988

The effect of bombesin on basal, alpha-methyl-p-tyrosine, haloperidol, morphine, bremazocine and stress-induced prolactin secretion.

Intravenously administered bombesin lowered basal PRL levels in conscious male rats and prevented the morphine, bremazocine and stress-induced PRL secretion. The same dose of bombesin had no effect on PRL levels in alpha-methyl-p-tyrosine pretreated rats and did not affect haloperidol-stimulated PRL release. These results show that bombesin given intravenously acts as an inhibitor of PRL secretion and suggests that it does not act on the lactotrope itself but rather by an increase of the inhibitory dopaminergic tone.

Analgesics↗
PubMed1988

Involvement of kappa type opioids on ethanol drinking.

The effects of the administration of the kappa agonist dynorphin1-17 and/or the kappa antagonist MR-2266-BS on ethanol preference was investigated using a paradigm by which rats develop alcohol preference. Administration of dynorphin shortly before or after the conditioning session (forced ethanol exposure) failed to affect later ethanol preference. However, dynorphin treatment prior to the first choice session reduced ethanol preference during the three consecutive testing days. This effect was reversed by the simultaneous administration of the kappa antagonist MR-2266-BS. The results of the present study provide further support for evidence of the involvement of dynorphinergic systems on drinking behavior and suggest that kappa-type opioid mechanisms may be involved in the consumption and development of preference to ethanol in rats.

Alcohol Drinking↗
PubMed1988

Interaction of U-69,593 with mu-, alpha- and kappa-opioid binding sites and its analgesic and intestinal effects in rats.

The kappa-opioid compound U-69,593 was studied in rats in vitro in binding assays to assess its selectivity at the single types of opioid sites and in vivo to assess its analgesic activity and effect on intestinal propulsion. In vitro the U-69,593 inhibition curve of [3H]-(-)-bremazocine binding suppressed at mu- and alpha-sites was biphasic and the inhibition constant (Kl) at the high-affinity site (10-18 nM) was two orders of magnitude smaller than the Kl at the low-affinity site. The Kl at mu- and alpha-sites were respectively 3.3 and 8.5 microM. Thus [3H]-(-)-bremazocine, suppressed at mu- and alpha-sites, may still bind more than one site, which U-69,593 might distinguish. In vivo U-69,593 i.p. prolonged the reaction time of rats on a 55 degrees C hot-plate and the dose of naloxone required to antagonize this effect was 40 times the dose that antagonized morphine-induced antinociception, suggesting the involvement of the kappa-receptor. In the intestinal transit test U-69,593 at doses between 0.5 and 15 mg/kg i.p. only slightly slowed intestinal transit of a charcoal meal in rats with no dose-relation; it partly but significantly antagonized morphine-induced constipation. These results suggest that the kappa-type of opioid receptor, with which U-69,593 interacts may induce analgesia, but has no appreciable role in the mechanisms of opioid-induced inhibition of intestinal transit in rats.

Animals↗
PubMed1988

Opioid binding site in EL-4 thymoma cell line.

Using EL-4 thymoma cell-line we found a binding site similar to the k opioid receptor of the nervous system. The Scatchard analysis of the binding of [3H] bremazocine indicated a single site with a KD = 60 +/- 17 nM and Bmax = 2.7 +/- 0.8 pmols/10(6) cells (51 pmols/mg total cell proteins). To characterize this binding site, competition studies were performed using selective compounds for the various opioid receptors. The k agonist U-50,488H was the most potent displacer of [3H] bremazocine with an IC50 value = 0.57 microM. The two stereoisomers levorphanol and dextrorphan showed the same affinity for this site (IC50 = 2.9 microM and 1.9 microM respectively). While morphine, [D-Pen2, D-Pen5] enkephalin and beta-endorphin failed to displace, except at very high concentrations, codeine demonstrated a IC50 = 60 microM, that was similar to naloxone (IC50 = 69 microM).

Analgesics↗
PubMed1989

Evidence for a model of activation of central sigma systems.

Evidence for a drug-induced activation of central sigma systems is presented. The model is the locomotor activation initiated by a subcutaneous (SC) challenge of 1.6 mg/kg of (+)-butaclamol, (+)-BUT, given 30 min before 10 mg/kg SC of (-)-N-allylnormetazocine, (-)-NAN, in Sprague-Dawley male rats which have been pretreated with four daily injections of 10 mg/kg SC of (-)-NAN. The locomotor activation is characterized by an initial 20 min period of retropulsion and sideways-circling followed by 90 to 100 min of forward locomotion. The locomotor syndrome is antagonized by 10 mg/kg of (+/-)-BMY 14802, 20 mg/kg of rimcazole, and 0.2 mg/kg of haloperidol, but not by 0.04 mg/kg of R(+)SCH23390, 100 mg/kg of S(-)sulpiride, 10 mg/kg of naltrexone, or 2.5 mg/kg of MR2266. The data suggest that the manifestation of the (+)-BUT/(-)-NAN-induced syndrome depends upon intact transmission at central sigma sites.

Animals↗
PubMed1989

Opioid binding properties of the purified kappa receptor from human placenta.

A glycoprotein with a molecular weight of 63,000 has been purified, in an active form, from human placental villus tissue membranes. The binding properties of this glycoprotein to opioid alkaloids and peptides indicates that it is the kappa opiate receptor of human placenta. The receptor binds the tritiated ligands etorphine, bremazocine, ethylketocyclazocine and naloxone specifically and reversibly with Kd values of 3.3, 4.4, 5.1 and 7.0nM, respectively. The binding of 3H-Bremazocine to the purified receptor is inhibited by the following compounds with the corresponding Ki values EKC, 1.3 x 10(-8)M; Dynorphin 1-8, 3.03 x 10(-7); U50,488H, 4.48 x 10(-9); U69-593,2.28 x 10(-8), morphine, 4.05 x 10(-6) DADLE, 6.47 x 10(-6) and naloxone, 2.64 x 10(-8). The purified receptor binds 8 nmole of 3H-Etorphine and 1.7 nmole 3H-BZC per mg protein. The theoretical binding capacity of a protein of this molecular weight is 15.8. Although the iodinated purified receptor appears by autoradiography as one band on SDS-PAGE, yet homogeneity of the preparation is not claimed.

Benzomorphans↗