dynorphins and tifluadom

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

Dynorphin 1-17 has been suggested to be the endogenous ligand for kappa opioid receptors. In this study motor effects of dynorphin 1-17, its N-terminal fragments d-Pen2,d-Pen5-enkephalin (DPDPE) and d-Ser2-[Leu5]enkephalin-Thr (DSLET) without or with pretreatment with naloxone, (-)-2-(furylmethyl)-noretacocine (Mr 2266) or tetrodotoxin (TTX) on the isolated rat colon were compared with those of nonpeptide kappa opioid receptor agonists. Intraluminal pressure changes were measured by perfusion manometry in preparations maintained in a standard organ bath. Dynorphin 1-17, 1-9, 1-8, 1-6, [Leu5]enkephalin, DPDPE and DSLET dose dependently stimulated the tone in the proximal, middle and distal colon with the maximum response at 10(-6) to 10(-5) M. The stimulation produced by Tyr-Gly-Gly-Phe and Tyr-Gly-Gly was 60 and 600 times less potent, respectively. Concentrations of 10(-10) to 10(-6) M des-Tyr1-[Leu5]enkephalin, dynorphin 3-13, 6-17, 1-methyl-2-(3-thienylcarbonyl)-amino-ethyl-5-(2-fluorophenyl)-H-2,3 dihydro-1,4-benzodiazepine, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl) cyclohexyl)-benzene- acetamide-methane sulfonate and (5a,7a,8B)-(-)-N-methyl-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8- yl) benzeneacet-amide produced no changes in motor activity of the rat colon. Only doses exceeding 10(-6) M of the latter three substances stimulated colonic tone. This action was inhibited neither by naloxone nor by Mr 2266. In contrast, the stimulation by dynorphin 1-17 and 1-6 was inhibited to a greater extent by naloxone than by Mr 2266.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antihypertensive Agents; Benzeneacetamides; Benzodiazepines; Benzomorphans; Colon; Diuretics; Dynorphins; Gastrointestinal Motility; In Vitro Techniques; Male; Muscle, Smooth; Naloxone; Narcotic Antagonists; Pressure; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

The intrathecal injection of a variety of selective kappa-opioid receptor ligands did not result in significant inhibition of thermal nociceptive tail flick responses in rats. In contrast, these compounds dose dependently inhibited pressure nociceptive responses. Cross-tolerance studies revealed that the kappa-opioid receptor ligands tifluadom, U-50488H and dynorphin-(1-17) act upon a receptor distinguishable from the receptor through which morphine exerts its inhibition of mechanical nociceptive responses. The less selective kappa-opiate receptor ligands bremazocine and ethylketocyclazocine (EKC), however, blocked both tail flick and tail pressure nociceptive responses and their effect showed marked cross-tolerance to morphine in the tail flick nociceptive test, but not for the pressure nociceptive responses. We suggest that EKC and bremazocine act upon the spinal kappa-opioid receptor to block mechanical nociceptive responses but that the analgesic effect of EKC and bremazocine on thermal nociceptive responses is probably mediated via spinal micron- and/or delta-, and delta-opioid receptors, respectively.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Cyclazocine; Drug Tolerance; Dynorphins; Ethylketocyclazocine; Injections, Spinal; Male; Morphine; Pyrrolidines; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Opioid; Receptors, Opioid, kappa; Spinal Cord

The effect of tifluadom (TIF), a postulated kappa-opiate agonist with a benzodiazepine (Bz) structure, on the binding of [3H][3-MeHis2]thyrotropin releasing hormone [( 3H]MeTRH) to receptors for thyrotropin releasing hormone (TRH) in membranes from rat brain was determined. Tifluadom inhibited the binding of [3H]MeTRH with an IC50 value of 1.88 microM. When the binding was carried out in the presence of an IC20 concentration of tifluadom, the Bmax value of [3H]MeTRH was decreased by 20% but no change in the Kd value was noted, indicating that the inhibition was apparently noncompetitive. Ro 15-1788 a benzodiazepine antagonist, as well as bicuculline, a gamma-aminobutyric acid (GABA) antagonist did not antagonize the effect of tifluadom on the binding of [3H]MeTRH suggesting that the benzodiazepine receptors are not involved in the action of tifluadom. Since tifluadom is suggested to be a kappa-opioid agonist, the effect of other kappa-opiate ligands were also tested for their ability to affect TRH receptors. The drugs used were ethylketocyclazocine, dynorphin(1-13) and 5-bromo-6-(2-imidazoline-2-ylamino)quinoxaline (U-50,488H). The order of potency of these compounds to inhibit the binding of [3H]MeTRH to membrane from the rat brain was in the following order: tifluadom greater than U-50,488H greater than dynorphin-(1-13) greater than ethylketocyclazocine. It is concluded that tifluadom inhibits the binding of [3H]MeTRH to receptors in brain in a noncompetitive manner. The effect does not appear to be mediated through benzodiazepine receptors but possibly through kappa-opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analysis of Variance; Animals; Benzodiazepines; Brain; Cyclazocine; Dynorphins; Ethylketocyclazocine; Kinetics; Male; Peptide Fragments; Pyrrolidines; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Thyrotropin-Releasing Hormone; Thyrotropin-Releasing Hormone

By selectively blocking cross-interferences from other types of binding sites, a binding site which likely represents kappa opioid binding sites was obtained in the guinea-pig brain suspension of the particulate fraction. Selective ligands for mu, sigma, delta and epsilon opioid binding sites were poor inhibitors for inhibiting [3H]ethylketocyclazocine binding to this site, whereas kappa opioids like oxilorphan, dynorphin(1-13), ethylketocyclazocine, butorphanol, cyclazocine, ketocyclazocine, tifluadom, nalorphine, pentazocine, U-50-488, nalbuphine and naloxone were potent ligands. Buprenorphine, generally believed to be a mu opiate, was the most potent inhibitor at the kappa site. Scatchard analysis of the saturation curve of [3H]ethylketocyclazocine binding revealed two subtypes of kappa binding sites: a high-affinity site and a low-affinity site with Kd = 0.7 and 78 nM and maximum binding = 22 and 101 fmol/mg of protein, respectively. Analysis of the inhibition curves suggested that tifluadom may be a selective ligand for the high-affinity site and that dynorphin(1-13) and U-50-488 may bind preferentially the high-affinity site but still possess appreciable affinity for the low-affinity site. This study demonstrates a selective assay for kappa opioid binding sites and indicates a possibility of the heterogeneity of kappa opioid binding sites in the brain.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Binding Sites; Brain; Cyclazocine; Dynorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethylketocyclazocine; Etorphine; Guinea Pigs; Levallorphan; Peptide Fragments; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism

3H-Tifluadom labels specifically recognition sites of opioid kappa receptors. Membranes of guinea-pig whole brain bind 3H-tifluadom with two affinities, in contrast to the cerebellum where almost all opioid sites are kappa.

Topics: Animals; Benzodiazepines; Benzomorphans; Binding Sites; Brain; Cyclazocine; Dihydromorphine; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Male; Morphine; Receptors, Opioid