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Sample records for opiate receptor heterogeneity

  1. Characterization of opiate receptor heterogeneity using affinity ligands and phospholipase A/sub 2/

    SciTech Connect

    Reichman, M.

    1985-01-01

    The primary aim of the dissertation was to study the heterogeneity of opiate receptors by utilizing affinity ligands, and by modification of the receptor lipid-microenvironment with phospholipase A/sub 2/ (PLA/sub 2/). The affinity ligands, 14-bromacetamidomorphine (BAM) and 14-chloroacetylnaltrexone (CAN), selectively inactivated high affinity dihydromorphine binding sites in an apparently irreversible manner (the inhibition was resistant to extensive washes of treated neural membrane homogenates). The inhibitory effect of PLA/sub 2/ (10 ng/ml) on opiate receptor subtypes was determined using (/sup 3/H)-dihydromorphine (..mu..-type agonist), (/sup 3/H)-enkephalin (delta agonist) and (/sup 3/H)-naloxone (..mu.. antagonist). PLA/sub 2/ abolished the high affinity antagonist binding site, whereas it inhibited high and low affinity agonist binding sites similarly. The results suggest that high affinity antagonist binding sites are different from high affinity agonist binding sites. Indirect binding assays demonstrated that the selectivities of ..mu..- and delta receptors are not affected significantly by PLA/sub 2/ treatment.

  2. In vivo studies of opiate receptors

    SciTech Connect

    Frost, J.J.; Dannals, R.F.; Duelfer, T.; Burns, H.D.; Ravert, H.T.; Langstroem, B.; Balasubramanian, V.; Wagner, H.N. Jr.

    1984-01-01

    To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented.

  3. Interaction of ethanol with opiate receptors

    SciTech Connect

    Yukhananov, R.Y.; Bujov, Y.V.; Maiskii, A.I.

    1986-04-01

    The authors study the action of ethanol on membrane-bound opiate receptors. Ethanol at 37/sup 0/C was shown to produce dose-dependent inhibition of binding of /sup 3/H-naloxone with opiate receptors. ID/sub 50/ under these conditions was 462 mM. Temperature-dependent inhibition of ligand-receptor binding suggests that ethanol does not compete for the stereospecific binding site of /sup 3/H-naloxone. Analysis of the inhibitory action of ethanol on /sup 3/H-naloxone binding in animals at different stages of experimental alcoholism revealed no differences between the control and experimental animals after 3.5 and 10 months of voluntary alcoholization.

  4. mu opiate receptor: cDNA cloning and expression.

    PubMed Central

    Wang, J B; Imai, Y; Eppler, C M; Gregor, P; Spivak, C E; Uhl, G R

    1993-01-01

    mu opiate receptors recognize morphine with high affinity. A 2.1-kb rat brain cDNA whose predicted translation product displays 63% identity with recently described delta and kappa opiate receptor sequences was identified through polymerase chain reaction and cDNA homology approaches. This cDNA recognizes a 10.5-kb mRNA that is expressed in thalamic neurons. COS-cell expression confers naloxonazine-, Na(+)-, and GTP-sensitive binding of mu but not delta or kappa opioid ligands. Expressing cells bind morphine, [D-Ala2,N-methyl-Phe4,glyol5]enkephalin (DAMGO), and [D-Ala2,D-Leu5]enkephalin (DADLE) with nanomolar or subnanomolar affinities, defining a mu opiate receptor that avidly recognizes analgesic and euphoric opiate drugs and opioid peptides. Images Fig. 1 Fig. 3 PMID:8234282

  5. Adenosine kinase inhibitors attenuate opiate withdrawal via adenosine receptor activation.

    PubMed

    Kaplan, G B; Coyle, T S

    1998-11-27

    Previous studies have demonstrated a role for adenosine in mediating opiate effects. This study examines the effects of indirect activation of adenosine receptors, via treatment with adenosine kinase inhibitors, on the expression of opiate withdrawal in mice. Mice receive chronic morphine treatment via implantation of subcutaneous morphine pellets (75 mg) for 72 h. Mice then receive parenteral treatment with adenosine kinase inhibitors, either 5'-amino-5'-deoxyadenosine (2, 5, 20, 40 mg/kg, intraperitoneal or i.p.) or iodotubericidin (1, 2, 5 mg/kg, i.p.), followed by naloxone injection and opiate withdrawal signs are measured over 20 min. Both adenosine kinase inhibitors significantly reduce the following opiate withdrawal signs in a dose-dependent manner compared to vehicle: withdrawal jumps, teeth chattering, forepaw tremors, and forepaw treads. Additionally, 5'-amino-5'-deoxyadenosine significantly reduces withdrawal-induced diarrhea and weight loss. Effects of 5'-amino-5'-deoxyadenosine (40 mg/kg) on opiate withdrawal signs appear to be mediated via adenosine receptor activation as they are reversed by pretreatment by adenosine receptor antagonist caffeine (20 mg, i.p.) but not by selective phosphodiesterase inhibitor Ro 20-1724 (10 mg/kg, i.p.). Adenosine receptor activation via adenosine kinase inhibitor treatment attenuates opiate withdrawal and these agents may be generally useful in the treatment of drug withdrawal syndromes. PMID:9865523

  6. Photoaffinity labeling of opiate receptors using intrinsically photoactive /sup 3/H-opiates

    SciTech Connect

    Kooper, G.N.; Levinson, N.R.; Copeland, C.F.; Bowen, W.D.

    1988-03-01

    Opiate receptors in rat and cow brain membranes have been labeled irreversibly using the intrinsic photolability of 3H-opiates. Membranes were incubated with 3H-ligand and then irradiated with UV light of 254 nm. Nonspecific binding was determined in the presence of 10 microM unlabeled levallorphan. Irreversible binding was defined as binding which survived heat or acid denaturation of membranes. Specific incorporation of label into denatured samples was observed only when unbound or loosely bound 3H-ligand was washed free from the membranes prior to irradiation. There was a general correlation between photosensitivity of the 3H-ligand and its ability to photolabel receptors. Hence, photolabeling presumably results by covalent attachment of highly reactive species generated during photochemical decomposition of ligand. With 3H-etorphine, optimal irradiation time was 5 min. In addition to 3H-etorphine, receptors could be labeled irreversibly with 3H-oxymorphone, 3H-dihydromorphine, and 3H-ethylketocyclazocine. Of the specific binding present in irradiated, nondenatured samples, 45-60% remained attached to receptors upon denaturation. 3H-Ethylketocyclazocine exhibited an 86% yield of incorporation. Signal-to-noise levels of 50-80% could be achieved in denatured samples. Therefore, this method provides a means of covalently labeling opiate receptors in high yield and with high signal-to-noise ratios. The opioid peptides, 3H-D-Ala2,D-Leu5-enkephalin, 3H-D-Ser2,Leu5,Thr6-enkephalin, 3H-D-Ala2,Met5-enkephalin amide, and 3H-D-Ala2,N-MePhe4,Gly-ol5-enkephalin, as well as the benzomorphan, 3H-bremazocine, apparently lack the structural characteristics which allow photolabeling.

  7. Multiple opiate receptors in the brain of spontaneously hypertensive rats

    SciTech Connect

    Das, S.; Bhargava, H.N.

    1986-03-01

    The characteristics of ..mu.., delta and kappa -opiate receptors in the brain of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats were determined using the receptor binding assays. The ligands used were /sup 3/H-naltrexone (..mu..), /sup 3/H-ethylketocyclazocine (EKC, kappa) and /sup 3/H-Tyr-D-Ser-Gly-Phe-Leu-Thr (DSTLE, delta). Since EKC binds to ..mu.. and delta receptors in addition to kappa, the binding was done in the presence of 100 nM each of DAGO and DADLE to suppress ..mu.. and delta sites, respectively. All three ligands bound to brain membranes of WKY rats at a single high affinity site with the following B/sub max/ (fmol/mg protein) and K/sub d/ (nM) values: /sup 3/H-naltrexone (130.5; 0.43) /sup 3/H-EKC (19.8, 1.7) and /sup 3/H-DSTLE (139, 2.5). The binding of /sup 3/H-naltrexone and /sup 3/H-DSTLE in the brain of WKY and SH did not differ. A consistent increase (22%) in B/sub max/ of /sup 3/H-EKC was found in SHR compared to WKY rats. However, the K/sub d/ values did not differ. The increase in B/sub max/ was due to increases in hypothalamus and cortex. It is concluded that SH rats have higher density of kappa-opiate receptors, particularly in hypothalamus and cortex, compared to WKY rats, and that kappa-opiate receptors may be involved in the pathophysiology of hypertension.

  8. Biological indications of a novel “short” µ opiate receptor in domestic chicken

    PubMed Central

    Sheehan, Melinda H.; Kream, Richard M.; Stefano, George B.

    2010-01-01

    Previous work from our laboratory has established that cellular signaling processes of endogenous morphine are mediated by cognate G protein coupled receptor (GPCR) proteins, designated µ3 and µ4 opiate receptors. µ3 and µ4 opiate receptors are structurally unique “short” 6 transmembrane helical (TMH) domain GPCRs that are selectively responsive to endogenous morphine, not to families of endogenous opioid peptides, and are uniquely coupled to activation of constitutive nitric oxide synthase (cNOS). Based on high resolution predictive measures, it appears likely that domestic poultry express a µ opiate receptor mRNA encoding potentially two novel GPCRs with similar biochemical characteristics as described for µ3 and µ4 opiate receptors as well as traditional µ1 opioid receptors. The biological indications of these novel µ opiate receptors are discussed within the context of this short review. PMID:22371789

  9. Study of gastrointestinal opiate receptors: the role of the mu receptor on gastric emptying: concise communication

    SciTech Connect

    Lamki, L.; Sullivan, S.

    1983-08-01

    Animal and in vitro experiments suggest that opiates exert their actions by interaction with possibly five different subtypes of opiate receptors, identified as mu, kappa, sigma, delta, and epsilon. As yet there is no conclusive evidence for their existence in man. Our experiments on morphine and the enkephalin analog DAMME have suggested at least two types of opiate receptors involved in gastric secretion. In this study we have used the very powerful and nonselective opiate agonist etorphine to stimulate as many of the different opiate receptors as possible. We have then attempted to block selectively the ..mu.. receptor by administering a small dose of naloxone. Etorphine delayed gastric emptying whereas naloxone alone had no effect. In combination, the inhibitory effect of etorphine on gastric emptying was incompletely prevented while the subjective effects of etorphoine were completely abolished. These results may indicate that ..mu.. receptors are important in the regulation of gastric emptying, but that other (non-..mu..) receptors are also involved. The radionuclide study of gastric emptying, as used here, is a potentially powerful tool in physiological research on the gastrointestinal tract.

  10. Adenosine receptor agonists attenuate and adenosine receptor antagonists exacerbate opiate withdrawal signs.

    PubMed

    Kaplan, G B; Sears, M T

    1996-01-01

    Previous studies have demonstrated a role for adenosine in mediating opiate effects. Adenosine receptors and their functions have been shown to be regulated by chronic opiate treatment. This study examines the role of adenosine receptors in the expression of opiate withdrawal behaviors. The effects of single doses of parenterally administered adenosine receptor subtype-selective agonists and antagonists on opiate withdrawal signs in morphine-dependent mice were measured. Mice received subcutaneous morphine pellet treatment for 72 h and then underwent naloxone-precipitated withdrawal after pretreatment with adenosinergic agents. Adenosine agonists attenuated different opiate withdrawal signs. The A1 agonist R-N6(phenylisopropyl)adenosine (0, 0.01, 0.02 mg/kg, IP) significantly reduced wet dog shakes and withdrawal diarrhea, while the A2a-selective agonist 2-p-(2-carboxethyl)phenylethylamino-5'-N-ethylcarboxamido adenosine or CGS 21680 (0, 0.01, 0.05 mg/kg, IP) significantly inhibited teeth chattering and forepaw treads. Adenosine receptor antagonists enhanced different opiate withdrawal signs. The adenosine A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (0, 1, 10 mg/kg, IP) significantly increased weight loss and the A2 antagonist, 3,7-dimethyl-1-propargylxanthine (0, 1 and 10 mg/kg, IP) enhanced wet dog shakes and withdrawal diarrhea. Treatment effects of adenosinergic agents were not due to nonspecific motor effects, as demonstrated by activity monitoring studies. These results support a role for adenosine receptors in the expression of opiate withdrawal and suggest the potential utility of adenosine agonists in its treatment. PMID:8741956

  11. Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

    SciTech Connect

    Martin, J.R.

    1985-01-01

    The present study was undertaken to determine whether there is an alteration of dopamine receptor sensitivity following opiate administration, and whether this alteration has any influence on the development of opiate tolerance and dependence. Behavioral hypersensitivity to direct-acting dopamine agonists was observed in mice following acute or chronic morphine administration. Acute levorphanol administration also resulted in potentiation of dopamine agonist-induced behaviors. An increase in density of dopamine receptors, as measured by (/sup 3/H)butyrophenone binding accompanied the development of behavioral hypersensitivity. This increase was localized to the striatum, an area important in the mediation of dopamine-agonist induced behaviors. Naloxone or LiCl coadministered with the opiates prevented the development of hypersensitivity and the increase in density of dopamine receptors. Coadministration of lithium enhanced the development of acute and chronic tolerance. Lithium enhanced the development of dependence as determined by naloxone-induced hypothermia in chronically morphine-treated mice. Apomorphine enhanced naloxone-induced withdrawal in acutely dependent mice. This enhancement was blocked by coadministration of lithium with the opiates. These results suggest that dopamine receptor supersensitivity influences the degree of tolerance and dependence.

  12. Disruption of the CRF2 Receptor Pathway Decreases the Somatic Expression of Opiate Withdrawal

    PubMed Central

    Papaleo, Francesco; Ghozland, Sandy; Ingallinesi, Manuela; Roberts, Amanda J; Koob, George F; Contarino, Angelo

    2009-01-01

    Escape from the extremely aversive opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF1 and CRF2. To investigate the role for the CRF2 receptor pathway in somatic opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF2 receptor (CRF2−/−). We employed a novel, clinically relevant mouse model of ‘spontaneous’ opiate withdrawal as well as a classical opioid receptor antagonist (naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence, mice were treated with intermittent escalating morphine doses (20–100 mg/kg, i.p.). We found that 8–128 h after the last opiate injection, CRF2−/− mice showed decreased levels of major somatic signs of spontaneous opiate withdrawal, such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with naloxone 2 h after the last morphine injection induced lower levels of paw tremor and wet dog shake in CRF2−/− mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF2−/− mice displayed similar plasma corticosterone responses to opiate dosing and withdrawal, indicating a marginal role for the hypothalamus–pituitary–adrenal axis in the CRF2 receptor mediation of opiate withdrawal. Our results unravel a novel role for the CRF2 receptor pathway in opiate withdrawal. The CRF2 receptor pathway might be a critical target of therapies aimed at alleviating opiate withdrawal symptoms and reducing relapse to drug intake. PMID:18288089

  13. Studies on rat intestinal epithelial cell receptors for serotonin and opiates.

    PubMed Central

    Gaginella, T S; Rimele, T J; Wietecha, M

    1983-01-01

    We have employed the receptor-ligand binding technique in an attempt to determine if specific binding sites (receptors) for serotonin and opiates are present on rat intestinal epithelial cell membranes. A wide variety of ligands for serotonin and opiate receptors bound to specific receptor sites in rat brain. However, the same ligands failed to bind in a specific (receptor-related) manner to isolated membranes of rat ileal and colonic cells. Additional washing of the tissue pellet (to remove soluble peptidases), pretreatment with p-chlorophenylalanine (to deplete endogenous serotonin), alteration of sodium concentration (to antagonize the effects of putative endogenous inhibitors of opiate ligand binding), changes in incubation time, temperature, tissue protein and tritiated ligand concentration failed to yield meaningful results with the enterocyte membranes. We conclude that, as assessed under the present conditions, serotonergic and opiate receptors are not present or are not accessible on rat intestinal epithelial cell membranes. PMID:6308215

  14. Dopamine D2 receptor availability in opiate addicts at baseline and during naloxone precipitated withdrawal

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Logan, J. ||

    1996-05-01

    To determine if changes in dopamine activity contribute to the clinical presentation of opiate withdrawal we assessed dopamine (DA) D2 receptor availability in opiate-dependent subjects at baseline and during naloxone-precipitated withdrawal. DA D2 receptor availability was evaluated in eleven male heroine and methadone users using positron emission tomography (PET) and [11-C]raclopride and compared to eleven age matched male control subjects. Nine of the opiate-dependent subjects and two of the control were tested twice after placebo and naloxone (0.02 mg/kg) iv injection 7-10 min. prior to [11-C]raclopride. DA D2 receptor availability was measured using the ratio of the distribution volume in the region of interest (caudate, putamen and ventral striatum) to that in the cerebellum which is a function of B{sub max}/K{sub d}. DA D2 receptor availability in putamen was significantly lower in opiate-dependent subjects (3.44 {plus_minus} 0.4) than that in controls (3.97 {plus_minus} 0.45, p {ge} 0.009). Naloxone induced a short lasting withdrawal in all of the opiate-dependent subjects (79 {plus_minus} 17% of maximum withdrawal), but not in controls, with significant increase in pulse (p {le} 0.006), blood pressure (p {le} 0.0001), lacrimation (p {le} 0.01), muscle twitches (p {le} 0.01), annoyance (p {le} 0.005), anxiety (p {le} 0.0006), restlessness (p {le} 0.0005) and unhappiness (p {le} 0.001). DA D2 receptor availability in basal ganglia after naloxone administration was not different from that of baseline. These results document abnormalities in DA D2 receptors in opiate-dependent subjects. However, DA D2 availability did not change with naloxone-precipitated withdrawal.

  15. Effect of thyrotrophin releasing hormone on opiate receptors of the rat brain

    SciTech Connect

    Balashov, A.M.; Shchurin, M.R.

    1987-01-01

    It has recently been shown that the hypothalamic thyrotropin releasing hormone (TRH) has the properties of a morphine antagonist, blocking its inhibitory action on respiration and, to a lesser degree, its analgesic action. This suggests that the antagonistic effects of TRH are mediated through its interaction with opiate receptors. The aim of this paper is to study this hypothesis experimentally. Tritium-labelled enkephalins in conjunction with scintillation spectroscopy were used to assess the receptor binding behavior. The results indicate the existence of interconnections between the opiate systems and TRH. Although it is too early to reach definite conclusions on the mechanisms of this mutual influence and its physiological significance it can be tentatively suggested that TRH abolishes the pharmacological effects of morphine by modulating the functional state of opiate reception.

  16. Conformationally restricted analogs of somatostatin with high mu-opiate receptor specificity.

    PubMed Central

    Pelton, J T; Gulya, K; Hruby, V J; Duckles, S P; Yamamura, H I

    1985-01-01

    A series of cyclic, conformationally restricted analogs of somatostatin have been prepared and tested for their ability to inhibit the binding of [3H]naloxone and [D-Ala2, D-Leu5] [3H]enkephalin to rat brain membranes. The most potent analog, D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 where Pen is penicillamine in [D-Phe5, Cys6, Tyr7, D-Trp8, Pen11]somatostatin-(5-12)-octapeptide amide, exhibited high affinity for mu-opiate receptors (IC50 value of [3H]naloxone = 3.5 nM), being 7800 times more potent than somatostatin. The cyclic octapeptide also displayed high mu-opiate receptor selectivity with an IC50 [( D-Ala2,D-Leu5]enkephalin)/IC50 (naloxone) ratio of 271. The high affinity and selectivity of the somatostatin analog for mu-opiate receptors may be of use in examining the physiological role(s) of the mu-opiate receptor. PMID:2857488

  17. The effect of hyperthyroidism on opiate receptor binding and pain sensitivity

    SciTech Connect

    Edmondson, E.A. ); Bonnet, K.A.; Friedhoff, A.J. )

    1990-01-01

    This study was conducted to determine the effect of thyroid hormone on opiate receptor ligand-binding and pain sensitivity. Specific opiate receptor-binding was performed on brain homogenates of Swiss-Webster mice. There was a significant increase in {sup 3}H-naloxone-binding in thyroxine-fed subjects (hyperthyroid). Scatchard analysis revealed that the number of opiate receptors was increased in hyperthyroid mice (Bmax = 0.238 nM for hyperthyroid samples vs. 0.174 nM for controls). Binding affinity was unaffected (Kd = 1.54 nM for hyperthyroid and 1.58 nM for control samples). When mice were subjected to hotplate stimulation, the hyperthyroid mice were noted to be more sensitive as judged by pain aversion response latencies which were half that of control animals. After morphine administration, the hyperthyroid animals demonstrated a shorter duration of analgesia. These findings demonstrate that thyroxine increases opiate receptor number and native pain sensitivity but decreases the duration of analgesia from morphine.

  18. Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

    PubMed Central

    Elhabazi, K; Trigo, JM; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, JJ; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

    2012-01-01

    BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. PMID:21718302

  19. An improved filtration procedure for measuring opiate receptors in small regions of rat brain.

    PubMed

    Bardo, M T; Bhatnagar, R K; Gebhart, G F

    1982-12-01

    A modified filtration method for in vitro receptor binding was used to determine specific binding of [3H]naloxone to small regions of adult rat brain. Reliable determinations of ligand binding were quantified with about 50 micrograms of protein per assay tube. Large differences in [3H]naloxone binding were obtained between various brain nuclei, and these differences were consistent with prior determinations of opiate receptor densities in various rat brain nuclei using autoradiographic techniques. PMID:6292368

  20. Opiate receptor agonists regulate phosphorylation of synapsin I in cocultures of rat spinal cord and dorsal root ganglion.

    PubMed Central

    Nah, S Y; Saya, D; Barg, J; Vogel, Z

    1993-01-01

    Kappa opiate receptor agonists applied to cocultures of spinal cord and dorsal root ganglion neurons have been previously shown to inhibit voltage-dependent Ca2+ influx and adenylate cyclase activity. Here we describe the effect of kappa opiate receptor agonists on phosphorylation of synapsin I, a synaptic-vesicle-associated protein whose phosphorylation was shown to be regulated by cAMP and Ca2+ concentrations. Depolarization of spinal cord-dorsal root ganglion cocultured cells (by high K+ or veratridine) and the addition of forskolin (which activates adenylate cyclase) led to increased phosphorylation of synapsin I. Addition of kappa opiate agonists attenuated both the depolarization- and the forskolin-induced phosphorylation of synapsin I. This attenuation was blocked by the opiate antagonist naloxone. mu and delta opiate receptor agonists had much weaker effects on the depolarization-induced phosphorylation of synapsin I. Similarly, kappa opiate agonists decreased (by 40-60%) the high-K+- or veratridine-induced phosphorylation of synapsin I in spinal cord synaptosomes. These results show that opiate ligands modulate synapsin I phosphorylation. Moreover, the data could explain the reduction in synaptic efficacy observed after opiate treatment. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 Fig. 7 PMID:8097883

  1. The CRF1 and the CRF2 receptor mediate recognition memory deficits and vulnerability induced by opiate withdrawal.

    PubMed

    Morisot, Nadège; Contarino, Angelo

    2016-06-01

    Opiate use disorders are associated with impaired cognitive function and altered stress-responsive systems. The corticotropin-releasing factor (CRF) system mediates stress responses via CRF1 and CRF2 receptors and may be implicated in substance use disorders. However, the specific role for each of the two known CRF receptor subtypes in cognitive impairment induced by opiate administration and withdrawal remains to be elucidated. In the present study, CRF1-/-, CRF2-/- and their respective wild-type mice are injected with escalating doses of morphine and cognitive function assessed by the novel object recognition (NOR) memory task throughout relatively long periods of opiate withdrawal. Early (2 days) phases of opiate withdrawal impair NOR memory in wild-type, CRF1-/- and CRF2-/- mice. However, the duration of opiate withdrawal-induced NOR memory deficits is prolonged in CRF1-/- but shortened in CRF2-/- mice, as compared to their respective wild-type mice, indicating opposite roles for the two CRF receptor subtypes. Nevertheless, following apparent recovery, exposure to an environmental stressor induces the reemergence of NOR memory deficits in long-term opiate-withdrawn wild-type but not CRF1-/- or CRF2-/- mice, indicating an essential role for both CRF receptor subtypes in stress vulnerability. These findings bring initial evidence of a complex physiopathological role for the CRF system in cognitive deficits and the long-lasting vulnerability induced by opiate drugs. PMID:26907806

  2. Angiotensin II receptor heterogeneity

    SciTech Connect

    Herblin, W.F.; Chiu, A.T.; McCall, D.E.; Ardecky, R.J.; Carini, D.J.; Duncia, J.V.; Pease, L.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L. )

    1991-04-01

    The possibility of receptor heterogeneity in the angiotensin II (AII) system has been suggested previously, based on differences in Kd values or sensitivity to thiol reagents. One of the authors earliest indications was the frequent observation of incomplete inhibition of the binding of AII to adrenal cortical membranes. Autoradiographic studies demonstrated that all of the labeling of the rat adrenal was blocked by unlabeled AII or saralasin, but not by DuP 753. The predominant receptor in the rat adrenal cortex (80%) is sensitive to dithiothreitol (DTT) and DuP 753, and is designated AII-1. The residual sites in the adrenal cortex and almost all of the sites in the rat adrenal medulla are insensitive to both DTT and DuP 753, but were blocked by EXP655. These sites have been confirmed by ligand binding studies and are designated AII-2. The rabbit adrenal cortex is unique in yielding a nonuniform distribution of AII-2 sites around the outer layer of glomerulosa cells. In the rabbit kidney, the sites on the glomeruli are AII-1, but the sites on the kidney capsule are AII-2. Angiotensin III appears to have a higher affinity for AII-2 sites since it inhibits the binding to the rabbit kidney capsule but not the glomeruli. Elucidation of the distribution and function of these diverse sites should permit the development of more selective and specific therapeutic strategies.

  3. Opiate receptor in praying mantis: effect of morphine and naloxone.

    PubMed

    Zabala, N A; Miralto, A; Maldonado, H; Nuñez, J A; Jaffe, K; Calderon, L D

    1984-05-01

    A praying mantis displays a "frightening reaction" called deimatic reaction (DR), any time that it is faced with a patterned visual stimulus that represents a potential damage for the insect. Results of the present paper show that the DR could be also elicited by an actual noxious (an electrical shock) and that this response is similar to that elicited by a potential nociceptive stimulus (a patterned visual stimulus). The DR elicited by the electric shock was used as a model for studying the analgesic effect of opiates. The mantis was placed in an apparatus that allowed us to give the insect an electrical shock and to measure the strength of its DR. During a first session the voltage threshold necessary to induce a full DR was determined, and then, the insect was injected with a certain solution. The voltage threshold was tested one, two and four hours after injection. Mantises that were injected with only distilled water showed no changes in their voltage threshold during the three tests. Injections of 300, 350 and 400 micrograms/g of morphine-HCl increased the voltage threshold in both a time-dependent and a dose related manner. A dose of 350 micrograms/g of morphine-HCl produced 50% of response inhibition after two hours of injections and is referred to as the median antinoxious dose ( AD50 ). Sixteen micrograms/g of naloxone given in conjunction with an AD50 of morphine, partially blocked the effect of morphine during the first hour and fully blocked it during the second hour. Thirty-two micrograms/g of naloxone fully blocked the morphine effect during the first and the second hour. However, more than 48 micrograms/g of naloxone alone also increased the voltage threshold in insects, similar to those described for vertebrates. PMID:6330763

  4. Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality

    SciTech Connect

    Herkenham, M.; Pert, C.B.

    1982-08-01

    A general technique is described for using slide-mounted unfixed tissue sections to characterize and visualize drug and neurotransmitter receptors in brain or other tissues. The preparation of material, from fresh frozen, unfixed brain to dried sections securely attached to slides, is described in detail. The tissue can be kept intact during incubation at varying temperatures in solutions containing radiolabeled ligand, ions, buffers, and allosteric effectors. Strategies are described for determining optimal stereospecific binding with highest signal-to-noise ratios and for determining that a meaningful receptor is being studied. Dry formaldehyde fixation by vapors from heated paraformaldehyde preserves the tissue quality and traps the ligand near its site on the receptor, permitting subsequent histological processing through alcohols, solvents, and aqueous media, including liquid nuclear track emulsion. Visualization of (/sup 3/H)naloxone- or (/sup 3/H)enkephalin-labeled opiate receptor distributions in rat and human brains is achieved by tritium-sensitive film or by classical wet emulsion autoradiography. The advantages of the film include its ease of use and the ability to quantify receptor density by densitometry which can be computer-assisted. The advantage of the emulsion is the greater resolution and the concomitant appearance of morphology in cell-stained sections. Examples of correlations of opiate receptor distributions which underlying cytoarchitecture illustrate the potential for receptor localization studies.

  5. Renal opiate receptor mediation of renin secretion to renal nerve stimulation in the dog.

    PubMed

    Koyama, S; Hosomi, H

    1986-06-01

    The present study was designed to evaluate renal opiate receptor mediation of the renin secretion response to electrical stimulation of the renal nerves in the pentobarbital sodium-anesthetized dog by use of the opiate agonist leucine-enkephalin (Leu-enk) and the opiate antagonist naloxone. In all animals studied, left kidneys were pump perfused at a constant renal blood flow. Renal perfusion pressure (RPP) and glomerular filtration rate (GFR) were unaltered at a stimulation frequency of 1.0 Hz; however, renin secretion rate (RSR) increased significantly in the nontreated group. High-frequency renal nerve stimulation (10 Hz) increased RPP and decreased GFR. RSR at the high-frequency stimulation was significantly augmented in the nontreated group. Renal arterial infusion of either Leu-enk (25 micrograms X kg-1 X min-1) or naloxone (7 micrograms X kg-1 X min-1) did not alter base-line levels of renal hemodynamics and RSR and did not produce significant changes in these variables even when renal nerves were stimulated at the low frequency; however, Leu-enk inhibited RPP and RSR responses to the high-frequency stimulation, and naloxone augmented these responses. Phentolamine (13 micrograms X kg-1 X min-1) prevented renal hemodynamic responses to the renal nerve stimulation, whereas RSR responses to the stimulation were unaffected. Propranolol (8 micrograms X kg-1 X min-1) resulted in decreases in RSR at the renal nerve stimulation despite the presence of changes in renal hemodynamics similar to the other groups. The results indicate that intrarenal opiate receptors may participate in inhibiting renal secretion of renin mediated by the renal nerves when renal vasoconstriction and reduction of GFR occurred at the high-frequency stimulation. PMID:3013030

  6. [Involvement of opiate receptors in the mode of action of trimebutine].

    PubMed

    Pascaud, X; Roman, F; Petoux, F; Vauche, D; Junien, J L

    1987-01-01

    Several studies in dogs, cats, rabbits and humans have suggested that the motility stimulating properties of trimebutine (TMB) are mediated by peripheral opiate receptors. The present work deals with the capacity of TMB and its N-desmethyl metabolite (NDTMB) to displace mu, delta and kappa specific ligands from their receptors using guinea-pig brain membranes and ileal myenteric plexus synaptosomal membrane preparations. The activity of both compounds on the twitch response induced by transmural stimulation on the guinea-pig ileum as well as the mouse and rabbit vas deferens was also investigated. These preparations have been proposed to be specific for the mu, delta and kappa receptor subtypes respectively. TMB (0.2 to 1.8 microM) and NDTMB (0.3 to 6 microM) displayed a good affinity for all receptor subtypes in brain and myenteric plexus preparations. Both compounds also inhibited the twitch response of all three isolated organ preparations. The decreasing order of IC50's of TMB ranged from 0.75 microM in the guinea-pig ileum to 7.1 and 39 microM in the vas deferens of the rabbit and the mouse respectively. These results indicate that TMB and NDTMB possess mu, delta as well as kappa agonist properties without true specificity for one or the other of these subtypes. They also confirm that activation of peripheral mu, delta and kappa opiate receptors mediate the gastrointestinal motility effect of TMB. PMID:3038655

  7. Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring.

    PubMed

    Vassoler, Fair M; Wright, Siobhan J; Byrnes, Elizabeth M

    2016-04-01

    Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA. PMID:26700246

  8. Targeted Expression of Mu-Opioid Receptors in a Subset of Striatal Direct-Pathway Neurons Restores Opiate Reward

    PubMed Central

    Cui, Yijun; Ostlund, Sean B.; James, Alex; Park, Chang Sin; Ge, Weihong; Roberts, Kristofer W.; Mittal, Nitish; Murphy, Niall P.; Cepeda, Carlos; Kieffer, Brigitte L.; Levine, Michael S.; Jentsch, J. David; Walwyn, Wendy M.; Sun, Yi E.; Evans, Christopher J.; Maidment, Nigel T.; Yang, X. William

    2014-01-01

    SUMMARY Mu-Opioid Receptors (MOR) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a novel conditional BAC rescue strategy to show that mice with targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restore opiate reward, opiate-induced striatal dopamine release, and partially restore motivation to self-administer opiates. However, they lack opiate analgesia or withdrawal. Importantly, we used Cre-mediated deletion of the rescued MOR transgene to establish that striatal, rather than a few extrastriatal sites of MOR transgene expression, is needed for the restoration of opiate reward. Together, our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a novel intersectional genetic approach to dissect neurocircuit-specific gene function in vivo. PMID:24413699

  9. A rapid filtration method for receptor binding: characterization with mu and delta opiate receptors.

    PubMed

    Zadina, J E; Kastin, A J

    1984-12-01

    A commercially available (Skatron) cell harvester was adapted for use in mu (3H-naloxone-labeled) and delta (3H-DADLE-labeled) opiate receptor assays and compared with a widely used conventional manifold for a number of binding characteristics. Whatman GF/B glass fiber filters and the less expensive filters available with the harvester were also compared and produced similar binding characteristics on the harvester and manifold if the harvester filters were used double-ply, and if the rinse time was less than 12.5 sec. Longer rinse times produced lower binding with 2-ply Skatron filters. Kd values, Hill coefficients, and Scatchard plot regression coefficients were very similar for the two filtration devices and filter types. A significantly reduced maximum number of sites (Bmax) was observed after filtration on the harvester, reflecting the smaller filter surface area relative to that of the manifold. The filter surface area on the harvester, nevertheless, is considerably larger than that of other manifolds with microplate spacing. This provides the advantages of rapid filtration with less restriction on tissue concentrations. Specific binding was linear with protein concentration up to at least 800 micrograms protein, which is well within the range of most neurotransmitter and peptide receptor binding studies. At about 1 mg protein the rinse buffer flow was slower due to the high tissue concentration. Although the results of filtration with the harvester and the conventional manifold were similar, the time requirements differed considerably. With the harvester, one experimenter could conduct the filtration process 2-3 times faster than 2 experimenters using the manifold.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6097920

  10. Photoaffinity labeling of opiate receptors with /sup 3/H-etorphine: possible species differences in glycosylation

    SciTech Connect

    Bowen, W.D.; Kooper, G.

    1986-01-01

    Opiate receptors from whole rat brain (minus cerebellum) and cow striatum were labeled irreversibly using the intrinsic photolability of /sup 3/H-etorphine. After incubation with 2 nM /sup 3/H-etorphine and centrifugal washing, membranes were irradiated with light of 254 nm. Non-specific binding was determined by carrying out incubations in presence and absence of 10 microM levallorphan. Specific binding in photolabeled membranes was 75-80%, with a photo-incorporation yield of approximately 50%. Photolabeled membranes were extracted with CHAPS/Lubrol and unbound /sup 3/H-etorphine was removed by dialysis and passage over Sephadex G-25. Solubilized proteins were then subjected to chromatography on wheat germ agglutinin, and retained proteins were eluted with N-acetyl D-glucosamine (NAG). Protein profiles from rat brain and cow striatum were identical, with 89% of the total protein flowing through unretained and 11% eluted by NAG. However, the profile of radioactivity was markedly different in the two species. With rat, the specific activity (cpm/A280) was the same for flow-through and NAG-eluate. With cow, the specific activity of the NAG-eluate was 17 times greater than the flow-through. These results indicate that cow striatum and rat whole brain contain populations of opiate receptors which are glycosylated differently.

  11. Opiate-induced constipation related to activation of small intestine opioid μ2-receptors

    PubMed Central

    Chen, Wency; Chung, Hsien-Hui; Cheng, Juei-Tang

    2012-01-01

    AIM: To investigate the role of opioid μ-receptor subtype in opiate-induced constipation (OIC). METHODS: The effect of loperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine (ACh). Then, decrease in muscle tone (relaxation) was characterized after cumulative administration of 0.1-10 μmol/L loperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreatment to compare the changes in loperamide-induced relaxation. RESULTS: In addition to the delay in intestinal transit, loperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K+ (KATP) channels, and by protein kinase A (PKA) inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate (cAMP). CONCLUSION: Loperamide induces intestinal relaxation by activation of opioid μ-2 receptors via the cAMP-PKA pathway to open KATP channels, relates to OIC. PMID:22493554

  12. Pharmacological differentiation of presynaptic inhibitory alpha-adrenoceptors and opiate receptors in the cat nictitating membrane.

    PubMed

    Dubocovich, M L; Langer, S Z

    1980-11-01

    1 The action of morphine, naturally occurring and synthetic opiate peptides on [3H]-noradrenaline release induced by nerve stimulation was studied in the isolated nerve muscle preparation of the cat nictitating membrane under experimental conditions in which the alpha-presynaptic receptors were blocked by phentolamine 1 microM. 2 Morphine and the naturally occurring peptides: [Met5]-enkephalin, [Leu5]-enkephalin and beta-endorphin reduced 3H-transmitter overflow and responses to nerve stimulation from the cat nictitating membrane, effects which were completely antagonized by naloxone 0.3 microM. The relative order of potency for the inhibition of the stimulation-induced 3H-transmitter overflow at the level of the IC50 (microM) was as follows: [Met5]-enkephalin (0.020 microM) greater than or equal to [Leu5]-enkephalin (0.036 microM) > morphine (0.3 microM) > beta-endorphin (1 microM). 3 The synthetic opiate pentapeptides: BW 180 C (Tyr-D-Ala-Gly-Phe-D-Leu), and BW834 C (Tyr-D-Ala-Gly-pClPhe-DLeu), which are resistant to enzymatic degradation were more potent than the enkephalins in reducing the stimulation-evoked transmitter overflow from the cat nictitating membrane. On the other hand, the tetrapeptide BW832 C, which lacks the D-leucine terminal of BW180 C l was less potent than the enkephalins in inhibiting neurotransmission. 4 In the presence of phenoxybenzamine 1 microM, 3H-transmitter overflow was increased 8 fold and the inhibition of neurotransmission by methionine-enkephalin was not affected. Exposure to phenoxybenzamine 10 microM increased [3H]-noradrenaline overflow 15 fold and antagonized the effects of methionine enkephalin on transmitter release. 5 In the cat nictitating membrane the inhibitory presynaptic opiate receptors are different from the presynaptic alpha-autoreceptors which regulate the release of noradrenaline elicited by nerve depolarization through a negative feed-back mechanism. PMID:6254597

  13. 1,3-Di(2-(5-/sup 3/H)tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs

    SciTech Connect

    Weber, E.; Sonders, M.; Quarum, M.; McLean, S.; Pou, S.; Keana, J.F.

    1986-11-01

    Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-(5-/sup 3/H)tolyl)guanidine ((/sup 3/H)Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The (/sup 3/H)Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the (/sup 3/H)Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of (/sup 3/H)Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (+)-(/sup 3/H)3-PPP) binding to guinea pig brain membrane receptors. (+)-(/sup 3/H)3-PPP has been proposed to be a selective sigma-receptor ligand (Largent, B. L., Gundlach, A. L. and Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987). Receptor autoradiography using (/sup 3/H)Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that (/sup 3/H)Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.

  14. Reevaluation of the effects of castration on naloxone-sensitive opiate receptors in the male rat brain.

    PubMed

    Cicero, T J; O'Connor, L H; Bell, R D

    1987-08-01

    There is a great deal of conflicting data regarding the issue of whether androgens influence opiate receptors in the whole male rat brain. Although Hahn and Fishman initially reported that long-term castration produced a large increase in the density of opiate-binding sites, relative to controls, no other independent group has been able to replicate these results. Recently, the former investigators reported that procedural differences could fully account for the discrepancies in the literature. Because of the importance of demonstrating a direct biochemical association between steroid- and endogenous opioid-containing neuronal elements in brain, we have reexamined the issue of whether long-term castration influences opiate receptors in whole male rat brain. To accomplish this goal, we incorporated all of the critical procedural variables which were identified by Hahn and Fishman as possible confounding variables in such studies. Our results clearly demonstrate that under identical conditions, we were unable to replicate the results of these investigators. In addition, we attempted to use other paradigms in an attempt to resolve this long-standing controversy in the literature, but these attempts were also unsuccessful. We are unable to explain our inability to replicate the results of Hahn and Fishman. However, it should be noted that at least 4 independent groups have now failed to reproduce their findings. Thus, it appears that the intrinsically attractive hypothesis that steroids influence opiate receptors cannot be addressed using whole brain analysis or relatively crude areas of brain and relatively nonspecific opiate ligands.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2819760

  15. Cholecystokinin-8 suppressed /sup 3/H-etorphine binding to rat brain opiate receptors

    SciTech Connect

    Wang, X.J.; Fan, S.G.; Ren, M.F.; Han, J.S.

    1989-01-01

    Radioreceptor assay (RRA) was adopted to analyze the influence of CCK-8 on /sup 3/H-etorphine binding to opiate receptors in rat brain synaptosomal membranes (P2). In the competition experiment CCK-8 suppressed the binding of /sup 3/H-etorphine. This effect was completely reversed by proglumide at 1/mu/M. Rosenthal analysis for saturation revealed two populations of /sup 3/H-etorphine binding sites. CCK-8 inhibited /sup 3/H-etorphine binding to the high affinity sites by an increase in Kd and decrease in Bmax without significant changes in the Kd and Bmax of the low affinity sites. This effect of CCK-8 was also completely reversed by proglumide at 1/mu/M. Unsulfated CCK-8 produced only a slight increase in Kd of the high affinity sites without affecting Bmax. The results suggest that CCK-8 might be capable of suppressing the high affinity opioid binding sites via the activation of CCK receptor.

  16. Psychotomimetic opiate receptors labeled and visualized with (+)-(/sup 3/H)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

    SciTech Connect

    Largent, B.L.; Gundlach, A.L.; Snyder, S.H.

    1984-08-01

    3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-(/sup 3/H)3-PPP in brain. The drug specificity of (+)-(/sup 3/H)3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-(/sup 3/H)3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10.047 at the sigma site, opposite to the stereoselectivity seen at ..mu.., sigma, and k opiate receptors. (+)-(/sup 3/H)3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-(/sup 3/H)3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-(/sup 3/H)3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavior effects of 3-PPP. 41 references, 2 figures, 1 table.

  17. Change in the properties of the opiate receptors of the brain under conditions of habituation of rats to morphine

    SciTech Connect

    Zaitsev, S.V.; Sergeeva, M.G.; Chichenkov, O.N.; Petrov, V.E.; Varfolomeev, S.D.

    1987-02-20

    The influence of prolonged administration of morphine on the properties of the opiate receptors of the rat brain was investigated. For this purpose they conducted an analysis of the isotherms of binding of labeled ..mu..-, sigma-, and chi-ligands: morphine, D-Ala/sup 2/, D-Leu/sup 5/-enkephalin, and ethylketocyclazocin, with membrane preparations of the brains of rats tolerant to morphine, as well as the control animals. For a quantitative determination of the dissociation constants of the ligand-receptor complexes (K) and the concentration of the reagents ((Q)), they used differential method and the method of simulation modeling. It was shown that the values of K and (Q) for individual animals are subjected to substantial dispersion, whereas the ratios (Q)/K undergo minor individual fluctuations, both in the control group and in the group of rats tolerant to morphine. This permits the ratio (Q)/K to be singled out as one of the main parameters for comparing the properties of opiate receptors of various groups of animals. Using this criterion, as well as the method of simulated modeling, it was shown that the development of tolerance is accompanied by a change in the properties of the delta-receptors (the ratio (Q)/K decreases by a factor of more than two). In contrast to the delta-receptors, no significant influence of the tolerance on the properties of the ..mu..- and chi-receptors, as well as the ultrahigh-affinity ligand binding sites, was detected.

  18. Opiate and opioid withdrawal

    MedlinePlus

    ... Oxycontin - opiate withdrawal; Hydrocodone - opiate withdrawal; Detox - opiates; Detoxification - opiates ... Using facilities set up to help people with detoxification (detox). In a regular hospital, if symptoms are ...

  19. Opiate and opioid withdrawal

    MedlinePlus

    ... opiate withdrawal; Oxycontin - opiate withdrawal; Hydrocodone - opiate withdrawal; Detox - opiates; Detoxification - opiates ... facilities set up to help people with detoxification (detox). In a regular hospital, if symptoms are severe. ...

  20. Evidence for association of two variants of the nociceptin/orphanin FQ receptor gene OPRL1 with vulnerability to develop opiate addiction in Caucasians

    PubMed Central

    Briant, Judith A.; Nielsen, David A.; Proudnikov, Dmitri; Londono, Douglas; Ho, Ann; Ott, Jurg; Kreek, Mary Jeanne

    2013-01-01

    Objectives The OPRL1 gene encodes the nociceptin/orphanin FQ receptor (NOP-R), which plays a role in regulating tolerance and behavioral responses to morphine. However, there is limited information on whether variants of OPRL1 are associated with vulnerability to develop opiate addiction. In this study, we examined five variants of OPRL1 and their role in determining vulnerability to develop opiate addiction. Methods We recruited 447 subjects: 271 former severe heroin addicts and 176 healthy controls. Using a 5′-fluorogenic exonuclease assay (TaqMan®), we genotyped subjects at five variants in OPRL1. It was then determined whether there was a significant association of allele, genotype, or haplotype frequency with vulnerability to develop opiate addiction. Results When the cohort was stratified by ethnicity, we found that, in Caucasians but not in African Americans or Hispanics, the allele frequency of rs6090041 and rs6090043 were significantly associated point-wise with opiate addiction (P = 0.03 and 0.04, respectively). Of the haplotypes formed by these two variants, one haplotype was found to be associated with protection from developing opiate addiction in both African Americans (point-wise P = 0.04) and Caucasians (point-wise P = 0.04), and another haplotype with vulnerability to develop opiate addiction in Caucasians only (P = 0.020). Conclusions This study provides evidence for an association of two variants of the OPRL1 gene, rs6090041 and rs6090043, with vulnerability to develop opiate addiction, suggesting a role for NOP-R in the development of opiate addiction. PMID:20032820

  1. Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.

    PubMed

    Lingford-Hughes, Anne; Myers, James; Watson, Ben; Reid, Alastair G; Kalk, Nicola; Feeney, Adrian; Hammers, Alexander; Riaño-Barros, Daniela A; McGinnity, Colm J; Taylor, Lindsay G; Rosso, Lula; Brooks, David J; Turkheimer, Federico; Nutt, David J

    2016-05-15

    The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [(11)C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [(11)C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [(11)C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [(11)C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an [(11)C]Ro15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [(11)C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [(11)C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [(11)C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates. PMID:26876472

  2. Using [11C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism

    PubMed Central

    Lingford-Hughes, Anne; Myers, James; Watson, Ben; Reid, Alastair G.; Kalk, Nicola; Feeney, Adrian; Hammers, Alexander; Riaño-Barros, Daniela A.; McGinnity, Colm J.; Taylor, Lindsay G.; Rosso, Lula; Brooks, David J.; Turkheimer, Federico; Nutt, David J.

    2016-01-01

    The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [11C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [11C]Ro15 4513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [11C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates. PMID:26876472

  3. Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

    PubMed Central

    Karchewski, Laurie; Gardon, Olivier; Matifas, Audrey; Filliol, Dominique; Becker, Jérôme A. J.; Wood, John N.; Kieffer, Brigitte L.; Gaveriaux-Ruff, Claire

    2013-01-01

    Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain. PMID:24069332

  4. Molecular orbital calculations of proton transfer involving amines as models for the clastic binding of opiates with their receptor

    SciTech Connect

    Bennett, L.K.; Beamer, R.L.

    1986-08-01

    Semi-empirical (CNDO) molecular orbital calculations, based on a previously reported ammonia-amine model system, were performed on an extended series of methyl-, ethyl-, and propylamines as models for the analgesic receptor. Methyl-, dimethyl-, and trimethylamines were chosen to represent the opiate molecules. Interatomic distances were varied within normally expected biological values. The results for the larger systems are similar to more elaborate calculations previously reported using smaller molecules. At internuclear distances of greater than 0.275 nm, the potential energy curves had two minima. At 0.2731 nm, the optimized N-N distance, the depth of the minima in the potential energy curve were not as great. Energy differences as well as population differences suggest deviation from the currently stated clastic binding theories mechanism for the analgesic response of the tertiary amines. The dimethylamine energy profile and population data indicate that the hypothesis of N-demethylated opiate as the active molecule needs further consideration and investigation. Investigation of larger systems is also indicated to develop increasingly realistic models for the analgesic response.

  5. The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog.

    PubMed

    Fioramonti, J; Fargeas, M J; Bueno, L

    1984-09-01

    The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2.5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors. PMID:6149288

  6. Imaging opiate receptors by positron tomography (PET): Evaluation by displacement of 3-Acetyl-6-Deoxy-6-Beta-/sup 18/F-flouronaltrexone with active and inactive naloxone

    SciTech Connect

    Larson, S.M.; Channing, M.A.; Rice, K.R.; Pert, C.B.; Eckelman, W.C.; Burke, T.R.; Bennett, J.M.; Carson, R.E.; Di Chiro, G.

    1985-05-01

    We recently reported the development of a new radiopharmaceutical for in vivo PET imaging of opiate receptors, 3-acetyl-6-deoxy-6-Beta-/sup 18/F-fluoronaltrexone: 3-acetylcyclofoxy, or /sup 18/F-ACF. These studies involved displacement of /sup 18/F-ACF from sites of uptake in the baboon sub-cortical gray matter, and provided strong proof of the opiate receptor specificity of the tracer. We now report on the anatomic localization of /sup 18/F-ACF in the sub-cortical grapy matter of baboon, and the kinetics of uptake and displacement of the tracer. /sup 18/F-ACF was prepared from the known 3-acetyl-6-alpha-naltrexol via the triflate, using /sup 18/F produced by neutron bombardment of /sup 6/Li/sub 2/CO/sub 3/. Anesthetized baboons were imaged after injection of /sup 18/F-ACF (sp.ac.=20Ci/mmol), using the NIH NEUROPET, a high resolution PET scanner. After bolus injection, the initial distribution to brain was rapid with peak uptake at 6 minutes post-injection. Clearance from opiate receptor rich regions of thalamus and basal ganglia was gradual, but after injection of active (but not after inactive), naloxone, clearance from these regions more than doubled. In non-opiate rich regions, (e.g. cerebellum), the predominant component of clearance was equally rapid with or without the active naloxone. Displacement studies of positron labelled ligands provide a powerful tool for non-invasive study of opiate receptor in living primates.

  7. Multicompartmental analysis of (/sup 11/C)-carfentanil binding to opiate receptors in humans measured by positron emission tomography

    SciTech Connect

    Frost, J.J.; Douglass, K.H.; Mayberg, H.S.; Dannals, R.F.; Links, J.M.; Wilson, A.A.; Ravert, H.T.; Crozier, W.C.; Wagner, H.N. Jr.

    1989-06-01

    (11C)-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of (11C)-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 +/- 0.92 to 0.26 +/- 0.13 in the thalamus (p less than 0.01) and from 1.8 +/- 0.33 to 0.16 +/- 0.065 in the frontal cortex (p less than 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35-70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35-70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

  8. Presynaptic Inhibition of Diverse Afferents to the Locus Coeruleus by Kappa Opiate Receptors: a Novel Mechanism for Regulating the Central Norepinephrine System

    PubMed Central

    Kreibich, Arati S.; Reyes, Beverly A. S.; Curtis, Andre L.; Ecke, Laurel; Chavkin, Charles; Van Bockstaele, Elisabeth J.; Valentino, Rita J.

    2008-01-01

    The norepinephrine nucleus, locus coeruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAA), corticotropin-releasing factor (CRF) and endogenous opioids acting at μ-opiate receptors. As the LC is also innervated by the endogenous κ-opiate receptor (κ-OR) ligand, dynorphin, and expresses κ-ORs, this study investigated κ-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of κ-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the κ-OR agonist, U50488, into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the κ-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that κ-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-NE system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate κ-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders or disorders characterized by abnormal sensory responses, such as autism. PMID:18562623

  9. Endogenous opiates and behavior: 2014.

    PubMed

    Bodnar, Richard J

    2016-01-01

    This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants). This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular

  10. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction.

    PubMed

    Yuferov, Vadim; Fussell, David; LaForge, K Steven; Nielsen, David A; Gordon, Derek; Ho, Ann; Leal, Suzanne M; Ott, Jurg; Kreek, Mary Jeanne

    2004-12-01

    The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine. KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine. The complete structure of the human KOR gene (hOPRK1) has not been previously determined. This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction. Analysis of 5'-RACE cDNA clones revealed the presence of a novel exon 1 ranging in length from 167 to 251 nucleotides in the 5' 5'-untranslated region of the hOPRK1 mRNA. We found that the hOPRK1 gene has four major exons and three introns, similar to rodent OPRK1 genes. Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls). Twelve SNPs were identified, nine novel variants and three previously reported SNPs. Using logistic regression with opioid dependence as the dependent variable, the 36G>T SNP exhibited a point-wise significant association (P = 0.016) with disease status. The number of haplotypes seen in the three ethnic groups were nine, six and five for African-Americans, Caucasians, and Hispanics, respectively, with corresponding significance levels for differences in haplotype frequencies between cases and controls of P = 0.0742, 0.1015 and 0.0041. Combining ethnicities by Fisher's method yields an empirical significance level of P = 0.0020. PMID:15608558

  11. Quantification of human opiate receptor concentration and affinity using high and low specific activity ( sup 11 C)diprenorphine and positron emission tomography

    SciTech Connect

    Sadzot, B.; Price, J.C.; Mayberg, H.S.; Douglass, K.H.; Dannals, R.F.; Lever, J.R.; Ravert, H.T.; Wilson, A.A.; Wagner, H.N. Jr.; Feldman, M.A. )

    1991-03-01

    (11C)Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769-5,920 Ci/mmol) and low (27-80 Ci/mmol) specific activity (SA) (11C)diprenorphine. Two subjects were studied a third time using high SA (11C)diprenorphine after a pretreatment with 1-1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 +/- 0.2 (occipital cortex) to 8.6 +/- 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of (11C)diprenorphine in plasma (f1) was 0.30 +/- 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 +/- 0.2, and the calculated free fraction of (11C)diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 +/- 0.5 (occipital cortex) to 20.6 +/- 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 +/- 0.17 nM.

  12. Black cohosh (Actaea racemosa, Cimicifuga racemosa) behaves as a mixed competitive ligand and partial agonist at the human mu opiate receptor

    PubMed Central

    Rhyu, Mee-Ra; Lu, Jian; Webster, Donna E.; Fabricant, Daniel S.; Farnsworth, Norman R.; Wang, Z. Jim

    2008-01-01

    Black cohosh is a commonly used botanical dietary supplement for the treatment of climacteric complaints. Since the opiate system in the brain is intimately associated with mood, temperature and sex hormonal levels, we investigated the activity of black cohosh extracts at the human μ opiate receptor (hMOR) expressed in Chinese hamster ovary cells. The 100% methanol-, 75% ethanol- and 40% 2-propanol- extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. Further studies of the clinically used ethanol extract indicated that black cohosh acted as a mixed competitive ligand, displacing 77 ± 4% [3H]DAMGO to hMOR (Ki = 62.9 μg/ml). Using the [35S]GTPγS assay, the action of black cohosh was found to be consistent with an agonist, with an EC50 of 68.8 ± 7.7 μg/ml. These results demonstrate for the first time that black cohosh contains active principle(s) that activate hMOR, supporting its beneficial role in alleviating menopausal symptoms. PMID:17177511

  13. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

    PubMed Central

    Furnari, Frank B.; Cloughesy, Timothy F.; Cavenee, Webster K.; Mischel, Paul S.

    2016-01-01

    As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance. PMID:25855404

  14. Endogenous opiates and behavior: 2001.

    PubMed

    Bodnar, Richard J; Hadjimarkou, Maria M

    2002-12-01

    This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:12535711

  15. Radiosynthesis of an opiate receptor-binding radiotracer for positron emission tomography: (C-11 methyl)-methyl-4-(N-(1-oxopropyl)-N-phenylamino)-4-piperidine carboxylate (C-11 4-carbomethoxyfentanyl)

    SciTech Connect

    Dannals, R.F.; Ravert, H.T.; Frost, J.J.; Wilson, A.A.; Burns, H.D.; Wagner, H.N. Jr.

    1984-01-01

    The development of high affinity, high specific activity tritium-labeled neurotransmitter receptor ligands has made it possible to determine the spatial distribution and relative regional concentration of several neuroreceptors by means of in vivo receptor labeling techniques in animals. This development made possible the biochemical identification of opiate receptors by autoradiographic visualization in experimental animals. The quantitation and localization of opiate receptors in man using non-invasive methods, such as positron emission tomography, could provide a means of obtaining information about a variety of receptor-linked neuropsychiatric diseases as well as normal brain mechanisms regulating pain and emotions. As part of a continuing program to identify and radiolabel high affinity, highly specific ligands for the opiate receptor, the authors have selected two derivatives of fentanyl, a well-known analgesic, as candidates for radiolabeling: R-31,833 (4-carbomethoxy-fentanyl) and R-34,995 (lofentanil). Carbon-11 labeled R-31,833 was synthesized by the methylation of the appropriate carboxylate with C-11 methyl iodide in dimethylformamide at room temperature and purified by high performance liquid chromatography. The average synthesis time from end-of-bombardment (E.O.B.) was 30 minutes. The average specific activity was determined by ultraviolet spectroscopy to be 890 mCi/..mu..mole end-of-synthesis (approx. 2500 mCi/..mu..mole E.O.B.).

  16. Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.

    PubMed

    Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y

    2006-02-15

    We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of opiate-treated rats that received low doses of naltrexone in their drinking water. No significant difference in PKA or pCREB was detected in these regions following drug treatment. To examine further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a significant increase in muOR expression in the NTS of morphine-dependent rats that received low doses of naltrexone in their drinking water, and increases in muOR expression were also found to be dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition of NTS neurons resulting from increased muOR expression in this region. PMID:16385558

  17. Effects of opiates on synaptosomal calmodulin and calcium uptake

    SciTech Connect

    Hoss, W.; Formaniak, M.

    1983-02-01

    Acute opiate administration in vivo increases the level of cytoplasmic calmodulin in isolated rat brain synaptosomes. These synaptosomes do not, however, display decreased K/sup +/-stimulated /sup 45/Ca uptake in vitro. Opiates affect neither cytoplasmic calmodulin nor Ca uptake after incubation of synaptosomes with the drugs in vitro. In contrast to the interpretation of electrophysiological data, these results suggest that the observed inhibition by opiates of the release of several transmitters may not be mediated by presynaptic opiate receptors that inhibit Ca uptake.

  18. Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated mu opioid receptor (MOR-1) splice variants

    PubMed Central

    Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R.; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W.

    2012-01-01

    3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogs were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3′ or 4′ position of the phenyl ring and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower delta opioid receptor affinity than its naltrexamine analog, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID:22734622

  19. Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants.

    PubMed

    Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W

    2012-07-26

    3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID:22734622

  20. Inflated reward value in early opiate withdrawal.

    PubMed

    Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E; Maidment, Nigel T; Ostlund, Sean B

    2016-03-01

    Through incentive learning, the emotional experience of a reward in a relevant need state (e.g. hunger for food) sets the incentive value that guides the performance of actions that earn that reward when the need state is encountered again. Opiate withdrawal has been proposed as a need state in which, through experience, opiate value can be increased, resulting in escalated opiate self-administration. Endogenous opioid transmission plays anatomically dissociable roles in the positive emotional experience of reward consumption and incentive learning. We, therefore, sought to determine if chronic opiate exposure and withdrawal produces a disruption in the fundamental incentive learning process such that reward seeking, even for non-opiate rewards, can become maladaptive, inconsistent with the emotional experience of reward consumption and irrespective of need. Rats trained to earn sucrose or water on a reward-seeking chain were treated with morphine (10-30 mg/kg, s.c.) daily for 11 days prior to testing in withdrawal. Opiate-withdrawn rats showed elevated reward-seeking actions, but only after they experienced the reward in withdrawal, an effect that was strongest in early (1-3 days), as opposed to late (14-16 days), withdrawal. This was sufficient to overcome a negative reward value change induced by sucrose experience in satiety and, in certain circumstances, was inconsistent with the emotional experience of reward consumption. Lastly, we found that early opiate withdrawal-induced inflation of reward value was blocked by inactivation of basolateral amygdala mu opioid receptors. These data suggest that in early opiate withdrawal, the incentive learning process is disrupted, resulting in maladaptive reward seeking. PMID:25081350

  1. Regional dependence of morphine-induced mu-opiate receptor down-regulation in perinatal rat brain.

    PubMed

    Hammer, R P; Seatriz, J V; Ricalde, A R

    1991-12-17

    The effect of perinatal morphine administration was examined in various brain regions using in vitro receptor autoradiography. Morphine was administered by continuous s.c. infusion of 10 mg/kg per day; brains of offspring were examined at five days of age. Morphine exposure reduced mu-receptor binding density in the preoptic area of hypothalamus, but not in the primary somatosensory cortex. mu-Receptor density was greater in the medial preoptic area of females than males, and in superficial layers of cortex in males than females. The results suggest that morphine has selective regional effects on mu-receptor ontogeny in rat brain. PMID:1665797

  2. Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats.

    PubMed

    Henderson, Fraser; May, Walter J; Gruber, Ryan B; Discala, Joseph F; Puskovic, Veljko; Young, Alex P; Baby, Santhosh M; Lewis, Stephen J

    2014-01-15

    This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient. PMID:24284037

  3. Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

    PubMed Central

    Henderson, Fraser; May, Walter J.; Gruber, Ryan B.; Discala, Joseph F.; Puscovic, Veljko; Young, Alex P.; Baby, Santhosh M.; Lewis, Stephen J.

    2015-01-01

    This study determined the effects of the peripherally restricted µ-opiate receptor (µ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25 µg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5 mg/kg of NLXmi but was attenuated by a 5.0 mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5 mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5 mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral µ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient. PMID:24284037

  4. Effects of opiates on brain development.

    PubMed

    Hammer, R P; Ricalde, A A; Seatriz, J V

    1989-01-01

    Perinatal morphine administration affects neuronal growth in the developing animal. Neuronal packing density was reduced by morphine treatment in both primary somatosensory cortex and preoptic area of the hypothalamus. However, glial packing density was increased, but only in hypothalamus, which could reflect greater severity of opiate-induced neurotoxicity in hypothalamus. Cortical pyramidal neurons show morphine-induced reduction of basilar dendritic growth limited to late-developing terminal branches. This effect is completely reversed by concurrent naltrexone administration. This selective effect could be caused by morphine acting at opiate receptors to inhibit extrinsic determinants of dendritic growth (e.g., afferent supply). The ontogeny of opiate receptors is also affected by perinatal morphine administration in a regionally-dependent manner. Mureceptors are downregulated by morphine in hypothalamus, but not in cortex. Differential maturity of receptors in these regions could be a factor in such differential drug effects. Therefore, different critical periods for opiate action in different regions of the developing brain could exist. PMID:2696899

  5. Glucocorticoid receptor content of T lymphocytes: evidence for heterogeneity.

    PubMed

    Distelhorst, C W; Benutto, B M

    1981-04-01

    Glucocorticoid receptors were measured in T lymphocytes that were isolated from peripheral blood by either nylon wool filtration or E-rosette sedimentation. T cells isolated by nylon wool filtration specifically bind 6.7 +/- 0.2 fmol of dexamethasone per million cells (equivalent to 4000 +/- 200 receptors per cell), whereas T cells isolated by E-rosette sedimentation bind 12.0 +/- 0.7 fmol of dexamethasone per million cells (equivalent to 7200 +/- 400 receptors per cell). This difference in the amount of dexamethasone bound by the two T cell preparations was significant (p less than .001) and was present immediately after cell isolation. The binding affinities of the different T cell preparations for dexamethasone were similar. T cells that are isolated by a combination of nylon wool filtration followed by E-rosette sedimentation bind the same amount of dexamethasone as T cells isolated by nylon wool filtration alone. T cells isolated by a combination of E-rosette sedimentation following by nylon wool filtration bind less dexamethasone than do T cells isolated by E-rosette sedimentation alone. These findings suggest that T cells are heterogeneous with respect to their quantity of glucocorticoid receptors. Isolation of T cells by E-rosette sedimentation enriches for T cells that have a greater number of glucocorticoid receptors, and isolation of T cells by nylon wool filtration enriches for T cells that have a lesser number of glucocorticoid receptors. PMID:6970782

  6. Effects of mitragynine on cAMP formation mediated by delta-opiate receptors in NG108-15 cells.

    PubMed

    Tohda, M; Thongpraditchote, S; Matsumoto, K; Murakami, Y; Sakai, S; Aimi, N; Takayama, H; Tongroach, P; Watanabe, H

    1997-04-01

    Mitragynine, a major constituent of the young leaves of Mitragyna speciosa KORTH., has been reported to exert antinociceptive activity in mice. To determine the mechanism the influence of mitragynine on cAMP content was measured in NG108-15 cells which possess delta opioid receptors and alpha 2B-adrenoceptors. Mitragynine inhibited the forskolin-stimulated cAMP content in a concentration dependent manner as well as morphine and noradrenaline. Mitragynine- and morphine-induced inhibition of cAMP content were blocked by naloxone. Although idazoxane inhibited noradrenaline-induced inhibition of the cAMP content, idazoxane had no effect on mitragynine-induced inhibition. These results suggest that mitragynine acts directly on opioid receptors, but not on alpha 2-adrenoceptors, to show antinociceptive activity. PMID:9145205

  7. Characterization and autoradiographic visualization of (+)-(3H)SKF10,047 binding in rat and mouse brain: further evidence for phencyclidine/sigma opiate receptor commonality

    SciTech Connect

    Sircar, R.; Nichtenhauser, R.; Ieni, J.R.; Zukin, S.R.

    1986-05-01

    The binding specificity of (+)-(/sup 3/H)N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the Kd values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-(/sup 3/H)SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the (/sup 3/H)phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opiods, PCP derivatives and dioxolanes for displacement of 100 nM (+)-(/sup 3/H)SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the (/sup 3/H)PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-(/sup 3/H)SKF10,047 binding was observed to follow the regional pattern of (3H)PCP binding but also to bind in other regions not associated with PCP receptors.

  8. Distribution of opiate-like substances in rat tissues.

    PubMed

    Neidle, A; Manigault, I; Wajda, I J

    1979-06-01

    Rat tissues were tested for their ability to inhibit the binding of [3H]dihydromorphine or [3H]naloxone to membrane-bound opiate receptors. By this criterion, morphine-like substances were found in lung, heart, liver, and kidney as well as in brain. The relative activity of the extracts, based on initial tissue weight, differed with the radioactive lignand employed. With dihydromorphine, the order was as above. With naloxone, lung was most active, followed by heart, brain, liver, and kidney. The ability of all tissue extracts to inhibit opiate binding was reduced by 100 mM NaC1 and slightly reduced by 1 mM MnC1(2). Gel filtration using Sephadex G-25 indicated that the inhibitory substances were heterogeneous in molecular weight. Only with brain and kidney extracts was there significant activity at the elution volume where enkephalins would be expected. Fractionation using Amberlite XAD-2, a resin which selectively absorbs hydrophobic materials, again indicated that the major protion of activity in all tissue extracts was due to substances other than enkephalins. PMID:223080

  9. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  10. A thalamic input to the nucleus accumbens mediates opiate dependence.

    PubMed

    Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

    2016-02-11

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction. PMID:26840481

  11. Photoaffinity labeling of opiate (enkephalin) receptor of rat brain plasma membranes with /sup 125/I(D-Ala/sup 2/, p-N/sub 3/-Phe/sup 4/-Met/sup 5/)-enkephalin

    SciTech Connect

    Yeung, C.W.T.

    1986-05-01

    A photoreactive (D-Ala/sup 2/, p-N/sub 3/-Phe/sup 4/-Met/sup 5/)enkephalin derivative was prepared, iodinated with carrier free /sup 125/I and then purified by high performance liquid chromatography. The purified radioactive photoprobe was monoiodinated at the amino terminal tyrosine residue. This radioactive photoprobe was used to photoaffinity label plasma membranes prepared from rat brain, spinal cord and cerebellum. The photolabeled plasma membranes were analyzed by sodium dodecyl sulfate gel electrophoresis. A 46,000-daltons band was specifically photolabeled in the plasma membranes of brain and spinal cord but not in the plasma membranes from cerebellum. The photolabeling of this band was inhibited by peptides related to enkephalin by not but substance P or gastrin tetrapeptide. These data demonstrate that the labeled 46,000-daltons band is a protein of the opiate (enkephalin)receptor.

  12. [Rapid opiate detoxification under anesthesia (RODA)].

    PubMed

    Dubols, N; Hallet, C; Luppens, D; Ansseau, M; Charlier, C

    2013-01-01

    Rapid Opiate Detoxification under Anesthesia (RODA) involves the use of opiate antagonists combined with anesthesia and pharmacotherapy to reduce withdrawal symptoms. The aim of our study was to measure the plasma concentrations of heroin metabolites and methadone during anesthesia and patient stay at the hospital in order to assess the amount of active substances at each protocol step. Plasma concentrations of antagonists were also quantified and compared to the recommended target values. Blood samples were drawn in 10 patients undergoing RODA at different times of the procedure (during anesthesia, in post-anesthesia care unit and in psychiatry unit). The plasma concentrations of heroin metabolites, methadone and antagonists were measured using a previously described method. Heroin active metabolites were no longer detected in the patient blood when helshe left the hospital; by contrast, methadone was still present at significant concentrations 3 days after the beginning of the detoxification procedure. Naltrexone analysis allowed us to adjust doses to insure opiate receptor blockade during acute withdrawal, which is a critical period. PMID:23888580

  13. Ki67 Heterogeneity in Estrogen Receptor-Positive Breast Cancers: Which Tumor Type Has the Most Heterogeneity?

    PubMed

    Himuro, Takanori; Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Saito, Mitsue

    2016-04-01

    Heterogeneity of Ki67 expression, often seen in breast cancer, can make evaluation of the expression of this marker difficult and give rise to confusion when considering adjuvant treatments for patients. Herein, we investigated estrogen receptor-positive breast cancers to reveal the tumor characteristics associated with Ki67 heterogeneity. Surgical specimens from 85 invasive ductal carcinomas of no special type and 13 invasive lobular carcinomas were examined. We first calculated the differences between Ki67 expression in a hot spot and those in 4 random fields on the same slide. We then evaluated Ki67 heterogeneity within the tumor, based on these differences. Among clinicopathological factors, solid-tubular carcinoma, an architectural growth pattern subtype of invasive ductal carcinoma, correlated with high Ki67 heterogeneity (P < .05). Our results indicate that we might need to be aware of histological patterns when selecting appropriate microscopic fields for evaluating Ki67 expression. PMID:26353854

  14. Neuroscience of opiates for addiction medicine: From stress-responsive systems to behavior.

    PubMed

    Zhou, Yan; Leri, Francesco

    2016-01-01

    Opiate addiction, similarly to addiction to other psychoactive drugs, is chronic relapsing brain disease caused by drug-induced short-term and long-term neuroadaptations at the molecular, cellular, and behavioral levels. Preclinical research in laboratory animals has found important interactions between opiate exposure and stress-responsive systems. In this review, we will discuss the dysregulation of several stress-responsive systems in opiate addiction: vasopressin and its receptor system, endogenous opioid systems (including proopiomelanocortin/mu opioid receptor and dynorphin/kappa opioid receptor), orexin and its receptor system, and the hypothalamic-pituitary-adrenal axis. A more complete understanding of how opiates alter these stress systems, through further laboratory-based studies, is required to identify novel and effective pharmacological targets for the long-term treatment of heroin addiction. PMID:26806779

  15. Perinatal opiate treatment delays growth of cortical dendrites.

    PubMed

    Ricalde, A A; Hammer, R P

    1990-07-31

    Basilar dendritic arborizations of layer II-III pyramidal neurons in primary somatosensory cortex of 5-day-old male rats were reconstructed following perinatal morphine, morphine/naltrexone, or saline vehicle administration. Morphine treatment was observed to reduce total dendritic length. This effect was limited to higher order dendritic branches, with terminal dendrites manifesting the greatest reduction of length. The action of morphine was presumably mediated by opiate receptors, since concurrent naltrexone administration completely reversed morphine effects on dendritic length and branching. These results suggest that opiates act during late ontogenesis to affect dendritic growth in cerebral cortex. PMID:2172870

  16. Heterogeneity and probabilistic binding contributions to receptor-mediated cell detachment kinetics.

    PubMed Central

    Saterbak, A; Kuo, S C; Lauffenburger, D A

    1993-01-01

    Biospecific cell adhesion is mediated by receptor-ligand bonds. Early theoretical work presented a deterministic analysis of receptor-mediated cell attachment and detachment for a homogeneous cell population. However, initial comparison of a deterministic framework to experimental detachment profiles of model "cells" (antibody-coated latex beads) did not show qualitative or quantitative agreement (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys. J. 58:857-872). Hence, we determine the contributions of population heterogeneity and probabilistic binding to the detachment behavior of this experimental system which was designed to minimize experimental and theoretical complications. This work also corrects an error in the numerical solution of the probabilistic model of receptor-mediated cell attachment and detachment developed previously (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys J. 58:841-856). Measurement of the population distribution of the number of receptors per bead has enabled us to explicitly consider the effect of receptor number heterogeneity within the cell-surface contact area. A deterministic framework that incorporates receptor number heterogeneity qualitatively and quantitatively accounts in large part for the model cell detachment data. Using measured and estimated parameter values for the model cell system, we estimate that about 90% of the observed kinetic detachment behavior originates from heterogeneity effects, while about 10% is due to probabilistic binding effects. In general, these relative contributions may differ for other systems. PMID:8396454

  17. The role of the endogenous opiates in zinc deficiency anorexia.

    PubMed

    Essatara, M B; Morley, J E; Levine, A S; Elson, M K; Shafer, R B; McClain, C J

    1984-03-01

    Anorexia is a major symptom of zinc deficiency, but the mechanism(s) for this anorexia are poorly defined. Recent studies have suggested an integral role for endogenous opiate peptides in appetite regulation. Dynorphin, a leucine-enkephalin containing opiate peptide, is a potent inducer of spontaneous feeding. In this study we showed that zinc deficient animals were relatively resistant to dynorphin-induced feeding. Measurement of dynorphin levels using a highly sensitive radioimmunoassay showed that zinc deficient animals had lower levels of dynorphin in the hypothalamus than did ad lib fed animals, with weight restricted animals having intermediate values. [3H]-naloxone binding was significantly increased to isolated brain membranes from zinc deficient animals using 1 nM unlabeled naloxone when compared to ad lib fed controls with the weight restricted animals again having intermediate values. These data suggest that abnormalities in endogenous opiate regulation of appetite may well play a role in the anorexia of zinc deficiency. The effects of zinc deficiency on endogenous opiate action appear to include alterations in receptor affinity, a post-receptor defect and alterations in the synthesis and/or release of dynorphin. PMID:6146993

  18. Heterogeneity of muscarinic receptor subtypes in cerebral blood vessels

    SciTech Connect

    Garcia-Villalon, A.L.; Krause, D.N.; Ehlert, F.J.; Duckles, S.P. )

    1991-07-01

    The identity and distribution of muscarinic cholinergic receptor subtypes and associated signal transduction mechanisms was characterized for the cerebral circulation using correlated functional and biochemical investigations. Subtypes were distinguished by the relative affinities of a panel of muscarinic antagonists, pirenzepine, AF-DX 116 (11-2-((2-(diethylaminomethyl)- 1-piperidinyl)acetyl)-5,11-dihydro-6H- pyrido(2,3-b)(1,4)benzodiazepine-6-one), hexahydrosiladifenidol, methoctramine, 4-diphenylacetoxy-N-methylpiperidine methobromide, dicyclomine, para-fluoro-hexahydrosiladifenidol and atropine. Muscarinic receptors characterized by inhibition of (3H)quinuclidinylbenzilate binding in membranes of bovine pial arteries were of the M2 subtype. In contrast pharmacological analysis of (3H)-quinuclidinylbenzilate binding in bovine intracerebral microvessels suggests the presence of an M4 subtype. Receptors mediating endothelium-dependent vasodilation in rabbit pial arteries were of the M3 subtype, whereas muscarinic receptors stimulating endothelium-independent phosphoinositide hydrolysis in bovine pial arteries were of the M1 subtype. These findings suggest that characteristics of muscarinic receptors in cerebral blood vessels vary depending on the type of vessel, cellular location and function mediated.

  19. Spinal sympathetic neurons: possible sites of opiate-withdrawal suppression by clonidine.

    PubMed

    Franz, D N; Hare, D B; McCloskey, K L

    1982-03-26

    Morphine, methadone, meperidine, fentanyl, and clonidine rapidly depressed transmission through sympathetic preganglionic neurons in cats with the spinal cord transected. Naloxone promptly antagonized this effect of the opiates but not that of clonidine which was reversed by alpha 2-adrenergic receptor antagonists. The independent depression of preganglionic neurons by clonidine may contribute to the ability of this drug to depress the symptoms of opiate withdrawal that are characterized by sympathetic hyperactivity. PMID:6280276

  20. N-linked oligosaccharides are responsible for rat striatal dopamine D2 receptor heterogeneity

    SciTech Connect

    Clagett-Dame, M.; McKelvy, J.F. )

    1989-10-01

    The glycoprotein nature of the binding subunit of the dopamine D2 receptor in rat striatum has been examined by photoaffinity labeling receptor preparations with N-(p-azido-m-(125I)iodophenethyl)spiperone followed by treatment of crude membrane receptor or receptor fractions isolated from sodium dodecyl sulfate (SDS) polyacrylamide gels with endo- and exoglycosidases. The major photoaffinity labeled protein migrates as a heterogeneous species on 10% SDS polyacrylamide gels and ranges from 130,000 to 75,000 relative molecular mass (Mr). This heterogeneity can be explained by glycosylation of the receptor by complex-type N-linked oligosaccharides. Three fractions of labeled receptor were isolated from SDS polyacrylamide gels over a range of 130,000 to 75,000 Mr; after digestion with peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase, all fractions yielded a single peptide approximately 40,000 Mr. Treatment of photoaffinity labeled membranes with alpha-mannosidase was without effect. The dopamine D2 receptor appears to contain substantial amounts of sialic acid as treatment of photoaffinity labeled membranes with neuraminidase increased the receptor mobility on SDS polyacrylamide gels to a species of 50,000-54,000 Mr. Treatment of the receptor with neuraminidase followed by endo-alpha-N-acetylgalactosaminidase did not change the electrophoretic migration pattern from that seen after neuraminidase treatment alone, suggesting that the binding peptide contains no serine- or threonine-linked oligosaccharides. A smaller binding peptide of approximately 31,000 Mr is also apparent in crude photoaffinity labeled membranes. This material also contains N-linked oligosaccharide.

  1. Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

    PubMed Central

    Weddell, Jared C.; Imoukhuede, P. I.

    2014-01-01

    Cell population heterogeneity can affect cellular response and is a major factor in drug resistance. However, there are few techniques available to represent and explore how heterogeneity is linked to population response. Recent high-throughput genomic, proteomic, and cellomic approaches offer opportunities for profiling heterogeneity on several scales. We have recently examined heterogeneity in vascular endothelial growth factor receptor (VEGFR) membrane localization in endothelial cells. We and others processed the heterogeneous data through ensemble averaging and integrated the data into computational models of anti-angiogenic drug effects in breast cancer. Here we show that additional modeling insight can be gained when cellular heterogeneity is considered. We present comprehensive statistical and computational methods for analyzing cellomic data sets and integrating them into deterministic models. We present a novel method for optimizing the fit of statistical distributions to heterogeneous data sets to preserve important data and exclude outliers. We compare methods of representing heterogeneous data and show methodology can affect model predictions up to 3.9-fold. We find that VEGF levels, a target for tuning angiogenesis, are more sensitive to VEGFR1 cell surface levels than VEGFR2; updating VEGFR1 levels in the tumor model gave a 64% change in free VEGF levels in the blood compartment, whereas updating VEGFR2 levels gave a 17% change. Furthermore, we find that subpopulations of tumor cells and tumor endothelial cells (tEC) expressing high levels of VEGFR (>35,000 VEGFR/cell) negate anti-VEGF treatments. We show that lowering the VEGFR membrane insertion rate for these subpopulations recovers the anti-angiogenic effect of anti-VEGF treatment, revealing new treatment targets for specific tumor cell subpopulations. This novel method of characterizing heterogeneous distributions shows for the first time how different representations of the same data set lead

  2. GABAA receptor beta subunit heterogeneity: functional expression of cloned cDNAs.

    PubMed Central

    Ymer, S; Schofield, P R; Draguhn, A; Werner, P; Köhler, M; Seeburg, P H

    1989-01-01

    Cloned cDNAs encoding two new beta subunits of the rat and bovine GABAA receptor have been isolated using a degenerate oligonucleotide probe based on a highly conserved peptide sequence in the second transmembrane domain of GABAA receptor subunits. The beta 2 and beta 3 subunits share approximately 72% sequence identity with the previously characterized beta 1 polypeptide. Northern analysis showed that both beta 2 and beta 3 mRNAs are more abundant in the brain than beta 1 mRNA. All three beta subunit encoding cDNAs were also identified in a library constructed from adrenal medulla RNA. Each beta subunit, when co-expressed in Xenopus oocytes with an alpha subunit, forms functional GABAA receptors. These results, together with the known alpha subunit heterogeneity, suggest that a variety of related but functionally distinct GABAA receptor subtypes are generated by different subunit combinations. Images PMID:2548852

  3. Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl(6-/sup 3/H)phenyl)-3-(2-methyl(4,6-/sup 3/H)phenyl)guanidine

    SciTech Connect

    Kavanaugh, M.P.; Tester, B.C.; Scherz, M.W.; Keana, J.F.W.; Weber, E.

    1988-04-01

    The sigma-type opiate receptor is a distinct binding site in the brain that may mediate some of the psychotomimetic effects caused by benzomorphan opiates and phencyclidine in humans. The authors have developed a synthetic, highly selective ligand for this receptor, 1,3-di-o-tolylguanidine (DTG). To identify the binding protein(s) of the sigma receptor, they have now synthesized a radiolabeled azide derivative of DTG, ((/sup 3/H)N/sub 3/DTG). In guinea pig brain membrane binding assays conducted in the dark, (/sup 3/H)N/sub 3/DTG bound reversibly, selectively, and with high affinity to sigma receptors. The drug specificity profile of reversible (/sup 3/H)-N/sub 3/DTG binding was identical to that of (/sup 3/H)DTG and /sup 3/H-labeled (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding indicating that (/sup 3/H)N/sub 3/DTG is a selective sigma receptor ligand. Guinea pig brain membranes were photoaffinity-labeled with (/sup 3/H)N/sub 3/DTG. NaDodSO/sub 4//PAGE of detergent-solubilized membrane extract identified a single 29-kDa radioactive band. Sepharose Cl-6B gel chromatography of photolabeled brain membranes solubilized with the nondenaturing detergent sodium cholate showed a radioactive complex with a Stoke's radius of 4.6 nm (M/sub r/, 150,000) that may represent the intact sigma receptor complex. NaDodSO/sub 4//PAGE of this complex showed the radiolabeled material was a 29-kDa polypeptide that may be binding subunit of the sigma receptor.

  4. Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature.

    PubMed

    Wills, Kiri L; Parker, Linda A

    2016-01-01

    Over the years, animal studies have revealed a role for the endocannabinoid system in the regulation of multiple aspects of opiate addiction. The current review provides an overview of this literature in regards to opiate withdrawal. The opiate withdrawal syndrome, hypothesized to act as a negative reinforcer in mediating continued drug use, can be characterized by the emergence of spontaneous or precipitated aversive somatic and affective states following the termination of drug use. The behaviors measured to quantify somatic opiate withdrawal and the paradigms employed to assess affective opiate withdrawal (e.g., conditioned place aversion) in both acutely and chronically dependent animals are discussed in relation to the ability of the endocannabinoid system to modulate these behaviors. Additionally, the brain regions mediating somatic and affective opiate withdrawal are elucidated with respect to their modulation by the endocannabinoid system. Ultimately, a review of these findings reveals dissociations between the brain regions mediating somatic and affective opiate withdrawal, and the ability of cannabinoid type 1 (CB1) receptor agonism/antagonism to interfere with opiate withdrawal within different brain sub regions. PMID:27445822

  5. Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature

    PubMed Central

    Wills, Kiri L.; Parker, Linda A.

    2016-01-01

    Over the years, animal studies have revealed a role for the endocannabinoid system in the regulation of multiple aspects of opiate addiction. The current review provides an overview of this literature in regards to opiate withdrawal. The opiate withdrawal syndrome, hypothesized to act as a negative reinforcer in mediating continued drug use, can be characterized by the emergence of spontaneous or precipitated aversive somatic and affective states following the termination of drug use. The behaviors measured to quantify somatic opiate withdrawal and the paradigms employed to assess affective opiate withdrawal (e.g., conditioned place aversion) in both acutely and chronically dependent animals are discussed in relation to the ability of the endocannabinoid system to modulate these behaviors. Additionally, the brain regions mediating somatic and affective opiate withdrawal are elucidated with respect to their modulation by the endocannabinoid system. Ultimately, a review of these findings reveals dissociations between the brain regions mediating somatic and affective opiate withdrawal, and the ability of cannabinoid type 1 (CB1) receptor agonism/antagonism to interfere with opiate withdrawal within different brain sub regions. PMID:27445822

  6. An allosteric model for heterogeneous receptor complexes: Understanding bacterial chemotaxis responses to multiple stimuli

    PubMed Central

    Mello, Bernardo A.; Tu, Yuhai

    2005-01-01

    The classical Monod-Wyman-Changeux model for homogeneous allosteric protein complex is generalized in this article to model the responses of heterogeneous receptor complexes to multiple types of ligand stimulus. We show that the recent in vivo experimental data of Escherichia coli chemotaxis responses for mutant strains with different expression levels of the chemo-receptors to different types of stimulus [Sourjik, V. & Berg, H. C. (2004) Nature 428, 437–441] all can be explained consistently within this generalized Monod-Wyman-Changeux model. Based on the model and the existing data, responses of all of the strains (studied in this article) to the presence of any combinations of ligand (Ser and MeAsp) concentrations are predicted quantitatively for future experimental verification. Through modeling the in vivo response data, our study reveals important information about the properties of different types of individual receptors, as well as the composition of the cluster. The energetic contribution of the nonligand binding, cytoplasmic parts of the cluster, such as CheA and CheW, is also discussed. The generalized allosteric model provides a consistent framework in understanding signal integration and differentiation in bacterial chemotaxis. It should also be useful for studying the functions of other heterogeneous receptor complexes. PMID:16293695

  7. Better retention of Malaysian opiate dependents treated with high dose methadone in methadone maintenance therapy

    PubMed Central

    2010-01-01

    Background Methadone is a synthetic opiate mu receptor agonist that is widely used to substitute for illicit opiates in the management of opiate dependence. It helps prevent opiate users from injecting and sharing needles which are vehicles for the spread of HIV and other blood borne viruses. This study has the objective of determining the utility of daily methadone dose to predict retention rates and re-injecting behaviour among opiate dependents. Methods Subjects comprised opiate dependent individuals who met study criteria. They took methadone based on the Malaysian guidelines and were monitored according to the study protocols. At six months, data was collected for analyses. The sensitivity and specificity daily methadone doses to predict retention rates and re-injecting behaviour were evaluated. Results Sixty-four patients volunteered to participate but only 35 (54.69%) remained active and 29 (45.31%) were inactive at 6 months of treatment. Higher doses were significantly correlated with retention rate (p < 0.0001) and re-injecting behaviour (p < 0.001). Of those retained, 80.0% were on 80 mg or more methadone per day doses with 20.0% on receiving 40 mg -79 mg. Conclusions We concluded that a daily dose of at least 40 mg was required to retain patients in treatment and to prevent re-injecting behaviour. A dose of at least 80 mg per day was associated with best results. PMID:21167035

  8. Opiate modulation of monoamines in the chick forebrain: possible role in emotional regulation?

    PubMed

    Baldauf, K; Braun, K; Gruss, M

    2005-02-01

    Numerous studies have shown that the opiate system is crucially involved in emotionally guided behavior. In the present study, we focussed on the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of the chick forebrain. This avian prefrontal cortex analogue is critically involved in auditory filial imprinting, a well-characterized juvenile emotional learning event. The high density of mu-opiate receptors expressed in the MNH led to the hypothesis that mu-opiate receptor-mediated processes may modulate the glutamatergic, dopaminergic, and/or serotonergic neurotransmission within the MNH and thereby have a critical impact on filial imprinting. Using microdialysis and pharmaco-behavioral approaches in young chicks, we demonstrated that: the systemic application of the mu-opiate receptor antagonist naloxone (5, 50 mg/kg) significantly increased extracellular levels of 5-HIAA and HVA; the systemic application of the specific mu-opiate receptor agonist DAGO (5 mg/kg) increased the levels of HVA and taurine, an effect that was antagonized by simultaneously applied naloxone (5 mg/kg); the local application of DAGO (1 mM) had no effects on 5-HIAA, HVA, glutamate, and taurine, however, the effects of systemically injected naloxone (5 mg/kg) were abolished by simultaneously applied DAGO (1 mM); the systemic application of naloxone (5 mg/kg) increased distress behavior (measured as the duration of distress vocalization during separation from the peer group). These results are in line with our hypothesis that the mu-opiate receptor-mediated modulation of serotonergic and dopaminergic neurotransmission alters the emotional and motivational status of the animal and thereby may play a modulatory role during filial imprinting in the newborn animal. PMID:15452850

  9. Achalasia and chronic opiate use: innocent bystanders or associated conditions?

    PubMed

    Ravi, K; Murray, J A; Geno, D M; Katzka, D A

    2016-01-01

    High-resolution manometry identifies three subtypes of achalasia. However, type 3 differs from classic achalasia. Although opiates affect esophageal motility, opiate use and achalasia have not been studied. Patients with a new diagnosis of achalasia at Mayo Clinic Rochester between June 1, 2012 and January 3, 2014 were identified. Clinical records were reviewed to assess symptoms, opiate use, and therapy. Fifty-six patients with achalasia were identified, 14 (25%) were on opiates. Opiate prescription was unrelated to achalasia in all cases, with chronic back and joint pain constituting the majority. Of patients on opiates, five (36%) had type 3 achalasia compared with four (10%) not on opiates (P = 0.02). No patients on opiates had type 1 achalasia. Clinical presentation did not differ with opiates, although those on opiates were more likely to report chest pain (39 vs. 14%, P = 0.05) and less likely to have esophageal dilation (62 vs. 82%, P = 0.13), none with greater than 5-cm diameter. Contractile vigor was greater with opiate use, with distal contractile integral of 7149 versus 2615.5 mmHg/cm/second (P = 0.08). Treatment response was inferior on opiates, with persistent symptoms in 22% compared with 3% without opiates (P = 0.06). Opiate use is common in type 3 achalasia, with the majority of patients on opiates. No patients on opiates were diagnosed with type 1 achalasia. Manometric findings of type 3 achalasia mimic those induced by opiates, suggesting a physiologic mechanism for opiate induced type 3 achalasia. Treatment outcome is inferior with opiates, with opiate cessation perhaps preferable. Further studies assessing opiate use and achalasia are needed. PMID:25604060

  10. Adrenocorticotropin- and opiate-like hormones from pituitaries of the sockeye salmon Oncorhynchus nerka.

    PubMed

    Ng, T B; Hon, W K; Idler, D R

    1987-04-01

    The pituitaries of vitellogenic sockeye salmon (Oncorhynchus nerka) were extracted with a mixture of acetone, water, and hydrochloric acid. The precipitate which formed upon the addition of a copious volume of acetone to the extract, designated acid acetone powder, was subjected to salt fractionation and desalting, followed by ion-exchange chromatography on CM-cellulose. An unadsorbed fraction (S-1) and four adsorbed fractions (S-2, S-3, S-4 and S-5) were obtained. Adrenocorticotropic activity was detected in the fractions by their ability to stimulate isolated rat adrenal decapsular cells to produce corticosterone and by their immunoreactivities in an adrenocorticotropin-specific radioimmunoassay. The steroidogenic activities of all fractions, except S-4, were blocked by corticotropin inhibiting peptide. Opiate activity was detected in the fractions by their ability to inhibit the binding of either [3H]naloxone or (D-ala2, D-leu5)-[3H]enkephalin to rat brain membranes. There was a discrepancy in the potencies of the five fractions in the two opiate radioreceptor assays, indicating the presence of opiate peptides with different affinities of binding to the micron- and delta-opiate receptors of the rat brain. There was a separation between adrenocorticotropic and opiate receptor binding activities, suggesting that the activities were due to separate molecular entities. PMID:3038149

  11. Heterogeneity of Drosophila nicotinic acetylcholine receptors: SAD, a novel developmentally regulated alpha-subunit.

    PubMed Central

    Sawruk, E; Schloss, P; Betz, H; Schmitt, B

    1990-01-01

    Two genes, ard and als, are known to encode subunits of the nicotinic acetylcholine receptor (nAChR) in Drosophila. Here we describe the isolation of cDNA clones encoding a novel member (SAD, or alpha 2) of this receptor protein family. The deduced amino acid sequence displays high homology to the ALS protein and shares structural features with ligand binding nAChR alpha-subunits. Sad transcripts accumulate during major periods of neuronal differentiation and, in embryos, are localized in the central nervous system. Expression of SAD cRNA in Xenopus oocytes generates cation channels that are gated by nicotine. These data indicate heterogeneity of nAChRs in Drosophila. Images Fig. 3. Fig. 4. PMID:1697262

  12. Quantitative EEG and Low-Resolution Electromagnetic Tomography (LORETA) Imaging of Patients Undergoing Methadone Treatment for Opiate Addiction.

    PubMed

    Wang, Grace Y; Kydd, Robert R; Russell, Bruce R

    2016-07-01

    Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal-interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference [MD] = 0.32, 95% CI = 0.09-0.55, P < .01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P = .01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT. PMID:26002855

  13. Structural Heterogeneity and Functional Domains of Murine Immunoglobulin G Fc Receptors

    NASA Astrophysics Data System (ADS)

    Ravetch, Jeffrey V.; Luster, Andrew D.; Weinshank, Richard; Kochan, Jarema; Pavlovec, Amalia; Portnoy, Daniel A.; Hulmes, Jeffrey; Pan, Yu-Ching E.; Unkeless, Jay C.

    1986-11-01

    Binding of antibodies to effector cells by way of receptors to their constant regions (Fc receptors) is central to the pathway that leads to clearance of antigens by the immune system. The structure and function of this important class of receptors on immune cells is addressed through the molecular characterization of Fc receptors (FcR) specific for the murine immunoglobulin G isotype. Structural diversity is encoded by two genes that by alternative splicing result in expression of molecules with highly conserved extracellular domains and different transmembrane and intracytoplasmic domains. The proteins encoded by these genes are members of the immunoglobulin supergene family, most homologous to the major histocompatibility complex molecule Eβ. Functional reconstitution of ligand binding by transfection of individual FcR genes demonstrates that the requirements for ligand binding are encoded in a single gene. These studies demonstrate the molecular basis for the functional heterogeneity of FcR's, accounting for the possible transduction of different signals in response to a single ligand.

  14. Heterogeneous receptor binding of classical quaternary muscarinic antagonists. I. Bovine tissue distribution.

    PubMed

    Roffel, A F; Ensing, K; in 't Hout, W G; de Zeeuw, R A; Zaagsma, J

    1991-01-01

    In competition experiments with the tertiary radioligand [3H]dexetimide, classical quaternary muscarinic antagonists like ipratropium bromide and N-methylscopolamine bromide distinguished two muscarinic binding sites in bovine brain (total brain minus cerebellum) membranes, in contrast to their tertiary analogues, atropine and scopolamine, which recognized only one binding site. This binding behavior was found to be almost identical in bovine striatal membranes, both in terms of binding affinities and proportions of high (Q1) and low (Q2) affinity binding sites. Both in total brain and in striatal membranes, the Q1/Q2 binding heterogeneity was independent of pirenzepine binding heterogeneity (M1/M2). In peripheral tissues, the binding properties of quaternary muscarinic antagonists varied. Whereas tertiary as well as quaternary compounds showed only high affinity binding towards muscarinic receptors in bovine atrial and left ventricular membranes, heterogeneous binding behavior was observed with quaternary but not with tertiary antagonists in bovine tracheal smooth muscle membranes. The tissue distribution found in the present study suggests that bovine tracheal smooth muscle contraction studies might shed light on the functional significance of the anomalous binding behavior of quaternary muscarinic antagonists. PMID:1824191

  15. Opiate withdrawal behavior after focal brain stimulation.

    PubMed

    Williams, D A; Thorn, B E

    1984-11-01

    Electrical stimulation of the brainstem abolishes pain, while continued stimulation induces tolerance to the analgesic effect. Analgesic drugs producing tolerance also induce physical dependence, suggesting that the phenomenon of tolerance is associated with addiction. There is evidence that the neural mechanism for stimulation-produced analgesia is related to the release of opiate substances within the brain. We therefore propose that repeated or protracted brain stimulation elicits dependence upon the endorphins released by electrical stimulation of the neurons themselves. To investigate this possibility, rats were given repetitive bursts of analgesic electrical brain stimulation for two hours. Immediately thereafter, they were injected with the opiate antagonist, naloxone. Behaviors associated with low grade opiate withdrawal were observed. These data suggest that prolonged analgesic stimulation can result in naloxone-precipitated behaviors similar to the behaviors exhibited during opiate withdrawal. PMID:6542676

  16. Heterogeneous estrogen receptor expression in circulating tumor cells suggests diverse mechanisms of fulvestrant resistance.

    PubMed

    Paoletti, Costanza; Larios, Jose M; Muñiz, Maria C; Aung, Kimberly; Cannell, Emily M; Darga, Elizabeth P; Kidwell, Kelley M; Thomas, Dafydd G; Tokudome, Nahomi; Brown, Martha E; Connelly, Mark C; Chianese, David A; Schott, Anne F; Henry, N Lynn; Rae, James M; Hayes, Daniel F

    2016-08-01

    Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch(®) system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B-cell lymphoma (BCL2) using the CellSearch(®) CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC-expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC-ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene (ESR1). All seven ER positive patients progressing on AIs had heterogeneous CTC-ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non-ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies. PMID:27178224

  17. Buprenorphine in the treatment of opiate dependence.

    PubMed

    Wesson, Donald R; Smith, David E

    2010-06-01

    Compelling clinical evidence establishes that buprenorphine is similar to methadone in efficacy for opiate detoxification and maintenance but safer than methadone in an overdose situation. The Drug Abuse Treatment Act of 2000 (DATA 2000) enabled US physicians with additional training to prescribe buprenorphine to a limited number of opiate-dependent patients. The sublingual tablets Subutex (buprenorphine alone) and Suboxone (a combination of buprenorphine and naloxone) meet the specifications of DATA 2000. Suboxone is intended to discourage intravenously administration and has less abuse potential than buprenorphine alone. Suboxone is generally recommended for maintenance treatment except for women who are pregnant. Subutex is recommended in treatment of pregnant women. A buprenorphine opiate withdrawal syndrome can occur in newborns. Although intravenous buprenorphine abuse is a significant public health problem in some countries, buprenorphine alone or in combination with naloxone has less potential for abuse than heroin and some prescription opiates, such as oxycodone. Pharmacotherapy from physicians' offices makes buprenorphine treatment acceptable to some opiate-dependent patients who would not accept treatment in traditional opiate-maintenance clinics. For reasons not adequately understood, some patients find discontinuation of buprenorphine following long-term use difficult. This article reviews the pharmacology of buprenorphine, summarizes evidence supporting the safety and efficacy of buprenorphine and provides clinical guidelines for treatment. PMID:20648912

  18. Effects of kappa- and mu-selective opiate agonists on colonic temperature in normoglycaemic and streptozotocin-treated hyperglycaemic mice.

    PubMed

    Bansinath, M; Ramabadran, K; Turndorf, H; Puig, M M

    1990-05-01

    The thermic responses of highly selective k-(U-69593 and U-50488H) and mu-(sufentanil and fentanyl) agonists were assessed in normoglycaemic and hyperglycaemic mice. Hyperglycaemia was induced by streptozotocin injection. The opiates were injected subcutaneously and colonic temperatures monitored for 90 min. after injection. In normoglycaemic animals the k-agonists induced a significant hypothermic response and hyperglycaemia did not modify this effect. In normoglycaemic mice, low doses of mu-selective agonists predominantly produced hypothermia, while in high doses resulted in hyperthermia. In chronic hyperglycaemic mice, hyperthermia was the predominant effect of mu-opiates. The present results characterize the time course and dose response of some of the currently available highly selective kappa- and mu-opiate agonists for the first time in mice and suggest that hyperglycaemia differentially affects the opiate receptor subtypes that mediate thermoregulatory events. PMID:2164667

  19. Dynamic heterogeneity and non-Gaussian statistics for acetylcholine receptors on live cell membrane

    PubMed Central

    He, W.; Song, H.; Su, Y.; Geng, L.; Ackerson, B. J.; Peng, H. B.; Tong, P.

    2016-01-01

    The Brownian motion of molecules at thermal equilibrium usually has a finite correlation time and will eventually be randomized after a long delay time, so that their displacement follows the Gaussian statistics. This is true even when the molecules have experienced a complex environment with a finite correlation time. Here, we report that the lateral motion of the acetylcholine receptors on live muscle cell membranes does not follow the Gaussian statistics for normal Brownian diffusion. From a careful analysis of a large volume of the protein trajectories obtained over a wide range of sampling rates and long durations, we find that the normalized histogram of the protein displacements shows an exponential tail, which is robust and universal for cells under different conditions. The experiment indicates that the observed non-Gaussian statistics and dynamic heterogeneity are inherently linked to the slow-active remodelling of the underlying cortical actin network. PMID:27226072

  20. Dynamic heterogeneity and non-Gaussian statistics for acetylcholine receptors on live cell membrane

    NASA Astrophysics Data System (ADS)

    He, W.; Song, H.; Su, Y.; Geng, L.; Ackerson, B. J.; Peng, H. B.; Tong, P.

    2016-05-01

    The Brownian motion of molecules at thermal equilibrium usually has a finite correlation time and will eventually be randomized after a long delay time, so that their displacement follows the Gaussian statistics. This is true even when the molecules have experienced a complex environment with a finite correlation time. Here, we report that the lateral motion of the acetylcholine receptors on live muscle cell membranes does not follow the Gaussian statistics for normal Brownian diffusion. From a careful analysis of a large volume of the protein trajectories obtained over a wide range of sampling rates and long durations, we find that the normalized histogram of the protein displacements shows an exponential tail, which is robust and universal for cells under different conditions. The experiment indicates that the observed non-Gaussian statistics and dynamic heterogeneity are inherently linked to the slow-active remodelling of the underlying cortical actin network.

  1. Membrane lipid heterogeneity associated with acetylcholine receptor particle aggregates in Xenopus embryonic muscle cells.

    PubMed Central

    Bridgman, P C; Nakajima, Y

    1981-01-01

    Filipin, digitonin, and saponin react with membrane cholesterol to produce unique membrane alterations (sterol-specific complexes) that are easily discernible in freeze-fracture replicas. We have treated both noninnervated and innervated Xenopus embryonic muscle cells in culture with these agents. Freeze-fracture of these treated muscle cells showed that most areas of the muscle plasma membrane contain sterol-specific complexes (19- to 40-nm protuberances and dimples with filipin, a scalloped appearance with digitonin, or an irregular, rough appearance with saponin). However, these complexes were virtually absent from membrane areas of junctional and nonjunctional aggregates of acetylcholine receptor particles. This result suggests that the membrane matrix of these aggregates is low in cholesterol and that this membrane lipid heterogeneity may be linked to the mechanisms involved in their formation and stabilization on muscle cells in culture. Images PMID:6940140

  2. Dynamic heterogeneity and non-Gaussian statistics for acetylcholine receptors on live cell membrane.

    PubMed

    He, W; Song, H; Su, Y; Geng, L; Ackerson, B J; Peng, H B; Tong, P

    2016-01-01

    The Brownian motion of molecules at thermal equilibrium usually has a finite correlation time and will eventually be randomized after a long delay time, so that their displacement follows the Gaussian statistics. This is true even when the molecules have experienced a complex environment with a finite correlation time. Here, we report that the lateral motion of the acetylcholine receptors on live muscle cell membranes does not follow the Gaussian statistics for normal Brownian diffusion. From a careful analysis of a large volume of the protein trajectories obtained over a wide range of sampling rates and long durations, we find that the normalized histogram of the protein displacements shows an exponential tail, which is robust and universal for cells under different conditions. The experiment indicates that the observed non-Gaussian statistics and dynamic heterogeneity are inherently linked to the slow-active remodelling of the underlying cortical actin network. PMID:27226072

  3. Molecular characterization of opioid receptors

    SciTech Connect

    Howard, A.D.

    1986-01-01

    The aim of this research was to purify and characterize active opioid receptors and elucidate molecular aspects of opioid receptor heterogeneity. Purification to apparent homogeneity of an opioid binding protein from bovine caudate was achieved by solubilization in the non-ionic detergent, digitonin, followed by sequential chromatography on the opiate affinity matrix, ..beta..-naltrexylethylenediamine-CH-Sepharose 4B, and on the lectine affinity matrix, wheat germ agglutinin-agarose. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) followed by autoradiography revealed that radioiodinated purified receptor gave a single band. Purified receptor preparations showed a specific activity of 12,000-15,000 fmol of opiate bound per mg of protein. Radioiodinated human beta-endorphin (/sup 125/I-beta-end/sub H/) was used as a probe to investigate the ligand binding subunits of mu and delta opioid receptors. /sup 125/I-beta-end/sub H/ was shown to bind to a variety of opioid receptor-containing tissues with high affinity and specificity with preference for mu and delta sites, and with little, if any, binding to kappa sites. Affinity crosslinking techniques were employed to covalently link /sup 125/I-beta-end/sub H/ to opioid receptors, utilizing derivatives of bis-succinimidyl esters that are bifunctional crosslinkers with specificities for amino and sulfhydryl groups. This, and competition experiments with high type-selective ligands, permitted the assignment of two labeled peptides to their receptor types, namely a peptide of M/sub r/ = 65,000 for mu receptors and one of M/sub r/ = 53,000 for delta receptors.

  4. Resolution of Disulfide Heterogeneity in Nogo Receptor 1 Fusion Proteins by Molecular Engineering

    SciTech Connect

    P Weinreb; D Wen; F Qian; C Wildes; E Garber; L Walus; M Jung; J Wang; J Relton; et al.

    2011-12-31

    NgRI (Nogo-66 receptor) is part of a signalling complex that inhibits axon regeneration in the central nervous system. Truncated soluble versions of NgRI have been used successfully to promote axon regeneration in animal models of spinal-cord injury, raising interest in this protein as a potential therapeutic target. The LRR (leucine-rich repeat) regions in NgRI are flanked by N- and C-terminal disulfide-containing 'cap' domains (LRRNT and LRRCT respectively). In the present work we show that, although functionally active, the NgRI(310)-Fc fusion protein contains mislinked and heterogeneous disulfide patterns in the LRRCT domain, and we report the generation of a series of variant molecules specifically designed to prevent this heterogeneity. Using these variants we explored the effects of modifying the NgRI truncation site or the spacing between the NgRI and Fc domains, or replacing cysteines within the NgRI or IgG hinge regions. One variant, which incorporates replacements of Cys{sup 266} and Cys{sup 309} with alanine residues, completely eliminated disulfide scrambling while maintaining functional in vitro and in vivo efficacy. This modified NgRI-Fc molecule represents a significantly improved candidate for further pharmaceutical development, and may serve as a useful model for the optimization of other IgG fusion proteins made from LRR proteins.

  5. Pharmacoepidemiology of opiate use in the Neonatal ICU: Increasing cumulative doses and iatrogenic opiate withdrawal

    PubMed Central

    Lewis, Tamorah; Erfe, Betty Luan; Ezell, Tarrah; Gauda, Estelle

    2015-01-01

    Objective Neonatal ICU care involves use of opiates to treat post-operative, ventilated or chronically ill infants. Opiates provide necessary analgesia and sedation, but the morbidities include prolonged Neonatal Abstinence Syndrome (NAS) and extended length of stay for dose tapering. Our objective was to quantify trends in opiate exposure in a tertiary care NICU. We hypothesize that medical opiate exposure and resultant ICU-acquired NAS would increase over time. Design retrospective cross-sectional cohort study Setting tertiary care NICU Patients high risk inborn infants admitted in fiscal years 2003–2004, 2007–2008 and 2010–2011 Main Outcome Measure Average cumulative morphine exposure (all opiate doses converted to morphine equivalents) per time epoch was compared in cohorts of clinically similar infants. Linear regression was used to assess the primary outcome, assessing changes in opiate exposure over time. Results 63 infants were included in the final analysis. The primary analysis assessing cumulative opiate exposure per infant showed an increase of 134 mg per time epoch (95% CI −12, 279 mg, p-value 0.071). There was a statistically significant increase in the percent of infants with a diagnosis of iatrogenic NAS, increasing from 9 to 35 to 50% (p-value 0.012). Conclusion Medical opiate exposure is increasing over time in ICU infants. In association, there are increased diagnoses of ICU-acquired NAS. This trend should be monitored closely and further studies to assess interventions including more strident pain and sedation monitoring, weaning protocols and other efforts to decrease opiate exposure are warranted. PMID:26312957

  6. [Impact of opiates on dopaminergic neurons].

    PubMed

    Kaufling, Jennifer; Freund-Mercier, Marie-José; Barrot, Michel

    2016-01-01

    Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should however be updated based on recent advances. Thus, the neuroanatomical location of the GABA neurons responsible for this desinhibition has been recently detailed: they belong to a brain structure in continuity with the posterior part of the ventral tegmental area and discovered this past decade. Other data also highlighted the critical role played by glutamatergic transmission in the opioid regulation of dopaminergic neuron activity. During protracted opiate withdrawal, the inhibitory/excitatory balance exerted on dopaminergic neurons is altered. These results are now leading to propose an original hypothesis for explaining the impact of protracted opiate withdrawal on mood. PMID:27406773

  7. Cyclosporine alters opiate withdrawal in rodents.

    PubMed

    Dafny, N; Wagle, V G; Drath, D B

    1985-05-01

    Opiates exert numerous effects on all levels of the central nervous system with tolerance, physical dependence and withdrawal being characteristics of this drug class. The degree of dependence is directly correlated to the intensity of withdrawal. Therefore, success in modifying the withdrawal syndrome may shed light on the dynamics of opiate addiction. The present study demonstrates that cyclosporine, a widely used immunosuppressive drug, considerably modified the behavioral signs of a naloxone-induced abstinence syndrome in morphine-addicted rats. In previous experiments, alpha-interferon has shown similar results. The similarity in actions of these two immunomodulator drugs is discussed and we suggest that opiate addiction may involve the immune system. PMID:4039025

  8. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells

    PubMed Central

    Eckle, Sidonia B.G.; Birkinshaw, Richard W.; Kostenko, Lyudmila; Corbett, Alexandra J.; McWilliam, Hamish E.G.; Reantragoon, Rangsima; Chen, Zhenjun; Gherardin, Nicholas A.; Beddoe, Travis; Liu, Ligong; Patel, Onisha; Meehan, Bronwyn; Fairlie, David P.; Villadangos, Jose A.; Godfrey, Dale I.

    2014-01-01

    Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) α-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR β-chains. MAIT TCRs can bind folate- and riboflavin-based metabolites restricted by the major histocompatibility complex (MHC)-related class I−like molecule, MR1. However, the impact of MAIT TCR and MR1-ligand heterogeneity on MAIT cell biology is unclear. We show how a previously uncharacterized MR1 ligand, acetyl-6-formylpterin (Ac-6-FP), markedly stabilized MR1, potently up-regulated MR1 cell surface expression, and inhibited MAIT cell activation. These enhanced properties of Ac-6-FP were attributable to structural alterations in MR1 that subsequently affected MAIT TCR recognition via conformational changes within the complementarity-determining region (CDR) 3β loop. Analysis of seven TRBV6-1+ MAIT TCRs demonstrated how CDR3β hypervariability impacted on MAIT TCR recognition by altering TCR flexibility and contacts with MR1 and the Ag itself. Ternary structures of TRBV6-1, TRBV6-4, and TRBV20+ MAIT TCRs in complex with MR1 bound to a potent riboflavin-based antigen (Ag) showed how variations in TRBV gene usage exclusively impacted on MR1 contacts within a consensus MAIT TCR-MR1 footprint. Moreover, differential TRAJ gene usage was readily accommodated within a conserved MAIT TCR-MR1-Ag docking mode. Collectively, MAIT TCR heterogeneity can fine-tune MR1 recognition in an Ag-dependent manner, thereby modulating MAIT cell recognition. PMID:25049336

  9. Opiate antagonist binding sites in discrete brain regions of spontaneously hypertensive and normotensive Wistar-Kyoto rats

    SciTech Connect

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. )

    1991-01-01

    The binding of {sup 3}H-naltrexone, an opiate receptor antagonist, to membranes of discrete brain regions and spinal cord of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. The brain regions examined were hypothalamus, amygdala, hippocampus, corpus striatum, pons and medulla, midbrain and cortex. {sup 3}H-Naltrexone bound to membranes of brain regions and spinal cord at a single high affinity site with an apparent dissociation constant value of 3 nM. The highest density of {sup 3}H-naltrexone binding sites were in hippocampus and lowest in the cerebral cortex. The receptor density (B{sub max}value) and apparent dissociation constant (K{sub d} value) values of {sup 3}H-naltrexone to bind to opiate receptors on the membranes of amygdala, hippocampus, corpus striatum, pons and medulla, midgrain, cortex and spinal cord of WKY and SHR rates did not differ. The B{sub max} value of {sup 3}H-naltrexone binding to membranes of hypothalamus of SHR rates was 518% higher than WKY rats but the K{sub d} values in the two strains did not differ. It is concluded that SHR rats have higher density of opiate receptors labeled with {sup 3}H-naltrexone in the hypothalamus only, in comparison with WKY rats, and that such a difference in the density of opiate receptors may be related to the elevated blood pressure in SHR rats.

  10. Endogenous opiates and behavior: 2004.

    PubMed

    Bodnar, Richard J; Klein, Gad E

    2005-12-01

    This paper is the 27th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over 30 years of research. It summarizes papers published during 2004 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses. PMID:16039752

  11. Endogenous opiates and behavior: 2013.

    PubMed

    Bodnar, Richard J

    2014-12-01

    This paper is the thirty-sixth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2013 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses. PMID:25263178

  12. Endogenous opiates and behavior: 2007.

    PubMed

    Bodnar, Richard J

    2008-12-01

    This paper is the thirtieth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2007 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses. PMID:18851999

  13. Effects of central opiate and serotoninergic structures on heart rhythm during acute myocardial ischemia.

    PubMed

    Prokop'eva, E V; Pivovarov, Y I

    2001-12-01

    Electrostimulation of the central gray matter in the sylvian aqueduct and nucleus raphe magnus produced an antiarrhythmic effect during acute myocardial ischemia. Stimulation and blockade of opiate receptors in the central amygdaloid nucleus and lateral hypothalamus with dalargin and naloxone induced the same effect. Destruction of the central gray matter in the sylvian aqueduct and nucleus raphe magnus decreased electrical stability of ischemic myocardium. PMID:12152875

  14. Endogenous Opiates and Behavior: 2006

    PubMed Central

    Bodnar, Richard J.

    2009-01-01

    This paper is the twenty-ninth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning thirty years of research. It summarizes papers published during 2006 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurological disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:17949854

  15. Endogenous opiates and behavior: 2012.

    PubMed

    Bodnar, Richard J

    2013-12-01

    This paper is the thirty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2012 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:24126281

  16. Endogenous opiates and behavior: 2009.

    PubMed

    Bodnar, Richard J

    2010-12-01

    This paper is the 32nd consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2009 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:20875476

  17. Endogenous opiates and behavior: 2005.

    PubMed

    Bodnar, Richard J; Klein, Gad E

    2006-12-01

    This paper is the 28th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2005 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity, neurophysiology and transmitter release (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); immunological responses (Section 17). PMID:16973239

  18. Endogenous opiates and behavior: 2008.

    PubMed

    Bodnar, Richard J

    2009-12-01

    This paper is the 31st consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2008 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:19793543

  19. Endogenous opiates and behavior: 2010.

    PubMed

    Bodnar, Richard J

    2011-12-01

    This paper is the thirty-third consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2010 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17). PMID:21983105

  20. Endogenous opiates and behavior: 2006.

    PubMed

    Bodnar, Richard J

    2007-12-01

    This paper is the 29th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning 30 years of research. It summarizes papers published during 2006 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurological disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:17949854

  1. Endogenous opiates and behavior: 2011.

    PubMed

    Bodnar, Richard J

    2012-12-01

    This paper is the thirty-fourth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2011 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17). PMID:23041439

  2. Endogenous opiates and behavior: 2002.

    PubMed

    Bodnar, Richard J; Hadjimarkou, Maria M

    2003-08-01

    This paper is the twenty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2002 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:14612197

  3. Endogenous opiates and behavior: 2003.

    PubMed

    Bodnar, Richard J; Klein, Gad E

    2004-12-01

    This paper is the 26th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2003 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). PMID:15572211

  4. Inhibition of melanocortin 1 receptor slows melanoma growth, reduces tumor heterogeneity and increases survival.

    PubMed

    Kansal, Rita G; McCravy, Matthew S; Basham, Jacob H; Earl, Joshua A; McMurray, Stacy L; Starner, Chelsey J; Whitt, Michael A; Albritton, Lorraine M

    2016-05-01

    Melanoma risk is increased in patients with mutations of melanocortin 1 receptor (MC1R) yet the basis for the increased risk remains unknown. Here we report in vivo evidence supporting a critical role for MC1R in regulating melanoma tumor growth and determining overall survival time. Inhibition of MC1R by its physiologically relevant competitive inhibitor, agouti signaling protein (ASIP), reduced melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. In the lungs of syngeneic C57BL/6 mice, mCherry-marked, ASIP-secreting lung tumors inhibited MC1R on neighboring tumors lacking ASIP in a dose dependent manner as evidenced by a proportional loss of pigment in tumors from mice injected with 1:1, 3:1 and 4:1 mixtures of parental B16-F10 to ASIP-expressing tumor cells. ASIP-expressing B16-F10 cells formed poorly pigmented tumors in vivo that correlated with a 20% longer median survival than those bearing parental B16-F10 tumors (p=0.0005). Mice injected with 1:1 mixtures also showed survival benefit (p=0.0054), whereas injection of a 4:1 mixture showed no significant difference in survival. The longer survival time of mice bearing ASIP-expressing tumors correlated with a significantly slower growth rate than parental B16-F10 tumors as judged by quantification of numbers of tumors and total tumor load (p=0.0325), as well as a more homogeneous size and morphology of ASIP-expressing lung tumors. We conclude that MC1R plays an important role in regulating melanoma growth and morphology. Persistent inhibition of MC1R provided a significant survival advantage resulting in part from slower tumor growth, establishing MC1R as a compelling new molecular target for metastatic melanoma. PMID:27028866

  5. Carbonylation Induces Heterogeneity in Cardiac Ryanodine Receptor Function in Diabetes Mellitus

    PubMed Central

    Shao, Chun Hong; Tian, Chengju; Ouyang, Shouqiang; Moore, Caronda J.; Alomar, Fadhel; Nemet, Ina; D'Souza, Alicia; Nagai, Ryoji; Kutty, Shelby; Rozanski, George J.; Ramanadham, Sasanka; Singh, Jaipaul

    2012-01-01

    Heart failure and arrhythmias occur at 3 to 5 times higher rates among individuals with diabetes mellitus, compared with age-matched, healthy individuals. Studies attribute these defects in part to alterations in the function of cardiac type 2 ryanodine receptors (RyR2s), the principal Ca2+-release channels on the internal sarcoplasmic reticulum (SR). To date, mechanisms underlying RyR2 dysregulation in diabetes remain poorly defined. A rat model of type 1 diabetes, in combination with echocardiography, in vivo and ex vivo hemodynamic studies, confocal microscopy, Western blotting, mass spectrometry, site-directed mutagenesis, and [3H]ryanodine binding, lipid bilayer, and transfection assays, was used to determine whether post-translational modification by reactive carbonyl species (RCS) represented a contributing cause. After 8 weeks of diabetes, spontaneous Ca2+ release in ventricular myocytes increased ∼5-fold. Evoked Ca2+ release from the SR was nonuniform (dyssynchronous). Total RyR2 protein levels remained unchanged, but the ability to bind the Ca2+-dependent ligand [3H]ryanodine was significantly reduced. Western blotting and mass spectrometry revealed RCS adducts on select basic residues. Mutation of residues to delineate the physiochemical impact of carbonylation yielded channels with enhanced or reduced cytoplasmic Ca2+ responsiveness. The prototype RCS methylglyoxal increased and then decreased the RyR2 open probability. Methylglyoxal also increased spontaneous Ca2+ release and induced Ca2+ waves in healthy myocytes. Treatment of diabetic rats with RCS scavengers normalized spontaneous and evoked Ca2+ release from the SR, reduced carbonylation of RyR2s, and increased binding of [3H]ryanodine to RyR2s. From these data, we conclude that post-translational modification by RCS contributes to the heterogeneity in RyR2 activity that is seen in experimental diabetes. PMID:22648972

  6. Acupuncture for the Treatment of Opiate Addiction

    PubMed Central

    Lin, Jaung-Geng; Chan, Yuan-Yu; Chen, Yi-Hung

    2012-01-01

    Acupuncture is an accepted treatment worldwide for various clinical conditions, and the effects of acupuncture on opiate addiction have been investigated in many clinical trials. The present review systematically analyzed data from randomized clinical trials published in Chinese and English since 1970. We found that the majority agreed on the efficacy of acupuncture as a strategy for the treatment of opiate addiction. However, some of the methods in several included trials have been criticized for their poor quality. This review summarizes the quality of the study design, the types of acupuncture applied, the commonly selected acupoints or sites of the body, the effectiveness of the treatment, and the possible mechanism underlying the effectiveness of acupuncture in these trials. PMID:22474521

  7. Regulation of neuronal ferritin heavy chain, a new player in opiate-induced chemokine dysfunction

    PubMed Central

    Abt, Anna Cook; Meucci, Olimpia

    2013-01-01

    The heavy chain subunit of ferritin (FHC), a ubiquitous protein best known for its iron-sequestering activity as part of the ferritin complex, has recently been described as a novel inhibitor of signaling through the chemokine receptor CXCR4. Levels of FHC as well as its effects on CXCR4 activation increase in cortical neurons exposed to mu-opioid receptor agonists such as morphine, an effect likely specific to neurons. Major actions of CXCR4 signaling in the mature brain include a promotion of neurogenesis, activation of pro-survival signals, and modulation of excitotoxic pathways; thus FHC up-regulation may contribute to the neuronal dysfunction often associated with opiate drug abuse. This review summarizes our knowledge of neuronal CXCR4 function, its regulation by opiates and the role of FHC in this process, and known mechanisms controlling FHC production. We speculate on the mechanism involved in FHC regulation by opiates, and offer FHC as a new target in opioid-induced neuropathology. PMID:21465240

  8. Prenatal opiate exposure impairs radial arm maze performance and reduces levels of BDNF precursor following training.

    PubMed

    Schrott, Lisa M; Franklin, La 'Tonya M; Serrano, Peter A

    2008-03-10

    Prenatal exposure to opiates, which is invariably followed by postnatal withdrawal, can affect cognitive performance. To further characterize these effects, we examined radial 8-arm maze performance and expression of brain derived neurotrophic factor (BDNF) in male rats prenatally exposed to the opiate l-alpha-acetylmethadol (LAAM). Female rats received 1.0 mg/kg/day LAAM or water via daily oral gavage for 28 days prior to breeding, during breeding, and throughout pregnancy. Pups were fostered to non-treated lactating dams at birth and underwent neonatal opiate withdrawal. At 5-6 months, prenatal water- and LAAM-exposed males (n=6 each; non-littermates) received radial arm maze training consisting of ten trials a day for five days and three retention trials on day six. Rats prenatally exposed to LAAM had poorer maze performance, decreased percent correct responding and more reference and working memory errors than prenatal water-treated controls. However, they were able to acquire the task by the end of training. There were no differences between the groups on retention 24 h after testing. Following retention testing, hippocampi were removed and protein extracted from cytosol and synaptic fractions. Western blots were used to measure levels of mature and precursor BDNF protein, as well as the BDNF receptor TrkB. BDNF precursor protein was significantly decreased in the synaptic fraction of trained prenatal LAAM-treated rats compared to prenatal water-treated trained controls. No effects were found for the full-length or truncated TrkB receptor. In untrained rats, prenatal treatment did not affect any of the measures. These data suggest that prenatal opiate exposure and/or postnatal withdrawal compromise expression of proteins involved in the neural plasticity underlying learning. PMID:18262500

  9. Evidence for a noncovalent intermolecular interaction of opiates with thiamine.

    PubMed

    Misra, A L; Vadlamani, N L; Pontani, R B

    1977-11-01

    Opiate agonists and antagonists formed reversible molecular complexes with thiamine. The absorption maxima of these complexes were at wavelengths longer than those of the individual components and their intensities depended on the concentration and nature of the opiate component. The possible implications of such an interaction are discussed. PMID:928957

  10. Hair analysis of opiates in mothers and newborns for evaluating opiate exposure during pregnancy.

    PubMed

    Vinner, Elisabeth; Vignau, Jean; Thibault, Denise; Codaccioni, Xavier; Brassart, Claudie; Humbert, Luc; Lhermitte, Michel

    2003-04-23

    The increasing interest in toxicological hair analysis as a marker of human exposure to xenobiotics such as illicit substances or therapeutic drugs, has been made feasible by the extension of mass spectrometry, a highly sensitive method of detection. A newborn exposed to drugs in utero can suffer from a varying degree of withdrawal syndrome, a few days after birth. If of opiate origin, the withdrawal syndrome can be treated with morphine, among other therapeutics, but it is not easy to diagnose because of atypical symptoms presented by neonates and especially when maternal drug addiction has not been revealed. To assess and measure toxicological factors linked with the appearance and the severity of this syndrome, maternal and neonatal matrices such as urine, meconium and hair were collected during a protocol approved by the ethical committee. Opiates in particular were measured with GC-MS and potential combined dependences (cannabis, cocaine, amphetamine, LSD and benzodiazepines) and/or substitutive therapeutics (methadone or buprenorphine) were also assessed in 17 mother/neonate couples. Gestational opiate exposure profiles were drawn up and linked with the observed withdrawal syndromes. A withdrawal syndrome seems to appear more frequently after foetal exposure to an association of opiates/substitutive molecules (8 out of 10 withdrawal syndromes observed in this study), although the impact of cocaine and benzodiazepines must also be taken into account. The results obtained in neonatal hair make it possible to affirm foetal drug exposure and are in accordance, for the majority, with the appearance of a neonatal withdrawal syndrome (NWS). Neonatal hair analysis could contribute to assess in utero exposure to opiates, particularly when results in urine and meconium are negative or when these matrices are not available. PMID:12742690

  11. Effect of opiates on the caudate spindle in the cat.

    PubMed

    Janicki, P K; Libich, J; Gumulka, W S

    1981-01-01

    The effect of opiate drugs on the caudate spindle (CS) in the cat was observed following both systemic and intracaudal administration. Systemic administration of morphine, pentazocine and pethidine inhibited the CS. The inhibitory effects of opiates were antagonized by lysergide and methysergide but not by naloxone, chlorpromazine, dehydrobenzperidol, amphetamine and atropine. Contrary to their systemic administration, the investigated opiates morphine, pentazocine, pethidine and Met5-Enkephaline enhanced the CS, when injected into the caudate nucleus close to the site of stimulation. Those facilitating effects of opiates on the CS were completely blocked by naloxone. The results suggest that serotoninergic mechanisms might be involved in the action of opiates on the neuronal activity of the caudate nucleus. PMID:6273943

  12. Burden and Nutritional Deficiencies in Opiate Addiction- Systematic Review Article

    PubMed Central

    NABIPOUR, Sepideh; AYU SAID, Mas; HUSSAIN HABIL, Mohd

    2014-01-01

    Abstract Addiction to the illicit and prescribed use of opiate is an alarming public health issue. Studies on addictive disorders have demonstrated severe nutritional deficiencies in opiate abusers with behavioral, physiological and cognitive symptoms. Opiate addiction is also link with a significant number of diseases including Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and other blood borne diseases generally stem from the use of needles to inject heroin. The use of medication assisted treatment for opioid addicts in combination with behavioural therapies has been considered as a highly effective treatment. Methadone is a long-lasting μ-opioid agonist and a pharmacological tool which attenuates withdrawal symptoms effectively replacement therapies. This review article aims to explain opiate addiction mechanisms, epidemiology and disease burden with emphasis on dietary and nutritional status of opiate dependent patients in methadone maintenance therapy. PMID:25927032

  13. Burden and nutritional deficiencies in opiate addiction- systematic review article.

    PubMed

    Nabipour, Sepideh; Ayu Said, Mas; Hussain Habil, Mohd

    2014-08-01

    Addiction to the illicit and prescribed use of opiate is an alarming public health issue. Studies on addictive disorders have demonstrated severe nutritional deficiencies in opiate abusers with behavioral, physiological and cognitive symptoms. Opiate addiction is also link with a significant number of diseases including Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and other blood borne diseases generally stem from the use of needles to inject heroin. The use of medication assisted treatment for opioid addicts in combination with behavioural therapies has been considered as a highly effective treatment. Methadone is a long-lasting μ-opioid agonist and a pharmacological tool which attenuates withdrawal symptoms effectively replacement therapies. This review article aims to explain opiate addiction mechanisms, epidemiology and disease burden with emphasis on dietary and nutritional status of opiate dependent patients in methadone maintenance therapy. PMID:25927032

  14. Lofexidine versus clonidine in rapid opiate detoxification.

    PubMed

    Gerra, G; Zaimovic, A; Giusti, F; Di Gennaro, C; Zambelli, U; Gardini, S; Delsignore, R

    2001-07-01

    The aim of the present study is to evaluate lofexidine and clonidine, in an accelerated opiate detoxification procedure (3 days), without anaesthesia. Forty heroin-dependent individuals were detoxified, evaluating withdrawal symptoms, craving levels, mood changes, urine toxicologic screens, and dropout during therapy with either (1) clonidine, oxazepam, baclofen, and ketoprofene, with naloxone and naltrexone for 3 days (20 subjects) or (2) lofexidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone for 3 days (20 subjects). Both clonidine and lofexidine rapid detoxifications were found effective. The subjects treated with lofexidine showed significantly lower levels of withdrawal symptoms, fewer mood problems, less sedation and hypotension. No significant differences in craving levels, morphine metabolites in urine, or dropout rate were evidenced between the two groups. The early use of naltrexone during detoxification in combination with either alpha-2-agonist facilitated the acceptance for long-term naltrexone treatment. Lofexidine appeared to be more useful than clonidine in a 3-day accelerated opiate detoxification, not only to counteract withdrawal symptoms, but also in the treatment of dysphoria and mood changes. Because lofexidine does not produce hypotension, safe outpatient treatment, without hospital support, could be possible. PMID:11516922

  15. Auditory event-related potentials in methadone substituted opiate users.

    PubMed

    Wang, Grace Y; Kydd, Robert; Russell, Bruce R

    2015-09-01

    The effects of methadone maintenance treatment (MMT) on neurophysiological function are unclear. Using an auditory oddball paradigm, event-related potential (ERP) amplitudes and latencies were measured in 32 patients undertaking MMT, 17 opiate users who were addicted but not receiving substitution treatment and 25 healthy control subjects. Compared with healthy control subjects, the MMT and opiate user groups showed an increased P200 amplitude in response to target stimuli. The opiate user group also exhibited a decreased amplitude and an increased latency of N200, and a greater number of task-related errors than either healthy control subjects or patients undertaking MMT. There were no significant group differences in the P300 amplitude. However, it is noteworthy that the frontal P300 amplitude of the MMT group was greater than that of opiate users or healthy controls. Our findings suggest that altered sensory information processing associated with a history of opiate use remains in patients undertaking MMT. However, there are less marked ERP abnormalities in those receiving MMT than in active opiate users. The deficits in information processing associated with illicit opiate use are likely to be reduced during MMT. PMID:26038111

  16. Baclofen-assisted detoxification from opiates. A pilot study.

    PubMed

    Krystal, J H; McDougle, C J; Kosten, T R; Price, L H; Aghajanian, G K; Charney, D S

    1992-01-01

    In an open label pilot study, five opiate-dependent patients underwent baclofen-assisted opiate detoxification after abrupt discontinuation of methadone. Patients received baclofen in oral doses up to 80 mg/day, and all patients subjectively reported some reduction in discomfort. However, 3 of 5 (60%) patients could not complete detoxification with baclofen, primarily because of insufficient suppression of vomiting, myalgias, and headache. These patients successfully completed their detoxification with clonidine. These findings suggest that, in the dose range studied, baclofen is of limited use as a primary treatment for opiate dependence, although adjunctive roles for this medication in detoxification should be explored. PMID:1324986

  17. Opiate dependence induces network state shifts in the limbic system.

    PubMed

    Dejean, C; Boraud, T; Le Moine, C

    2013-11-01

    Among current theories of addiction, hedonic homeostasis dysregulation predicts that the brain reward systems, particularly the mesolimbic dopamine system, switch from a physiological state to a new "set point." In opiate addiction, evidence show that the dopamine system principal targets, prefrontal cortex (PFC), nucleus accumbens (NAC) and basolateral amygdala complex (BLA) also adapt to repeated drug stimulation. Here we investigated the impact of chronic morphine on the dynamics of the network of these three interconnected structures. For that purpose we performed simultaneous electrophysiological recordings in freely-moving rats subcutaneously implanted with continuous-release morphine pellets. Chronic morphine produced a shift in the network state underpinned by changes in Delta and Gamma oscillations in the LFP of PFC, NAC and BLA, in correlation to behavioral changes. However despite continuous stimulation by the drug, an apparent normalization of the network activity and state occurred after 2 days indicating large scale adaptations. Blockade of μ opioid receptors was nonetheless sufficient to disrupt this acquired new stability in morphine-dependent animals. In line with the homeostatic dysregulation theory of addiction, our study provides original direct evidence that the PFC-NAC-BLA network of the dependent brain is characterized by a de novo balance for which the drug of abuse becomes the main contributor. PMID:23911767

  18. Heterogeneous function of ryanodine receptors, but not IP3 receptors, in hamster cremaster muscle feed arteries and arterioles

    PubMed Central

    Westcott, Erika B.

    2011-01-01

    The roles played by ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in vascular smooth muscle in the microcirculation remain unclear. Therefore, the function of both RyRs and IP3Rs in Ca2+ signals and myogenic tone in hamster cremaster muscle feed arteries and downstream arterioles were assessed using confocal imaging and pressure myography. Feed artery vascular smooth muscle displayed Ca2+ sparks and Ca2+ waves, which were inhibited by the RyR antagonists ryanodine (10 μM) or tetracaine (100 μM). Despite the inhibition of sparks and waves, ryanodine or tetracaine increased global intracellular Ca2+ and constricted the arteries. The blockade of IP3Rs with xestospongin D (5 μM) or 2-aminoethoxydiphenyl borate (100 μM) or the inhibition of phospholipase C using U-73122 (10 μM) also attenuated Ca2+ waves without affecting Ca2+ sparks. Importantly, the IP3Rs and phospholipase C antagonists decreased global intracellular Ca2+ and dilated the arteries. In contrast, cremaster arterioles displayed only Ca2+ waves: Ca2+ sparks were not observed, and neither ryanodine (10–50 μM) nor tetracaine (100 μM) affected either Ca2+ signals or arteriolar tone despite the presence of functional RyRs as assessed by responses to the RyR agonist caffeine (10 mM). As in feed arteries, arteriolar Ca2+ waves were attenuated by xestospongin D (5 μM), 2-aminoethoxydiphenyl borate (100 μM), and U-73122 (10 μM), accompanied by decreased global intracellular Ca2+ and vasodilation. These findings highlight the contrasting roles played by RyRs and IP3Rs in Ca2+ signals and myogenic tone in feed arteries and demonstrate important differences in the function of RyRs between feed arteries and downstream arterioles. PMID:21357503

  19. THE CONTRIBUTION OF TYRO3 FAMILY RECEPTOR TYROSINE KINASES TO THE HETEROGENEITY OF APOPTOTIC CELL UPTAKE BY MONONUCLEAR PHAGOCYTES

    PubMed Central

    Curtis, Jeffrey L.; Todt, Jill C.; Hu, Bin; Osterholzer, John J.; Freeman, Christine M.

    2014-01-01

    Mononuclear phagocytes comprise a mobile, broadly dispersed and highly adaptable system that lies at the very epicenter of host defense against pathogens and the interplay of the innate and adaptive arms of immunity. Understanding the molecular mechanisms that control the response of mononuclear phagocytes to apoptotic cells and the anti-inflammatory consequences of that response is an important goal with implications for multiple areas of biomedical sciences. This review details current understanding of the heterogeneity of apoptotic cell uptake by different members of the mononuclear phagocyte family in humans and mice. It also recounts the unique role of the Tyro3 family of receptor tyrosine kinases, best characterized for Mertk, in the signal transduction leading both to apoptotic cell ingestion and the anti-inflammatory effects that result. PMID:19273223

  20. Heterogeneous function of ryanodine receptors, but not IP3 receptors, in hamster cremaster muscle feed arteries and arterioles.

    PubMed

    Westcott, Erika B; Jackson, William F

    2011-05-01

    The roles played by ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP₃Rs) in vascular smooth muscle in the microcirculation remain unclear. Therefore, the function of both RyRs and IP₃Rs in Ca(²+) signals and myogenic tone in hamster cremaster muscle feed arteries and downstream arterioles were assessed using confocal imaging and pressure myography. Feed artery vascular smooth muscle displayed Ca(²+) sparks and Ca(²+) waves, which were inhibited by the RyR antagonists ryanodine (10 μM) or tetracaine (100 μM). Despite the inhibition of sparks and waves, ryanodine or tetracaine increased global intracellular Ca(²+) and constricted the arteries. The blockade of IP₃Rs with xestospongin D (5 μM) or 2-aminoethoxydiphenyl borate (100 μM) or the inhibition of phospholipase C using U-73122 (10 μM) also attenuated Ca(2+) waves without affecting Ca(²+) sparks. Importantly, the IP₃Rs and phospholipase C antagonists decreased global intracellular Ca(2+) and dilated the arteries. In contrast, cremaster arterioles displayed only Ca(²+) waves: Ca(²+) sparks were not observed, and neither ryanodine (10-50 μM) nor tetracaine (100 μM) affected either Ca(²+) signals or arteriolar tone despite the presence of functional RyRs as assessed by responses to the RyR agonist caffeine (10 mM). As in feed arteries, arteriolar Ca(²+) waves were attenuated by xestospongin D (5 μM), 2-aminoethoxydiphenyl borate (100 μM), and U-73122 (10 μM), accompanied by decreased global intracellular Ca(²+) and vasodilation. These findings highlight the contrasting roles played by RyRs and IP₃Rs in Ca(²+) signals and myogenic tone in feed arteries and demonstrate important differences in the function of RyRs between feed arteries and downstream arterioles. PMID:21357503

  1. Heterogeneity of clinical features and corresponding antibodies in seven patients with anti-NMDA receptor encephalitis

    PubMed Central

    SÜHS, KURT-WOLFRAM; WEGNER, FLORIAN; SKRIPULETZ, THOMAS; TREBST, CORINNA; TAYEB, SAID BEN; RAAB, PETER; STANGEL, MARTIN

    2015-01-01

    Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is the most common type of encephalitis in the spectrum of autoimmune encephalitis defined by antibodies targeting neuronal surface antigens. In the present study, the clinical spectrum of this disease is presented using instructive cases in correlation with the anti-NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and serum. A total of 7 female patients admitted to the hospital of Hannover Medical School (Hannover, Germany) between 2008 and 2014 were diagnosed with anti-NMDA receptor encephalitis. Among these patients, 3 cases were selected to illustrate the range of similar and distinct clinical features across the spectrum of the disease and to compare anti-NMDA antibody levels throughout the disease course. All patients received immunosuppressive treatment with methylprednisolone, intravenous immunoglobulin and/or plasmapheresis, followed in the majority of patients by second-line therapy with rituximab and cyclophosphamide. The disease course correlated with NMDA receptor antibody titers, and to a greater extent with the ratio between antibody titer and protein concentration. A favorable clinical outcome with a modified Rankin Scale (mRS) score of ≤1 was achieved in 4 patients, 1 patient had an mRS score of 2 after 3 months of observation only, whereas 2 patients remained severely impaired (mRS score 4). Early and aggressive immunosuppressive treatment appears to support a good clinical outcome; however, the clinical signs and symptoms differ distinctively and treatment decisions have to be made on an individual basis. PMID:26622479

  2. Attribution to Heterogeneous Risk Factors for Breast Cancer Subtypes Based on Hormone Receptor and Human Epidermal Growth Factor 2 Receptor Expression in Korea.

    PubMed

    Park, Boyoung; Choi, Ji-Yeob; Sung, Ho Kyung; Ahn, Choonghyun; Hwang, Yunji; Jang, Jieun; Lee, Juyeon; Kim, Heewon; Shin, Hai-Rim; Park, Sohee; Han, Wonshik; Noh, Dong-Young; Yoo, Keun-Young; Kang, Daehee; Park, Sue K

    2016-04-01

    We conducted a heterogeneous risk assessment of breast cancer based on the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) calculating the risks and population-based attributable fractions (PAFs) for modifiable and nonmodifiable factors.Using matched case-control study design from the Seoul Breast Cancer Study and the national prevalence of exposure, the risks and PAFs for modifiable and nonmodifiable factors were estimated for total breast cancers and subtypes.The attribution to modifiable factors was different for each subtype (luminal A, PAF = 61.4% [95% confidence interval, CI = 54.3%-69.8%]; luminal B, 21.4% [95% CI = 18.6-24.9%]; HER2-overexpression, 59.4% [95% CI = 47.8%-74.3%], and triple negative tumors [TNs], 27.1% [95% CI = 22.9%-32.4%)], and the attribution to the modifiable factors for the luminal A and HER2-overexpression subtypes was higher than that of the luminal B and TN subtypes (P heterogeneity ≤ 0.001). The contribution of modifiable reproductive factors to luminal A type in premenopausal women was higher than that of the other subtypes (18.2% for luminal A; 3.1%, 8.1%, and -3.1% for luminal B, HER2-overexpression, and TN subtypes, respectively; P heterogeneity ≤ 0.001). Physical activity had the highest impact preventing 32.6% of luminal A, 14.5% of luminal B, 38.0% of HER2-overexpression, and 26.9% of TN subtypes (P heterogeneity = 0.014). Total reproductive factors were also heterogeneously attributed to each breast cancer subtype (luminal A, 65.4%; luminal B, 24.1%; HER2-overexpression, 57.9%, and TN subtypes, -3.1%; P heterogeneity ≤ 0.001).Each pathological subtype of breast cancer by HRs and HER2 status may be associated with heterogeneous risk factors and their attributable risk, suggesting a different etiology. The luminal B and TN subtypes seemed to be less preventable despite intervention for alleged risk factors, even though physical activity had a high preventable

  3. Heterogeneity in the physicochemical properties of deoxycholate-solubilized benzodiazepine receptors from calf cerebral cortex.

    PubMed

    Sherman-Gold, R; Dudai, Y

    1983-07-01

    The hydrodynamic behaviour of benzodiazepine receptors solubilized by deoxycholate from calf cerebral cortex reveals two molecular forms. The Stokes radii are 46.5 A and 67.2 A, and the sedimentation coefficients are 10.9 S and 14.6 S. The calculated apparent molecular weights and frictional ratios suggest either two nearly globular proteins of ca. 200K and 400K daltons each, or two ca. 300K daltons proteins which differ significantly in their degree of asymmetry. The benzodiazepine binding site is located on ca. 51K daltons component(s) in both forms. PMID:6312347

  4. The antinociceptive effects of epidural opiates in the cat: studies of the pharmacology and the effects of lipophilicity in spinal analgesia.

    PubMed

    Tung, A S; Yaksh, T L

    1982-04-01

    In cats implanted chronically with catheters in the lumbar epidural space, the pharmacology of the analgesia of 4 opiates, which varied widely in their physicochemical properties, was studied. Results revealed the following order of epidural analgesic potency as indicated by suppression of the spinally mediate skin twitch reflex: lofentanyl greater than morphine greater than L-methadone greater than meperidine greater than D-methadone. With the doses used in these experiments the duration of action was: morphine greater than lofentanyl greater than L-methadone = meperidine. In addition, antagonism of these effects by systemic naloxone and the development of tolerance after daily epidural administration of morphine were demonstrated. These data, jointly, indicate a specific receptor mechanism of action. We suggest that this animal model may be useful for the evaluation of new opiates and non-opiates to be given via the epidural route. PMID:7099701

  5. Atrial natriuretic peptide receptor heterogeneity and effects on cyclic GMP accumulation

    SciTech Connect

    Leitman, D.C.

    1988-01-01

    The effects of atrial natriuretic peptide (ANP), oxytocin (OT) and vasopressin (AVP) on guanylate cyclase activity and cyclic GMP accumulation were examined, since these hormones appear to be intimately associated with blood pressure and intravascular volume homeostasis. ANP was found to increase cyclic GMP accumulation in ten cell culture systems, which were derived from blood vessels, adrenal cortex, kidney, lung, testes and mammary gland. ANP receptors were characterized in intact cultured cells using {sup 125}I-ANP{sub 8-33}. Specific {sup 125}I-ANP binding was saturable and of high affinity. Scratchard analysis of the binding data for all cell types exhibited a straight line, indicating that these cells possessed a single class of binding sites. Despite the presence of linear Scatchard plots, these studies demonstrated that cultured cells possess two functionally and physically distinct ANP-binding sites. Most of the ANP-binding sites in cultured cells have a molecular size of 66,000 daltons under reducing conditions. The identification of cultured cell types in which hormones (ANP and oxytocin) regulate guanylate cyclase activity and increase cyclic GMP synthesis will provide valuable systems to determine the mechanisms of hormone-receptor coupling to guanylate cyclase and the cellular processes regulated by cyclic GMP.

  6. Limited heterogeneity of rearranged T-cell receptor Vα transcripts in brains of multiple sclerosis patients

    NASA Astrophysics Data System (ADS)

    Oksenberg, Jorge R.; Stuart, Simon; Begovich, Ann B.; Bell, Robert B.; Erlich, Henry A.; Steinman, Lawrence; Bernard, Claude C. A.

    1990-05-01

    THE identification of activated ? cells in the brain of individuals with multiple sclerosis (MS) indicates that these cells are critical in the pathogenesis of this disease. In an attempt to elucidate the nature of the lymphocytic infiltration, we used the polymerase chain reaction to amplify T-cell antigen receptor (TCR) Vα sequences from transcripts derived from MS brain lesions. In each of three MS brains, only two to four rearranged TCR Vα transcripts were detected. No Vα transcripts could be found in control brains. Sequence analysis of transcripts encoded by the Vα 12.1 region showed rearrangements to a limited number of Jα region segments. These results imply that TCR Vα gene expression in MS brain lesions is restricted.

  7. A new, highly selective CCK-B receptor radioligand (( sup 3 H)(N-methyl-Nle28,31)CCK26-33): Evidence for CCK-B receptor heterogeneity

    SciTech Connect

    Knapp, R.J.; Vaughn, L.K.; Fang, S.N.; Bogert, C.L.; Yamamura, M.S.; Hruby, V.J.; Yamamura, H.I. )

    1990-12-01

    (N-methyl-Nle28,31)CCK26-33 (SNF 8702) is a nonsulfated cholecystokinin octapeptide analog that is highly selective for cholecystokinin-B (CCK-B) receptors. Inhibition studies using (125I) Bolton-Hunter-labeled CCK-8 show that SNF 8702 has over 4,000-fold greater affinity for CCK receptors in guinea pig cortex relative to those in guinea pig pancreas. SNF 8702 was tritium-labeled to a specific activity of 23.7 Ci/mmol and its binding properties characterized for guinea pig brain membrane preparations. (3H)SNF 8702 binds to a single site with high affinity (Kd = 0.69-0.90 nM) in guinea pig cortex, cerebellum, hippocampus and pons-medulla. Of these four tissues, the highest receptor density was measured in the cortex (86 fmol/mg of protein) and the lowest in the pons-medulla (22 fmol/mg of protein). In contrast to findings of single-site binding in some brain regions, evidence for CCK-B receptor heterogeneity is observed under other conditions. (3H)SNF 8702 binding to membranes prepared from whole guinea pig brain shows biphasic association kinetics at a concentration of 2.0 nM consistent with the presence of binding site heterogeneity. Binding site heterogeneity is consistently observed for (3H)SNF 8702 binding to guinea pig whole brain membranes in saturation studies where a high-affinity site (Kd = 0.31 nM) is distinguished from a low-affinity site (Kd = 3.3 nM). Binding site heterogeneity is also observed for the midbrain-thalamic region. CCK-B receptor heterogeneity is suggested by the effect of the guanyl nucleotide analogue, guanylyl-imidodiphosphate (Gpp(NH)p), on (3H)SNF 8702 binding to CCK-B receptors in the cerebellum.

  8. Enhanced bioavailability of opiates after intratracheal administration

    SciTech Connect

    Findlay, J.W.A.; Jones, E.C.; McNulty, M.J.

    1986-03-01

    Several opiate analgesics have low oral bioavailabilities in the dog because of presystemic metabolism. Intratracheal administration may circumvent this first-pass effect. Three anesthetized beagles received 5-mg/kg doses of codeine phosphate intratracheally (i.t.), orally (p.o.) and intravenously (i.v.) in a crossover study. The following drugs were also studied in similar experiments: ethylmorphine hydrochloride (5 mg/kg), pholcodine bitartrate (10 mg/kg, hydrocodone bitartrate (4 mg/kg) and morphine sulfate (2.5 mg/kg). Plasma drug concentrations over the 24- to 48-hr periods after drug administrations were determined by radioimmunoassays. I.t. bioavailabilities (codeine (84%), ethylmorphine (100%), and morphine (87%)) of drugs with poor oral availabilities were all markedly higher than the corresponding oral values (14, 26, and 23%, respectively). I.t. bioavailabilities of pholcodine (93%) and hydrocodone (92%), which have good oral availabilities (74 and 79%, respectively), were also enhanced. In all cases, peak plasma concentrations occurred more rapidly after i.t. (0.08-0.17 hr) than after oral (0.5-2 hr) dosing and i.t. disposition often resembled i.v. kinetics. I.t. administration may be a valuable alternative dosing route, providing rapid onset of pharmacological activity for potent drugs with poor oral bioavailability.

  9. Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

    PubMed Central

    Lorier, Amanda R.; Funk, Gregory D.; Greer, John J.

    2010-01-01

    Background Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of μ-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity. Methodology/Principal Findings A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the μ-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons. Conclusions/Significance The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract μ-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron

  10. Role of Src in C3 transient receptor potential channel function and evidence for a heterogeneous makeup of receptor- and store-operated Ca2+ entry channels.

    PubMed

    Kawasaki, Brian T; Liao, Yanhong; Birnbaumer, Lutz

    2006-01-10

    Receptor-operated Ca2+ entry (ROCE) and store-operated Ca2+ entry (SOCE) are known to be inhibited by tyrosine kinase inhibitors and activation of C-type transient receptor potential channel (TRPC) isoform 3 (TRPC3), a cation channel thought to be involved in SOCE and/or ROCE, was recently shown to depend on src tyrosine kinase activity. What is not known is the step at which src acts on TRPC3 and whether the role for tyrosine kinases in ROCE or SOCE is a general phenomenon. Using in vitro and in cell protein-protein interaction assays we now report that src phosphorylates TRPC3 at Y226 and that formation of phospho-Y226 is essential for TRPC3 activation. This requirement is unique for TRPC3 because (i) mutation of the cognate tyrosines of the closely related TRPC6 and TRPC7 had no effect; (ii) TRPC6 and TRPC7 were activated in src-, yes-, and fyn-deficient cells; and (iii) src, but not yes or fyn, rescued TRPC3 activation in src-, yes-, and fyn-deficient cells. The Src homology 2 domain of src was found to interact with either the N or the C termini of all TRPCs, suggesting that other tyrosine kinases may play a role in ion fluxes mediated by TRPCs other than TRPC3. A side-by-side comparison of the effects of genistein (a general tyrosine kinase inhibitor) on endogenous ROCE and SOCE in mouse fibroblasts, HEK and COS-7 cells, and ROCE in HEK cells mediated by TRPC3, TRPC6, TRPC7, and TRPC5 showed differences that argue for ROCE and SOCE channels to be heterogeneous. PMID:16407161

  11. Castration affects male rat brain opiate receptor content.

    PubMed

    Hahn, E F; Fishman, J

    1985-07-01

    We previously reported that saturable stereospecific binding of [3H]-naltrexone in rat brain homogenates prepared from castrated male rats was greater than the corresponding binding in intact animals. We now report that we have replicated these results and that the difficulty of other investigators in observing these differences is due to methodological factors. Specifically, when samples were filtered individually and rapidly, differences between castrated and intact rats were maintained. The increase in binding was also observed when tissues were washed to remove endogenous opioids prior to incubation, when [3H]-naloxone was used as the ligand, and when various antagonists were used as displacers in the radioreceptor assay. PMID:2991795

  12. Heterogeneous Inhibition in Macroscopic Current Responses of Four Nicotinic Acetylcholine Receptor Subtypes by Cholesterol Enrichment.

    PubMed

    Báez-Pagán, Carlos A; Del Hoyo-Rivera, Natalie; Quesada, Orestes; Otero-Cruz, José David; Lasalde-Dominicci, José A

    2016-08-01

    The nicotinic acetylcholine receptor (nAChR), located in the cell membranes of neurons and muscle cells, mediates the transmission of nerve impulses across cholinergic synapses. In addition, the nAChR is also found in the electric organs of electric rays (e.g., the genus Torpedo). Cholesterol, which is a key lipid for maintaining the correct functionality of membrane proteins, has been found to alter the nAChR function. We were thus interested to probe the changes in the functionality of different nAChRs expressed in a model membrane with modified cholesterol to phospholipid ratios (C/P). In this study, we examined the effect of increasing the C/P ratio in Xenopus laevis oocytes expressing the neuronal α7, α4β2, muscle-type, and Torpedo californica nAChRs in their macroscopic current responses. Using the two-electrode voltage clamp technique, it was found that the neuronal α7 and Torpedo nAChRs are significantly more sensitive to small increases in C/P than the muscle-type nAChR. The peak current versus C/P profiles during enrichment display different behaviors; α7 and Torpedo nAChRs display a hyperbolic decay with two clear components, whereas muscle-type and α4β2 nAChRs display simple monophasic decays with different slopes. This study clearly illustrates that a physiologically relevant increase in membrane cholesterol concentration produces a remarkable reduction in the macroscopic current responses of the neuronal α7 and Torpedo nAChRs functionality, whereas the muscle nAChR appears to be the most resistant to cholesterol inhibition among all four nAChR subtypes. Overall, the present study demonstrates differential profiles for cholesterol inhibition among the different types of nAChR to physiological cholesterol increments in the plasmatic membrane. This is the first study to report a cross-correlation analysis of cholesterol sensitivity among different nAChR subtypes in a model membrane. PMID:27116687

  13. Heterogeneity of the M1 muscarinic receptor subtype between peripheral lung and cerebral cortex demonstrated by the selective antagonist AF-DX 116

    SciTech Connect

    Bloom, J.W.; Halonen, M.; Seaver, N.A.; Yamamura, H.I.

    1987-07-27

    Recent studies have demonstrated that the majority of muscarinic receptors in rabbit peripheral lung homogenates bind pirenzepine with high affinity (putative M1 subtype). In experiments of AF-DX 116 inhibiting (TH)(-)quinuclidinyl benzilate or (TH)pirenzepine, the authors found similar inhibitory constants for AF-DX 116 binding in rat heart and rabbit peripheral lung that were 4-fold smaller (i.e. of higher affinity) than the inhibitory constant for rat cerebral cortex. This results demonstrates heterogeneity of the M1 muscarinic receptor subtype between peripheral lung and cerebral cortex. 20 references, 1 figure, 2 tables.

  14. Suboxone misuse along the opiate maintenance treatment pathway.

    PubMed

    Furst, R Terry

    2013-01-01

    This study explores strategies that Suboxone misusers utilize while in drug treatment. Ethnographic interviews were conducted with 14 patients who had cycled in and out of Suboxone treatment. The objective of the study is to identify strategies implemented by patients who intermittently use opiates/opioids while in Suboxone treatment. Findings indicate that some patients serially stop and start treatment in a Harm Reduction setting in New York City. Many patients suggest that they manage their opiate/opioid dependency through a sequential use of Suboxone and heroin to avoid withdrawal and to continue their misuse of opiates/opioids. Results are discussed in conjunction with the difficulties inherent to substance abuse treatment and suggestions for improvement are offered. PMID:23480248

  15. Maintenance medication for opiate addiction: the foundation of recovery.

    PubMed

    Bart, Gavin

    2012-01-01

    Illicit use of opiates is the fastest growing substance use problem in the United States, and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to human immunodeficiency virus, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication-assisted detoxification. This article provides a topical review of the three medications approved by the Food and Drug Administration for long-term treatment of opiate dependence: the opioid-agonist methadone, the partial opioid-agonist buprenorphine, and the opioid-antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction, but recent studies using extended-release naltrexone injections have shown promise. Although no direct comparisons between extended-release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared with methadone and buprenorphine. Further work is needed to directly compare each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication. PMID:22873183

  16. Maintenance Medication for Opiate Addiction: The Foundation of Recovery

    PubMed Central

    Bart, Gavin

    2012-01-01

    Illicit use of opiates is the fastest growing substance use problem in the United States and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to HIV, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication assisted detoxification. This article provides a topical review of the three medications approved by the FDA for long-term treatment of opiate dependence: the opioid agonist methadone, the opioid partial agonist buprenorphine, and the opioid antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction but recent studies using extended release naltrexone injections have shown promise. While no direct comparisons between extended release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared to methadone and buprenorphine. Further work is needed to compare directly each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication. PMID:22873183

  17. Pholcodine interference in the immunoassay for opiates in urine.

    PubMed

    Svenneby, G; Wedege, E; Karlsen, R L

    1983-01-01

    The excretion in urine after single oral therapeutic doses of morphine derivatives was analysed with radioimmunoassay (RIA) and homogeneous enzyme immunoassay (EMIT) for opiates. In contrast to the rapid excretion of ethylmorphine and codeine, pholcodine showed positive results for opiates 2-6 weeks after intake when the urines were analysed with the RIA-method. When analysed with the EMIT-method, positive results were obtained for pholcodine for approximately 10 days. As pholcodine is a common component in cough mixtures, its prolonged excretion could represent a hazard in interpreting the results from drug analyses of urines. PMID:6347841

  18. The Neuropsychology of Amphetamine and Opiate Dependence: Implications for Treatment

    PubMed Central

    Sahakian, Barbara J

    2013-01-01

    Chronic use of amphetamines and/or opiates has been associated with a wide range of cognitive deficits, involving domains of attention, inhibitory control, planning, decision-making, learning and memory. Although both amphetamine and opiate users show marked impairment in various aspects of cognitive function, the impairment profile is distinctly different according to the substance of abuse. In light of evidence showing that cognitive impairment in drug users has a negative impact on treatment engagement and efficacy, we review substance-specific deficits on executive and memory function, and discuss possibilities to address these during treatment intervention. PMID:17690986

  19. Preventing Opiate Overdose Deaths: Examining Objections to Take-Home Naloxone

    PubMed Central

    Bazazi, Alexander R.; Zaller, Nickolas D.; Fu, Jeannia J.; Rich, Josiah D.

    2010-01-01

    Opiate overdose persists as a major public health problem, contributing to significant morbidity and mortality among opiate users globally. Opiate overdose can be reversed by the timely administration of naloxone. Programs that distribute naloxone to opiate users and their acquaintances have been successfully implemented in a number of cities around the world and have shown that non-medical personnel are able to administer naloxone to reverse opiate overdoses and save lives. Objections to distributing naloxone to non-medical personnel persist despite a lack of scientific evidence. Here we respond to some common objections to naloxone distribution and their implications. PMID:21099064

  20. 21 CFR 862.3650 - Opiate test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Opiate test system. 862.3650 Section 862.3650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  1. 21 CFR 862.3650 - Opiate test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Opiate test system. 862.3650 Section 862.3650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  2. 21 CFR 862.3650 - Opiate test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Opiate test system. 862.3650 Section 862.3650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  3. 21 CFR 862.3650 - Opiate test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Opiate test system. 862.3650 Section 862.3650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  4. 21 CFR 862.3650 - Opiate test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Opiate test system. 862.3650 Section 862.3650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL... include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and...

  5. Drug Craving Terminology among Opiate Dependents; A Mixed Method Study

    PubMed Central

    Maarefvand, Masoomeh; Ghiasvand, Hamid Reza

    2013-01-01

    Objective Drug craving is defined as an urge to continue substance abuse. Drug dependents use different terms to express their subjective feeling of craving. This study was an attempt to generate an understanding of craving terminology among different groups of Persian speaking Iranian opiate dependents. Method Terms used for the meaning of drug craving were listed by 36 ex-opiate dependents in focus group discussion meetings in the first phase of the study. These terms were composed from Craving Terms Questionnaire. In the second phase, 120 subjects in 3 groups of opiate dependents and a group of Current Opiate Abusers rated usage frequency of each term in the questionnaire under a Twelve-Step Program, Methadone Maintenance, and Other Abstinence-based Programs. Results Eighty nine terms were categorized in stimulation and triggering, attention bias and obsession, decision making difficulty, information processing impairment, withdrawal induction, drug euphoric experience, mental urge, motor control problem, negative valancing and stigmatizing. Terms for the three categories of mental urge, attention bias and obsession and motor control problem were used more than others. Patients in Methadone Maintenance Treatment (MMT) group used different categories of craving terms in comparison to other groups. Abstinent cases reported higher total score for craving terms in comparison to other groups in Twelve-Step Program and other abstinence-based programs. Conclusion Each craving-related term is associated with some aspects of the multidimensional concept of craving. A drug-craving thesaurus could provide a better understanding of craving nature from a drug dependent point of view. There are differences among abstinence vs. maintenance based treated opiate dependents in using craving terms. Addiction therapists will benefit from accessing drug dependents’ lexicon to assess and create therapeutic alliance with their clients. PMID:24130609

  6. Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.

    PubMed

    Ignatowski, T A; Aalinkeel, R; Reynolds, J L; Nair, B B; Sykes, D E; Gleason, C P K; Law, W C; Mammen, M J; Prasad, P N; Schwartz, S A; Mahajan, Supriya D

    2015-03-01

    Opiates act on the dopaminergic system of the brain and perturb 32 kDa dopamine and adenosine 3', 5'-monophosphate-regulated phosphoprotein (DARPP-32) function. The DARPP-32 mediated inhibition of protein phosphatase-1 (PP-1) and modulation of transcriptional factor CREB is critical to the changes in neuronal plasticity that result in behavioral responses during drug abuse. To investigate the role of DARPP-32 mediated signaling on withdrawal behavior in a rat model of opiate addiction, we used intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. We hypothesized that DARPP-32 siRNA will suppress the neurochemical changes underlying the withdrawal syndrome and therefore prevent conditioned place aversion by suppressing or removing the constellation of negative effects associated with withdrawal, during the conditioning procedure. Our results showed that opiate addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology based delivery systems could allow sustained knockdown of DARPP-32 gene expression which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses. PMID:25604667

  7. Adolescent exposure to chronic delta-9-tetrahydrocannabinol blocks opiate dependence in maternally deprived rats.

    PubMed

    Morel, Lydie J; Giros, Bruno; Daugé, Valérie

    2009-10-01

    Maternal deprivation in rats specifically leads to a vulnerability to opiate dependence. However, the impact of cannabis exposure during adolescence on this opiate vulnerability has not been investigated. Chronic dronabinol (natural delta-9 tetrahydrocannabinol, THC) exposure during postnatal days 35-49 was made in maternal deprived (D) or non-deprived (animal facility rearing, AFR) rats. The effects of dronabinol exposure were studied after 2 weeks of washout on the rewarding effects of morphine measured in the place preference and oral self-administration tests. The preproenkephalin (PPE) mRNA levels and the relative density and functionality of CB1, and mu-opioid receptors were quantified in the striatum and the mesencephalon. Chronic dronabinol exposure in AFR rats induced an increase in sensitivity to morphine conditioning in the place preference paradigm together with a decrease of PPE mRNA levels in the nucleus accumbens and the caudate-putamen nucleus, without any modification for preference to oral morphine consumption. In contrast, dronabinol treatment on D-rats normalized PPE decrease in the striatum, morphine consumption, and suppressed sensitivity to morphine conditioning. CB1 and mu-opioid receptor density and functionality were not changed in the striatum and mesencephalon of all groups of rats. These results indicate THC potency to act as a homeostatic modifier that would worsen the reward effects of morphine on naive animals, but ameliorate the deficits in maternally D-rats. These findings point to the self-medication use of cannabis in subgroups of individuals subjected to adverse postnatal environment. PMID:19553915

  8. OPIATE EXPOSURE AND WITHDRAWAL DYNAMICALLY REGULATE mRNA EXPRESSION IN THE SEROTONERGIC DORSAL RAPHE NUCLEUS

    PubMed Central

    Lunden, Jason; Kirby, Lynn G.

    2013-01-01

    Previous results from our lab suggest that hypofunctioning of the serotonergic (5-HT) dorsal raphe nucleus (DRN) is involved in stress-induced opiate reinstatement. To further investigate the effects of morphine dependence and withdrawal on the 5-HT DRN system, we measured gene expression at the level of mRNA in the DRN during a model of morphine dependence, withdrawal and post withdrawal stress exposure in rats. Morphine pellets were implanted for 72h and then either removed or animals were injected with naloxone to produce spontaneous or precipitated withdrawal, respectively. Animals exposed to these conditions exhibited withdrawal symptoms including weight loss, wet dog shakes and jumping behavior. Gene expression for brain-derived neurotrophic factor (BDNF), TrkB, corticotrophin releasing-factor (CRF)-R1, CRF-R2, GABAA-α1, μ-opioid receptor (MOR), 5-HT1A, tryptophan hydroxylase2 and the 5-HT transporter was then measured using quantitative real-time PCR at multiple time-points across the model of morphine exposure, withdrawal and post withdrawal stress. Expression levels of BDNF, TrkB and CRF-R1 mRNA were decreased during both morphine exposure and following seven days of withdrawal. CRF-R2 mRNA expression was elevated after seven days of withdrawal. 5-HT1A receptor mRNA expression was decreased following 3 hours of morphine exposure, while TPH2 mRNA expression was decreased after seven days of withdrawal with swim stress. There were no changes in the expression of GABAA-α1, MOR or 5-HT transporter mRNA. Collectively these results suggest that alterations in neurotrophin support, CRF-dependent stress signaling, 5-HT synthesis and release may underlie 5-HT DRN hypofunction that can potentially lead to stress-induced opiate relapse. PMID:24055683

  9. Biphasic competition between opiates and enkephalins: does it indicate the existence of a common high affinity (mu-1) binding site

    SciTech Connect

    Sarne, Y.; Kenner, A.

    1987-08-03

    Displacement from brain membranes of labeled opiates by low concentrations of enkephalins and of labeled enkephalins by low concentrations of opiates has been previously explained by the existance of a common high affinity site termed mu-1. An alternative interpretation of the same results is that the trough seen in the low concentration zone of the displacement curves represents cross binding of mu and delta opioid ligands to delta and mu receptors, respectively. In three sets of experiments with brain membranes, the size of the trough is shown to be dependent on the labeled ligand used: The ratio between the size of troughs seen with (TH)D-Ala, D-Leu enkephalin and with (TH)morphine varies with experimental conditions (storage of membranes at 4C for 72h), with ratio of mu:delta receptors (e.g. in thalamus and cortex which are enriched in mu and delta sites, respectively) and with pretreatment of membranes with naloxonazine. These results cannot be explained by a common high affinity site, but rather by binding of (TH)D-Ala, D-Leu enkephalin to mu and of (TH)morphine to delta opioid receptors. 17 references, 3 figures.

  10. Amenability to counseling of opiate addicts on probation or parole.

    PubMed

    Goodkin, K; Wilson, K E

    1982-08-01

    Fifty-two opiate addicts were classified as abstainers or continued abusers by their probation or parole officer. Eighteen variables--nine demographic and nine psychological--were evaluated for all subjects. Following factor analysis, 13 remaining variables were entered into a stepwise discriminant function analysis which significantly differentiated the abstaining and abusing groups. Abstainers were characterized by less dogmatism, higher education and personality integration, fewer aggressive incidents and previous drug arrests, and older age. The discriminant function classified 78.8% of the observations correctly and accounted for 27% of the variance. Rokeach's Dogmatism Scale, the Personality Integration Subscale of the Tennessee Self-Concept Scale, and the effective demographic discriminators have been included in a screening battery for counseling amenability by which incoming opiate addicts scoring like abstainers are granted priority in treatment assignment. PMID:7141765

  11. Profound opiate toxicity in gastroparesis following therapeutic dose.

    PubMed

    Craven, Henry; Iftikhar, Hina; Bhatnagar, Pallav

    2016-01-01

    Gastroparesis is defined by the presence of delayed gastric emptying without mechanical obstruction. Patients may present with severe discomfort that can mimic an acute abdomen including abdominal pain, vomiting, nausea, bloating, fullness and early satiety. The prevalence of gastroparesis is estimated at 24 per 100 000 and women are more commonly affected than men. It is associated with a number of conditions including diabetes, Parkinson's disease, multiple sclerosis, previous abdominal surgeries and connective tissue disorders, including scleroderma and Ehlers-Danlos syndrome. Drugs known to prolong gastric transit time, such as opiates, have been shown to exacerbate symptoms. We report a case of a 20-year-old woman with Ehlers-Danlos syndrome who developed respiratory depression after being administered a therapeutic dose of morphine. This occurred due to opiate toxicity confounded by gastroparesis. The patient required further support from intensive care until she recovered, and eventually underwent a gastric pacing procedure for symptomatic relief. PMID:27147632

  12. Opiate versus psychostimulant addiction: the differences do matter

    PubMed Central

    Badiani, Aldo; Belin, David; Epstein, David; Calu, Donna; Shaham, Yavin

    2013-01-01

    The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction — hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction — all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research. PMID:21971065

  13. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

    PubMed

    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior. PMID:19956087

  14. Medication-assisted treatment of opiate dependence is gaining favor.

    PubMed

    Jerry, Jason M; Collins, Gregory B

    2013-06-01

    People addicted to opiates are more likely to avoid returning to these drugs if they participate in a program that includes taking maintenance doses of methadone or buprenorphine than with an abstinence program. Although medical opinion has long been divided on the issue of abstinence vs medication-assisted treatment, the latter seems to be gaining respect as an evidence-based approach. PMID:23733899

  15. Prescription opiate misuse among rural stimulant users in a multi-state community-based study

    PubMed Central

    Havens, Jennifer R.; Stoops, William W.; Leukefeld, Carl G.; Garrity, Thomas F.; Carlson, Robert G.; Falck, Russel; Wang, Jichuan; Booth, Brenda M.

    2013-01-01

    Objectives The purpose of the current analysis was to examine the factors associated with prescription opiate misuse among stimulant users from rural counties in Arkansas, Kentucky, and Ohio (N=714). Methods Multiple logistic regression was utilized to determine the independent correlates of recent (prior 6 months) prescription opiate misuse. Results More than half of participants (53.2%) reported prescription opiate misuse in the previous 6 months. Other drug use (heroin, cocaine, methamphetamine and marijuana) and anxiety (Adjusted Odds Ratio: 2.04, 95% Confidence Interval: 1.60, 2.59) were independently associated with prescription opiate misuse. Chronic pain and other health indicators were not associated with prescription opiate misuse after adjustment for covariates. Conclusions Results indicate that illicit drug involvement and psychiatric symptoms may be driving the high rates of prescription opiate misuse among rural stimulant users. These findings have implications for the provision of treatment in resource-deprived rural areas. PMID:19152201

  16. Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli.

    PubMed

    Nakagawa, Akira; Matsumura, Eitaro; Koyanagi, Takashi; Katayama, Takane; Kawano, Noriaki; Yoshimatsu, Kayo; Yamamoto, Kenji; Kumagai, Hidehiko; Sato, Fumihiko; Minami, Hiromichi

    2016-01-01

    Opiates such as morphine and codeine are mainly obtained by extraction from opium poppies. Fermentative opiate production in microbes has also been investigated, and complete biosynthesis of opiates from a simple carbon source has recently been accomplished in yeast. Here we demonstrate that Escherichia coli serves as an efficient, robust and flexible platform for total opiate synthesis. Thebaine, the most important raw material in opioid preparations, is produced by stepwise culture of four engineered strains at yields of 2.1 mg l(-1) from glycerol, corresponding to a 300-fold increase from recently developed yeast systems. This improvement is presumably due to strong activity of enzymes related to thebaine synthesis from (R)-reticuline in E. coli. Furthermore, by adding two genes to the thebaine production system, we demonstrate the biosynthesis of hydrocodone, a clinically important opioid. Improvements in opiate production in this E. coli system represent a major step towards the development of alternative opiate production systems. PMID:26847395

  17. Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli

    PubMed Central

    Nakagawa, Akira; Matsumura, Eitaro; Koyanagi, Takashi; Katayama, Takane; Kawano, Noriaki; Yoshimatsu, Kayo; Yamamoto, Kenji; Kumagai, Hidehiko; Sato, Fumihiko; Minami, Hiromichi

    2016-01-01

    Opiates such as morphine and codeine are mainly obtained by extraction from opium poppies. Fermentative opiate production in microbes has also been investigated, and complete biosynthesis of opiates from a simple carbon source has recently been accomplished in yeast. Here we demonstrate that Escherichia coli serves as an efficient, robust and flexible platform for total opiate synthesis. Thebaine, the most important raw material in opioid preparations, is produced by stepwise culture of four engineered strains at yields of 2.1 mg l−1 from glycerol, corresponding to a 300-fold increase from recently developed yeast systems. This improvement is presumably due to strong activity of enzymes related to thebaine synthesis from (R)-reticuline in E. coli. Furthermore, by adding two genes to the thebaine production system, we demonstrate the biosynthesis of hydrocodone, a clinically important opioid. Improvements in opiate production in this E. coli system represent a major step towards the development of alternative opiate production systems. PMID:26847395

  18. Comparing the Iowa and soochow gambling tasks in opiate users.

    PubMed

    Upton, Daniel J; Kerestes, Rebecca; Stout, Julie C

    2012-01-01

    The Iowa Gambling Task (IGT) is in many respects the gold standard for demonstrating decision making in drug using groups. However, it is not clear how basic task properties such as the frequency and magnitude of rewards and losses affect choice behavior in drug users and even in healthy players. In this study, we used a variant of the IGT, the Soochow Gambling Task (SGT), to observe choice behavior in opiate users and healthy decision makers in a task where reward frequency is not confounded with the long-term outcome of each alternative. In both opiate users (n = 26) and healthy controls (n = 27), we show that reward frequency strongly influences choice behavior in the IGT and SGT. Neither group showed a consistent preference across tasks for alternatives with good long-term outcomes, but rather, subjects appeared to prefer alternatives that win most frequently. We interpret this as evidence to suggest that healthy players perform better than opiate users on the IGT because they are able to utilize gain-loss frequencies to guide their choice behavior on the task. This challenges the previous notion that poorer performance on the IGT in drug users is due to an inability to be guided by future consequences. PMID:22435045

  19. [Detoxication in opiate addiction and prevention of recurrence: administration of naltrexone and cognitive behavior therapy].

    PubMed

    Roozen, H G; Deden, A L; Kerkhof, A J; Vorsteveld, J P; van den Brink, W

    1997-12-01

    Rapid opiate withdrawal and relapse prevention in opiate addicts are made possible by naltrexone, clonidine and diazepam in combination with cognitive behavioural therapy according to the Community Reinforcement Approach. In an open pilot experiment 12 addicted patients achieved initial detoxification. At follow-up after a minimum of 6 months, 10 of these had not relapsed. Good results with this detoxification method could be booked by selecting highly motivated opiate addicts. PMID:9554156

  20. What happens to opiate addicts immediately after treatment: a prospective follow up study.

    PubMed Central

    Gossop, M; Green, L; Phillips, G; Bradley, B

    1987-01-01

    In the first British study to investigate systematically what happens to opiate addicts after treatment 50 opiate addicts admitted for inpatient treatment of their drug dependence were followed up for six months after discharge. All had been withdrawn from opiates before follow up. Six months later 26 were not using opiates: 12 had not used opiates at any time since discharge. When subjects in hospital or in prison were excluded from the analysis 21 (47%) of the subjects living in the community were not taking opiates. Many subjects used opiates within days of leaving the inpatient unit, but this first lapse did not necessarily lead to a full relapse into addictive use. During the six months after discharge several subjects used opiates on a less than daily basis. During each two month period throughout the six months of follow up the proportion of subjects who were occasional users fell, the proportion of abstinent subjects grew, and the proportion of daily users (assumed to be readdicted) remained constant. Although many of the addicts relapsed soon after treatment, it was encouraging that almost half were opiate free after six months. These results have important implications for the treatment of drug addicts. PMID:3109662

  1. Intracerebroventricular opiate infusion for refractory head and facial pain

    PubMed Central

    Lee, Darrin J; Gurkoff, Gene G; Goodarzi, Amir; Muizelaar, J Paul; Boggan, James E; Shahlaie, Kiarash

    2014-01-01

    AIM: To study the risks and benefits of intracerebroventricular (ICV) opiate pumps for the management of benign head and face pain. METHODS: SSix patients with refractory trigeminal neuralgia and/or cluster headaches were evaluated for implantation of an ICV opiate infusion pump using either ICV injections through an Ommaya reservoir or external ventricular drain. Four patients received morphine ICV pumps and two patientS received a hydromorphone pump. Of the Four patients with morphine ICV pumps, one patient had the medication changed to hydromorphone. Preoperative and post-operative visual analog scores (VAS) were obtained. Patients were evaluated post-operatively for a minimum of 3 mo and the pump dosage was adjusted at each outpatient clinic visit according to the patient’s pain level. RESULTS: All 6 patients had an intracerebroventricular opiate injection trial period, using either an Ommaya reservoir or an external ventricular drain. There was an average VAS improvement of 75.8%. During the trial period, no complications were observed. Pump implantation was performed an average of 3.7 wk (range 1-7) after the trial injections. After implantation, an average of 20.7 ± 8.3 dose adjustments were made over 3-56 mo after surgery to achieve maximal pain relief. At the most recent follow-up (26.2 mo, range 3-56), VAS scores significantly improved from an average of 7.8 ± 0.5 (range 6-10) to 2.8 ± 0.7 (range 0-5) at the final dose (mean improvement 5.0 ± 1.0, P < 0.001). All patients required a stepwise increase in opiate infusion rates to achieve maximal benefit. The most common complications were nausea and drowsiness, both of which resolved with pump adjustments. On average, infusion pumps were replaced every 4-5 years. CONCLUSION: These results suggest that ICV delivery of opiates may potentially be a viable treatment option for patients with intractable pain from trigeminal neuralgia or cluster headache. PMID:25133146

  2. Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates.

    PubMed

    García-Pardo, María Pilar; Roger-Sanchez, Concepción; Rodríguez-Arias, Marta; Miñarro, Jose; Aguilar, María Asunción

    2016-06-15

    Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C (PKC) family (including PKMζ), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target mammalian target of Rapamycin (mTOR), cyclin-dependent kinase 5 (Cdk5), heat-shock proteins (Hsp) and other enzymes and proteins. Research suggests that drugs of abuse induce dependence and addiction by modifying the signalling pathways that involve these memory-related protein kinases, and supports the idea that drug addiction is an excessive aberrant learning disorder in which the maladaptive memory of drug-associated cues maintains compulsive drug use and contributes to relapse. Moreover, the studies we review offer new pharmacological strategies to treat opiate and cocaine dependence based on the manipulation of these protein kinases. In particular, disruption of reconsolidation of drug-related memories may have a high therapeutic value in the treatment of drug addiction. PMID:27056740

  3. Radiosynthesis of F-18-3-acetylcyclofoxy: A high affinity opiate antagonist

    SciTech Connect

    Channing, M.A.; Eckelman, W.C.; Bennett, J.M.; Burke, T.R. Jr.; Rice, K.C.; Larson, S.M.

    1985-05-01

    A convenient method for the preparation of F-18-3-acetylcyclofoxy (3-acetyl-6-deoxy-6-beta-F-18-fluoronaltrexone was developed. The method uses reactor-produced F-18-fluoride as its tetraethylammonium salt. F-18 fluoride is produced at the National Bureau of Standards nuclear reactor by the Li-6(n,..cap alpha..)H-3, 0-16(H-3,n) F-18 nuclear reaction. A sealed quartz tube containing enriched lithium carbonate (0.4 g) was irradiated in a neutron flux of 1.1 x 10/sup 14/ n/cm/sup 2//s for 2h to produce 80 mCi. The lithium is removed by cation exchange resin. The fluoride is then adsorbed on a strong anion exchange column which is rinsed to remove H-3 and any remaining cations. The F-18 is then eluted with tetraethylammonium hydroxide to produce tetraethylammonium fluoride (TEAF). The triflate of 3-acetyl-6-alpha-naltrexol, synthesized by reaction of the alcohol with trifluoromethanesulfonic anhydride was added in anhydrous acetonitrile to the dry F-18 TEAF containing 0.2 ..mu..mol F-19 TEAF. The mixture was refluxed for 15 minutes after which the product was purified by reversed phase chromatography. F-18-acetylcyclofoxy was prepared in 35% radiochemical yield. About 55% of the F-18 was lost by decay (36%) and by incomplete transfer (19%). The specific activity of the final product was approximately 50 Ci/mmol but the effective specific activity was approximately 25 Ci/mmol. Visualization of the basal ganglia in baboons was possible using PET. F-18 3-acetylcyclofoxy is the first positron-emitting opiate for which the active and inactive forms of naloxone were used to unequivocially demonstrate stereospecific displacement from opiate receptor-rich regions.

  4. Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats.

    PubMed

    Helms, Christa M; McCracken, Aubrey D; Heichman, Sharon L; Moschak, Travis M

    2013-04-01

    Past studies have suggested that progesterone-derived ovarian hormones contribute to the discriminative stimulus effects of ethanol, particularly via progesterone metabolites that act at γ-aminobutyric acid type A (GABA(A)) receptors. It is unknown whether loss of ovarian hormones in women, for example, after menopause, may be associated with altered receptor mediation of the effects of ethanol. The current study measured the substitution of allopregnanolone, pregnanolone, pentobarbital, midazolam, dizocilpine, TFMPP, and RU 24969 in female sham and ovariectomized rats trained to discriminate 1.0 g/kg ethanol from water. The groups did not differ in the substitution of GABA(A)-positive modulators (barbiturates, benzodiazepines, neuroactive steroids) or the N-methyl-D-aspartate receptor antagonist dizocilpine. Similarly, blood-ethanol concentration did not differ between the groups, and plasma adrenocorticotropic hormone, progesterone, pregnenolone, and deoxycorticosterone were unchanged 30 min after administration of 1.0 g/kg ethanol or water. However, substitution of neuroactive steroids and RU 24969, a 5-hydroxytryptamine (5-HT)(1A/1B) receptor agonist, was lower than observed in previous studies of male rats, and TFMPP substitution was decreased in ovariectomized rats. Ovarian hormones appear to contribute to 5-HT receptor mediation of the discriminative stimulus effects of ethanol in rats. PMID:23399883

  5. Studies in the primate on the analgetic effects associated with intrathecal actions of opiates, alpha-adrenergic agonists and baclofen.

    PubMed

    Yaksh, T L; Reddy, S V

    1981-06-01

    The effects of intrathecally administered opiates (morphine sulfate and meperidine), alpha-adrenergic agonists (clonidine and ST-91) and baclofen were examined on the shock titration threshold of macaque monkeys chronically prepared with intrathecal (I) or epidural (E) catheters. Spinal opiates produced a long-lasting analgesia which was antagonized by naloxone. The order of potency was I morphine greater than I meperidine greater than E meperidine greater than E morphine. Clonidine and ST-91, also produced a dose-dependent, long-lasting elevation in the shock titration threshold, antagonized by phentolamine, but not naloxone. L-baclofen, but not D-baclofen, resulted in a dose-dependent elevation of shock titration threshold, which was not antagonized by naloxone. Repeated administration at 24-h intervals over a 7-day period of morphine, clonidine or baclofen, resulted in a significant reduction in the analgetic effects of each drug. Cross tolerance between the three classes of agents was not observed. Intrathecal co-administration of inactive doses of ST-91 and morphine resulted in a near maximal increase in the shock titration threshold, which failed to show any significant tolerance over 21 days. Intrathecal ST-91 and morphine produced no change in either muscle strength, tendon reflexes, respiratory rate, urine formation, or the ability to locomote. Baclofen, in contrast, produced a dose-dependent decrease in muscle strength. That the intrathecal drugs did not produce anesthesia was demonstrated by their failure to block the avoidance response to ensuing ear shock cued by a light tactile stimulus applied to the hind paw. These results clearly indicate that a powerful analgesia can be produced by selectively activating adrenergic, opiate, and baclofenergic receptor systems in the spinal cord. PMID:6112935

  6. Individual variation of human S1P₁ coding sequence leads to heterogeneity in receptor function and drug interactions.

    PubMed

    Obinata, Hideru; Gutkind, Sarah; Stitham, Jeremiah; Okuno, Toshiaki; Yokomizo, Takehiko; Hwa, John; Hla, Timothy

    2014-12-01

    Sphingosine 1-phosphate receptor 1 (S1P₁), an abundantly-expressed G protein-coupled receptor which regulates key vascular and immune responses, is a therapeutic target in autoimmune diseases. Fingolimod/Gilenya (FTY720), an oral medication for relapsing-remitting multiple sclerosis, targets S1P₁ receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P₁ receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P₁ coding region from exon sequencing of >12,000 individuals and their functional consequences. We conducted functional analyses of 14 nonsynonymous single nucleotide polymorphisms (SNPs) of the S1PR1 gene. One SNP mutant (Arg¹²⁰ to Pro) failed to transmit sphingosine 1-phosphate (S1P)-induced intracellular signals such as calcium increase and activation of p44/42 MAPK and Akt. Two other mutants (Ile⁴⁵ to Thr and Gly³⁰⁵ to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg¹³ to Gly) demonstrated protection from coronary artery disease in a high cardiovascular risk population. Individuals with this mutation showed a significantly lower percentage of multi-vessel coronary obstruction in a risk factor-matched case-control study. This study suggests that individual genetic variations of S1P₁ can influence receptor function and, therefore, infer differential disease risks and interaction with S1P₁-targeted therapeutics. PMID:25293589

  7. Structural determinants of sigma receptor affinity

    SciTech Connect

    Largent, B.L.; Wikstroem, H.G.; Gundlach, A.L.; Snyder, S.H.

    1987-12-01

    The structural determinants of sigma receptor affinity have been evaluated by examining a wide range of compounds related to opioids, neuroleptics, and phenylpiperidine dopaminergic structures for affinity at sigma receptor-binding sites labeled with (+)-(/sup 3/H)3-PPP. Among opioid compounds, requirements for sigma receptor affinity differ strikingly from the determinants of affinity for conventional opiate receptors. Sigma sites display reverse stereoselectivity to classical opiate receptors. Multi-ringed opiate-related compounds such as morphine and naloxone have negligible affinity for sigma sites, with the highest sigma receptor affinity apparent for benzomorphans which lack the C ring of opioids. Highest affinity among opioids and other compounds occurs with more lipophilic N-substituents. This feature is particularly striking among the 3-PPP derivatives as well as the opioids. The butyrophenone haloperidol is the most potent drug at sigma receptors we have detected. Among the series of butyrophenones, receptor affinity is primarily associated with the 4-phenylpiperidine moiety. Conformational calculations for various compounds indicate a fairly wide range of tolerance for distances between the aromatic ring and the amine nitrogen, which may account for the potency at sigma receptors of structures of considerable diversity. Among the wide range of structures that bind to sigma receptor-binding sites, the common pharmacophore associated with high receptor affinity is a phenylpiperidine with a lipophilic N-substituent.

  8. Enlarged cerebrospinal fluid spaces in opiate-dependent male patients: a stereological CT study.

    PubMed

    Danos, P; Van Roos, D; Kasper, S; Brömel, T; Broich, K; Krappel, C; Solymosi, L; Möller, H J

    1998-01-01

    Computed tomography was performed in 9 male patients with a diagnosis of opiate dependence and in 9 age-matched psychiatric controls (neurotic depression). Patients with a history or diagnosis of another substance dependence (alcohol, cocaine, cannabis) were excluded from the study. The volumes of internal and external components of cerebrospinal fluid (CSF) were measured with a point-counting stereological method. Analysis of variance with age as a covariate revealed a significant enlargement of external and external CSF spaces in male patients with opiate dependence. There was no significant correlation between the length of opiate dependence and the volumes of internal and external CSF spaces. The present results suggest that opiate dependence is associated with structural brain alterations. However, the relationship between opiate dependence and structural brain changes is complex and still not well understood. PMID:9732207

  9. Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas.

    PubMed

    Gerlinger, Marco; Quezada, Sergio A; Peggs, Karl S; Furness, Andrew J S; Fisher, Rosalie; Marafioti, Teresa; Shende, Vishvesh H; McGranahan, Nicholas; Rowan, Andrew J; Hazell, Steven; Hamm, David; Robins, Harlan S; Pickering, Lisa; Gore, Martin; Nicol, David L; Larkin, James; Swanton, Charles

    2013-12-01

    The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches. PMID:24122851

  10. Is opiate action in cough due to sedation?

    PubMed Central

    Dickinson, Rebecca S.; Morjaria, Jaymin B.; Wright, Caroline E.

    2014-01-01

    Objectives: Opiates have been used for cough suppression for centuries. It is unclear whether this antitussive action is due to their known sedative effects. We aimed to assess correlation between cough suppression and opiate usage. Methods: We performed a post hoc analysis of two published trials with three opioids. In study one, patients with chronic cough were treated with 4 weeks of modified release morphine sulphate (5 mg twice daily) or placebo in a double-blinded placebo-controlled fashion. Cough suppression was assessed subjectively by the Leicester Cough Questionnaire and objectively by citric acid aerosol (CAA) induced cough challenge. In study 2, normal volunteers were given single doses of placebo, codeine 30 mg or dextromethorphan 50 mg and cough suppression assessed using the CAA-induced cough challenge. Sedation was contemporaneously assessed by direct questioning. Results: There were 14 episodes of patient-reported sedation; 2 with modified release morphine sulphate, 9 with codeine and 3 with dextromethorphan. There was no correlation between change in the Leicester Cough Questionnaire or the CAA-induced cough challenge and reported sedation. Conclusion: This observational study suggests that sedation is unlikely to underlie the antitussive properties of these opioids. Eliciting the mechanism of these medications in cough may be a target for future tailored drug development. PMID:25177477

  11. Binding of kappa- and sigma-opiates in rat brain

    SciTech Connect

    Wolozin, B.L.; Nishimura, S.; Pasternak, G.W.

    1982-06-01

    Detailed displacements of (/sup 3/H)dihydromorphine by ketocyclazocine and SKF 10,047, (/sup 3/H)ethylketocyclazocine by SKF 10,047, and (/sup 3/H)SKF 10,047 by ketocyclazocine are all multiphasic, suggesting multiple binding sites. After treating brain tissue in vitro with naloxazone, all displacements lose the initial inhibition of /sup 3/H-ligand binding by low concentrations of unlabeled drugs. Together with Scatchard analysis of saturation experiments, these studies suggest a common site which binds mu-, kappa, and sigma-opiates and enkephalins equally well and with highest affinity (KD less than 1 nM). The ability of unlabeled drugs to displace the low affinity binding of (/sup 3/H)dihydromorphine (KD . 3 nM), (/sup 3/H)ethylketocyclazocine (KD . 4 nM), (/sup 3/H)SKF 10,047 (KD . 6 nM), and D-Ala2-D-Leu5-(/sup 3/H)enkephalin (KD . 5 nM) remaining after treating tissue with naloxazone demonstrates unique pharmacological profiles for each. These results suggest the existence of distinct binding sites for kappa- and sigma-opiates which differ from those sites which selectively bind morphine (mu) and enkephalin (delta).

  12. The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis.

    PubMed

    Yu, Shan; Allen, Joselyn N; Dey, Adwitia; Zhang, Limin; Balandaram, Gayathri; Kennett, Mary J; Xia, Mingcan; Xiong, Na; Peters, Jeffrey M; Patterson, Andrew; Hankey-Giblin, Pamela A

    2016-07-01

    Obesity is a chronic inflammatory disease mediated in large part by the activation of inflammatory macrophages. This chronic inflammation underlies a whole host of diseases including atherosclerosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer, among others. Macrophages are generally classified as either inflammatory or alternatively activated. Some tissue-resident macrophages are derived from yolk sac erythromyeloid progenitors and fetal liver progenitors that seed tissues during embryogenesis and have the ability to repopulate through local proliferation. These macrophages tend to be anti-inflammatory in nature and are generally involved in tissue remodeling, repair, and homeostasis. Alternatively, during chronic inflammation induced by obesity, bone marrow monocyte-derived macrophages are recruited to inflamed tissues, where they produce proinflammatory cytokines and exacerbate inflammation. The extent to which these two populations of macrophages are plastic in their phenotype remains controversial. We have demonstrated previously that the Ron receptor tyrosine kinase is expressed on tissue-resident macrophages, where it limits inflammatory macrophage activation and promotes a repair phenotype. In this study, we demonstrate that Ron is expressed in a subpopulation of macrophages during chronic inflammation induced by obesity that exhibit a repair phenotype as determined by the expression of arginase 1. In addition, we demonstrate that the Ron receptor plays a protective role in the progression of diet-induced obesity, hepatosteatosis, and atherosclerosis. These results suggest that altering macrophage heterogeneity in vivo could have the potential to alleviate obesity-associated diseases. PMID:27233965

  13. Genetic heterogeneity of activating mutations of the luteinizing hormone receptor gene in familial male-limited precocious puberty

    SciTech Connect

    Laue, L.; Chan, W.Y.; Wu, S.M.

    1994-09-01

    Familial male-limited precocious puberty (FMPP) is an autosomal dominant disorder characterized by elevated serum levels of testosterone, low levels of gonadotropins, and Leydig cell hyperplasia. Recently, 3 mutations have been found in FMPP families which encode substitution of Gly for Asp 578, Ile for Met 571, and Ile for Thr 577 in transmembrane helix 6 (TM 6) of the luteinizing hormone receptor (LHR). We have studied 28 additional unrelated FMPP families. Genomic DNA was isolated from affected males and PCR was performed to amplify a fragment of the LHR gene encoding amino acid residues 441 to 594. MspI restriction enzyme digests were positive for the Asp 578 to Gly mutation in 22 families. Four new mutations were found in the remaining 6 families: an A to C transition encoding substitution of Leu for Ile 542 in transmembrane helix 5 (TM 5), an A to G transition encoding substitution of Gly for Asp 564 in the third cytoplasmic loop, a G to T transition encoding substitution of Try for Asp 578 in TM 6, and a T to C transition encoding substitution of Arg for Cys 581 in TM 6 of the LHR. 293 cells transfected with cDNAs for each of the 4 mutant LHRs, created by site-directed mutagenesis of the wild-type LHR cDNA, exhibited markedly increased levels of basal cAMP production in the absence of agonist, indicating constitutive activation of the mutant LHRs. We conclude that substitution of residues at multiple sites with TM 5, TM 6, and the intervening third cytoplasmic loop of the LHR cause constitutive receptor activation resulting in FMPP. These findings allow future diagnosis of affected patients and provide the basis to study the receptor domains involved in G-protein activation.

  14. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.

    PubMed

    Lucas, Philippe

    2012-01-01

    There is a growing body of evidence to support the use of medical cannabis as an adjunct to or substitute for prescription opiates in the treatment of chronic pain. When used in conjunction with opiates, cannabinoids lead to a greater cumulative relief of pain, resulting in a reduction in the use of opiates (and associated side-effects) by patients in a clinical setting. Additionally, cannabinoids can prevent the development of tolerance to and withdrawal from opiates, and can even rekindle opiate analgesia after a prior dosage has become ineffective. Novel research suggests that cannabis may be useful in the treatment of problematic substance use. These findings suggest that increasing safe access to medical cannabis may reduce the personal and social harms associated with addiction, particularly in relation to the growing problematic use of pharmaceutical opiates. Despite a lack of regulatory oversight by federal governments in North America, community-based medical cannabis dispensaries have proven successful at supplying patients with a safe source of cannabis within an environment conducive to healing, and may be reducing the problematic use of pharmaceutical opiates and other potentially harmful substances in their communities. PMID:22880540

  15. Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis.

    PubMed Central

    Howell, M D; Diveley, J P; Lundeen, K A; Esty, A; Winters, S T; Carlo, D J; Brostoff, S W

    1991-01-01

    Rheumatoid arthritis (RA) is a disease affecting the synovial membranes of articulating joints that is thought to result from T-cell-mediated autoimmune phenomena. T cells responsible for the pathogenesis of RA are likely present in that fraction of synovial T cells that expresses the interleukin 2 receptor (IL-2R), one marker of T-cell activation. We report herein an analysis of T-cell receptor (TCR) beta-chain gene expression by IL-2R-positive synovial T cells. These T cells were isolated from uncultured synovial tissue specimens by using IL-2R-specific monoclonal antibodies and magnetic beads, and TCR beta-chain transcription was analyzed by PCR-catalyzed amplification using a panel of primers specific for the human TCR beta-chain variable region (V beta). Multiple V beta gene families were found to be transcribed in these patients samples; however, three gene families, V beta 3, V beta 14, and V beta 17, were found in a majority of the five synovial samples analyzed, suggesting that T cells bearing these V beta s had been selectively retained in the synovial microenvironment. In many instances, the V beta 3, V beta 14, or V beta 17 repertoires amplified from an individual patient were dominated by a single rearrangement, indicative of clonal expansion in the synovium and supportive of a role for these T cells in RA. Of note is a high sequence similarity between V beta 3, V beta 14, and V beta 17 polypeptides, particularly in the fourth complementarity-determining region (CDR). Given that binding sites for superantigens have been mapped to the CDR4s of TCR beta chains, the synovial localization of T cells bearing V beta s with significant CDR4 homology indicates that V beta-specific T-cell activation by superantigen may play a role in RA. PMID:1660155

  16. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics

    PubMed Central

    Kreek, Mary Jeanne; Levran, Orna; Reed, Brian; Schlussman, Stefan D.; Zhou, Yan; Butelman, Eduardo R.

    2012-01-01

    Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction. PMID:23023708

  17. Behavioral evidence for an opiate pituitary mechanism subserving conditioned analgesia.

    PubMed

    Gaiardi, M; Bartoletti, M; Gubellini, C; Bacchi, A; Babbini, M

    1983-09-01

    The effect of a naloxone or a dexamethasone pretreatment on the conditioned analgesia resulting from the exposure of rats to an experimental chamber repeatedly paired with a grid shock was investigated. Shock induced disruption of bar pressing activity was taken as a behavioral measure of pain responsiveness. It was found that a 6, but not a 3, mg/kg dose of naloxone i.p. is hyperalgesic in unconditioned rats and effectively antagonizes conditioned analgesia. Dexamethasone (up to a dose of 2 + 1 mg/kg i.p. 23 and 1 h prior) did not alter the pain responsiveness of unconditioned rats, but caused a dose dependent suppression of conditioned analgesia. These results are discussed in terms of an opiate pituitary mechanism subserving conditioned analgesia. PMID:6314229

  18. Rapid and semi-quantitative presumptive tests for opiate drugs.

    PubMed

    Choodum, Aree; Daeid, Niamh Nic

    2011-10-30

    Digital image analysis was applied to the products of simple colour presumptive tests for opiates. Adobe Photoshop software was used for colour analysis to obtain analytical data in the form of a Red Green Blue (RGB) value. Calibration curves were developed for morphine, codeine, and diamorphine hydrochloride and the developed tests successfully applied to seized heroin samples to demonstrate the application of the technique in a forensic case context. Good agreement with gas chromatographic quantification results was obtained for the illicit samples analysed and a wide linear range and low detection limit for all drugs under test facilitated the application to illicit samples. The results show great potential for use as a semi-quantitative field test for illicit drug compounds. PMID:22063543

  19. T cell receptor β-chain repertoire analysis reveals intratumour heterogeneity of tumour-infiltrating lymphocytes in oesophageal squamous cell carcinoma.

    PubMed

    Chen, Zengchao; Zhang, Chaoting; Pan, Yaqi; Xu, Ruiping; Xu, Changqing; Chen, Ziping; Lu, Zheming; Ke, Yang

    2016-08-01

    Oesophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, due to the lack of effective treatment methods. Immunotherapeutic approaches based on tumour-infiltrating lymphocytes (TILs) have demonstrated that durable responses are produced in some patients with solid tumours, which suggests the potential feasibility of clinical application of immunotherapy for ESCC. However, many of the basic characteristics of TILs in ESCC are poorly understood, including clonality, specificity and spatial heterogeneity of the response of TILs, which depends on the interaction between antigens and T cell receptors (TCRs). We used ultra-deep sequencing of rearranged genes in TCR β-chain (TCRβ) to profile the basic characteristics of T cells in tumour tissues (four to six regions from each tumour) as well as matched adjacent normal tissue and peripheral blood from seven patients diagnosed with primary ESCC. We found that T cell clones within ESCCs were quite different from those of the peripheral blood and even the adjacent normal tissues in general. Although there was a relatively higher degree of overlap of intratumoural TCRβ repertoires than those between the tumour and other tissues, intratumoural TCRβ repertoires were spatially heterogeneous. Due to the restricted sampling, high-throughput TCRβ sequencing could characterize the diversity and composition of a limited (compartment-dependent) fraction of the respective T cell clones in any individual ESCC, expanding our understanding of immune behaviour and immune response and shedding more light on ESCC immunotherapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27171315

  20. Determination of opiates in human fingernail--comparison to hair.

    PubMed

    Shen, Min; Chen, Hang; Xiang, Ping

    2014-09-15

    6-Monoacetylmorphine in keratinized matrices can be used to discriminate between heroin users and individuals exposed to other sources of morphine alkaloids. Frozen pulverization is effective in preventing 6-monoacetylmorphine hydrolysis. The main aim of this study was to develop an LC-MS/MS method for the determination of five opiates in human fingernails using a frozen pulverization preparation method and to investigate the correlation between the concentration of opiates in nail and hair samples from subjects whose urine specimens were positive for morphine. Borate buffer (500 μL; pH 9.2) was added to 20mg of pulverized fingernail, followed by ultrasonication and liquid-liquid extraction. Analytes were analyzed on an Allure PFP propyl column by gradient elution. The mass spectrometer was operated in the positive electrospray ionization mode and multiple reactions monitoring mode. A total of 12 of 18 fingernail samples contained detectable 6-monoacetylmorphine (mean=0.43 ng/mg, range=0.10-1.37 ng/mg), morphine (mean=1.74 ng/mg, range=0.58-3.16 ng/mg) and codeine (range from

  1. Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas

    PubMed Central

    Gerlinger, Marco; Quezada, Sergio A; Peggs, Karl S; Furness, Andrew JS; Fisher, Rosalie; Marafioti, Teresa; Shende, Vishvesh H; McGranahan, Nicholas; Rowan, Andrew J; Hazell, Steven; Hamm, David; Robins, Harlan S; Pickering, Lisa; Gore, Martin; Nicol, David L; Larkin, James; Swanton, Charles

    2013-01-01

    The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367–16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, –0.218 to 0.465). 3–93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches. Copyright © 2013 Pathological Society of

  2. Prognostic significance of the heterogenous expression of IgG Fc receptors in B-cell chronic lymphocytic leukemia.

    PubMed

    Schranz, V; Gráf, F

    1992-03-01

    Receptors for the Fc part of IgG (Fc gamma R) are expressed in three forms on peripheral blood lymphocytes. The presence of the releasable form (Fc gamma R(REL.)) as well as of the two nonreleasable forms with lower (Fc gamma R(LOW)) and higher (Fc gamma R(HIGH)) cellular avidity was correlated with survival in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL). High percentage of cells with Fc gamma R(LOW) as well as high "absolute" number of cells carrying the two nonreleasable forms of Fc gamma R were connected to unfavorable prognosis. Combining these three parameters, an Fc gamma R constellation was defined which pointed to a favorable prognosis (in 24 patients) when all three parameters were low, but detected short survivors when all three data were high (in 14 patients). The Fc gamma R constellation was capable of identifying patients with better or worse prognosis within groups that were homogeneous regarding some other known prognostic factors. Fc gamma R constellation as a prognostic factor was shown to be independent of age, sex, and Rai and Binet stages, but it was found to be connected with the total tumor mass score (TTM). The three forms of Fc gamma R on B cells might reflect stages of B-cell activation. Differences in Fc gamma R constellations between patients with B-CLL would thus correspond to differently activated B-cell clones with variable prognosis. PMID:1571409

  3. Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

    NASA Astrophysics Data System (ADS)

    Trujillo, Keith A.; Akil, Huda

    1991-01-01

    The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

  4. Analytical considerations in the use of capture-recapture to estimate prevalence: case studies of the estimation of opiate use in the metropolitan area of Barcelona, Spain.

    PubMed

    Domingo-Salvany, A; Hartnoll, R L; Maguire, A; Brugal, M T; Albertín, P; Caylà, J A; Casabona, J; Suelves, J M

    1998-10-15

    Capture-recapture, an indirect method widely used to estimate undetected populations, has been criticized because it causes problems due to a lack of compliance with several important assumptions and model selection strategies. This paper expands on the problems encountered when applying this methodology to drug abuse estimations, specifically the prevalence of opiate use in the metropolitan area of Barcelona, Spain, in 1993. Three samples of opiate users (from hospital emergency rooms, treatment centers, and prisons) were available in the area studied; an additional sample (mortality data) was analyzed for the city of Barcelona. Log-linear models that provided a good fit were considered, to which further model selection strategies were applied. A total of 3,207 unique individuals aged 15-44 years were identified in the three samples from the greater Barcelona area; the mortality sample from the city of Barcelona contained an additional 83 individuals. Heterogeneity was observed in different age, sex, and residence area subgroups. Population estimates differed widely according to the log-linear model chosen. Minimum Akaike's information criterion model and saturated model estimates were used to produce population prevalence rates. The main problems the authors encountered in this study were related to population definition, source heterogeneity, and assessment of an adequate model, a problem associated with sample size. PMID:9786228

  5. Receipt of prescribed controlled substances by adolescents and young adults prior to presenting for opiate dependence treatment.

    PubMed

    Matson, Steven C; Bentley, Cathleen; Hughes Dughman, Vicki; Bonny, Andrea E

    2013-01-01

    Purpose. The objective of this study was to document the number of controlled substance prescriptions filled by adolescents and young adult patients in the 2 years prior to presentation for opiate dependence treatment. Methods. Opiate-dependent youth (N = 125) presenting to our Medication-Assisted Treatment for Addiction program from January 1, 2008 to June 30, 2010 were identified via electronic medical record. Subjects were further classified based on their opiate use as dependent to heroin-only, prescription (Rx) opiate-only, or combined heroin + Rx opiate only. The Ohio Automated Rx Reporting System (OARRS) was used to identify each subject's controlled substance prescription history. Negative binomial regression was used to examine the relationships between patient characteristics and the total number of prescriptions filled. Results. Twenty-five percent of subjects had filled ≥6 prescriptions, and 15% had filled ≥11 prescriptions. The mean number of prescriptions filled was 5 (range: 0-59). Thirteen percent had filled ≥6 opiate/narcotic prescriptions, and 8% had filled ≥11 prescriptions. Conclusions. A subset of opiate-dependent youth had filled multiple opiate/narcotic prescriptions providing some evidence that physician-provided prescriptions may be a source of opiate abuse or diversion for a minority of opiate-dependent adolescents and young adults. PMID:24826367

  6. The physiology of opiate hedonic effects and the role of opioids in motivated behavior.

    PubMed

    Carr, K D

    1984-01-01

    The topics discussed in this article are the neural mechanisms of opiate hedonic effects and the role of endogenous opioids in regulating motivational-affective responses of the organism. First, research on the mechanisms of opiate hedonic effects is briefly reviewed; evidence is discussed which suggests the existence of separate neural substrates for the mediation of opiate analgesia, amelioration of aversive emotion, and reward. In the remainder of the article, recent work of our laboratory is summarized which concerns the role of endogenous opioids in regulating feeding and reward elicited by electrical stimulation in the lateral hypothalamus; evidence is presented which indicates that opioid activity associated with the state of food motivation potentiates reward processes. In addition, evidence is discussed which suggests that this opioid activity may concurrently diminish the organism's emotional responsiveness to competing aversive stimuli. The relevance of this area of research to human opiate abuse is discussed. PMID:6388274

  7. Effects of opiates on sodium excretion in the isolated perfused rat kidney.

    PubMed

    Ellis, A G; Adam, W R

    1991-12-01

    1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates. PMID:1797448

  8. Opiate Addicted and Non-Addicted Siblings in a Slum Area

    ERIC Educational Resources Information Center

    Glaser, Daniel; And Others

    1971-01-01

    Compares addicted and non-addicted siblings of families residing in and around a slum block in New York. Data supporting an ideographic relative deprivation-differential anticipation" explanation for current opiate addiction in the U. S. was produced. (JM)

  9. Opiate addiction and the entanglements of imperialism and patriarchy in Manchukuo, 1932-45.

    PubMed

    Smith, Norman

    2005-01-01

    In the Japanese colonial state of Manchukuo, opiate addiction was condemned by officials and critics alike. But the state-sponsored creation of a monopoly, opium laws, and rehabilitation programs failed to reduce rates of addiction. Further, official media condemnation of opiate addiction melded with local Chinese-language literature to stigmatise addiction, casing a negative light over the state's failure to realise its own anti-opiate agenda. Chinese writers were thus transfixed in a complex colonial environment in which they applauded measures to reduce harm to the local population while levelling critiques of Japanese colonial rule. This paper demonstrates how the Chinese-language literature of Manchukuo did not simply parrot official politics. It also delegitimised Japanese rule through opiate narratives that are gendered, consistently negative, and more critical of the state than might be expected in a colonial literature. PMID:20058395

  10. Stereospecific potentiation of opiate analgesia by cocaine: predominant role of noradrenaline.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1987-01-01

    Cocaine hydrochloride (50 mg) pellets implanted subcutaneously in male Wistar rats potentiated the analgesia of morphine, levorphanol, methadone and buprenorphine as measured by the tail-withdrawal test. Potentiated opiate analgesia was abolished by naloxone and further enhanced by desipramine and phenoxybenzamine. Yohimbine, alpha-methyl p-tyrosine, haloperidol, zimelidine, methysergide, p-chlorophenylalanine produced no significant effect on potentiated opiate analgesia. Pseudo-cocaine (dextro-cocaine), which is several-fold less potent than cocaine as an inhibitor of noradrenaline and dopamine reuptake in the CNS, had no significant effect on opiate analgesia. Analgesia produced by low doses of baclofen, a GABA agonist, was also not potentiated by cocaine. This study suggests a predominant role for noradrenaline in the stereospecific potentiation of opiate analgesia by cocaine. PMID:3822492

  11. Persistent Adaptations in Afferents to Ventral Tegmental Dopamine Neurons after Opiate Withdrawal

    PubMed Central

    Kaufling, Jennifer

    2015-01-01

    Protracted opiate withdrawal is accompanied by altered responsiveness of midbrain dopaminergic (DA) neurons, including a loss of DA cell response to morphine, and by behavioral alterations, including affective disorders. GABAergic neurons in the tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, are important for behavioral responses to opiates. We investigated the tVTA–VTA circuit in rats after chronic morphine exposure to determine whether tVTA neurons participate in the loss of opiate-induced disinhibition of VTA DA neurons observed during protracted withdrawal. In vivo recording revealed that VTA DA neurons, but not tVTA GABAergic neurons, are tolerant to morphine after 2 weeks of withdrawal. Optogenetic stimulation of tVTA neurons inhibited VTA DA neurons similarly in opiate-naive and long-term withdrawn rats. However, tVTA inactivation increased VTA DA activity in opiate-naive rats, but not in withdrawn rats, resembling the opiate tolerance effect in DA cells. Thus, although inhibitory control of DA neurons by tVTA is maintained during protracted withdrawal, the capacity for disinhibitory control is impaired. In addition, morphine withdrawal reduced both tVTA neural activity and tonic glutamatergic input to VTA DA neurons. We propose that these changes in glutamate and GABA inputs underlie the apparent tolerance of VTA DA neurons to opiates after chronic exposure. These alterations in the tVTA–VTA DA circuit could be an important factor in opiate tolerance and addiction. Moreover, the capacity of the tVTA to inhibit, but not disinhibit, DA cells after chronic opiate exposure may contribute to long-term negative affective states during withdrawal. SIGNIFICANCE STATEMENT Dopaminergic (DA) cells of the ventral tegmental area (VTA) are the origin of a brain reward system and are critically involved in drug abuse. Morphine has long been known to affect VTA DA cells via GABAergic interneurons. Recently, GABAergic neurons

  12. Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression

    PubMed Central

    Currin, Erin; Peterson, Lanell M.; Schubert, Erin K.; Link, Jeanne M.; Krohn, Kenneth A.; Livingston, Robert B.; Mankoff, David A.; Linden, Hannah M.

    2016-01-01

    Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using 18F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging. PMID:26850484

  13. Role of Temperament, Personality Traits and Onset Age of Smoking in Predicting Opiate Dependence

    PubMed Central

    Amirabadi, Bahareh; Nikbakht, Mohammad; Nokani, Mostafa; Alibeygi, Neda; Safari, Hadi

    2015-01-01

    Background: According to drug gateway theory, smoking cigarettes, especially, low onset age of smoking, is one of the risk factors for future use. Objectives: The present study aimed to compare nicotine and opiate addicts to identify the differences in personality traits and onset age of smoking in the two groups that cause some individuals to appeal to other substances after starting to use cigarettes. Patients and Methods: Two groups of opiate and nicotine addicts were randomly selected. Revised version of the Cloninger temperament inventory questionnaire, the Fagrastrom nicotine dependence and the Maudsley addiction profile were used. ANOVA and logistic regression were applied for data analysis. Results: Opiate addicts had higher scores in novelty seeking dimension and lower scores in cooperativeness compared to nicotine addicts. The onset age of smoking cigarette in opiate addicts was lower than nicotine addicts. Conclusions: Low onset age of smoking cigarettes, high novelty seeking and low cooperativeness in opiate dependents are among the important personality traits in future use of drugs that can predict the subsequent onset of using opiate drugs. PMID:26870712

  14. Characteristics and Outcomes of Young Adult Opiate Users Receiving Residential Substance Abuse Treatment.

    PubMed

    Morse, Siobhan; MacMaster, Samuel

    2015-01-01

    Opiate use patterns, user characteristics, and treatment response among young adults are of interest due to current high use prevalence and historical low levels of treatment engagement relative to older populations. Prior research in this population suggests that overall, young adults present at treatment with different issues. In this study the authors investigated potential differences between young adult (18-25 years of age) and older adult (26 and older) opiate users and the impact of differences relative to treatment motivation, length and outcomes. Data for this study was drawn from 760 individuals who entered voluntary, private, residential treatment. Study measures included the Addiction Severity Index (ASI), the Treatment Service Review (TSR), and University of Rhode Island Change Assessment (URICA). Interviews were conducted at program intake and 6-month post-discharge. Results indicate that older adults with a history of opiate use present at treatment with higher levels of severity for alcohol, medical, and psychological problems and young adults present at treatment with greater drug use and more legal issues. Significant improvement for both groups was noted at 6 months post treatment; there were also fewer differences between the two age groups of opiate users. Results suggest different strategies within treatment programs may provide benefit in targeting the disparate needs of younger opiate users. Overall, however, results suggest that individualized treatment within a standard, abstinence-based, residential treatment model can be effective across opiate users at different ages and with different issues, levels of severity, and impairment at intake. PMID:25879396

  15. The Role of Family Atmosphere in the Relapse Behavior of Iranian Opiate Users: a Qualitative Study

    PubMed Central

    Peyrovi, Hamid; Seyedfatemi, Naiemeh; Jalali, Amir

    2015-01-01

    Introduction Many Iranian opiate users live with family members and family atmosphere can be influential on reducing such social behaviors of opiate users as substance use and relapses. This paper reports the impact of family atmosphere on relapse behavior as a part of the findings of a larger study that explored the relapse process among Iranian opiate users. Methods: In this qualitative research, we selected 17 participants (5 women and 12 men). The questions were been asked through semi-structured interviews. The researchers analyzed the verbatim transcripts using content analysis method. Results: "Family atmosphere" with three sub-themes (family and tribes' interaction, family challenges and family structure) was been found as determinants of relapse behavior. The quality of the family atmosphere could be in harmony with or against the willingness or motivation of the opiate user towards the relapse. Conclusion Health care providers should reinforce involvement of the family members in the treatment and rehabilitation of opiate users. The opiate user's family and even relatives may benefit from learning how to manage their own feelings and attitude towards the client and being supportive during interactions. PMID:26464835

  16. The contribution of opiate analgesics to the development of infectious complications in trauma patients

    PubMed Central

    Oppeltz, Richard F; Holloway, Travis L; Covington, Cody J; Schwacha, Martin G

    2015-01-01

    Trauma-related pain is a natural consequence of injury and its surgical management; however, the relationship between opiates and complications in trauma patients is unknown. To study this a retrospective chart review of selected subjects following traumatic injury with admission to the SICU for > 3 days was performed, and opiate administration data was collected for the first 3 days of admission. Associated data from each subject’s chart was also collected. Analysis of the data revealed that increased opiate intake after admission to the SICU was associated with significantly increased SICU and hospital LOS independent of injury severity. This increase in LOS was independent of mechanical ventilation in the moderate ISS group. Infectious complications were also more prevalent in the moderate ISS group with higher opiate use. These findings suggest that increased doses of opiate analgesics in trauma patients may contribute to an increased overall LOS and associated infectious complications. Analgesic regimes that minimize opiate intake, while still providing adequate pain relief, may be advantageous in reducing LOS, complications and reduce hospitalization costs. PMID:26309777

  17. Effect of moderate alcohol consumption on plasma opiate levels in premenopausal women

    SciTech Connect

    Bhathena, S.J.; Kim, Y.C.; Law, J.S.; Berlin, E.; Judd. J.T.; Reichman, M.E.; Taylor, P.R.; Schatzkin, A. NCI, Bethesda, MD )

    1991-03-15

    Opiate changes have been reported in response to excessive alcohol consumption. Different phases of the menstrual cycle also affect the opiate tone. The authors studied the effect of moderate alcohol consumption and the menstrual cycle per se on plasma opiates. Forty premenopausal women were given alcohol or a soft drink of equal caloric value for 3 menstrual cycles in a cross over study. The subjects were fed a controlled diet containing 35% of energy from fat. Blood was collected in the third menstrual cycle of each period during follicular (F), ovulatory (O) and luteal (L) phases. {beta}-endorphin, met-enkephalin and lwu-enkephalin (LE) were measured by radioimmunoassay. None of the opiates showed significant change after alcohol consumption though LE was consistently higher after alcohol consumption during all three phases of the menstrual cycle. There was a significant decrease in BEN during L phase compared to F phase while both enkephalins were higher during L phase than during F phase. Opiate levels during O phase were intermediate between F and L. Thus, in contrast to previously observed opiate changes following excessive alcohol consumption, they did not observe changes with moderate consumption.

  18. Electrophysiological evidence that drug cues have greater salience than other affective stimuli in opiate addiction.

    PubMed

    Lubman, D I; Allen, N B; Peters, L A; Deakin, J F W

    2008-11-01

    Previous research has demonstrated that drug cues are able to capture attentional resources in addicted populations. However, few studies have controlled for the possibility that drug users find all motivationally significant (i.e., affective) stimuli particularly salient. We examined this issue in opiate addiction, by exploring the impact of drug-related and affective stimuli on central attentional processes. Sixteen male heroin addicts (seven on opiate pharmacotherapy and nine recently detoxified subjects) and 12 matched controls were studied. Subjects were fitted with a 32-channel electrode cap and were instructed to passively view a series of neutral, affective and opiate-related images. The P300 elicited by drug-related stimuli was significantly larger than that elicited by affective and neutral stimuli in opiate users but not controls. Baseline ratings of craving were also found to predict the degree of P300 facilitation to the drug-related stimuli in the addicted group. Further, the opiate group demonstrated an absence of the typical enhancement of ERP responses to non-drug affective stimuli. These results suggest that opiate addicts demonstrate greater cortical processing of drug cues than other types of affective stimuli. Further research is required to assess whether addiction is specifically associated with reduced sensitivity to natural rewards, aversive stimuli or affective cues in general. PMID:18208907

  19. Tumor Heterogeneity in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Gastric Cancer Assessed by CT Texture Analysis: Association with Survival after Trastuzumab Treatment

    PubMed Central

    Yoon, Sung Hyun; Lee, Yoon Jin; Park, Jihoon; Kim, Jin Won; Lee, Hye Seung; Kim, Bohyoung

    2016-01-01

    Background Image texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment. Methods and Findings Patients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan–Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10−3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan–Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger

  20. Kinetic analysis of the opiate antagonist cyclofoxy in rat brain: Simultaneous infusion of active and inactive enantiomers

    SciTech Connect

    Kawai, R.; Sawada, Y.; Channing, M.; Dunn, B.; Newman, A.H.; Rice, K.C.; Blasberg, R.G. )

    1990-11-01

    The opiate antagonist (-)-cyclofoxy ((-)-CF) and the receptor inert enantiomer (+)-CF were radiolabeled with 18F or 3H and administered to conscious Sprague-Dawley rats; an isotope effect was not observed. Constant i.v. infusion of both 18F-(-)-CF and 3H-(+)-CF in tracer amounts showed a marked difference in the tissue level of 18F-(-)-CF among various brain structures, whereas the values for 3H-(+)-CF were lower and much less variable. Co-infusion of unlabeled (-)-CF (1 mg/rat) did not change the tissue binding of 3H-(+)-CF in any brain structure, but reduced that of 18F-(-)-CF to the same level as 3H-(+)-CF. These results demonstrate an identical nonspecific tissue binding for (+)- and (-)-CF in vivo, and suggest that (+)-CF can be used to measure the nonspecific component of (-)-CF binding in brain. A nonlinear analysis of the 3H-(+)-CF data indicated the presence of both instantaneous and time-dependent components in nonspecific tissue binding and that nonspecific binding varied 1.5-fold in different brain structures. The combined 3H-(+)-CF and 18F-(-)-CF data were fitted to a four-compartment model, which includes parameters for capillary transport, instantaneous and time-dependent nonspecific tissue binding, as well as receptor association and dissociation. The receptor-association rate constant varied considerably in various structures of cerebrum (2.0-8.7 min-1), whereas receptor dissociation was estimated within a narrow range (0.12-0.17 min-1). The receptor binding potential (receptor association/dissociation) ranged between 12.7 and 56.2 and was in good agreement with previous estimates in vitro.

  1. Migrating opiate pump: atypical [corrected] cause of meralgia paresthetica.

    PubMed

    Windsor, Robert E; Thampi, Samuel

    2003-10-01

    This is a case report of a 60 year-old female who presented with pain on the anterolateral aspect of her right thigh. The patient had a history of placement of a Drug Administration System (DAS, Opiate pump) in August, 1998 for chronic lumbar radiculopathy and a multiply operated on spine which she had suffered with since October, 1991. She presented with the subacute onset of focal pain on the anterior aspect of her right superior iliac crest region and dysesthesias on the anterolateral aspect of her right thigh. There was no history of recent trauma, worsening low back pain, or any other sensori-motor change. There was no history of anterior iliac crest bone graft for her spinal fusion and she had no anterolateral thigh symptoms related to her lumbar radiculopathy. Her neurological examination was significant only for decreased sensation on the anterolateral aspect of her right thigh. On abdominal examination the DAS pump was found at a low-lying location and was closely abutting the anterior and medial aspect of her superior iliac spine. She underwent revision of the DAS pump site with obliteration of the inferior and lateral aspect of the pump pocket. Her symptoms improved by 30% immediately and completely dissipated within two month following the procedure. This is the first reported case of lateral femoral cutaneous nerve neuropathy with DAS use. Recognition of focal compressive neuropathy by distal migration of a DAS is important, as they are potentially treatable with recognition. PMID:16871302

  2. Basic epidemiology of opiate misuse substitution treatment in Belgium.

    PubMed

    Ledoux, Y

    2012-09-01

    The Substitution Treatment National Registry provided from mid 2006 till mid 2009 an exhaustive documentation on all patients being prescribed methadone or buprenorphine in Belgium. This endeavour was possible through cooperation of all community pharmacies and their representative organizations was supported at the time by the former Health federal minister. The Liberal belgian opiate medical substitution process authorizes untill now de facto any doctor to prescribe methadone and pharmacists are supported to dispense it. Results show the regional, provincial and county numbers of professionals and patients prevalence in the population. Nationwide, n = 16974 patients (prevalence for population aged 20-64: 26/10000) have been offered substitution from mid 2008 till mid 2009, n = 3390 pharmacies 164,4% of all pharmacies) and n = 2937 MDs (16,75% of all MDs) have been involved. Subutex or Suboxone have been dispensed to 11,1% of substitution patients with 7,4% receiving only buprenorphine on a yearly basis. Number of substitution patients by MD and prevalence by gender, age group and region are presented. Important variations are observed locally, possibly mirroring heroin addiction due to widespread access to substitution treatment. Younger patients are more prevalent in semi rural or border areas. The exhaustivity of available data enables also to observe patients quitting substitution altogether and a strong difference of maintenance rate is observed favoring methadone over buprenorphine. PMID:23697094

  3. Relationship of marital structure and interactions to opiate abuse relapse.

    PubMed

    Kosten, T R; Jalali, B; Steidl, J H; Kleber, H D

    1987-01-01

    Several aspects of marital functioning were associated with subsequent relapse to opiate abuse in 17 married addicts. The addicts and spouses were evaluated in a task-oriented interview and rated using the Beavers Timberlawn Family Assessment instrument. The global health-pathology ratings on this instrument indicated that most couples had rigid patterns of interacting, rather than a chaotic lack of structure or a flexible, negotiated partnership. Within this range of rigid functioning, higher ratings were associated with longer times drug-free (up to 18 months with a mean of 7 months). On the seven subscales of the Beavers', five were significantly correlated with the time drug-free: effective and clear leadership, closeness between the spouses, a nonhostile mood, empathy, and efficient negotiation and problem solving. The subscales associated with drug abstinence were quite different for a group of seven single ex-addicts participating in the same outpatient program, but living with their parents. For these single ex-addicts three subscales were correlated with the time drug-free: parental reaction to separation strivings, the open expression of thoughts and feelings, and empathy. This difference in the subscales associated with abstinence for married versus single addicts suggested some specificity in the characteristics of family structure and interaction that may be related to drug abstinence. PMID:3687898

  4. Six-Month Follow-Up Study of Ultrarapid Opiate Detoxification With Naltrexone

    PubMed Central

    Forozeshfard, Mohammad; Hosseinzadeh Zoroufchi, Babak; Saberi Zafarghandi, Mohammad Bagher; Bandari, Razieh; Foroutan, Behzad

    2014-01-01

    Background: Illicit opiate use has an increasing incidence and prevalence, which increases mortality and morbidity, marginalization, and criminal behaviors, and causes major adverse effects on society. Objectives: This study aimed to investigate and follow the outcome of patients who underwent ultrarapid opiate detoxification (UROD) prospectively. Patients and Methods: In this randomized clinical trial, 64 patients who underwent UROD were evaluated. The opiate antagonist regimen of naloxone was administered intravenously under general anesthesia, and detoxification was confirmed by naloxone challenge test. All patients were cared in intensive care unit (ICU) for 24 hours, and oral naltrexone was prescribed the next day, after recovery and discharge. Patients were followed up for one month after the procedure. Relapse was considered if routine use of opiates (daily use for at least two weeks) was reported by the patient after detoxification. The data was analyzed by SPSS 16.5 and the study was performed using descriptive analysis and Chi square test. Results: All 64 participants were opiate-dependent males (ASA physical status of I or II) who aged over 18 years with a mean age of 31.11 ± 8.93 years at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 (25%) reported abstinence; however, four patients of the non-relapsed group reported one episode of opiate use. There was no significant difference between relapsed and non-relapsed patients regarding their marital status, level of education, and family history of opiate dependency (P > 0.05). Conclusions: Although UROD by naloxone is a safe and effective method of detoxification, if used alone, it has a very high relapse rate in long term. PMID:25741479

  5. Fiscal strain and access to opiate substitution therapy at Department of Veterans Affairs Medical Centers.

    PubMed

    Rosenheck, Robert; Leslie, Douglas; Woody, George

    2003-01-01

    This study examines the relationship between institutional fiscal strain and the availability of opiate substitution therapy (eg, methadone maintenance), an effective but relatively expensive treatment for heroin addiction. An observational design was used to examine the association of changes in funding and changes in provision for treating opiate addiction at 29 VA Medical Centers (VAMCs). We hypothesized that VAMCs experiencing greater fiscal strain would show reduced availability of opiate substitution treatment. Administrative records from each of 29 VAMCs that provided opiate substitution therapy in both Fiscal Year (FY) 1995 and FY 1999 were used to measure changes in the availability of this service, ie, the percent change in total patients treated, annual visits per patient, and total services delivered. Institutional fiscal strain was measured by the percent decline in per capita funding at four levels at each VAMC: the entire medical center, all mental health programs, all substance abuse programs (inpatient and outpatient), and outpatient substance abuse programs alone. The total number of patients receiving opiate substitution increased from 5,549 in FY 1995 to 6,884 in FY 1999 (24%), annual visits per patient decreased by 16%, and the total number of units of services increased by 4%. There were no significant relationships between changes in the delivery of opiate substitution services and changes in per capita funding at any of the four institutional levels. No new programs were started during these years. Although no new programs were started, the availability of opiate substitution therapy at VA facilities with existing programs was maintained over a five-year period regardless of local funding changes, although at somewhat reduced intensity. PMID:12851018

  6. Opioid receptor desensitization: mechanisms and its link to tolerance

    PubMed Central

    Allouche, Stéphane; Noble, Florence; Marie, Nicolas

    2014-01-01

    Opioid receptors (OR) are part of the class A of G-protein coupled receptors and the target of the opiates, the most powerful analgesic molecules used in clinic. During a protracted use, a tolerance to analgesic effect develops resulting in a reduction of the effectiveness. So understanding mechanisms of tolerance is a great challenge and may help to find new strategies to tackle this side effect. This review will summarize receptor-related mechanisms that could underlie tolerance especially receptor desensitization. We will focus on the latest data obtained on molecular mechanisms involved in opioid receptor desensitization: phosphorylation, receptor uncoupling, internalization, and post-endocytic fate of the receptor. PMID:25566076

  7. Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: Evidence for further genetic heterogeneity in this syndrome

    SciTech Connect

    Brown, T.R.; Lubahn, D.B.; Wilson, E.M.; Joseph, D.R.; French, F.S.; Migeon, C.J. )

    1988-11-01

    The cloning of a cDNA for the human androgen receptor gene has resulted in the availability for cDNA probes that span various parts of the gene, including the entire steroid-binding domain and part of the DNA-binding domain, as well as part of the 5' region of the gene. The radiolabeled probes were used to screen for androgen receptor mutations on Southern blots prepared by restriction endonuclease digestion of genomic DNA from human subjects with complete androgen insensitivity syndrome (AIS). In this investigation, the authors considered only patients presenting complete AIS and with the androgen receptor (-) form as the most probably subjects to show a gene deletion. One subject from each of six unrelated families with the receptor (-) form of complete AIS and 10 normal subjects were studied. In the 10 normal subjects and in 5 of the 6 patients, identical DNA restriction fragment patterns were observed with EcoRI and BamHI. Analysis of other members of this family confirmed the apparent gene deletion. The data provide direct proof that complete AIS in some families can result from a deletion of the androgen receptor structural gene. However, other families do not demonstrate such a deletion, suggesting that point mutations may also result in the receptor (-) form of complete AIS, adding further to the genetic heterogeneity of this syndrome.

  8. Opiates inhibit ion conductances elicited by cell swelling and cAMP in cultured cells.

    PubMed

    Callaghan, R; Riordan, J R

    1995-10-15

    The effect of several opiate compounds on I- efflux was investigated in cultured cell lines. I- efflux was evoked by two distinct stimuli, namely cell swelling and elevation of cellular cAMP levels by prostaglandin E2. Cells expressing the multidrug resistance P-glycoprotein were found to have increased I- efflux in response to hypo-osmotic challenge. This increased I- efflux in P-glycoprotein containing cells was reduced to levels found in parental cells by the opiates morphine, pentazocine and naloxone. Addition of prostaglandin E2 to T84 cells resulted in elevated cellular cAMP levels and a significant I- efflux. This cAMP stimulated efflux was also inhibited by several opiates. None of the opiates was able to alter cAMP levels or protein kinase A mediated phosphorylation of immunoprecipitated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel in T84 cells. The ability of opiates to alter ion conductances is discussed in relation to the anti-diarrheal effects of these compounds. PMID:8566169

  9. Opiate Addiction Therapies and HIV-1 Tat: Interactive Effects on Glial [Ca2+]i, Oxyradical and Neuroinflammatory Chemokine Production and Correlative Neurotoxicity

    PubMed Central

    Fitting, Sylvia; Zou, Shiping; El-Hage1, Nazira; Suzuki, Masami; Paris, Jason J.; Schier, Christina J.; Rodríguez, José W.; Rodriguez, Myosotys; Knapp, Pamela E.; Hauser, Kurt F.

    2014-01-01

    Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca2+]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca2+]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca2+]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca2+]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS. PMID:25760046

  10. Porcine pituitary peptides with opiate-like activity: partial purification and effects in the rat after intraventricular injection.

    PubMed

    Teschemacher, H; Bläsig, J; Kromer, W

    1976-09-01

    A peptide material with opiate-like activity in the guinea-pig ileum was extracted from porcine pituitaries using a hot glacial acetic acid extraction method and was partially purified by gel filtration. When injected intraventricularly in rats, these purified peptides induced strong analgesia, catelepsy, respiratory depression and other opiate-like effects, which lasted for several hours. PMID:1034219

  11. Differential effects of opiates on the incorporation of [14C] thiamine in the central nervous system of the rat.

    PubMed

    Misra, A L; Vadlamani, N L; Pontani, R B

    1977-03-15

    Opiate agonist (morphine), pure antagonist (naloxone), mixed agonist-antagonist (nalorphine) and analgesically inactive enantiomorph (dextrorphan) produced differential stereoselective effects on the incorporation of [14C] thiamine in the central nervous system of the rats. The possible role of thiamine in opiate effects and its implications are discussed. PMID:858372

  12. Involvement of nuclear factor-kB in the expression of opiate withdrawal.

    PubMed

    Capasso, A

    2001-08-01

    1. To investigate the role of NF-kB in the expression of opiate withdrawal, the effects of PDTC, an inhibitor of NF-kB activation, was studied on acute opiate withdrawal induced by morphine in vitro. 2. After a 4 min in vitro exposure to morphine, a strong contracture of guinea pig isolated ileum was observed after the addition of naloxone. 3. PDTC (1x10(-8)-5x10(-8)-1x10(-7) M) was able to reduce the naloxone-induced contracture after exposure to the opioid agonist in a concentration-dependent fashion. 4. The results of the present study indicate that NF-kB is involved in the expression of opiate withdrawal thus extending and explaining previous papers performed with dexamethasone and selective arachidonic acid metabolites inhibitors. PMID:11474844

  13. Opiate refractory pain from an intestinal obstruction responsive to an intravenous lidocaine infusion.

    PubMed

    Bafuma, Patrick J; Nandi, Arun; Weisberg, Michael

    2015-10-01

    A 24-year-old female patient presented to our community emergency department (ED) for abdominal pain that had progressively worsened over the last 28 hours. Of note, 1 month prior to her presentation, the patient had a colostomy due to a rectal abscess and required stoma revision 5 days prior to her visit to our ED. The patient's pain was refractory to opiate analgesia in our ED, but experienced significant relief after an intravenous lidocaine infusion. Computer tomography of the abdomen and pelvis ultimately revealed a large bowel obstruction just proximal to the colostomy site. Historically, options for ED management of severe pain have been limited beyond narcotic analgesia. For patients whom are refractory to opiates in the ED, or for whom opiates are contraindicated, lidocaine infusions have shown promise for a variety of both acute and chronic painful conditions. PMID:26306434

  14. Vocalizations during withdrawal from opiates and cocaine: possible expressions of affective distress.

    PubMed

    Covington, Herbert E; Miczek, Klaus A

    2003-04-25

    Intense anxiety has been postulated to trigger relapse to abuse of opiates and psychomotor stimulants. Preclinical research methodologies need to be developed to adequately characterize the affective or emotional component of withdrawal. Classically, withdrawal from psychomotor stimulants and opiates focuses on somatic and autonomic indices, foremost based on observational assessments and, additionally, on measures of disrupted conditioned behavior. These measures depict the intensity and time course of withdrawal from specific doses of opiates and psychomotor stimulants, but require large numbers of subjects due to single use of each individual. Behavioral disruptions have been attributed to anhedonia, a core symptom of drug withdrawal, as well as major depressive and psychotic disorders. In spite of some pharmacological validation, inferences about anxiety-like disturbances, based on observed somatic and autonomic signs or on changes in conditioned responses, have to remain tentative. High-pitched vocalizations may communicate affective expressions and, in rodents, different kinds of ultrasonic vocalizations communicate maternal separation distress in infants, accompany the intensely arousing phases of agonistic confrontations, signal submission and distress in defensive responses to threats and painful events, and are part of the excitatory and inhibitory phases of sexual behavior. While acute treatment with opiates, psychomotor stimulants, alcohol and benzodiazepines suppresses ultrasonic vocalizations in the 22-25-kHz range, rats emit high rates of ultrasonic vocalizations upon withdrawal from prolonged exposure to these drugs, particularly if they have been startled. Peak rates of ultrasonic distress calls occur ca. 1-3 days after cessation of cocaine or opiate treatment and decline within 5-7 days. Ultrasonic vocalizations during withdrawal from cocaine, alcohol or benzodiazepines can be attenuated by renewed access to the drug. It will be informative to

  15. Auditory target processing in methadone substituted opiate addicts: The effect of nicotine in controls

    PubMed Central

    Müller, Bernhard W; Specka, Michael; Steinchen, Nicolai; Zerbin, Dieter; Lodemann, Ernst; Finkbeiner, Thomas; Scherbaum, Norbert

    2007-01-01

    Background The P300 component of the auditory evoked potential is an indicator of attention dependent target processing. Only a few studies have assessed cognitive function in substituted opiate addicts by means of evoked potential recordings. In addition, P300 data suggest that chronic nicotine use reduces P300 amplitudes. While nicotine and opiate effects combine in addicted subjects, here we investigated the P300 component of the auditory event related potential in methadone substituted opiate addicts with and without concomitant non-opioid drug use in comparison to a group of control subjects with and without nicotine consumption. Methods We assessed 47 opiate addicted out-patients under current methadone substitution and 65 control subjects matched for age and gender in an 2-stimulus auditory oddball paradigm. Patients were grouped for those with and without additional non-opioid drug use and controls were grouped for current nicotine use. P300 amplitude and latency data were analyzed at electrodes Fz, Cz and Pz. Results Patients and controls did not differ with regard to P300 amplitudes and latencies when whole groups were compared. Subgroup analyses revealed significantly reduced P300 amplitudes in controls with nicotine use when compared to those without. P300 amplitudes of methadone substituted opiate addicts were in between the two control groups and did not differ with regard to additional non-opioid use. Controls with nicotine had lower P300 amplitudes when compared to patients with concomitant non-opioid drugs. No P300 latency effects were found. Conclusion Attention dependent target processing as indexed by the P300 component amplitudes and latencies is not reduced in methadone substituted opiate addicts when compared to controls. The effect of nicotine on P300 amplitudes in healthy subjects exceeds the effects of long term opioid addiction under methadone substitution. PMID:17986348

  16. Comparison of methadone and buprenorphine for opiate detoxification (LEEDS trial): a randomised controlled trial

    PubMed Central

    Wright, Nat MJ; Sheard, Laura; Adams, Clive E; Rushforth, Bruno J; Harrison, Wendy; Bound, Nicole; Hart, Roger; Tompkins, Charlotte NE

    2011-01-01

    Background Many opiate users require prescribed medication to help them achieve abstinence, commonly taking the form of a detoxification regime. In UK prisons, drug users are nearly universally treated for their opiate use by primary care clinicians, and once released access GP services where 40% of practices now treat drug users. There is a paucity of evidence evaluating methadone and buprenorphine (the two most commonly prescribed agents in the UK) for opiate detoxification. Aim To evaluate whether buprenorphine or methadone help to achieve drug abstinence at completion of a reducing regimen for heroin users presenting to UK prison health care for detoxification. Design Open-label, pragmatic, randomised controlled trial in three prison primary healthcare departments in the north of England. Method Prisoners (n = 306) using illicit opiates were recruited and given daily sublingual buprenorphine or oral methadone, in the context of routine care, over a standard reduced regimen of not more than 20 days. The primary outcome measure was abstinence from illicit opiates at 8 days post detoxification, as indicated by urine test (self-report/clinical notes where urine sample was not feasible). Secondary outcomes were also recorded. Results Abstinence was ascertained for 73.7% at 8 days post detoxification (urine sample = 52.6%, self report = 15.2%, clinical notes = 5.9%). There was no statistically significant difference in the odds of achieving abstinence between methadone and buprenorphine (odds ratio [OR] = 1.69; 95% confidence interval [CI] = 0.81 to 3.51; P = 0.163). Abstinence was associated solely with whether or not the participant was still in prison at that time (15.22 times the odds; 95% CI = 4.19 to 55.28). The strongest association for lasting abstinence was abstinence at an earlier time point. Conclusion There is equal clinical effectiveness between methadone and buprenorphine in achieving abstinence from opiates at 8 days post detoxification within prison

  17. Chronic infusion of opiate peptides to rat cerebrospinal fluid with osmotic minipumps.

    PubMed

    Saland, L C; Ortiz, E; Samora, A

    1984-09-01

    Beta-endorphin-related opiate peptides or the opiate antagonist naloxone were chronically infused for periods of 24 to 48 hours to the lateral cerebral ventricle of adult male rats using Alza osmotic minipumps. Previous studies have suggested a "chemotactic"-like effect of opiate peptides for supraependymal macrophages in the region of the third ventricle of the brain. The present study demonstrates a stimulatory effect of beta-endorphin infusion on the appearance of lymphocyte and neutrophil-like cells, in addition to macrophages, in the region of the third ventricle, suggestive of an intracerebral inflammatory response. None of the other molecules, including alpha-endorphin, methionine-enkephalin, naloxone, or sterile saline produced similar cellular responses after infusion, although some of the latter substances may have induced the appearance of supraependymal neuron-like cells in the area. Observations suggest that the chronic presence of beta-endorphin, a biologically active opiate peptide, will interact with cells of the immune system, which have the ability to gain access to the cerebrospinal fluid. PMID:6091499

  18. Drugs and Personality: Personality Correlates and Predictors of Non-Opiate Drug Use. Research Issues 14.

    ERIC Educational Resources Information Center

    Austin, Gregory A., Ed.; And Others

    This collection of abstracts from current research and theoretical studies explores various aspects of the relationship between non-opiate drug use and personality. The literature covers a period from 1968 through 1975 and focuses on tests that were conducted on adolescents and college students from the United States, Canada and Sydney, Australia.…

  19. 49 CFR 40.139 - On what basis does the MRO verify test results involving opiates?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false On what basis does the MRO verify test results... Verification Process § 40.139 On what basis does the MRO verify test results involving opiates? As the MRO, you... laboratory confirms the presence of 6-acetylmorphine (6-AM) in the specimen, you must verify the test...

  20. 49 CFR 40.139 - On what basis does the MRO verify test results involving opiates?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false On what basis does the MRO verify test results... Verification Process § 40.139 On what basis does the MRO verify test results involving opiates? As the MRO, you... laboratory confirms the presence of 6-acetylmorphine (6-AM) in the specimen, you must verify the test...

  1. 49 CFR 40.139 - On what basis does the MRO verify test results involving opiates?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false On what basis does the MRO verify test results involving opiates? 40.139 Section 40.139 Transportation Office of the Secretary of Transportation PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Medical Review Officers and the Verification Process § 40.139 On what basis...

  2. Predicting Sobriety from the Employment Status of Dually Diagnosed Clients Who Are Opiate Dependent

    ERIC Educational Resources Information Center

    Scorzelli, James F.

    2007-01-01

    The purpose of this study was to determine the relationship between Minnesota Multiphasic Personality Inventory-2 (E. S. Neukrug & R. C. Fawcett, 2006) profiles and employment status for clients who are opiate dependent. A discriminant function analysis indicated that employment was a predictor in maintaining sobriety after 6 months. (Contains 4…

  3. Dissociation of POMC Peptides after Self-Injury Predicts Responses To Centrally Acting Opiate Blockers.

    ERIC Educational Resources Information Center

    Sandman, Curt A.; Hetrick, William; Taylor, Derek V.; Chicz-DeMet, Aleksandra

    1997-01-01

    This study investigated whether blood plasma levels of pro-opiomelanocortin-derived (POMC) peptides, beta-endorphin-like activity, adrenocorticotrophic hormone, and adrenal cortisol immediately after self injurious behavior (SIB) episodes predicted subsequent response to an opiate blocker in 10 patients with mental retardation. Results suggest…

  4. Psychometric Evaluation of the Life Orientation Test-Revised in Treated Opiate Dependent Individuals

    ERIC Educational Resources Information Center

    Hirsch, Jameson K.; Britton, Peter C.; Conner, Kenneth R.

    2010-01-01

    We examined internal consistency and test-retest reliability of a measure of dispositional optimism, the Life Orientation Test-Revised, in 121 opiate-dependent patients seeking methadone treatment. Internal consistency was adequate at baseline (alpha = 0.69) and follow-up (alpha = 0.72). Low socioeconomic status and being on disability were…

  5. Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats: monoaminergic correlates.

    PubMed

    Espejo, E F; Serrano, M I; Caillé, S; Stinus, L

    2001-08-01

    The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists. PMID:11425504

  6. Monitoring Pregnant Women’s Illicit Opiate and Cocaine Use With Sweat Testing

    PubMed Central

    Brunet, Bertrand R.; Barnes, Allan J.; Choo, Robin E.; Mura, Patrick; Jones, Hendrée E.; Huestis, Marilyn A.

    2011-01-01

    Dependence on illicit drugs during pregnancy is a major public health concern as there may be associated adverse maternal, fetal, and neonatal consequences. Sweat patches (n = 389) were collected from 39 pregnant volunteers who provided written informed consent for this Institutional Review Board-approved protocol and wore patches, replaced approximately weekly, from study entry until delivery. Patches were analyzed for opiates (heroin, 6-acetylmor-phine, 6-acetylcodeine, morphine and codeine) and cocaine (cocaine, benzoylecgonine, ecgonine methyl ester, anhydroecgonine methyl ester) by solid phase extraction and gas chromatography mass spectrometry. Seventy-one percent (276) of collected sweat patches were ≥5 ng per patch (limit of quantification) for one or more analytes. Cocaine was present in 254 (65.3%) patches in concentrations ranging from 5.2 to 11,835 ng per patch with 154 of these high enough to satisfy the proposed Substance Abuse and Mental Health Services Administration guidelines for a confirmatory drug test (25 ng per patch). Interestingly, 6-acetylmorphine was the most prominent opiate analyte documented in 134 patches (34.4%) with 11.3% exceeding the proposed opiate Substance Abuse and Mental Health Services Administration cut-off (25 ng per patch). Heroin was identified in fewer patches (77), but in a similar concentration range (5.3–345.4 ng per patch). Polydrug use was evident by the presence of both cocaine and opiate metabolites in 136 (35.0%) patches. Sweat testing is an effective method for monitoring abstinence or illicit drug use relapse in this high-risk population of pregnant opiate- and/or cocaine-dependent women. PMID:19927046

  7. Cocaine, opiates, and ethanol in homicides in New York City: 1990 and 1991.

    PubMed

    Tardiff, K; Marzuk, P M; Leon, A C; Hirsch, C S; Stajić, M; Portera, L; Hartwell, N

    1995-05-01

    Studies using medical examiner cases are useful in monitoring drug use in special populations. This study assesses the presence of cocaine and its metabolite, benzoylecgonine (BE), opiates and ethanol in all homicide victims who were injured and who survived two hours or less after injury in 1990 and 1991 in New York City. There were 2824 homicides in the study period and cocaine and/or BE were found in 884 (31.3%) of cases. In over half of the cases positive for cocaine/BE, ethanol or opiates were found. African-Americans and Latinos were much more likely than whites or Asians to be positive for cocaine/BE. There were no differences between men and women in regard to being positive for cocaine/BE. Cocaine/BE was most frequently identified among victims 25 to 44 years of age. Males were more likely to be positive for ethanol. There were no differences among age groups or ethnic groups in regard to ethanol except for a very low ethanol incidence among Asians. Victims positive for cocaine/BE were more likely to be killed with firearms in open places. The percentage of victims positive for cocaine/BE remains approximately that found by other studies in the late 1980s, however, the percentage of opiate-positive homicides seems to be increasing. Opiates usually were found with cocaine/BE. Two-thirds of the cocaine and/or BE positive cases had cocaine present, thus they were under the influence of the drug at the time they were injured. The authors discuss how the use of cocaine, ethanol and opiates may be related to one's becoming a homicide victim. PMID:7782745

  8. The effect of opiates on the terminal nerve impulse and quantal secretion from visualized amphibian nerve terminals.

    PubMed Central

    Lavidis, N. A.

    1995-01-01

    1. Secretion of transmitter from amphibian motor nerve terminal release sites is intermittent, spatially non-uniform and varies considerably throughout the year and during development. The role of opioid receptors in modulating transmitter secretion from amphibian motor nerve terminals is evaluated in this study. 2. Dynorphin-A (24 microM) and morphine (500 microM) did not significantly change the shape of the nerve impulse or the consistency with which it was observed, but decreased evoked quantal secretion by more than 50%. These effects of dynorphin-A and morphine were largely reversed by naloxone (50 microM). 3. Dynorphin-A and morphine did not significantly change either the amplitude or the frequency of spontaneous quantal secretions. 4. There was a uniform decrease in evoked quantal secretion from release sites along terminal branches, irrespective of the quantal content value before drug treatment, indicating no difference in the susceptibility of proximal vs distal release sites to opiates. 5. Increasing the extracellular calcium concentration (0.3 to 0.4 mM) or trains of conditioning-test impulses (25 to 100 Hz) resulted in smaller dynorphin-A or morphine-induced decreases in evoked quantal secretion. 6. The decrease in evoked quantal secretion occurs as a result of a uniform decrease in the probability of quantal secretion from release sites without any affect on the propagation of the nerve terminal impulse. Low probability release sites become effectively silent. PMID:7582455

  9. Heterogeneous Catalysis.

    ERIC Educational Resources Information Center

    Miranda, R.

    1989-01-01

    Described is a heterogeneous catalysis course which has elements of materials processing embedded in the classical format of catalytic mechanisms and surface chemistry. A course outline and list of examples of recent review papers written by students are provided. (MVL)

  10. Effects of membrane polyunsaturated fatty acids on opiate peptide inhibition of basal and prostaglandin E1-stimulated cyclic AMP formation in intact N1E-115 neuroblastoma cells.

    PubMed

    Murphy, M G; Moak, C M; Rao, B G

    1987-12-01

    The effects of membrane polyunsaturated fatty acids (PUFA) on opiate peptide-mediated inhibition of basal and prostaglandin E1-stimulated cyclic AMP formation were examined in intact N1E-115 neuroblastoma cells. Addition of opiate peptides such as methionine 5-enkephalin (metEnk) to control cultures and to cultures that had been supplemented for 48 hr with 50 microM linoleic acid resulted in dose-dependent decreases in cAMP formation; these decreases were blocked by naloxone. Maximum inhibition of basal cyclase activity was 50-55% in both control and PUFA-enriched cells; however, half-maximal inhibition required ten times more metEnk in supplemented cultures than in controls. This is consistent with our observation that the affinity of binding of [tyrosyl-3',5'-3H(N)](2-D-alanine-5-D-leucine)enkephalin ([3H]DADLE) to intact PUFA-enriched cells was lower than that to control cells. Receptor density was not modified as a result of supplementation. Addition of prostaglandin E1 (PGE1) to the cells produced rapid dose-dependent increases in cAMP formation. Maximum responses were higher in PUFA-enriched than in control cells (1924 and 972 pmol cAMP formed/mg protein respectively). Also, the apparent value for EC50 for PGE1 was consistently lower in supplemented cultures. MetEnk reduced PGE1-stimulated cAMP formation by 45-55% in both control and supplemented cells, and values for IC50 were similar (approximately 30 nM) in both. In the presence of the opiate peptide, values for EC50 for PGE1 were similar in control and PUFA-enriched cultures (0.07 and 0.09 microM respectively). The data from these studies suggest that membrane PUFA increase the efficiency of coupling of receptors that stimulate cAMP formation and decrease the efficiency of those that mediate inhibition. PMID:2825714