Disease relevance of U 50488

• However, after exposure to U-50,488H (5 x 10(-7) M), naloxone (10(-6) M) produced a strong contracture if the agonist was washed out 1 min before the addition of the antagonist [1].
• Previous studies have reported that large (microM) concentrations of kappa opioids, e.g. dynorphin and 3,4 dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzene-acetamide (U-50,488H), shorten the duration of the calcium component of the action potential of dorsal root ganglion neurons by decreasing a voltage-sensitive Ca2+ conductance [2].
• The effects of the optical isomers and the racemic form of ketocyclazocine (KC) were compared with morphine and U-50,488H in the chronic spinal dog. l-KC and dl-KC produced depression of nociceptive reflexes, miosis, relaxation of the nictitating membrane and sedation, whereas d-KC lacked pharmacological activity [3].
• Similarly, U-50,488H also produced a dose-dependent hypothermia in mice [4].
• The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone [5].

Psychiatry related information on U 50488

• No significant change in spontaneous locomotor activity was measured in the open field apparatus, suggesting that U-50,488H was devoid of sedative effects in the dose range tested (0.1-1000 micrograms/kg, IP) [6].
• The effect of U-50,488H was consistent with de-satiation, so that the increase in feeding duration was in evidence from the start of the test period, while the temporal pattern of later satiation was preserved but lagged behind that of control animals [7].
• Day-night rhythms in feeding behavior and response to the specific kappa opioid agonist U-50,488H (0.10-10. mg/kg) were measured in young (1-2 months), mature (8-12 months) and old (24-30 months) male CF-1 mice [8].
• Effects of a selective kappa-opioid agonist, U-50,488H, on morphine dependence in rats [9].
• Intra-VTA NBNI prevented U-50,488H-induced decreases in the mean number of ejaculations, intra-NAS NBNI prevented U-50,488H-induced increases in copulation latencies [10].

High impact information on U 50488

• These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H [11].
• Leucine enkephalin (10(-8) M) had no effect, whereas U-50,488H (10(-5) M) increased myofilament responsiveness to Ca2+ [12].
• Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice [13].
• The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U-50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats [14].
• In single cardiac myocytes, acute stimulation of K opioid receptors with dynorphin B or with the selective agonist U-50,488H increased the level of cytosolic calcium [15].

Chemical compound and disease context of U 50488

• The aim of the present study was to determine whether U-50,488H and U-62,066E, kappa-opioid receptor agonists cause a neuroprotective action against hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose (2-DG) uptake of hippocampal slices from U-50,488H-tolerant rats [16].
• Effects of pertussis toxin on behavioural responses of guinea-pigs to centrally administered substance P, quinpirole, carbachol, U-50,488H, morphine and morphine withdrawal [17].
• The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex [5].
• Multiple injections of U-50,488H resulted in a slower gain in body weight which was not modified by treatment with NMMA [18].

Biological context of U 50488

• The kappa-opioid receptor agonists including U-50,488H and dynorphin A (1-17) in ranges of 0.1-100 nM inhibited the hydrolysis of GTP to GDP (P(i) release) inherent in GTP-binding proteins (G proteins) in guinea pig cerebellar membranes [19].
• Thus, U-50,488H-induced prolongation of the action potential appears to be mediated by a kappa subtype of receptor that produces the opposite effect on Ca2+ channels to that which occurs during kappa opioid-induced shortening of the action potential.(ABSTRACT TRUNCATED AT 250 WORDS)[2]
• 2. U-50,488H dose-dependently decreased left-ventricular peak systolic pressure and beating rate in vitro and reduced blood pressure and heart rate in vivo [20].
• Both DPDPE (30 micrograms) and U-50,488H (100 micrograms) caused decreases in body temperature which were accompanied by a selection of a cool ambient temperature [21].
• Using a receptor binding assay, repeated treatment with (-)U-50,488H significantly increased the density of [3H]DAMGO binding sites in membranes of the mouse spinal cord [22].

Anatomical context of U 50488

• Pretreatment of the membranes with kappa-selective compounds [ethylketocyclazocine (EKC), dynorphin (1-13), or U-50,488H] but not with [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO; mu specific ligand) or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DADLE; delta specific ligand) strongly protects the binding of the radioligands against NEM inactivation [23].
• Using immunohistochemical staining of Fos, the present results indicate that acute treatment with either morphine or U-50,488H induces marked Fos immunoreactivity within the hypothalamus, including the medial parvicellular PVN and supraoptic and suprachiasmatic nuclei [24].
• In addition, spinal U-50,488H produced changes in mechanical and thermal thresholds of the majority of superficial dorsal horn neurons [25].
• Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding assay, we found that (-)U-50,488H was able to produce a nor-BNI-reversible increase in [35S]GTP gamma S binding to membranes of the mouse thalamus, which has a high level of kappa-opioid receptors [26].
• One-third of the cells exhibited expansion of their receptive fields as defined using mechanical stimuli following a spinal kappa agonist (dynorphin or U-50,488H); receptive field expansions were of the same order as those observed immediately after a conditioning electrical stimulus applied to a peripheral nerve [25].

Associations of U 50488 with other chemical compounds

• Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTP gamma S binding in this region, whereas chronic treatment with (-)U-50,488H exhibited the increase in the endomorphin-1-, endomorphin-2- and DAMGO-stimulated [35S]GTP gamma S bindings in membranes of the thalamus and periaqueductal gray [26].
• All compounds were found to produce analgesia after i.c.v. administration; the rank order of potency by the i.c.v. route was DAGO greater than DTTLE greater than morphine greater than DPLPE greater than DPDPE greater than U-50,488H [27].
• Sufentanil, morphine, met-enkephalin, and kappa-agonist (U-50,488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions [28].
• Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia [29].
• Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 mumol) > PD117302 (2 mumol); spiradoline (11 mumol) morphine (9 mumol) > DPDPE (> 5 mumol); DADL (18 mumol) > U-50,488H (22 mumol) > naloxone = 0 [30].

Gene context of U 50488

• Changes in the properties of the kappa-opioid, 5-HT1 and 5-HT2 receptor binding sites in the cortical, striatal and spinal tissues of control and U-50,488H-tolerant mice were investigated [31].
• 5-HT receptor antagonists (pindolol or ketanserin) were coadministered with U-50,488H to test for their effect on the development of tolerance to U-50,488H [31].
• Mice deficient in the kappa-opioid receptor (KOR) gene have recently been developed by the technique of homologous recombination and shown to lack behavioural responses to the selective kappa1-receptor agonist U-50,488H [32].
• Generalization of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists U-50,488H, but not TRK-820 in rats [33].
• We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic kappa-agonist U-50,488H [34].

Analytical, diagnostic and therapeutic context of U 50488

• We found similar dose-related analgesia when we tested the selective mu agonist [Try-D-Ala-Gly-NMe-Phe-Gly-ol] (0.01-1 microgram), the selective kappa receptor ligand U-50,488H (100-500 micrograms), the selective delta agonist [D-Pen2,5]-enkephalin (50-200 micrograms) and beta-endorphin (0.1-10 micrograms) [35].
• Unilateral microinjections of specific mu (DAGO), delta (DPDPE) and kappa (U-50,488H) ligands into the substantia nigra pars reticulata of rats produced dose-dependent contralateral turning [36].
• Rats were made tolerant dependent on U-50,488H by intraperitoneal injections of the drug (25 mg/kg) twice a day for 4 days [37].
• No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H [38].
• 6. In conclusion, U-50,488H at high concentration, had direct depressant actions on cardiac contractility, electrical excitability and the ECG [20].

References