Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

At least 163 records · Page 9Linked to original sources

PubMed1991

Interaction of beta-funaltrexamine with [3H]cycloFOXY binding in rat brain: further evidence that beta-FNA alkylates the opioid receptor complex.

beta-Funaltrexamine (beta-FNA) is an alkylating derivative of naltrexone. In addition to acting as an irreversible inhibitor of mu-receptor-mediated physiological effects, intracerebroventricular (i.c.v.) administration of beta-FNA to rat attenuates the ability of selective delta receptor antagonists and naloxone to reverse delta receptor-mediated effects. Moreover, recent work demonstrated that i.c.v. administration of beta-FNA alters the conformation of the opioid receptor complex, as inferred by a decrease in the Bmax of the lower affinity [3H][D-ala2,D-leu5]enkephalin binding site. Consistent with the decreased potency of naloxone as an inhibitor of delta receptor mediated effects, beta-FNA doubled the naloxone IC50 for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site. These data collectively support the hypothesis that the opioid receptor complex postulated to mediate mu-delta interactions in vivo is identical to the opioid receptor complex as defined by vitro ligand binding studies. A direct prediction of this hypothesis is that beta-FNA should increase the Kd of antagonists for the mu binding site (mu cx) of the receptor complex. The data reported in this paper demonstrate that beta-FNA doubled the IC50 of the potent narcotic antagonist, 6-desoxy-6 beta-fluoronaltrexone (cycloFOXY) for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site, and doubled the Kd of [3H]cycloFOXY for its mu binding site, providing additional data that the mu binding site labeled by [3H]cycloFOXY is the mu binding site of the opioid receptor complex. beta-FNA also altered the kappa binding site labeled by [3H]cycloFOXY, and when administered intrathecally to mice, beta-FNA produced a longlasting antinociception in the acetic acid writhing test.

Alkylating Agents↗

PubMed1991

[3H]1-[2-(2-thienyl)cyclohexyl]piperidine labels two high-affinity binding sites in human cortex: further evidence for phencyclidine binding sites associated with the biogenic amine reuptake complex.

Previous work demonstrated two high-affinity PCP binding sites in guinea pig brain labeled by [3H]TCP (1-(1-[2-thienyl]cyclohexyl)piperidine): site 1 (N-methyl-D-aspartate [NMDA]-associated) and site 2 (dopamine-reuptake complex associated). The present study examined brain membranes prepared from various species, including human, for the presence of site 2, defined as binding in the presence of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d]cyclohepten-5,10-imine maleate ((+)-MK801) minus binding in the presence of 10 microM TCP (nonspecific binding). Studies were conducted in absence of sodium which was found to be inhibitory to [3H]TCP binding. The results demonstrated detectable levels of site 2 in brain membranes of guinea pig, rabbit, pig, mouse, sheep, and human but not in the rat or chicken. Using human cortical membranes, site 2 was the predominant binding site. Detailed studies conducted with human cortical tissue showed that high-affinity dopamine (1-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909)], [1,2]benzo(b)thiophenylcyclo-hexylpiperidine (BTCP), and serotonin (fluoxetine) uptake inhibitors produced a wash-resistant inhibition of [3H]TCP binding to site 2, but not site 1. Preincubation of guinea pig brain membranes with BTCP was shown to produce an increase in the dissociation rate of [3H]TCP from PCP site 2. Structure activity studies with various uptake inhibitors showed that GBR12909, benztropine, fluoxetine, and BTCP have higher affinity for site 2 than for site 1. (+)-MK801, ketamine, and tiletamine were very selective for site 1, whereas dexoxadrol and TCP were moderately selective for site 1. These results suggest that human cortex possesses high-affinity PCP binding sites associated with biogenic reuptake binding sites, and that guinea pig brain, but not rat brain, may be an appropriate animal model for studying PCP site 2 in human brain.

Animals↗

PubMed1991

Preliminary ligand binding data for subtypes of the delta opioid receptor in rat brain membranes.

Delta opioid binding sites were assayed using [3H][D-ala2,D-leu5]enkephalin and rat brain membranes depleted of mu binding sites with the site-directed acylating agent, 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimid a zole-HCI. [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Pen2,L-Pen5]enkephalin, [D-Ala2]deltorphin-I and [D-Ala2]deltorphin-II inhibition curves were characterized by slope factors (Hill coefficients) less than 1. The low slope factor of DPDPE persisted in the presence of 50 microM 5'-guanylyimidodiphosphate in the assay Quantitative analysis of [D-ala2,D-leu5]enkephalin, DPDPE and [D-Ala2]deltorphin-I binding surfaces resolved two binding sites. Whereas [D-ala2,D-leu5]enkephalin had equal affinity for both sites, DPDPE and [D-Ala2]deltorphin-I had high affinity for the high capacity binding site, and low affinity for the low capacity binding site. These data support pharmacological studies demonstrating delta receptor subtypes which mediate antinociception.

Amino Acid Sequence↗

PubMed1991

RTI-4614-4: an analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites.

The objective of this study was to determine the binding affinities of (+/-)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]- N-phenylpropanamide-HCI (RTI-4614-4), which is an analog of (+)-cis-3-methylfentanyl for opioid receptor subtypes. The Ki values (nM) of this agent for opioid receptor subtypes were as follows: mu (0.0055), delta (148), kappa 1 (84.8), kappa 2a (2275), and kappa 2b (22.3). The selectivity of this agent for the mu binding site was 27,000 vs. the delta binding site, 15,400 vs. the kappa 1 binding site, 413,700 vs the kappa 2a and 4,054 vs the kappa 2b binding site. In contrast, two other fentanyl analogs, N-(2-(4-methylpyridinyl))-N-(1-phenethyl-4-piperidinyl) 2-furamide and N-(2-pyrazinyl)-N-(1-phenethyl-4-piperdinyl)2-furamide had considerably higher Ki values at, and were less selective for, the mu binding site. Since RTI-4614-4 is composed of a mixture of four stereoisomers, the resolution of these isomers should permit identification of an extremely potent and selective agent for the opioid mu receptor.

Animals↗

PubMed1991

Enantioselective kappa opioid binding sites on the macrophage cell line, P388d1.

A kappa (kappa) opioid binding site has been characterized on the macrophage cell line, P388d1, using the kappa selective affinity ligand, [3H] (1S,2S)-(-)-trans-2-isothiocyanato-N-methyl-N-[2-(1- pyrrolidinyl) cyclohexyl] benzeneacetamide (-)BD166). The kappa site has a relative molecular mass (Mr) of 38,000 under nonreducing conditions and 42,000 under reducing conditions. Moreover, it exhibits enantioselectivity in that 1S,2S-(-)-trans-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)cyclohexyl] benzeneacetamide ((-)-U-50,488) blocks [3H](5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro-(4,5)-dec-8-yl]benzeneacetamide (U-69,593) binding to P388d1 cells with an IC50 = 7.0 nM whereas 1R,2R-(+)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide ((+)U-50,488) blocks [3H]U-69,593 binding to P388d1 cells with an IC50 = 7000 nM.

Autoradiography↗

PubMed1991

(+)-cis-3-methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: evidence for pseudoallosteric modulation.

Previous studies demonstrated that preincubation of membranes from the brain of the rat with 1 microM (+)-cis-3-methylfentanyl produced a wash-resistant inhibition of mu receptor binding. The present study was designed to: (1) determine the mechanism by which (+)-cis-3-methylfentanyl produced a wash-resistant inhibition of mu receptor binding, and (2) to generate a structure-activity study, using wash-resistant inhibition as the end-point. Pretreatment of membranes with 500 nM (+)-cis-3-methylfentanyl increased the Kd of binding sites for [3H]ohmefentanyl, without altering the Bmax. The increase in the Kd was only partially due to the presence of residual drug and was accompanied by an increase in the dissociation rate of the binding of [3H]ohmefentanyl. Therefore, pretreatment of membranes with (+)-cis-3-methylfentanyl resulted in a lower affinity interaction of [3H]ohmefentanyl with the mu binding site, consistent with a model postulating pseudoallosteric modulation of mu binding sites by (+)-cis-3-methylfentanyl and its analogs. The rank order of potencies for wash-resistant inhibition of the binding of [3H]6 beta-fluoro-6-desoxyoxymorphone or [3H]ohmefentanyl, was lofentanil greater than (+)-cis-3-methylfentanyl greater than ohmefentanyl greater than sufentanil. All other opioids tested (1 microM morphine, 1 microM naloxone, 1 microM fentanyl, 1 microM (+)-cyclazocine, 1 microM (-)-cis-3-methylfentanyl) did not act as wash-resistant inhibitors of mu binding sites. Although the pseudoirreversible IC50 of these agents did not correlate with their ED50 values for producing antinociception, after intravenous administration, the authors speculate that this property, termed "pseudoirreversible inhibition", might contribute to the extraordinary potency of (+)-cis-3-methylfentanyl and its analogs as antinociceptive agents.

Allosteric Regulation↗

PubMed1991

In vivo study of NMDA-sensitive glutamate receptor by fluorothienylcyclohexylpiperidine [correction of fluorothienylcycloexylpiperidine], a possible ligand for positron emission tomography.

As a preliminary to positron emission tomography (PET) studies of excitatory amino acid neurotransmission, N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors of mice and rats were labelled in vivo with [3H]fluorothienylcyclohexylpiperidine [corrected] (FTCP), which binds to the phencyclidine site of the NMDA receptor. After intravenous injection, the half-life of clearance of authentic FTCP from blood was 4.2 min in mice, 12 min in rats and 45 min in a rhesus monkey. In rodent brain, the specific binding of [3H]FTCP, 10 min after intravenous injection, was 10-20% of the total binding and no regional differences were observed. However, if animals were treated with NMDA intraperitoneally (0.68 mmol/kg), 10 min before injection of [3H]FTCP, a three- to five-fold increase in specific binding was observed in hippocampus, cerebral cortex and striatum but not in cerebellum. Thus, specific binding of [3H]FTCP in vivo revealed the physiological status of the NMDA receptor; in fact, preliminary PET studies with [18F]FTCP in monkeys indicated increased binding after activation of NMDA receptors. These data suggest that PET with [18F]FTCP can be a tool to evaluate physiological or pathological modifications of the function of NMDA receptors.

Animals↗

PubMed1991

GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine.

Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at -70 degrees C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [3H]cocaine or [3H]GBR12935 to the DA transporter (ED50 about 10 mg/kg). Saturation binding studies with [3H]GBR12935 showed that this was due to both an increase in the Kd, due to residual drug, and to a decrease in the Bmax. At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the Bmax, and a 3.4-fold increase in the Kd. In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that at a dose sufficient to decrease by 50% the Bmax of [3H]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction.

Animals↗

PubMed1991

The partial opioid agonist, buprenorphine, protects against lethal effects of cocaine.

Buprenorphine (0.3-3.0 mg/kg) produced dose-dependent protection against the lethal effects of cocaine in mice. The (+)-enantiomer of buprenorphine did not protect up to doses over 100 times greater than the lowest effective dose of its (-)-enantiomer. The protective effects were also produced by the opioid agonists morphine and methadone, but not by the opioid antagonist, naltrexone. Low doses of naltrexone (0.3-1.0 mg/kg) blocked the protective effects of buprenorphine. Protection conferred by buprenorphine was not observed in CXBK mice, a recombinant inbred strain relatively devoid of mu-opioid receptors. Thus, buprenorphine appears to protect against the lethal effects of cocaine by a process mediated by mu-opioid receptors. The present results should provide some additional safety assurance in future clinical trials with buprenorphine, especially in outpatient trials where cocaine abuse may continue along with treatment.

Animals↗

PubMed1991

Novel site-directed affinity ligands for GABA-gated chloride channels: synthesis, characterization, and molecular modeling of 1-(isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo[2.2.2]octanes .

p-, m-, and o-isothiocyanate derivatives (1-3, respectively) of tert-butylbicycloorthobenzoate (TBOB) were synthesized from 3-tert-butyloxetane-3-methanol (4) as the starting material. While 2 was readily obtained in four steps via catalytic hydrogenation of the m-nitro-tert-butylbicycloorthobenzoate (9) intermediate, 1 and 3 could not be obtained this way. 1 and 3 were instead synthesized by an alternative four-step approach while made use of the stability of the isothiocyanate moiety to strong Lewis acids such as boron trifluoride etherate, conditions that would isomerize isothiocyanato oxetane ester intermediates to their corresponding orthoesters. The p-isothiocyanate derivative of TBOB, compound 1, inhibited [35S]-tert-butylbicyclophosphorothionate (TBPS) binding to rat cortical membranes with a potency (IC50 62 nM) comparable to the parent compound while 2 and 3 were approximately 10-fold less potent (IC50 values 570 and 609 nM, respectively). Preincubating tissue with radioligand further reduced the potencies of 2 and 3 by approximately 1 order of magnitude (IC50 values 5400 and 7500 nM, respectively) while the potency of 1 (IC50 90 nM) was only marginally affected by this procedure. Pretreatment of membranes with 1 and 2 followed by extensive washing resulted in a concentration-dependent inhibition of [35S]TBPS binding. In contrast, preincubating tissues with up to 2.4 microM of 3 did not elicit an apparent acylation of [35S]TBPS binding sites. Molecular modeling of the effective diameters of 1-3 in their thermodynamically most stable conformations indicates a relationship between these diameters and their relative efficacies as site-directed acylators; the smaller the diameter, the more potent the acylator. This hypothesis explains both the relative potencies of these compounds and their differential abilities to acylate the TBPS binding site.

Animals↗

PubMed1991

Regional brain measurement of Bmax and KD with the opiate antagonist cyclofoxy: equilibrium studies in the conscious rat.

Brain distribution of the opiate receptor antagonist, cyclofoxy (CF), was evaluated at equilibrium in rats. A combination of i.v. injection and constant i.v. infusion was used to administer CF over a wide dose range (2.4-450 nmol/rat). Kinetic simulations and experimental results showed that this administration schedule accomplishes "true" tissue-blood equilibrium of CF within 60 min. To estimate the receptor-ligand binding parameters, we assumed that the CF concentration at the receptor site is identical to that in plasma water at equilibrium, and can be calculated from measured blood data after corrections for radiolabeled metabolites and plasma protein binding. This assumption was supported by CSF and plasma water measurements at equilibrium. Regional KD, Bmax, and a nonspecific tissue binding equilibrium constant (Keq) were estimated by fitting the tissue and plasma water concentrations to a single receptor model; the estimated values were 1.4-2.9 nM, 15-74 pmol/g of tissue, and 5.2-8.0, respectively. They are in good agreement with previous in vitro measurements (Rothman and McLean, 1988) as well as in vivo estimates from i.v. injection experiments (Sawada et al., 1990c). The conventional method to estimate the receptor-ligand binding parameters using data from cerebellum to approximate nonspecific tissue binding was found to be unacceptable. Although cerebellum is a brain region with no opiate receptors in rats, small differences in nonspecific tissue binding in different brain regions resulted in significant overestimations of KD and Bmax with this method. Receptor-active and -inactive enantiomers [[18F](-)-CF and [3H](+)-CF)] were simultaneously administered to the same animal and the receptor-bound CF concentration could be accurately measured; this method was used to estimate Bmax from a single study in a single animal and has potential for direct application in human studies using positron emission tomography.

Animals↗

PubMed1991

Kinetic analysis of transport and opioid receptor binding of [3H](-)-cyclofoxy in rat brain in vivo: implications for human studies.

[3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model (Sawada et al., 1990a) and a classical compartmental pharmacokinetic model (Wong et al., 1986a) were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis (Patlak and Blasberg, 1985) of the data is inappropriate due to the high tissue-loss rate constant (kb = 0.03-0.07 min-1) for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography.

Animals↗

PubMed1991

Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT: evidence of kappa opioid receptor multiplicity in mice.

The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrol idinyl) cyclohexyl]benzeneacetamide), on U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)benzeneacetamide]- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2, NMePhe4, Gly-ol]enkephalin- (mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significantly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, beta-funaltrxamine (mu antagonist) and ICI 174,864 [N,N,-diallyl-Tyr-(alpha-aminoisobutyric acid)2-Phe-Leu-OH] (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinociception produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.

Analgesics↗

PubMed1991

Mirfentanil: pharmacological profile of a novel fentanyl derivative with opioid and nonopioid effects.

Mirfentanil [N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide] was studied for its binding affinity in isolated neuronal membranes, and for its effects in vivo. In binding to opioid receptors in monkey brain membranes, mirfentanil was much more selective for mu sites (7.99 nM) than for either kappa (1428 nM) or delta (480 nM) sites as measured by displacement of [3H]DAMGO. [3H]U-69.593 or [3H]DPDPE, respectively. In morphine-treated pigeons discriminating among naltrexone, saline and morphine, mirfentanil failed to substitute for either training drug; in morphine-abstinent pigeons, mirfentanil reversed responding on the naltrexone key (i.e., reversed withdrawal). In morphine-treated monkeys discriminating between saline and naltrexone, mirfentanil substituted completely for naltrexone, and this effect was attenuated by an acute injection of morphine; mirfentanil also attenuated the withdrawal-reversing effects of alfentanil in morphine-abstinent monkeys. Administered i.v., mirfentanil maintained rates of self-administration responding only slightly below rates maintained by alfentanil, and this effect of mirfentanil was antagonized by quadazocine. Small doses of mirfentanil (0.032-0.32 mg/kg) antagonized the analgesic effects of alfentanil; larger doses of mirfentanil both antagonized the analgesic effects of alfentanil and produced analgesic effects when administered alone. The analgesic effects of mirfentanil were not attenuated by large doses of opioid antagonists. Mirfentanil had modest respiratory depressant effects that were not altered by quadazocine; however, mirfentanil antagonized the respiratory depressant effects of large doses of alfentanil. Both in vivo and in vitro, mirfentanil appears to have selectivity for opioid mu receptors. Moreover, at doses larger than those which exert opioid effects, mirfentanil has nonopioid analgesic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗

PubMed1991

Effects of drugs that bind to PCP and sigma receptors on punished responding.

Several arylcyclohexylamines and opioid benzomorphans that bind to phencyclidine (PCP) receptors were studied for their effects on punished and unpunished responding maintained under fixed-interval schedules of food presentation. All of these drugs increased both punished and unpunished responding, although higher doses decreased responding. The order of potency for increasing punished responding was MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzoa(a,d)-cyclohepten-5,1 0-imine] greater than [1-[1-(2-thienyl)cyclohexyl]piperidine] = PCP greater than (+)-N-allylnormetazocine = (-)-N-allynormetazocine. There was a high correlation (0.95) between the relative potency of these drugs in increasing punished responding and their relative affinity for PCP receptors. Because some of these drugs also bind to sigma receptors, drugs with a high affinity for sigma receptors, such as haloperidol, BD 737 [1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(1-pyrrolidinyl) cyclohexylamine] and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, were also studied for their effects on punished and unpunished responding. These drugs produced only rate-decreasing effects. The correlation between the relative potency of drugs in increasing punished responding and their relative affinity for sigma receptors was low (-0.19). These data suggest that the PCP receptor is involved in some drug-induced increases in punished responding.

Animals↗

PubMed1991

Phencyclidine increased release of beta-endorphin from anterior lobe of the pituitary.

Phencyclidine (PCP) has been found to affect neuroendocrine function by altering the release of the anterior pituitary hormones, adrenocorticotrophin, luteinizing hormone and prolactin. The purpose of this study was to examine the effect of PCP on release of the two pituitary hormones also derived from the adrenocorticotropin precursor, namely, alpha-melanocyte-stimulating hormone and beta-endorphin (beta-E), synthesized in the neurointermediate and anterior lobes of the pituitary. At behaviorally active doses, PCP administered i.c.v. increased plasma levels of immunoreactive beta-E (i beta-E) without affecting the concentration of immunoreactive alpha-melanocyte-stimulating hormone, suggesting that PCP increased the release of beta-E from only the anterior lobe of the pituitary. Dexamethasone pretreatment blocked the PCP-induced increase in i beta-E which indicated further the anterior lobe effects of PCP. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate), a selective PCP ligand, at behaviorally active doses also increased the plasma concentration of i beta-E. The dose-response curves for induction of behavior was very different from that for increasing the concentration of i beta-E in plasma. The increase in release of i beta-E was stereoselective as (+)-(1-(1-phenylcyclohexyl)-3 methylpiperidine but not (-)-(1-(1-phenylcyclohexyl)-3 methylpiperidine increased release of i beta-E. The increase in plasma levels of beta-E was not due to an interaction with opioid receptors because naloxone did not block PCP-induced release of beta-E. In vitro, PCP also significantly increased release of i beta-E from anterior lobe of the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Selective antagonism by naltrindole of the antinociceptive effects of the delta opioid agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin in the rat.

Spinal delta opioid receptors have been proposed to mediate antinociception in the rat on the basis of 1) the efficacy of a small number of agonists; 2) the lack of effect of mu-selective antagonists; and 3) the lack of cross-tolerance with mu-selective agonists. However, direct evidence to support or refute this postulate has not been obtained in the rat due to a lack of suitable delta-selective antagonists. The present study characterized the ability of Naltrindole (NTI, 17-cyclopropylmethyl-6,7-dehydro-4,5 alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan), a recently discovered delta-selective antagonist, to antagonize the antinocieption produced by intrathecal (i.t.) administration of the prototypic delta-selective agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin (DPDPE) or the mu-selective agonists morphine and [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO) in the rat. Intrathecal coadministration of NTI with DPDPE significantly antagonized the increase in tail-flick latency (TFL) and hot-plate latency (HPL) produced by DPDPE. In the absence of NTI, the ED50 values and 95% CL of DPDPE in the tail-flick and hot-plate tests were 2.8 (1.1-4.7) and 19.5 (13.3-33.7) micrograms, respectively. In the presence of 10 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was unchanged and was increased by 2-fold in the hot-plate test to 35.9 (26.2-60.1) micrograms. In the presence of 30 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was increased by 5-fold to 14.5 (8.5-24.9) micrograms and its antinociceptive effect in the hot-plate test was antagonized completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel.

Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of metaphit in addition to dopamine uptake blockade. Electrically induced overflow of radioactivity from normal slices was stimulated by nomifensin and PCP, and by metaphit at 3 microM; it was unaffected by metaphit at 10 and 25 microM, and inhibited by higher concentrations of metaphit. Evidence that the latter effect is due to blockade of voltage-dependent sodium channels is as follows. First, metaphit, as did PCP, inhibited the binding of [3H]batrachotoxinin A 20-alpha benzoate to rat striatal synaptoneurosomes by increasing its dissociation rate; the effect of PCP, but not that of metaphit, was reversible by washing. Second, metaphit, as did PCP, inhibited veratridine (5 microM)-induced influx of [14C]guanidinium ion into synaptoneurosomes. Third, metaphit inhibited overflow of radioactivity from [3H]dopamine-preloaded slices induced by 2.5 microM veratridine, as did the sodium channel blocker tetrodotoxin.

3,4-Dihydroxyphenylacetic Acid↗