Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

384 records · Page 22Linked to original sources

PubMedDate not supplied

Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the kappa 2B (enkephalin-sensitive) binding site.

Certain opioid antagonists of the phenylpiperidine series (PPAs), such as LY255582, seem uniquely efficacious at producing weight loss in lean and meal-fed obese Zucker rats. Comparison of the pharmacological and receptor binding profile of PPAs that promote marked weight loss with those that do not has failed to find any obvious differences between these two groups of narcotic antagonists, which might explain the differences in their biological activities. The potent stimulatory effect of dynorphin, and other kappa agonists, on feeding behavior suggests that the antagonists that promote weight loss might have high affinity for kappa receptors. The recent demonstration by several laboratories of kappa receptor heterogeneity prompted us to test the hypothesis that the antagonists that promote weight loss might have high affinity for a subtype of kappa binding sites. In the present study, therefore, we determined the Ki values of five PPAs, naloxone, and naltrexone at mu, delta, kappa 1, kappa 2a, and kappa 2b binding sites. The data indicate that antagonists have subnanomolar Ki values and high selectivity for the kappa 2b binding site (relative to the kappa 2a binding site) are efficacious at promoting weight loss.

Animals↗

PubMedDate not supplied

Differential binding of opioid peptides and other drugs to two subtypes of opioid delta ncx binding sites in mouse brain: further evidence for delta receptor heterogeneity.

Research into the functional role of the opioid delta receptor has intensified with the recent in vivo identification of delta receptor subtypes, termed delta 1 and delta 2, which mediate antinociception in the mouse. A variety of data also support the hypothesis of an opioid receptor complex composed of distinct, yet interacting, mu, delta, and perhaps kappa binding sites. This model postulates two classes of delta binding sites: a delta binding site not associated with the opioid receptor complex, termed the delta ncx site, and a delta site associated with the receptor complex, termed the delta cx site. A major purpose of this study was to clarify the relationship between the delta ncx binding sites and the delta 1 and delta 2 receptors. Mouse brain membranes were depleted of mu sites by pretreatment with the site-directed acylating agent, BIT, and the delta ncx binding sites were labeled with [3H][D-Ala2,D-Leu5]enkephalin. Binding surface analysis readily resolved two binding sites (delta ncx-1 and delta ncx-2) in the absence and presence of 100 mM NaCl. Control experiments with guanine nucleotides and the ligand-selectivity analysis indicated that the two sites were not two states of a single receptor. Pretreatment of membranes with DALCE, but not [Cys4]deltorphin, decreased [3H] [D-Ala2,D-Leu5]enkephalin and [3H][D-Ser2,Thr6]enkephalin binding. Ligand-selectivity analysis of the two binding sites suggested that neither delta ncx binding site had the characteristics expected of the delta 2 receptor, and that the delta ncx-1 site, but not the delta ncx-2 site, was synonymous with the delta 1 receptor. Moreover, our finding that the racemic nonpeptide delta agonist, BW373U86, had high affinity at and selectivity for the delta ncx-2 site suggests that this site may be a novel delta receptor that mediates some of the effects of BW373U86.

Alkylating Agents↗

PubMedDate not supplied

Selective labeling of kappa 2 opioid receptors in rat brain by [125I]IOXY: interaction of opioid peptides and other drugs with multiple kappa 2a binding sites.

Recent studies from our laboratory resolved two subtypes of the kappa 2 binding site, termed kappa 2a and kappa 2b, using guinea pig, rat, and human brain membranes depleted of mu and delta receptors by pretreatment with the site-directed acylating agents BIT (mu-selective) and FIT (delta-selective). 6 beta-Iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan (IOXY), an opioid antagonist that has high affinity for kappa 2 sites, was radioiodinated to maximum specific activity (2200 Ci/mmol) and purified by high pressure liquid chromatography and used to characterize multiple kappa 2 binding sites. The results indicated that [125I]IOXY, like [3H]bremazocine, selectively labels kappa 2 binding sites in rat brain membranes pretreated with BIT and FIT. Using 100 nM [D-Ala2-MePhe4,Gly-ol5]enkephalin to block [125I]IOXY binding to the kappa 2b site, two subtypes of the kappa 2a binding site were resolved, both in the absence and presence of 50 microM 5'-guanylyimidodiphosphate. Viewed collectively, these results provide further evidence for heterogeneity of the kappa opioid receptor, which may provide new targets for drug design, synthesis, and therapeutics.

Animals↗

PubMedDate not supplied

Electroencephalographic characteristics of audiogenic seizures induced in metaphit-treated small rodents.

Adult male mice, rats, and guinea pigs were subjected to intense sound stimulation of an electric bell (100 dB, 12 kHz for 60 s) after a single intraperitoneal (i.p.) injection of metaphit (1-(1-(3 isothiocyanatophenyl)-cyclohexyl)piperidine) (50 mg/kg). When the animals were tested 24 h after administration of metaphit, audiogenic seizures were observed. None of the control saline-injected animals had convulsions. EEG recordings demonstrated the appearance of paroxysmal activity and spike-wave complexes in the trace from cortical and hippocampal electrodes, with frequency and amplitude increasing with time. Behaviorally, myoclonic jerks of facial muscles, ears, and neck appeared, but no correlation was noted between EEG and the motor phenomena. Auditory stimulation was necessary to elicit the full-blown sequence of seizure responses consisting of wild running followed by clonic and then tonic extension. At the time of seizures, repetitive high-amplitude spikes and waves appeared in the EEG, followed by profound EEG and behavioral depression. None of the animals died during or immediately after seizures. The seizure response to sound stimulation of mice, rats, and guinea pigs was phenomenologically similar, with minor differences in quantitative pattern of convulsive components, which suggests that all three animal species share the common property of extreme susceptibility to audiogenic stimulation caused by metaphit administration.

Acoustic Stimulation↗

PubMedDate not supplied

Metaphit-induced audiogenic seizures in mice: I. Pharmacologic characterization.

Metaphit [an analogue of phencyclidine (PCP) with an acylating isothiocyanate group] induced audiogenic clonic to clonic-tonic seizures in mice exposed to audio stimulation 24 h after metaphit administration. The incidence of seizures was reduced by treatment 30 min before audio stimulation with specific PCP-like compounds [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), and PCP itself], competitive N-methyl-D-aspartate antagonists 2-amino-5-phosphonopentanoic acid (AP-5 and NPC-12626), antiepileptic drugs [phenobarbital (PB), phenytoin (PHT)], and gamma-aminobutyric acid (GABA) agonists (muscimol and diazepam). In contrast, when given in conjunction with metaphit, most of these drugs were ineffective in protecting animals from audiogenic seizures 24 h later. Only compounds with long half-lives (t1/2) such as MK-801, PB, and PHT had a protective effect. High-performance liquid chromatography (HPLC) determination of [3H]MK-801 showed its long-term presence in the brain after intraperitoneal (i.p.) administration of [3H]MK-801. Audiogenic seizures observed 24 h after metaphit administration were potentiated by administration of the GABA antagonist picrotoxin 15 min before audio stimulation, and picrotoxin-induced spontaneous seizures were enhanced by pretreatment (24 h earlier) with a dose of metaphit that in itself did not produce spontaneous seizures at the time of the picrotoxin test. Similar observations were made with N-methyl D-aspartic acid (NMDA) instead of picrotoxin. Thus, an interplay exists between excitatory glutaminergic and inhibitory GABAergic circuitries in the metaphit seizure model.

Acoustic Stimulation↗

PubMedDate not supplied

Metaphit-induced audiogenic seizures in mice: II. Studies on N-methyl-D-aspartic acid, GABA, and sodium channel receptors and on the disposition of metaphit in the brain.

We previously demonstrated that metaphit (a phencyclidine analogue with an acylating isothiocyanate group) induces occurrence of audiogenic seizures in mice exposed to audio stimulation 24 h after metaphit administration. We have studied various receptor systems associated with excitatory and inhibitory networks: sites for competitive and noncompetitive antagonists of the N-methyl D-aspartic acid (NMDA) receptor complex, for [3H]muscimol on the gamma-aminobutyric acid (GABA) receptor complex, and for [3H]batrachotoxinin A20-alpha-benzoate on the voltage-dependent sodium channel. Mice were examined for neurochemical changes at 24 h after pretreatment with metaphit, when susceptibility to audiogenic seizures is greatest. Ex vivo receptor binding studies detected no changes; in vivo labeling of the phencyclidine site in the NMDA receptor complex was reduced by 20% in cortical and midbrain regions. A separate group of experiments was aimed at measuring brain levels of metaphit. One minute after retroorbital administration of [3H]metaphit at a dose sufficient to produce susceptibility to audiogenic seizures 24 h later, the brain level of [3H]metaphit (determined by high-performance liquid chromatography, HPLC) was 49 pmol/mg tissue; at 1, 4, and 24 h, the level was 12, 6, and 1.4 pmol/mg tissue or microM if metaphit was evenly distributed throughout the brain. Although the observed metaphit concentrations during the first 4 h are high enough to acylate receptors, no firm evidence for acylation was found for most of the examined receptors. Finally, the time course of the brain level of metaphit showing a continuous decrease is entirely different from that of development of the seizure susceptibility, which peaks at 18-24 h.

Acoustic Stimulation↗