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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. Imaging opiate receptors with positron emission tomography

    SciTech Connect

    Frost, J.J.; Dannals, R.F.; Ravert, H.T.; Wilson, A.A.; Wong, D.F.; Links, J.M.; Burns, H.D.; Kuhar, M.J.; Snyder, S.H.; Wagner, H.N. Jr.

    1984-01-01

    Opiate receptors exist in the mammalian brain and are thought to meditate the diverse pharmacological actions of the opiates, such as analgesia, euphoria, and sedation. The 4-carbomethoxyl derivatives of fentanyl, such as lofentanil and R31833 (4-carbomethoxyfentanyl) bind to the opiate receptor with high affinity. C-11 R31833 was synthesized by reacting C-11 methyl iodide with the appropriate carboxylate. Male ICR mice were injected intravenously with C-11 R31833 (5..mu..g/kg), killed 30 minutes later, and the brains rapidly dissected. The thalami, striata, and cerebral cortex are rich in opiate receptors, but the cerebellum contains a very low concentration of opiate receptors. The thalamus/cerebellum and striatum/cerebellum activity ratios, calculated per mg of wet tissue, were 4.1 and 5.2 respectively. Coinjection of 5mg/kg naloxone reduced the ratios to 1.1, which indicates that the preferential localization of C-11 R31833 in the thalami and striata is due to binding to opiate is due to binding to opiate receptors. A 22 kg anesthetized male baboon was imaged using the NeuroECAT after injection of 18.9 mCi of C-11 R13833 (0.50 ..mu..g/kg, specific activity 616 Ci/mmole at time of injection). From 15-70 minutes after injection preferential accumulation of activity could be seen in the thalami, caudate nuclei, and cerebral cortex and, conversely, low activity was demonstrated in the cerebellum. At one hour postinjection the maximum measured caudate/cerebellum activity ratio per pixel was 2.9. For the NeuroECAT the recovery coefficient for the baboon caudate is ca. 0.2-0.3, and therefore the actual caudate/cerebellum ratio is ca. 10-15.

  4. 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.

  5. [Interaction of ethanol with opiate receptors].

    PubMed

    Iukhananov, R Iu; Maĭskiĭ, A I; Burov, Iu V

    1985-11-01

    Addition of ethanol to rat brain homogenate containing opiate receptors inhibits at a concentration of 50 mM the stereospecific binding of 3H-naloxone at 37 degrees C but not at 0 degree C, with the ID50 being 462 mM under these conditions. The temperature-dependent inhibition of the ligand binding suggests that ethanol does not compete with naloxone for specific binding sites of opiate receptors and changes the structure of lipids in biological membranes. Scatchard's analysis has demonstrated that apart from a decrease in the number of highly affinity binding sites of 3H-naloxone, the total amount of the binding sites remains unchanged both in the presence and absence of ethanol and constitutes 453 and 549 fmol/mg protein. It is assumed that ethanol might interconvert highly and low-affinity binding sites. Analysis of the effect of ethanol on 3H-naloxone binding with opiate receptors contained by synaptic membranes obtained from animals with varying predisposition to voluntary alcoholization has shown that ethanol inhibits to a greater degree ligand binding with membranes obtained from rats predisposed to alcoholization. The possibility of the involvement of receptors in the biochemical mechanisms by which the initial alcoholic motivation is effected is under discussion.

  6. Production of antibodies which recognize opiate receptors on murine leukocytes

    SciTech Connect

    Carr, D.J.J.; Bost, K.L.; Blalock, J.E.

    1988-01-01

    An antibody has been developed which recognizes opiate receptors on cells of the immune system. This antibody blocks specific binding of the radiolabeled opiate receptor ligand, /sup 3/H-dihydromorphine, to receptors on murine splenocytes. Additionally, the anti-receptor antibody competes with ..beta..-endorphin, meta-enkephalin, and naloxone for the same binding site on the leukocytes. Moreover, the anti-receptor antibody possesses agonist activity similar to ..beta..-endorphin in suppressing cAMP production by lymphocytes. These results suggest the development of an antibody which recognizes classical opiate receptors on cells of the immune system.

  7. Visualization of opiate receptor upregulation by light microscopy autoradiography.

    PubMed Central

    Tempel, A; Gardner, E L; Zukin, R S

    1984-01-01

    Light microscopy autoradiography has been used to visualize neuroanatomical patterns of brain opiate receptor upregulation in response to chronic naltrexone administration. Slide-mounted brain sections of frozen rat brain were labeled in vitro with dihydro[3H]morphine, a relatively selective mu opioid ligand. The greatest relative increases in opiate receptor density were observed in the nucleus accumbens, the amygdala, striatal patches, nuclei of the thalamus and hypothalamus, layers I and III of neocortex, substantia nigra compacta, midbrain periaqueductal gray regions, and the parabrachial nuclei of the brainstem. The substantia nigra reticulata, surrounding areas of striatal patches, and the locus ceruleus, were not affected by this drug treatment. These findings demonstrate that chronically administered naltrexone differentially regulates opiate receptors throughout the brain. In particular, three brain systems appear to be target areas of receptor upregulation : (i) the dopamine A9/A10 systems, (ii) the limbic system, and (iii) structures that receive input from afferent sensory pathways. Two possible mechanisms to account for this finding are (i) that the drug does not have uniform effects throughout the brain or (ii) that the receptors themselves may be associated with different functional systems. Receptor density changes are paralleled by increases in methionine-enkephalin content in the striatum, nucleus accumbens, periaqueductal gray, and hypothalamic areas of chronic naltrexone-treated rats relative to control rats. Thus opiate receptors and opioid peptides appear to be subject to regulatory mechanisms similar to those that modulate other neurotransmitters and their receptors. These results document in a visual manner brain patterns of opiate receptor upregulation . Images PMID:6328530

  8. Galanin negatively modulates opiate withdrawal via galanin receptor 1

    PubMed Central

    Holmes, Fiona E.; Armenaki, Athena; Iismaa, Tiina P.; Einstein, Emily B.; Shine, John; Picciotto, Marina R.; Wynick, David; Zachariou, Venetia

    2012-01-01

    Rationale The neuropeptide galanin has been shown to modulate opiate dependence and withdrawal. These effects could be mediated via activation of one or more of three distinct G-protein coupled receptors, namely GalR1, GalR2 and GalR3. Objectives In this study, we used several transgenic mouse lines to further define the mechanisms underlying the role played by galanin and its receptors in the modulation of morphine dependence. Firstly, transgenic mice expressing β-galactosidase under the control of the galanin promoter were used to assess the regulation of galanin expression in response to chronic morphine administration and withdrawal. Next, the behavioural responses to chronic morphine administration and withdrawal were tested in mice that over-express galanin, lack the GalR1 gene or lack the GalR2 gene. Methods Transgenic and matched wild-type mice were given increasing doses of morphine followed by precipitation of withdrawal by naloxone and behavioral responses to withdrawal assessed. Results Both morphine administration and withdrawal increases galanin gene transcription in the locus coerulus (LC). Increasing galanin levels in the brain reduced signs of opiate withdrawal. Mice lacking GalR1 undergo more severe opiate withdrawal, whereas mice lacking GalR2 show no significant difference in withdrawal signs, compare to matched wild type controls. Conclusions Opiate administration and withdrawal increase galanin expression in the LC. Galanin opposes the actions of morphine which lead to opiate dependence and withdrawal, an effect that is mediated via GalR1. PMID:21969124

  9. 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.

  10. 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.

  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. Gestational cocaine exposure increases opiate receptor binding in weanling offspring.

    PubMed

    Clow, D W; Hammer, R P; Kirstein, C L; Spear, L P

    1991-04-24

    The use of cocaine during pregnancy produces a variety of adverse effects in offspring. Gestational cocaine exposure is known to affect developing dopamine systems, but other neurochemical systems may also be at risk. Regional density of opiate receptors labeled with [3H]naloxone was examined in the brains of 21-day-old male rats exposed to cocaine (0, 10, 20, or 40 mg/kg/day s.c.) between gestation days 8 and 20. Gestational cocaine exposure significantly increased labeling in a dose-dependent fashion in dopaminergic terminal (e.g. the nucleus accumbens, medial prefrontal cortex, olfactory tubercle, and caudatoputamen), limbic (e.g. basolateral amygdaloid nucleus, lateral habenula, hippocampus, dentate gyrus, entorhinal and cingulate cortices) and neocortical (e.g. somatosensory and motor cortices) regions, but had little effect in diencephalic or brainstem regions. The results suggest a functional linkage whereby drug-induced alteration of dopamine systems can regulate developing opioid systems in the brain. Moreover, gestational cocaine exposure produced long-lasting changes of opiate receptor labeling in certain brain regions. The implications of these results are uncertain. However, such effects on endogenous opioid systems could contribute to a developmental delay, cognitive or motor dysfunction.

  13. CRF2 receptor-deficiency eliminates opiate withdrawal distress without impairing stress coping.

    PubMed

    Ingallinesi, M; Rouibi, K; Le Moine, C; Papaleo, F; Contarino, A

    2012-12-01

    The opiate withdrawal syndrome is a severe stressor that powerfully triggers addictive drug intake. However, no treatment yet exists that effectively relieves opiate withdrawal distress and spares stress-coping abilities. The corticotropin-releasing factor (CRF) system mediates the stress response, but its role in opiate withdrawal distress and bodily strategies aimed to cope with is unknown. CRF-like signaling is transmitted by two receptor pathways, termed CRF(1) and CRF(2). Here, we report that CRF(2) receptor-deficient (CRF(2)(-/-)) mice lack the dysphoria-like and the anhedonia-like states of opiate withdrawal. Moreover, in CRF(2)(-/-) mice opiate withdrawal does not increase the activity of brain dynorphin, CRF and periaqueductal gray circuitry, which are major substrates of opiate withdrawal distress. Nevertheless, CRF(2) receptor-deficiency does not impair brain, neuroendocrine and autonomic stress-coping responses to opiate withdrawal. The present findings point to the CRF(2) receptor pathway as a unique target to relieve opiate withdrawal distress without impairing stress-coping abilities.

  14. Interconverting mu and delta forms of the opiate receptor in rat striatal patches.

    PubMed Central

    Bowen, W D; Gentleman, S; Herkenham, M; Pert, C B

    1981-01-01

    The binding of a radiolabeled "mu receptor" prototype opiate, dihydromorphine (H2morphine), and the binding of a "delta receptor" prototype, [D-Ala2,D-Leu5]enkephalin (D-Enk), to slide-mounted rat caudate slices were simultaneously compared quantitatively and visualized by autoradiography. Generally, D-Enk bound to opiate receptors distributed evenly throughout the entire striatum (type 2 pattern), whereas H2morphine labeled discrete islands or patches of receptors (type 1 pattern). In the presence of Mn2+ (3 mM) or other divalent cations, however, Na+ and GTP at 25 degrees C caused an increase in D-Enk binding at the expense of H2morphine binding at striatal opiate receptor patches. Thus, these conditions shifted D-Enk binding from an even pattern to one that included both an even and patchy distribution. These incubation conditions not only promoted D-Enk binding to striatal patches but also enabled the opiate receptor to regulate adenylate cyclase with the same (P less than 0.01) ligand selectivity pattern as that obtained by the displacement of D-Enk binding. The relative affinity of opiate receptors in striatal patches for opiate peptides, naloxone, and morphine appears to be a function of incubation conditions and coupling to adenylate cyclase and is not indicative of distinctly different opiate receptors. We postulate a three-state allosteric model consisting of mu agonist-, mu antagonists-, and adenylate cyclase-coupled delta-agonist-preferring states, whose equilibrium may be regulated by a sulfhydryl group mechanism. Images PMID:6272275

  15. The kappa-opiate receptor impacts the pathophysiology and behavior of substance use.

    PubMed

    Mysels, David; Sullivan, Maria A

    2009-01-01

    There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and behavior. As dopamine activity is upregulated through chronic substance use, kappa receptor activity, mediated through the peptide dynorphin, is upregulated in parallel. Dynorphin causes dysphoria and decreased locomotion, and the upregulation of its activity on the kappa receptor likely dampens the excitation caused by increased dopaminergic activity. This feedback mechanism may have significant clinical implications for treating drug dependent patients in various stages of their pathology.

  16. Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms.

    PubMed

    Ahmad, Tasha; Lauzon, Nicole M; de Jaeger, Xavier; Laviolette, Steven R

    2013-09-25

    Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways. PMID:24068830

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

    PubMed

    Elhabazi, K; Trigo, J M; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, J J; 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  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. [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

  5. 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

  6. Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.

    PubMed

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

    2014-02-01

    μ-opioid receptors (MORs) 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 new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo. PMID:24413699

  7. 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

  8. Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.

    PubMed

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

    2014-02-01

    μ-opioid receptors (MORs) 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 new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.

  9. Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis.

    PubMed

    Bigliardi-Qi, M; Lipp, B; Sumanovski, L T; Buechner, S A; Bigliardi, P L

    2005-01-01

    There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.

  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. Mu-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin.

    PubMed

    Bigliardi-Qi, M; Sumanovski, L T; Büchner, S; Rufli, T; Bigliardi, P L

    2004-01-01

    We have previously shown that human epidermal keratinocytes express a functionally active micro-opiate receptor, which adds a new dimension to the recently developed research in neuroimmunodermatology and neurogenic inflammation in skin diseases. Human keratinocytes specifically bind and also produce beta-endorphin, the endogenous micro-opiate receptor ligand. Using confocal imaging microscopy, we could now demonstrate that micro-opiate receptors are not only expressed in keratinocytes, but also on unmyelinated peripheral nerve fibers in the dermis and epidermis. Some of the peripheral nerve fibers also express the ligand beta-endorphin. The keratinocytes positive for beta-endorphin staining are clustered around the terminal ends of the unmyelinated nerve fibers. Therefore the opiate receptor system seems to be crucial in the direct communication between nerves and skin. The keratinocytes can influence the unmyelinated nerve fibers in the epidermis directly via secreting beta-endorphin. On the other hand, nerve fibers can also secrete beta-endorphin and influence the migration, differentiation and probably also the cytokine production pattern of keratinocytes.

  12. Mu opioid receptor (OPRM1) as a predictor of treatment outcome in opiate-dependent individuals of Arab descent

    PubMed Central

    AL-Eitan, Laith N; Jaradat, Saied A; Su, Steve YS; Tay, Guan K; Hulse, Gary K

    2012-01-01

    Background: A number of research studies on the genetics of opiate dependence have focused on the μ-opioid receptor (OPRM1), which is a primary target for opiates. This study aims to identify genetic polymorphisms within the OPRM1 gene involved in response to the biopsychosocial treatment in opiate-dependent individuals of Arab descent. Methods: Unrelated Jordanian Nationals of Arab descent (N = 183) with opiate dependence were selected for this study. These individuals, all males, met the DSM-IV criteria for opiate dependence and were undergoing a voluntary 8-week treatment program at a Jordanian Drug Rehabilitation Centre. All individuals were genotyped for 22 single nucleotide polymorphisms (SNPs) within the OPRM1 gene using the Sequenom MassARRAY® system (iPLEX GOLD). Statistical analyses were carried out using the R package. Results: Patients receiving biopsychosocial treatment showed that there was a significant difference in their OPRM1 SNPs’ genotyping distribution between good, moderate, and poor responders to the treatment at two sites (rs6912029 [G-172T], and rs12205732 [G-1510A], P < 0.05, Fisher’s exact test). Conclusion: This study is the first report of an association between the OPRM1 G-172T and G-1510A polymorphisms and treatment response for opiate dependence. Specifically, this study demonstrated that the OPRM1 GG-172 and GG-1510 genotypes were more frequent among patients who were nonresponders to the biopsychosocial treatment. However, further pharmacogenetic studies in a larger cohort of opiate-dependent patients of Arab descent are needed to confirm these findings and identify individuals with increased chance of relapse. PMID:23226066

  13. 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

  14. Potential probe for examining opiate-receptor interactions: model compound study of dynamic effects on /sup 15/N INEPT enhancements

    SciTech Connect

    Schilling, K.H.; Mikita, M.A.

    1987-10-01

    Model systems were chosen in an attempt to mimic the proton exchange environment of an agonist nitrogen in an opiate-receptor interaction. The two model systems studied were an ammonium: 18-crown-6 ether complex and a quinuclidine-trifluoroacetic acid ion pair. Each system was examined for their effects on /sup 15/N NMR INEPT enhancements. Both models were found to retard proton exchange dynamics, as observed by increased enhancements relative to free ions in neutral aqueous solutions. These results suggest that the confinement of a protonated nitrogen, such as that expected in receptor binding, may alter exchange dynamics to favor INEPT enhancements, while unbound agonists would remain unenhanced. As a result, /sup 15/N NMR INEPT enhancements from a solution of receptor subtypes with an appropriate /sup 15/N-labeled agonist may present a means of exploring the dynamics of direct opiate-receptor interactions.

  15. 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.

  16. 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.

  17. Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels.

    PubMed

    Jacobs, M M; Ökvist, A; Horvath, M; Keller, E; Bannon, M J; Morgello, S; Hurd, Y L

    2013-11-01

    Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

  18. Dopamine receptor D1 and post-synaptic density gene variants associate with opiate abuse and striatal expression levels

    PubMed Central

    Jacobs, Michelle M.; Ökvist, Anna; Horvath, Monika; Keller, Eva; Bannon, Michael J.; Morgello, Susan; Hurd, Yasmin L.

    2013-01-01

    Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the USA. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amgydala; the correlation was inversed in opiate abusers as compared to controls. Cumulatively, these results support the hypothesis that there may be significant, genetically-influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers. PMID:23044706

  19. [Influence of Opiate Abuse on Expression of Toll-like Receptor 9 in Peripheral Blood Mononuclear Cells of HIV-1-Infected Individuals].

    PubMed

    Pan, Peijiang; Wei, Fumei; Jiang, Junjun; Liang, Bingyu; Huang, Jiegang; Liao, Yanyan; Su, Jinming; Li, Yu; Yang, Xiaoyi; Chen, Hui; Ye, Li; Liang, Hao

    2015-03-01

    The aim of this study was to investigate the influence of opiate abuse on the expression of Toll-like receptor 9 (TLR9) in the peripheral blood mononuclear cells (PBMCs) of HIV-1-infected patients and to elucidate possible mechanisms involved in the enhancement of HIV-1 replication by opiate abuse. A total of 200 participants were enrolled in the study by random selection from methadone treatment centers and voluntary HIV counseling and testing centers in the cities of Nanning, Liuzhou, and Qinzhou. These participants included 50 HIV-positive opiate abusers (Opiates HIV(+) group), 50 HIV-negative opiate abusers (Opiates HIV(-) group), 50 HIV-positive subjects who were not opiate abusers (Non-opiates HIV (+) group), and 50 HIV-negative subjects who were not opiate abusers (Control group). PBMCs were isolated from the peripheral blood samples from the subjects and the expression levels of TLR9 mRNA and protein were determined by q-PCR and western blot respectively. There was no significant difference among the four groups in age, gender, nationality, domicile, marital status, educational background or duration of drug abuse (P > 0.05). The median viral loads of the Opiates HIV(+) were significantly higher than those of the Non-Opiates HIV(+) groups (4.450 x 10(3) and 3.977 x 10(3) copies/mL respectively, P < 0.05). The relative expression levels of TLR9 mRNA in the Opiates HIV(+), Non-Opiates HIV(+), Opiates HIV(-) and Control groups were (2.13 +/- 1.59) x 10(-3), (3.66 +/- 2.22) x 10(-3), (1.96 +/- 1.42) x 10(-3) and (7.66 +/- 4.87) x 10(-3), respectively. The expression of TLR9 mRNA was significantly lower in both HIV-1-infected and -uninfected groups of opiate abusers compared with groups of non-abusers (P < 0.05). There was no significant difference in TLR9 mRNA expression levels between the Opiates HIV(+) group and the Opiates HIV(-) group (P > 0.05). However, in the non-opiate groups, the expression levels of TLR9 mRNA in the HIV(+) group were significantly

  20. 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.

  1. Opiate drug use and the pathophysiology of neuroAIDS.

    PubMed

    Hauser, Kurt F; Fitting, Sylvia; Dever, Seth M; Podhaizer, Elizabeth M; Knapp, Pamela E

    2012-07-01

    Opiate abuse and HIV-1 have been described as interrelated epidemics, and even in the advent of combined anti-retroviral therapy, the additional abuse of opiates appears to result in greater neurologic and cognitive deficits. The central nervous system (CNS) is particularly vulnerable to interactive opiate-HIV-1 effects, in part because of the unique responses of microglia and astroglia. Although neurons are principally responsible for behavior and cognition, HIV-1 infection and replication in the brain is largely limited to microglia, while astroglia and perhaps glial progenitors can be latently infected. Thus, neuronal dysfunction and injury result from cellular and viral toxins originating from HIV-1 infected/exposed glia. Importantly, subsets of glial cells including oligodendrocytes, as well as neurons, express µ-opioid receptors and therefore can be direct targets for heroin and morphine (the major metabolite of heroin in the CNS), which preferentially activate µ-opioid receptors. This review highlights findings that neuroAIDS is a glially driven disease, and that opiate abuse may act at multiple glial-cell types to further compromise neuron function and survival. The ongoing, reactive cross-talk between opiate drug and HIV-1 co-exposed microglia and astroglia appears to exacerbate critical proinflammatory and excitotoxic events leading to neuron dysfunction, injury, and potentially death. Opiates enhance synaptodendritic damage and a loss of synaptic connectivity, which is viewed as the substrate of cognitive deficits. We especially emphasize that opioid signaling and interactions with HIV-1 are contextual, differing among cell types, and even within subsets of the same cell type. For example, astroglia even within a single brain region are heterogeneous in their expression of µ-, δ-, and κ-opioid receptors, as well as CXCR4 and CCR5, and Toll-like receptors. Thus, defining the distinct targets engaged by opiates in each cell type, and among brain

  2. Opiate withdrawal.

    PubMed

    Farrell, M

    1994-11-01

    Opiate withdrawal is one of the longest studied and most well described withdrawal syndromes. Opiate withdrawal has been described as akin to a moderate to severe flu-like illness. Opiate withdrawal is appropriately described as subjectively severe but objectively mild. This paper describes the mechanisms of opiate dependence and opiate withdrawal and reviews the available instruments for the measurement of withdrawal. The time course of assisted and unassisted withdrawal is described and the range of options for the management of assisted withdrawal are described. This review concludes that the most effective and least time- and resource-consuming approach to opiate withdrawal will substantially contribute to the overall social management of opiate dependence.

  3. 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

  4. 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.

  5. 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

  6. Effects of dopamine receptor stimulation on opiate-induced modifications of pituitary-gonadal function.

    PubMed

    Vescovi, P P; Pezzarossa, A; Ceresini, G; Rastelli, G; Valenti, G; Gerra, G

    1985-01-01

    We evaluated the effects of the dopaminergic drug bromocriptine (Br) on prolactin (PRL), luteinizing hormone (LH) and testosterone (Te) levels in a homogeneous group of opiate addicts in a methadone maintenance program (20 mg twice daily). Basal blood levels of PRL, LH and Te were determined in 15 adult male drug addicts, before 30 and 60 days after Br administration (7.5 mg/day) was started. 15 healthy volunteers served as controls for the evaluation of basal values of the hormones. Before treatment PRL values were high, while LH and Te levels were lower than normal. 30 days later, PRL lowered significantly while LH and Te increased significantly. 60 days later, the blood hormone values were still significantly different from pretreatment values, and close to the normal range. This observation shows that Br, probably through an increase of dopaminergic tone, may counteract some effects of opiates on the hypothalamic-pituitary-gonadal axis.

  7. 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

  8. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist.

    PubMed

    Coleman, Brian R; Carlezon, William A; Myers, Karyn M

    2013-04-29

    Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-d-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist d,l-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex. PMID:23416323

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression.

    PubMed

    Bigliardi, P L; Sumanovski, L T; Büchner, S; Rufli, T; Bigliardi-Qi, M

    2003-01-01

    There is evidence that neuropeptides, especially the opiate receptor agonists, are involved in wound healing. We have previously observed that beta-endorphin, the endogenous ligand for the mu-opiate receptor, stimulates the expression of cytokeratin 16 in a dose-dependent manner in human skin organ cultures. Cytokeratin 16 is expressed in hyperproliferative epidermis such as psoriasis and wound healing. Therefore we were interested to study whether epidermal mu-opiate receptor expression is changed at the wound margins in acute and chronic wounds. Using classical and confocal microscopy, we were able to compare the expression level of mu-opiate receptors and the influence of beta-endorphin on transforming growth factor beta type II receptor in organ culture. Our results show indeed a significantly decreased expression of mu-opiate receptors on keratinocytes close to the wound margin of chronic wounds compared to acute wounds. Additionally beta-endorphin upregulates the expression of transforming growth factor beta type II receptor in human skin organ cultures. These results suggest a crucial role of opioid peptides not only in pain control but also in wound healing. Opioid peptides have already been used in animal models in treatment of wounds; they induce fibroblast proliferation and growth of capillaries, and accelerate the maturation of granulation tissue and the epithelization of the defect. Furthermore opioid peptides may fine-tune pain and the inflammatory response while healing takes place. This new knowledge could potentially be used to design new locally applied drugs to improve the healing of painful chronic wounds.

  14. Appraising the instantaneous secretory rates of luteinizing hormone and testosterone in response to selective mu opiate receptor blockade in late pubertal boys.

    PubMed

    Mauras, N; Rogol, A D; Veldhuis, J D

    1987-01-01

    The pulsatile properties of gonadotropin and testosterone release were examined before and after chronic mu opiate receptor blockade with naltrexone, 50 mg every other day, in four normal boys in late puberty (ages 14 8/12 to 15 1/12 years). The nature of spontaneous secretory events was appraised for immunoactive LH and testosterone in blood withdrawn every 20 minutes for 24 hours, using a novel, discrete deconvolution algorithm to estimate apparent instantaneous secretory rates. The application of this methodology revealed that the frequency of discrete LH instantaneous secretory rates increased after mu opiate receptor blockade (P = 0.011). More strikingly, all parameters of testosterone secretory events responded significantly to mu opiate receptor blockade, including increases in mean estimated secretory rate (+47%, P = 0.02), testosterone pulse frequency (+ 64%, P less than 0.001) and amplitude (+ 20%, P = 0.027). Correspondingly, decreases in testosterone interpulse secretory intervals (-35%, P = 0.001), secretory pulse duration (-19%, P = 0.042) and interpulse valley duration (-35%, P = 0.006) also were noted. There was a prominent diurnal rhythm in testosterone secretion with maximal values in the morning and late evening, and marked reductions in the afternoon, sometimes to prepubertal levels. This variation in the testosterone secretory profile paralleled that of LH. In response to naltrexone, the FSH concentration series showed a significant increase in the mean FSH concentration (+ 18%) P = 0.003) and mean peak amplitude (+ 15%, P = 0.002). These data provide indirect evidence of functional coupling of the opiate system with the hypothalamic GnRH pulse generator.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3040654

  15. 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.

  16. Intracerebroventricular injection of mu- and delta-opiate receptor antagonists block 60 Hz magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

    PubMed

    Lai, H; Carino, M

    1998-01-01

    In previous research, we have found that acute exposure to a 60 Hz magnetic field decreased cholinergic activity in the frontal cortex and hippocampus of the rat as measured by sodium-dependent high-affinity choline uptake activity. We concluded that the effect was mediated by endogenous opioids inside the brain because it could be blocked by pretreatment of rats before magnetic field exposure with the opiate antagonist naltrexone, but not by the peripheral antagonist naloxone methiodide. In the present study, the involvement of opiate receptor subtypes was investigated. Rats were pretreated by intracerebroventricular injection of the mu-opiate receptor antagonist, beta-funaltrexamine, or the delta-opiate receptor antagonist, naltrindole, before exposure to a 60 Hz magnetic field (2 mT, 1 hour). It was found that the effects of magnetic field on high-affinity choline uptake in the frontal cortex and hippocampus were blocked by the drug treatments. These data indicate that both mu- and delta-opiate receptors in the brain are involved in the magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

  17. Differences of binding characteristics of non-selective opiates towards and delta receptor types

    SciTech Connect

    Delay-Goyet, P.; Roques, B.P.; Zajac, J.M.

    1987-08-10

    (TH)ET (etorphine), which is considered either as an universal ligand or a agonist, interacts with identical affinities K/sub D/ = 0.33 - 0.38 nM to hybrid cells and rabbit cerebellum, pure delta and -enriched opioid receptor preparations, respectively. In rat brain tissue, (TH)ET binding is inhibited by DAGO (Tyr-D-Ala-Gly-(Me)-Phe-Gly-ol), a selective agonist, in a competitive manner without apparent modification of the maximal number of sites. Furthermore, even at a DAGO concentration (300 nM) which should be sufficient to block (TH)ET interaction with sites, no variation in the total capacity of the tritiated ligand is observed. In contrast, DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr), a delta-preferential agonist, blocks (TH)ET binding in rat brain at a concentration able to saturate delta-sites. At higher concentrations, where DTLET cross reacts with -sites, this ligand exhibits similar properties to those of DAGO. These data are very different from those obtained with (TH)EKC (ethylketocyclazocine), another universal ligand, the binding properties of which are easily explained by the occurrence in rat brain tissue of independent sites exhibiting pharmacological profiles of , delta and kappa sites. The authors results underline the possible misinterpretation of binding data obtained by using (TH) etorphine as a non-selective ligand. 28 references, 1 figure, 2 tables.

  18. 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

  19. Phagocytosis in Tetrahymena thermophila: naloxone-reversible inhibition by opiates.

    PubMed

    De Jesus, S; Renaud, F L

    1989-01-01

    1. Nanomolar concentrations of opiates inhibit phagocytosis in the ciliated protozoan Tetrahymena thermophila. 2. Naloxone and naltrexone counteract the effect of the opiate agonists tested. 3. The dose-response curves are U-shaped, with no detectable effect at low or high concentrations. 4. An increase in extracellular calcium and dopamine counteract the inhibition caused by metenkephalin. 5. The recognition mechanism for opiates in Tetrahymena cannot be classified as belonging to any of the mammalian opiate receptor subtypes and is perhaps a primitive receptor.

  20. 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.).

  1. Neurochemical substrates for opiate reinforcement.

    PubMed

    Koob, G F; Vaccarino, F J; Amalric, M; Bloom, F E

    1986-01-01

    The studies reported herein summarize our work to date aimed at determining the neurochemical substrates for the reinforcing properties of opiates. Rats were trained to self-administer heroin intravenously in daily 3-hour sessions, and pharmacological blockade and neurotoxin-induced lesions were used to define the neurochemical substrates for this reinforcing action. Low-dose DA receptor blockade failed to alter heroin self-administration but significantly increased cocaine self-administration, presumably reflecting a decrease in the reinforcing effectiveness of cocaine. Destruction of presynaptic DA terminals within the N.Acc. produced extinction of cocaine, but not heroin, self-administration. Opiate receptor blockade with systemic naloxone increased heroin, but not cocaine, self-administration. Methylnaloxonium injections into the N.Acc. were effective in increasing heroin self-administration at doses one-eighth those observed for intracerebroventricular injections. Reinforcement has been explored using a place-preference procedure and a self-administration drug-substitution paradigm. Mu/delta agonists such as B-END readily produce a naloxone-reversible place preference. Fentanyl derivatives also produce place preference and substitute for heroin during self-administration. The kappa agonist U50-488 produces place aversion, not place preference, and does not readily substitute for heroin. Altogether, these results suggest that mu/delta receptor subtypes in the region of the N.Acc. may be an important neurochemical substrate for opiate reinforcement.

  2. 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.

  3. 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

  4. (/sup 3/H)U-69593 labels a subtype of kappa opiate receptor with characteristics different from that labeled by (/sup 3/H)ethylketocyclazocine

    SciTech Connect

    Nock, B.; Rajpara, A.; O'Connor, L.H.; Cicero, T.J.

    1988-01-01

    (/sup 3/H)U-69593 is an opiate agonist that has been reported to bind in vitro with high affinity and selectivity to the kappa receptor subtype. The studies reported here were designed to determine the optimal conditions for labeling kappa receptors with (/sup 3/H)U-69593 and to further characterize the binding site. The effects of temperature and NaCl on (/sup 3/H)U-69593 binding were of particular interest because previous studies reported that (/sup 3/H)ethylketocyclazocine ((/sup 3/H)EKC) and (/sup 3/H)bremazocine binding to kappa receptors was optimal at 4/sup 0/C in the presence of NaCl. Those conditions were not found to be optimal for (/sup 3/H)U-69593 binding. Although the pharmacological specificity and Bmax of (/sup 3/H)U-69593 binding was similar at room temperature and at 4/sup 0/C, the binding affinity was approximately three times lower at 4/sup 0/C than at room temperature. In addition, NaCl had an effect on (/sup 3/H)U-69593 binding that was opposite that on (/sup 3/H)EKC binding at 4/sup 0/C. These differences between (/sup 3/H)U-69593 and (/sup 3/H)EKC binding at 4/sup 0/C were accentuated by a vast difference in the density of the binding sites and suggested that (/sup 3/H)U-69593 might bind selectively to a kappa receptor subtype.

  5. Inflated Reward Value in Early Opiate Withdrawal

    PubMed Central

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

    2014-01-01

    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 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/k.g., s.c.) daily for 11 d 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 d), as opposed to late (14-16 d) 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

  6. Drugs of abuse--opiates.

    PubMed Central

    Ling, W; Wesson, D R

    1990-01-01

    Treating opiate-dependent patients can be difficult for many physicians because the patients' life-styles, values, and beliefs differ from those of the physicians. Primary care physicians, however, are often involved in the treatment of the medical complications of opiate abuse, and physicians must often manage a patient's opiate dependence until appropriate referral to a drug abuse treatment program can be arranged. Treatment is guided by an understanding of the patient's addictive disease, for which there are specific diagnostic criteria, and an understanding of the pharmacology of opiates of abuse and the medications used in treating opiate dependence. The opiate agonist, methadone, is useful for both detoxification and maintenance. The opiate antagonist, naloxone, is the treatment of choice for opiate overdose, and naltrexone, also an opiate antagonist, is a useful adjunct in subgroups of opiate-dependent patients for preventing relapse. New medications for the treatment of opiate dependence are being developed. PMID:2161588

  7. 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

  8. The effects of opioid receptor antagonists suggest that testicular opiates regulate Sertoli and Leydig cell function in the neonatal rat.

    PubMed

    Gerendai, I; Shaha, C; Gunsalus, G L; Bardin, C W

    1986-05-01

    beta-Endorphin and other peptides derived from proopiomelanocortin are synthesized in testicular Leydig cells. To better understand the possible function of these and other endogenous opioid peptides in the testis, the opioid antagonists naloxone and nalmefene were administered intratesticularly to hemicastrated 5-day-old rats. Both naloxone and nalmefene potentiated testicular hypertrophy induced by unilateral orchidectomy at 11 days of age. Unexpectedly, at least a 100-fold lower dose of nalmefene was required to produce maximal hypertrophy than that previously reported for naloxone. Leydig and Sertoli cell functions were evaluated, respectively, by measurement of basal testosterone production in vitro and rat androgen-binding protein (rABP) in serum. The optimal dose of naloxone for hypertrophy (1 microgram/testis) suppressed testosterone production and had a nonuniform effect on rABP secretion (either had no effect or produced a slight increase). By contrast, the optimal dose of nalmefene for hypertrophy (0.01 microgram/testis) not only suppressed basal testosterone secretion, but also uniformly increased rABP levels in serum. Larger doses of this opioid antagonist, up to 1 microgram/testis, were not as effective on the three parameters measured (hypertrophy, testosterone secretion, and rABP levels). These results suggest that this agent has both antagonistic and agonistic activities in the testis. At the doses that produced optimal effects on hypertrophy, systemic administration of these antagonists produced no effects. The results of these studies suggest that intratesticular opiates exert a suppressive effect on Sertoli cell growth and rABP secretion. In addition, these peptides may modulate testosterone secretion by Leydig cells. PMID:3698906

  9. 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

  10. Subcellular plasticity of the corticotropin-releasing factor (CRF) receptor in dendrites of the mouse bed nucleus of the stria terminalis following chronic opiate exposure

    PubMed Central

    Jaferi, Azra; Lane, Diane A.; Pickel, Virginia M.

    2009-01-01

    Chronic opiate administration alters the expression levels of the stress-responsive peptide, corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST). This brain region contains CRF receptors that drive drug-seeking behavior exacerbated by stress. We used electron microscopy to quantitatively compare immunolabeling of the CRF receptor (CRFr) and CRF in the anterolateral BNST (BSTal) of mice injected with saline or morphine in escalating doses for 14 days. We also compared the results with those in non-injected control mice. The tissue was processed for CRFr immunogold and CRF immunoperoxidase labeling. The non-injected controls had a significantly lower plasmalemmal density of CRFr immunogold particles in dendrites compared with mice receiving saline, but not those receiving morphine, injections. Compared with saline, however, mice receiving chronic morphine showed a significantly lower plasmalemmal, and greater cytoplasmic, density of CRFr immunogold in dendrites. Within the cytoplasmic compartment of somata and dendrites of the BSTal, the proportion of CRFr gold particles associated with mitochondria was three times as great in mice receiving morphine compared with saline. This subcellular distribution is consistent with morphine-, and CRFr-associated modulation of intracellular calcium release or oxidative stress. The between-group changes occurred without effect on the total number of dendritic CRFr immunogold particles, suggesting that chronic morphine enhances internalization or decreases delivery of the CRFr to the plasma membrane, a trafficking effect that is also affected by the stress of daily injections. In contrast, saline and morphine treatment groups showed no significant differences in the total number of CRF-immunoreactive axon terminals, or the frequency with which these terminals contacted CRFr-containing dendrites. This suggests that morphine does not influence axonal availability of CRF in the BSTal. The results

  11. Preoperative ultra-rapid opiate detoxification for the treatment of post-operative surgical pain.

    PubMed

    Blum, James M; Biel, Sarang S; Hilliard, Paul E; Jutkiewicz, Emily M

    2015-06-01

    Over the past two decades, the prescription of high dose opiate therapy has continued to accelerate in an attempt to treat patients with chronic pain. This presents a substantial challenge when patients on high dose opiate therapy require surgery, as opiate pain relief is a cornerstone of postoperative pain management. These patients have exceptionally challenging pain to control. This is likely due to downregulation of existing opiate receptors and the reluctance of clinicians to increase doses of opiates to exceptionally high levels to facilitate pain relief. We hypothesize that using the method of ultra-rapid opiate detoxification (UROD), it would be possible to rapidly increase the number of opiate receptors and return patients to a more naive state, which would be susceptible to exogenous opiate administration. Validation of this hypothesis is supported by two mechanisms, the first of which are reports of patients that underwent UROD for opiate addition that subsequently suffer respiratory arrests when beginning to rapidly abuse opiates shortly after treatment. Additionally there are data demonstrating the tapering of opiate therapy prior to elective surgery results in better pain control. In conclusion, we hypothesize that patients on chronic high dose opiates could obtain substantially better pain relief if they underwent UROD prior to surgery. This technique could be administered shortly before surgery and may dramatically improve the patients' recoveries.

  12. 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

  13. 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.

  14. 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.

  15. Distribution of opiate alkaloids in brain tissue of experimental animals

    PubMed Central

    Pilija, Vladimir; Mimica-Dukic, Neda; Budakov, Branislav; Cvjeticanin, Stanko

    2012-01-01

    The present study examined regional distribution of opiate alkaloids from seized heroin in brain regions of experimental animals in order to select parts with the highest content of opiates. Their analysis should contribute to resolve causes of death due to heroin intake. The tests were performed at different time periods (5, 15, 45 and 120 min) after male and female Wistar rats were treated with seized heroin. Opiate alkaloids (codeine, morphine, acetylcodeine, 6-acetylmorphine and 3,6-diacetylmorphine) were quantitatively determined in brain regions known for their high concentration of µ-opiate receptors: cortex, brainstem, amygdala and basal ganglia, by using gas chromatography–mass spectrometry (GC–MS). The highest content of opiate alkaloids in the brain tissue of female animals was found 15 min and in male animals 45 min after treatment. The highest content of opiates was determined in the basal ganglia of the animals of both genders, indicating that this part of brain tissue presents a reliable sample for identifying and assessing contents of opiates after heroin intake. PMID:23554560

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

    PubMed Central

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

    2016-01-01

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both rewarding effects of drug and the desire to avoid withdrawal symptoms motivate continued drug use1-3, and the nucleus accumbens (NAc) is important for orchestrating both processes4,5. While multiple inputs to the NAc regulate reward6-9, little is known about the NAc circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus (PVT) as a prominent input to the NAc mediating the expression of opiate withdrawal induced physical signs and aversive memory. Activity in the PVT to NAc pathway is necessary and sufficient to mediate behavioral 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 PVT and D2-receptor-expressing medium spiny neurons (D2-MSNs) via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at PVT→D2-MSNs synapses and robustly suppresses morphine withdrawal symptoms. These results link morphine-evoked pathway- and cell type-specific plasticity in the PVT→NAc circuit to opiate dependence, and suggest that reprogramming this circuit holds promise for treating opiate addiction. PMID:26840481

  17. 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.

  18. Nuclear estrogen receptor molecular heterogeneity in the mouse uterus.

    PubMed Central

    Golding, T S; Korach, K S

    1988-01-01

    Holomeric estrogen receptor (ER) prepared from ovariectomized mouse uteri displays heterogeneous electrophoretic mobility when analyzed by NaDodSO4/PAGE. ER derived from nuclei (ERn) appears as a closely spaced doublet having apparent molecular masses of 66.4 and 65 kDa, while ER from the cytosolic compartment (ERc) has a single band of 65 kDa. Both partially purified ERc and the 8S form of unactivated ERc show only the 65-kDa band. The appearance of the ERn doublet is hormonally inducible, and the relative proportions of the two doublet bands are influenced by the type of hormone treatment, with weakly estrogenic compounds yielding the lower band as predominant while potent estrogens increase the proportion of the upper band. Steroid binding of the ERn doublet was determined by [3H]tamoxifen aziridine affinity labeling of both the 66.4- and the 65-kDa peptides; binding to the 65-kDa peptide was predominant. The ERn doublet displays a time dependency after estrogen administration with maximal amounts occurring in a bimodal fashion at 1 and 8 hr. Images PMID:3422428

  19. Nuclear estrogen receptor molecular heterogeneity in the mouse uterus

    SciTech Connect

    Golding, T.S.; Korach, K.S.

    1988-01-01

    Holomeric estrogen receptor (ER) prepared from ovariectomized mouse uteri displays heterogeneous electrophoretic mobility when analyzed by NaDodSO/sub 4//PAGE. ER derived from nuclei (ER/sub n/) appears as a closely spaced doublet having apparent molecular masses of 66.4 and 65 kDa, while ER from the cytosolic compartment (ER/sub c/) has a single band of 65 kDa. Both partially purified ER/sub c/ and the 8S form of unactivated ER/sub c/ show only the 65-kDa band. The appearance of the ER/sub n/ doublet is hormonally inducible, and the relative proportions of the two doublet bands are influenced by the type of hormone treatment, with weakly estrogenic compounds yielding the lower band as predominant while potent estrogens increase the proportion of the upper band. Steroid binding of the ER/sub n/ doublet was determined by (/sup 3/H)tamoxifen aziridine affinity labeling of both the 66.4- and the 65-kDa peptides; binding to the 65-kDa peptide was predominant. The ER/sub n/ doublet displays a time dependency after estrogen administration with maximal amounts occurring in a bimodal fashion at 1 and 8 hr.

  20. 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.

  1. Genetics of opiate addiction.

    PubMed

    Reed, Brian; Butelman, Eduardo R; Yuferov, Vadim; Randesi, Matthew; Kreek, Mary Jeanne

    2014-11-01

    Addiction to MOP-r agonists such as heroin (and also addiction to prescription opioids) has reemerged as an epidemic in the twenty first century, causing massive morbidity. Understanding the genetics contributing to susceptibility to this disease is crucial for the identification of novel therapeutic targets, and also for discovery of genetic markers which would indicate relative protection or vulnerability from addiction, and relative responsiveness to pharmacotherapy. This information could thus eventually inform clinical practice. In this review, we focus primarily on association studies of heroin and opiate addiction, and further describe the studies which have been replicated in this field, and are thus more likely to be useful for translational efforts.

  2. Mammalian opiate alkaloid synthesis: lessons derived from plant biochemistry.

    PubMed

    Meijerink, W J; Molina, P E; Abumrad, N N

    1999-09-01

    The presence of opiate receptors in mammalian tissues has stimulated the search for endogenous ligands to these receptors and has led to the discovery and characterization of endogenous opioid peptides. However, recent studies have provided evidence for the presence of opiate alkaloids in mammalian tissues and for their endogenous synthesis. The study of their origin and synthetic pathway has been significantly influenced by the early classical biochemical studies performed in plants. This review is a historical account of the use and abuse of opiates, the elucidation of morphine's synthetic pathway in the poppy plant, and the subsequent characterization of its presence in mammalian tissues. Clearly, our understanding of its synthetic pathway and regulation is a reflection of observations originally made in plant biochemistry.

  3. Opiate use and sexual function.

    PubMed

    Mirin, S M; Meyer, R E; Mendelson, J H; Ellingboe, J

    1980-08-01

    Although opiate addicts often equate the drug experience with sexual orgasm, diminished libido and impaired sexual performance are common sequelae of chronic use. Early clinical studies suggested that opiates may interfere with sex hormone secretion. The authors carried out three sequential studies which demonstrated that heroin use in man results in acute suppression of luteinizing hormone (LH) release from the pituitary followed by a secondary drop in plasma testosterone levels. The time course of these neuroendocrine events correlates well with the tension-reducing effects of heroin and suggests that drive reduction is an important component of opiate reinforcement. PMID:6774622

  4. 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.

  5. 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

  6. Bioluminescence Microscopy as a Method to Measure Single Cell Androgen Receptor Activity Heterogeneous Responses to Antiandrogens

    PubMed Central

    Jain, Pallavi; Neveu, Bertrand; Velot, Lauriane; Wu, Lily; Fradet, Yves; Pouliot, Frédéric

    2016-01-01

    Cancer cell heterogeneity is well-documented. Therefore, techniques to monitor single cell heterogeneous responses to treatment are needed. We developed a highly translational and quantitative bioluminescence microscopy method to measure single cell androgen receptor (AR) activity modulation by antiandrogens from fluid biopsies. We showed that this assay can detect heterogeneous cellular response to drug treatment and that the sum of single cell AR activity can mirror the response in the whole cell population. This method may thus be used to monitor heterogeneous dynamic treatment responses in cancer cells. PMID:27678181

  7. 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

  8. Personality dimensions of opiate addicts.

    PubMed

    Vukov, M; Baba-Milkic, N; Lecic, D; Mijalkovic, S; Marinkovic, J

    1995-02-01

    A survey of 80 opiate addicts included in a detoxification program was conducted at the Institute on Addictions in Belgrade. In addition to a dependence diagnosis and mental disorders based on DSM-III-R, we applied a Tridimensional Personality Questionnaire (TPQ) that measures the 3 major personality dimensions: novelty-seeking (NS), harm avoidance (HA) and reward dependence (RD). When compared with a control group (a sample of Yugoslav undergraduate students), the opiate addicts demonstrate significantly high NS dimension as well as significant divergences of HA and RD subscales. The surveyed opiate addicts demonstrate a high percentage of personality disorders specifically in cluster B. The personality dimensions of opiate addicts showed certain temperament traits, such as: impulsiveness, shyness with strangers, fear of uncertainty and dependence. NS, HA and RD determined by temperament specifics may be an etiological factor in forming of a personality disorder, an affective disorder as well as of a drug choice.

  9. GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia.

    PubMed

    Gong, Kerui; Bhargava, Aditi; Jasmin, Luc

    2016-01-01

    The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. In this study, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in the expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions. Patch clamp recordings from intact dorsal root ganglions (ex vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (>30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree by the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1. Coadministration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and excitatory amino acid transporter 3/excitatory amino acid carrier 1, but not of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2. These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDA receptors in the periphery may be a target for therapy.

  10. Opiate antagonists stimulate affiliative behaviour in monkeys.

    PubMed

    Fabre-Nys, C; Meller, R E; Keverne, E B

    1982-04-01

    The effects of treating captive talapoin monkeys acutely (twice daily for 7 days) with naltrexone hydrochloride (0.25 mg 0.5 mg and 1 mg/kg intramuscular injections twice daily), naloxone hydrochloride (0.5 mg/kg IM twice daily) and sulpiride (1.5 mg/kg IM twice daily) was studied in social pairs and singly caged animals. The behaviour of social pairs and endocrine changes in all treated monkeys were monitored before, during and after withdrawal of the course of drug treatment. Naltrexone and naloxone, but not sulpiride, significant increased grooming and grooming invitations while aggressive behaviour, self grooming, scratching and general locomotor activity were unaffected. There was an overall increase in LH, testosterone and cortisol in plasma samples taken 60 mins after opiate receptor blockade. Prolactin was unchanged but increased dramatically in animals treated with sulpiride. No significant endocrine changes were observed to precede the increased grooming behaviour which opiate receptor blockade induced. The behavioural changes reported for this primate support the view that positive affect arising from social bonds may be mediated by cerebral endorphin containing systems. PMID:6280208

  11. 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.

  12. Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries.

    PubMed Central

    Simonsen, U.; Prieto, D.; Rivera, L.; Hernández, M.; Mulvany, M. J.; García-Sacristán, A.

    1993-01-01

    1. In vitro experiments in a microvascular myograph were designed to characterize postjunctional muscarinic receptors producing contraction both in the presence and absence of the endothelium in coronary resistance arteries (normalized diameter of 150-450 microns), isolated from the left ventricle of hearts from 3-6 month old lambs. Preferential muscarinic receptor antagonists were used to determine the receptor subtype: pirenzepine (M1 receptor), AFDX 116 (M2 receptor), 4-DAMP and pFHHSiD (M3 receptor). 2. The rank order of potency for muscarinic agonist-induced increases in tension in endothelium-intact preparations was oxotremorine-M = methacholine = acetylcholine (ACh) > carbachol. Removal of the endothelium increased the potency of ACh, but this procedure did not change either the sensitivity or maximal response to carbachol. 3. The contractile response to ACh was reproducible. Incubation with 3 x 10(-7)-3 x 10(-6) M pirenzepine induced non-parallel rightward shifts and depressed the maximum of the concentration-response curve to ACh in endothelium-intact arteries. The slope by Schild analysis was 2.9 +/- 0.8 (P < 0.05, n = 7). Atropine, AFDX 116, 4-DAMP and pFHHSiD produced parallel rightward shifts of the curves to ACh and the slopes of the Schild plots were not significantly different from unity. The pKB values for the antagonists from plots constrained to unity in endothelium-intact segments were: atropine (9.4), 4-DAMP (9.0), pFHHSiD (7.9) and AFDX 116 (6.2). 4. In endothelium-denuded arteries, pirenzepine, AFDX 116 and pFHHSiD caused concentration-dependent, parallel rightward displacements of the concentration-response curves to ACh and the slopes of the Schild plots were not significantly different from unity. The plots constrained to a slope of unity gave the following pKB values: pFHHSiD (8.7), pirenzepine (7.5) and AFDX 116 (6.2). 5. In the presence of the endothelium, low concentrations of pirenzepine (10(-9)-10(-7) M) produced leftward shifts of

  13. Heterogeneous expression of Drosophila gustatory receptors in enteroendocrine cells.

    PubMed

    Park, Jeong-Ho; Kwon, Jae Young

    2011-01-01

    The gastrointestinal tract is emerging as a major site of chemosensation in mammalian studies. Enteroendocrine cells are chemosensory cells in the gut which produce regulatory peptides in response to luminal contents to regulate gut physiology, food intake, and glucose homeostasis, among other possible functions. Increasing evidence shows that mammalian taste receptors and taste signaling molecules are expressed in enteroendocrine cells in the gut. Invertebrate models such as Drosophila can provide a simple and genetically tractable system to study the chemosensory functions of enteroendocrine cells in vivo. To establish Drosophila enteroendocrine cells as a model for studying gut chemosensation, we used the GAL4/UAS system to examine the expression of all 68 Gustatory receptors (Grs) in the intestine. We find that 12 Gr-GAL4 drivers label subsets of enteroendocrine cells in the midgut, and examine colocalization of these drivers with the regulatory peptides neuropeptide F (NPF), locustatachykinin (LTK), and diuretic hormone 31 (DH31). RT-PCR analysis provides additional evidence for the presence of Gr transcripts in the gut. Our results suggest that the Drosophila Grs have chemosensory roles in the intestine to regulate physiological functions such as food uptake, nutrient absorption, or sugar homeostasis. PMID:22194978

  14. [Effect of blockade of opiate receptors by naloxone on lutropin (LH), follitropin (FSH) and testosterone secretion in patients after kidney transplantation].

    PubMed

    Grzeszczak, W; Zukowska-Szczechowska, E; Kokot, F

    1992-01-01

    The influence of opioid receptors blockade by naloxone on lutropin (LH), follitropin (FSH) and testosterone secretion induced by LH-RH was assessed in 12 male kidney transplant patients with stable graft function (KTP) treated by cyclosporine A and prednisone and in 15 healthy subjects. In KTP normal plasma levels of LH in spite of significantly reduced testosteronemia and a reduced response of LH to LH-RH was observed. After blockade of opioid receptors by naloxone normalization of the response of LH secretion to LH-RH was found and a higher increase of the plasma testosterone level was observed in KTP than in healthy subjects. Results obtained in this study suggest abnormal functioning of the hypothalamic-pituitary--gonadal axis in KTP and participation of opioid receptors in its pathogenesis.

  15. Modulation of the estrogen receptor structure, evidence of a heterogeneity

    SciTech Connect

    Toulas, C.; Guilbaud, N.; Delassus, F.; Bayard, F.; Faye, J.C. )

    1990-01-01

    In order to analyse the molecular weight polymorphism of the estrogen receptor (ER) in MCF-7 cells, we have developed a procedure which allowed in situ linkage of ER by (3H) tamoxifen aziridine and provided labelled proteins in conditions which minimized protease activities. After labelling, cell lysis was performed in SDS buffer containing various concentrations of mercaptoethanol. Proteins extracted with phenolic solution and precipitated by cold acetone were analysed by SDS PAGE. It appears that beside the form of 67 kDa already described, binding entities of tamoxifen aziridine were also present at a molecular mass of 110 kDa and 45 kDa. On the other hand, investigations on the effect of 12-0-Tetradecanoyl Phorbol 13-Acetate (TPA) showed that TPA induces a decrease of the 67 kDa entity.

  16. Bullfrog retinal bipolar cells may express heterogeneous glycine receptors at dendrites and axon terminals.

    PubMed

    Du, Jiu-Lin; Yang, Xiong-Li

    2002-04-12

    Subcellular localization and properties of glycine receptors on bipolar cells (BCs) were studied using whole-cell recordings and non-stationary noise analysis (NSNA) in bullfrog retinal slices. The currents elicited by focally applied glycine were of comparable amplitudes at the dendrites and axon terminals of both OFF and ON BCs. Moreover, glycine receptors were also expressed at the axons of some BCs. NSNA revealed that the weighted mean single-channel conductance of the glycine receptors at the dendrites (18.2 pS) was significantly larger than that of those at the axon terminals (8.1 pS), thus implying that the glycine receptors on bullfrog retinal BCs may be heterogeneous at these two sites.

  17. 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

  18. Genetic toxicology of remifentanil, an opiate analgesic.

    PubMed

    Allen, Jane S; Campbell, James A; Cariello, Neal F; Kutz, Stephen A; Thilagar, Arul; Xu, Jing; Ham, Andrea L; Mitchell, Ann D

    2003-01-01

    Compounds that interact with opioid receptors are commonly used as analgesics. Opioid agonists vary in their potency and pharmacokinetic properties as well as in their affinity for distinct opioid receptors. The fentanyl opiate analogues are an important group of analgesics that interact with the mu opioid receptor. Remifentanil (GI87084) is a particularly interesting member of this group of opioids because its action is especially short in duration. This report examines the genetic toxicology of remifentanil. Remifentanil was not genotoxic in an Ames test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro L5178Y tk(+/-) mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels >or=308 microg/mL only in the presence of rat liver S9 metabolic activation; primarily tiny and small mutant colonies were produced. This pattern of activity in a battery of genetic toxicology assays is not unique to remifentanil, but has also been observed for other pharmaceuticals, including the opioid fentanyl. A weight-of-evidence analysis, taking into consideration genotoxic mechanisms, in vivo results, and the conditions of clinical use, suggests remifentanil does not pose a genotoxic risk to patients.

  19. ERrrr…where are the progenitors? Hormone receptors and mammary cell heterogeneity.

    PubMed

    Tornillo, Giusy; Smalley, Matthew J

    2015-06-01

    The mammary epithelium is a highly heterogenous and dynamic tissue that includes a range of cell types with varying levels of proliferative capacity and differentiation potential, from stem to committed progenitor and mature cells. Generation of mature cells through expansion and specification of immature precursors is driven by hormonal and local stimuli. Intriguingly, although circulating hormones can be directly sensed only by a subset of mammary cells, they also regulate the behaviour of cells lacking their cognate receptors through paracrine mechanisms. Thus, mapping the hormonal signalling network on to the emerging mammary cell hierarchy appears to be a difficult task. Nevertheless, a first step towards a better understanding is the characterization of the hormone receptor expression pattern across individual cell types in the mammary epithelium. Here we review the most relevant findings on the cellular distribution of hormone receptors in the mammary gland, taking into account differences between mice and humans, the methods employed to assess receptor expression as well as the variety of approaches used to resolve the mammary cell heterogeneity.

  20. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    SciTech Connect

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

  1. 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

  2. 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.

  3. 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

  4. The effect of opiates and opiate antagonists on heat latency response in the parasitic nematode Ascaris suum.

    PubMed

    Pryor, Stephen C; Nieto, Fernando; Henry, Sherwyn; Sarfo, Jennifer

    2007-04-10

    The effects of the opiates morphine and morphine-6-glucuronide (M6G), the mu opioid receptor specific antagonist D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH(2) (CTOP), and the general opiate antagonist naloxone on the latency of response to thermal stimulation were determined in the parasitic nematode Ascaris suum. Thermal detection and avoidance behaviors of the worms were evaluated with a tail flick analgesia meter using a modification of a technique employed for nociception experiments in rodents. Morphine and M6G were shown to have a dose dependent analgesic effect on A. suum's latency of response to heat with morphine being the most potent. The analgesic effect of morphine was reversed by naloxone but not CTOP. Neither naloxone nor CTOP was able to block the analgesia of M6G. CTOP but not naloxone had significant analgesic effects on its own. These findings are generally consistent with previous results on the effects of opiates and nitric oxide release from A. suum tissue. Apparently these nematodes possess opioid receptors that effect nociception.

  5. Opiate and Cocaine Exposed Newborns: Growth Outcomes.

    ERIC Educational Resources Information Center

    Butz, Arlene M.; Kaufmann, Walter E.; Royall, Richard; Kolodner, Ken; Pulsifer, Margaret B.; Lears, Mary Kathleen; Henderson, Robin; Belcher, Harolyn; Sellers, Sherri; Wilson, Modena

    1999-01-01

    Examines growth parameters at birth in 204 infants born to mothers who used cocaine and/or opiates during pregnancy. Outcome measures included birth weight, length, and head circumference. Study provides support that in utero cocaine exposure may confer more risk for somatic growth retardation at birth than opiate exposure. (Author/GCP)

  6. Opiate modification of intracranial self-stimulation in the rat.

    PubMed

    Weibel, S L; Wolf, H H

    1979-01-01

    Studies were conducted to confirm the involvement of central opiate receptors in the expression of opiate modulation of intracranial self-stimulation (ICSS). Biphasic, dose-related changes in ICSS responding are described following IP administration of morphine sulfate (1-25 mg/kg) and levorphanol tartrate (LEV, 0.5-5 mg/kg). Similar patterns of response modification are reported following intraventricular (IVt) administration of LEV (0.01-0.2 muMoles) LEV's enantiomorph, dextrorphan, was not found to elicit comparable effects after either IP or IVt administration. Both the facilitatory and the depressant phases of LEV's action were antagonized by naltrexone (10 microgram, IVt), which had no apparent effect on ICSS by itself. Complete tolerance developed to the suppression of responding by 2.5 mg/kg LEV (IP) but not to the facilitatory effect of 0.5 mg/kg (IP), during a 5-day course of administration. The implications of these results for opiate reinforcement theory are discussed and possible mechanisms are advanced.

  7. 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.

  8. 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

  9. 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

  10. Significance of GABA(A) receptor heterogeneity: clues from developing neurons.

    PubMed

    Fritschy, Jean-Marc

    2015-01-01

    Briefly after the landmark discovery by Hanns Möhler that GABA(A) receptors (GABA(A)R) are the site of action of benzodiazepine site ligands, their distribution in the rodent CNS during development was mapped by autoradiography, demonstrating early and widespread expression of GABA(A)R in the brain and spinal cord. Ten years later, the first studies using subunit-specific antibodies revealed unsuspected heterogeneity in the subunit composition of GABA(A)R in developing brain, with striking regional specificity and rapid changes in expression and subcellular localization correlating with the maturation of neuronal circuits. These data contributed to the wealth of evidence that GABAergic neurotransmission, acting both synaptically and extrasynaptically, modulates major steps of neuronal development (proliferation, migration, differentiation, and circuit formation). In immature neurons, GABA(A)R activation leads to neuronal depolarization and activation of Ca(2+) signals, which mediate many of the developmental effects of GABA. Therefore, GABA(A)R heterogeneity might be essential to fine-tune GABA actions in the dynamics of CNS maturation. Furthermore, since a disturbance of GABAergic function during ontogeny can potentially affect many aspects of CNS maturation and contribute to the etiology of major brain disorders, GABA(A)R heterogeneity provides a substrate for the development of a tailored pharmacology targeting specific receptor subtypes. This chapter provides a brief overview of these issues with a special focus on the seminal contributions of Hanns Möhler to the emergence of these concepts of fundamental relevance in today's neuroscience research and pharmacological developments. PMID:25637436

  11. 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

  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.

  13. Opiate Exposure State Controls a D2-CaMKIIα-Dependent Memory Switch in the Amygdala-Prefrontal Cortical Circuit.

    PubMed

    Rosen, Laura G; Zunder, Jordan; Renard, Justine; Fu, Jennifer; Rushlow, Walter; Laviolette, Steven R

    2016-02-01

    The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. In the opiate-naïve state, reward memory formation in the BLA involves a functional link between dopamine (DA) D1 receptor (D1R) and extracellular signal-related kinase 1/2 (ERK1/2) signaling substrates, but switches to a DA D2 (D2R)/Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα)-dependent memory substrate following chronic opiate exposure and spontaneous withdrawal. Using conditioned place preference (CPP) in rats paired with molecular analyses, we examined the role of intra-mPFC CaMKII, ERK and DAergic activity during the formation of opiate associative memories, and how opiate exposure state may regulate the functions of these molecular memory pathways. We report that the role of CaMKIIα signaling is functionally reversed within the BLA-mPFC pathway depending on opiate exposure state. Thus, in the opiate-naïve state, intra-mPFC but not intra-BLA blockade of CaMKII signaling prevents formation of opiate reward memory. However, following chronic opiate exposure and spontaneous withdrawal, the role of CaMKII signaling in the BLA-mPFC is functionally reversed. This behavioral memory switch corresponds to a selective increase in the expression of D2R and CaMKIIα, but not other calcium/calmodulin-related molecules, nor D1R expression levels within the mPFC.

  14. Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries.

    PubMed

    Prieto, Dolores; Arcos, Luis Rivera de Los; Martínez, Pilar; Benedito, Sara; García-Sacristán, Albino; Hernández, Medardo

    2004-12-01

    -36) evoked potent slow relaxations in NA-precontracted arteries, under conditions of nitric oxide (NO) synthase blockade. Mechanical removal of the endothelium markedly enhanced contractions of NPY on NA-precontracted arteries, whereas blockade of the neuronal voltage-dependent Ca(2+) channels did not alter NPY responses. These results demonstrate that NPY can elicit dual contractile/relaxing responses in penile small arteries through a heterogeneous population of postjunctional NPY receptors. Potentiation of the contractions evoked by NA involve both NPY Y(1) and NPY Y(2) receptors. An NO-independent relaxation probably mediated by an atypical endothelial NPY receptor is also shown and unmasked in the presence of selective antagonists of the NPY contractile receptors.

  15. Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries

    PubMed Central

    Prieto, Dolores; Arcos, Luis Rivera de los; Martínez, Pilar; Benedito, Sara; García-Sacristán, Albino; Hernández, Medardo

    2004-01-01

    relaxations in NA-precontracted arteries, under conditions of nitric oxide (NO) synthase blockade. Mechanical removal of the endothelium markedly enhanced contractions of NPY on NA-precontracted arteries, whereas blockade of the neuronal voltage-dependent Ca2+ channels did not alter NPY responses. These results demonstrate that NPY can elicit dual contractile/relaxing responses in penile small arteries through a heterogeneous population of postjunctional NPY receptors. Potentiation of the contractions evoked by NA involve both NPY Y1 and NPY Y2 receptors. An NO-independent relaxation probably mediated by an atypical endothelial NPY receptor is also shown and unmasked in the presence of selective antagonists of the NPY contractile receptors. PMID:15557288

  16. Differentiation of personality types among opiate addicts.

    PubMed

    Blatt, S J; Berman, W H

    1990-01-01

    A wide range of studies indicate that although sociopathic characteristics are predominant in opiate addiction, depressive and psychotic features are also frequently observed. To test the hypothesis that there are really three types of individuals who become addicted to opiates (rather than a single, predominant personality style), fifty-three opiate addicts were given the Loevinger Sentence Completion Test, the Bellak Ego Functions Interview, and the Rorschach. Variables derived from these three procedures were submitted to cluster and discriminant function analyses. Three groups of addicts were identified--those primarily with impaired interpersonal relationships and affective lability (42%), those primarily characterized by thought disorder and impaired ego functioning (30%), and a group with diminished ideational and verbal activity (28%). Comparison of the assessment of these three groups with independently defined normal, neurotic, and schizophrenic samples provided support for three opiate-addicted personality types, each respectively characterized as character disordered, borderline psychotic, and depressed. Although there seems to be a predominance of character-disordered individuals who become addicted to opiates, the data indicate several additional types of opiate addicts with different types of psychopathology who may require different approaches to management and treatment.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. Multiple effects of opiates on intracellular calcium level and on calcium uptake in three neuronal cell lines.

    PubMed

    Fields, A; Gafni, M; Oron, Y; Sarne, Y

    1995-07-31

    The present study examines the modulation by opiates of intracellular calcium levels and calcium entry, using fura-2 imaging and 45Ca2+ uptake, in three neuronal cell lines. We show that opiates (10(-7)-10(-5) M morphine and 10(-9)-10(-7) M etorphine) exert both inhibitory and excitatory effects on KCl-induced elevation in intracellular calcium level in SK-N-SH, NG108-15 and NMB cell lines. In addition, opiates elevate basal (non KCl-stimulated) intracellular calcium level in all three cell cultures. 45Ca2+ uptake is augmented by opiates in SK-N-SH cells and this stimulatory effect is not blocked by pertussis toxin. In NMB cells, an additional inhibitory effect of opiates on basal calcium takes place: opiates reduce intracellular calcium level as measured by fura-2, and decrease calcium influx as detected by 45Ca2+ uptake. The heterogeneity in the opioid regulation of calcium could not be attributed to the type of opioid drug, neither to its concentration nor to the experimental conditions, since neighboring cells within the same culture responded differently.

  3. An opiate cocktail that reduces morphine tolerance and dependence.

    PubMed

    He, Li; Whistler, Jennifer L

    2005-06-01

    Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor [1]. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [2], whereas the endogenous ligands and methadone do facilitate endocytosis [3]. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [4], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors.

  4. Opiate-induced changes in brain adenosine levels and narcotic drug responses.

    PubMed

    Wu, M; Sahbaie, P; Zheng, M; Lobato, R; Boison, D; Clark, J D; Peltz, G

    2013-01-01

    We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid-induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10-40 mg/kg) administered over a 4-day period selectively induced a twofold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (p<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor(1) (A(1)) agonist (2-chloro-N6-cyclopentyladenosine, 0.5mg/kg) or an A(2a) receptor (A(2a)) antagonist (SCH 58261, 1mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal.

  5. Opiate agonists and antagonists modulate taste perception in opiate-maintained and recently detoxified subjects.

    PubMed

    Green, Amy; Kaul, Arun; O'Shea, Jacinta; Sharma, Ekta; Bennett, Lisa; Mullings, Emma L; Munafò, Marcus R; Nutt, David J; Melichar, Jan K; Donaldson, Lucy F

    2013-03-01

    Heroin addicts consume large quantities of refined sugars. This study investigated the effect of opiate use and antagonism on sweet taste in opiate-maintained drug users and detoxified former chronic opiate users, using a within-subject design. Seven opiate users received methadone and seven buprenorphine maintenance. Six detoxified subjects received naltrexone. Sucrose recognition thresholds and measurements of pleasantness and intensity were determined before and four hours after 1) a single dose of methadone or buprenorphine or 2) naltrexone. Control data were taken from a cohort of healthy volunteers including smokers. All measures of sweet and salt taste perception were significantly greater in opiate users and recently detoxified subjects compared to control subjects, with the exception of sweet pleasantness, which returned to control level after detoxification. Acute methadone administration reduced salt thresholds and unpleasantness to control levels. Increased sweet thresholds and salt unpleasantness in detoxified subjects were reversed by acute opioid antagonism, returning to control levels. These results suggest that opiate use and antagonism alters taste perception. Some of the alterations reverse on detoxification (sweet pleasantness), and others can be reversed by opioid antagonism (sweet threshold, salt unpleasantness). Changes in taste perception may underlie altered consumption of refined sugars in opiate users.

  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. 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... DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3650 Opiate test system. (a) Identification. An opiate test system is a device intended to measure any of...

  8. 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... DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3650 Opiate test system. (a) Identification. An opiate test system is a device intended to measure any of...

  9. The poet syndrome: opiates, psychosis and creativity.

    PubMed

    Rauch, L

    2000-01-01

    For some people, heroin is a self-medicating tool used to control innate psychic sensitivity. The habitual use of heroin provides the sensitive addict with a definition of consciousness by containment, psychic buffering, and psychic marking. This article is an examination of the political and social history of opiates, opiates as antipsychotics, "drug of choice" as a determinant of self-medication, and the connection between creativity, spirituality, psychosis and addiction. Using clinical observation, the article explores the poet syndrome hypothesis and offers direction for an alternative drug treatment paradigm.

  10. 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.

  11. PROGNOSTIC SIGNIFICANCE OF PSYCHOPATHOLOGY IN THE ABSTINENCE FROM OPIATE ADDICTION

    PubMed Central

    Satija, D.C.; Sharma, D.K.; Gaur, Arun; Nathawat, S.S.

    1989-01-01

    SUMMARY The aim of the present study was to find out the influence of psychopathology on abstinence from opiate addiction. A group of 54 opiate addicts with psychopathology was compared with another group of 55 opiate addicts without psychopathology. Both the groups were detoxified and followed up for a period of 12 months. Common psychopathology in opiate addicts consisted of psychopathic personality disorder, manic depressive psychosis, schizophrenia and psychosomatic and neurotic disorders. Abstinence rate was 18.8% in opiate addicts with psychopathology in contrast to 60.8% in addicts without psychopathology. The implications of the findings have been discussed. PMID:21927375

  12. Effects of exogenous and endogenous opiates on the hypothalamic--pituitary--gonadal axis in the male.

    PubMed

    Cicero, T J

    1980-06-01

    Narcotics acutely depress serum testosterone levels in the male. Three mechanisms could be involved: an enhancement of the degradation of testosterone; a direct inhibition of testicular steroidogenesis; or, finally, an inhibition of the hypothalamic-pituitary-luteinizing hormone (LH) axis resulting in a reduction in LH-dependent testicular steroidogenesis. The currently available evidence indicates that narcotics do not affect the catabolism of testosterone by the liver or testicular steroidogenesis. Rather, the data favor a direct action on the hypothalamic--pituitary--LH axis, probably by inhibiting the secretion of LH-releasing hormone (LH-RH) from the hypothalamus. The effects of narcotics on serum LH appear to be mediated via specific opioid receptors, suggesting that a naturally occurring opioid-like substance exists that normally inhibits LH. In support of this conclusion, opiate receptor blockers markedly increase serum LH levels shortly after their subcutaneous administration. In addition, endogenous opioids also seem to participate in testosterone's negative feedback control of the hypothalamic--pituitary--LH axis. Thus, it appears that opiate drugs inhibit the function of the hypothalamic-pituitary-gonadal axis by occupying opiate receptors in the hypothalamus and, moreover, that endogenous opioids exist that normally bind to these receptors and regulate activity in this axis.

  13. Adjunctive drug use among opiate addicts.

    PubMed

    Navaratnam, V; Foong, K

    1990-01-01

    In a study of 249 opiate (mainly heroin) addicts special attention was paid to adjunctive drug use. Generally, nicotine (cigarette smoking), alcohol and cannabis preceded the use of heroin, and continued to be used as adjunctive drugs after the establishment of heroin addiction. Nicotine was the most common substance used together with opiates. Alcohol and cannabis were used as adjunctive drugs in about two-thirds of the cases. In the late stages of heroin addiction, benzodiazepines were also used concomitantly with opiates. The most frequently reported reason for the use of adjunctive drugs was to intensify the effect of the opiate. Three-quarters or more of the addicts had used different adjunctive drugs to boost the euphoric feeling derived from the primary drug, i.e. heroin. Attempt at self-treatment of withdrawal symptoms was a less frequently reported reason for adjunctive drug use. The findings show that heroin addiction is the major problem. The use of adjunctive drugs, especially benzodiazepines, can be partly explained on economic grounds. They must be clearly distinguished from the primary drug of abuse, heroin. For policy-making decisions, it is important that the elimination of heroin abuse through effective prevention measures would ultimately wipe out the problem of adjunctive drug use, while reduction of the overall supply of heroin without reduction in actual demand might result in an increasing trend to adjunctive drug use.

  14. Attributions and Relapse in Opiate Addicts.

    ERIC Educational Resources Information Center

    Bradley, Brendan P.; And Others

    1992-01-01

    Investigated whether attributions of opiate addicts would predict abstinence and reactions to abstinence violations. Found that addicts who at admission attributed to themselves greater responsibility for negative outcomes and who attributed relapse episodes to more personally controllable factors were subsequently more likely either to be…

  15. Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus

    PubMed Central

    Höft, Simon; Griemsmann, Stephanie; Seifert, Gerald; Steinhäuser, Christian

    2014-01-01

    Astrocytes may express ionotropic glutamate and gamma-aminobutyric acid (GABA) receptors, which allow them to sense and to respond to neuronal activity. However, so far the properties of astrocytes have been studied only in a few brain regions. Here, we provide the first detailed receptor analysis of astrocytes in the murine ventrobasal thalamus and compare the properties with those in other regions. To improve voltage-clamp control and avoid indirect effects during drug applications, freshly isolated astrocytes were employed. Two sub-populations of astrocytes were found, expressing or lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptor-bearing astrocytes displayed a lower Kir current density than cells lacking the receptors. In contrast, all cells expressed GABAA receptors. Single-cell RT-PCR was employed to identify the receptor subunits in thalamic astrocytes. Our findings add to the emerging evidence of functional heterogeneity of astrocytes, the impact of which still remains to be defined. PMID:25225096

  16. Pattern of oestrogen, progesterone and Her2neu receptors expression in a heterogeneous carcinoma of the breast in a lactating woman.

    PubMed

    Naim, Mohammed; Kumar, Amit; Gaur, Kavita; John, Vanesa T

    2010-11-23

    Oestrogen-progestrone-Her2neu receptor status was studied in various loci/foci of heterogeneous carcinoma of the breast and its metastatic secretory component in the lymph node in a lactating woman. All the carcinoma variants were negative for the trio markers except tumour components evolved to secretory or lactating carcinoma, which showed focal positivity. Findings showed that oestrogenic receptors, progesterone receptors and Her2neu negative primitive carcinoma in a heterogenous breast cancer may evolve into oestrogen receptor, progesterone receptor and Her2neu positive secretory/lactating carcinoma alongside other receptor negative carcinoma variants. Focal marker positivity/negativity underlined the fact that a diagnostic/prognostic marker status report may account for the tumour area included in the section/sample only. Study of the immune marker expression/status in various loci may help identification of the components, morphogenesis and dynamics of heterogeneous carcinoma of the breast.

  17. The heterogeneity in GABAA receptor-mediated IPSC kinetics reflects heterogeneity of subunit composition among inhibitory and excitatory interneurons in spinal lamina II

    PubMed Central

    Labrakakis, Charalampos; Rudolph, Uwe; De Koninck, Yves

    2014-01-01

    GABAergic inhibition displays rich functional diversity throughout the CNS, which arises from variations in the nature of inputs, subunit composition, subcellular localization of receptors and synapse geometry, or reuptake mechanisms. In the spinal dorsal horn (SDH), GABAA and glycine receptors play a major role in the control of excitability and accuracy of nociceptive processing. Identifying which components shape the properties of the inhibitory synapses in different cell types is necessary to understand how nociceptive information is integrated. To address this, we used transgenic mice where inhibitory interneurons express GAD65-EGFP. We found that GABAA, but not glycine receptor-mediated evoked IPSCs displayed slower kinetics in EGFP+ vs. EGFP− interneurons. GABAA miniature IPSC decay kinetics showed a large variability in both populations, however the distribution of decays differed between EGFP+ and EGFP− interneurons. The range of mIPSC decay kinetics observed was replicated in experiments using rapid application of GABA on outside-out patches taken from SDH neurons in slices. Furthermore, GABAA decay kinetics were not affected by uptake blockers and were not different in mice lacking δ or α5 subunits, indicating that intrinsic channel properties likely underlie the heterogeneity. To identify whether other α subunits shape the various kinetic properties observed we took advantage of knock-in mice carrying point mutations in either the α1, α2, or α3 subunits rendering Ro 15-4513 a selective agonist at the benzodiazepine modulatory site. We found that α1 and α2 subunit underlie the fast decaying component of IPSCs while the slow component is determined by the α3 subunit. The differential distribution of GABAA subunits at inhibitory synapses thus sculpts the heterogeneity of the SDH inhibitory circuitry. This diversity of inhibitory elements can be harnessed to selectively modulate different components of the spinal nociceptive circuitry for

  18. 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.

  19. 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

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

    PubMed Central

    Kansal, Rita G.; McCravy, Matthew S.; Basham, Jacob H.; Earl, Joshua A.; McMurray, Stacy L.; Starner, Chelsey J.

    2016-01-01

    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

  1. 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

  2. The significance of functional receptor heterogeneity in the biological responses of the rabbit neutrophil to stimulation by chemotactic formyl peptides.

    PubMed Central

    Kermode, J C; Freer, R J; Becker, E L

    1991-01-01

    The characteristics of binding to the chemotactic receptors on rabbit peritoneal neutrophils were examined for seven formyl peptide analogues. These receptor-binding characteristics were compared with the abilities of the analogues to induce the biological responses of degranulation and chemotaxis. Five of the analogues showed distinct functional heterogeneity in their receptor-binding patterns, whereas the two most potent compounds displayed homogeneous binding patterns. The relative potencies of the formyl peptide analogues for stimulation of degranulation correlated well with their relative potencies for high-affinity, but not low-affinity, binding. The biphasic patterns for stimulation of chemotactic migration were similar for the less potent analogues, and their potencies paralleled those for both degranulation and receptor binding. In contrast, the most potent analogues induced a greater maximal extent of chemotactic migration than the other compounds, but displayed a lower than expected potency (i.e. they required higher than expected concentrations). These anomalies in the patterns of the chemotactic response cannot be reconciled with a simple receptor model comprising two independent classes of receptors. Instead, a model comprising interconvertible states of different affinities is proposed. The state of higher affinity appears to play a central role in initiation of both degranulation and chemotaxis. The more potent formyl peptide analogues are thought to stabilize an activated, higher-affinity, state of the receptor; this can explain their greater efficacy in stimulating chemotaxis. The proposed model may also be applicable to other receptors that are coupled by a guanine-nucleotide-binding regulatory protein to their associated effector. PMID:2064609

  3. Forensic drug testing for opiates. IV. Analytical sensitivity, specificity, and accuracy of commercial urine opiate immunoassays.

    PubMed

    Cone, E J; Dickerson, S; Paul, B D; Mitchell, J M

    1992-01-01

    Four commercial immunoassays, TDx Opiates (TDx), Coat-A-Count Morphine in Urine (CAC), Abuscreen Radioimmunoassay for Morphine (ABUS) and Emit d.a.u. Opiate Assay (EMIT), were tested for sensitivity, specificity, and accuracy with urine specimens containing known amounts of opiates and opiate metabolites. The immunoassays were evaluated in a semiquantitative mode by comparison of morphine equivalents to GC/MS assay of free and total morphine and codeine or to target concentrations. In all cases, the apparent sensitivities of the assays were higher than those required for detection of morphine at cutoffs mandated by the Health and Human Services guidelines for testing of Federal workers. The apparent specificities of the immunoassays varied considerably. The CAC assay was found to be highly selective for free morphine, whereas TDx, ABUS, and EMIT demonstrated broad cross-reactivity with other opiates. Comparison of semiquantitative results from the immunoassays with GC/MS data indicated a high degree of accuracy for determination of morphine levels. Generally, the patterns of sensitivity and cross-reactivity were unique for each assay, indicating that a detailed knowledge of assay performance characteristics is necessary for accurate interpretation of forensic urine testing data.

  4. Do testicular opiates regulate Leydig cell function?

    PubMed

    Gerendai, I; Shaha, C; Thau, R; Bardin, C W

    1984-10-01

    beta-Endorphin is believed to be synthesized in testicular Leydig cells. To gain more information about the role of this and other endogenous opioid peptides in the testis, opiate antagonists (naloxone and nalmefene, 100 micrograms/testis) were administered intratesticularly to hemicastrated adult rats. Leydig cell function was evaluated by measurement of serum testosterone and testosterone production in vitro. Estimation of androgen binding protein (rABP) was used as an index of Sertoli cell function. Serum testosterone was reduced significantly by intratesticular administration of naloxone and nalmefene in treated animals. Systemic administration of these antagonists had no effect at the doses used. Testes from treated animals incubated in vitro with or without hCG produced significantly less testosterone than vehicle-treated control testes. Hemicastration reduced rABP synthesis and secretion; however, treatment with opiate antagonists did not alter the amount of this protein in the serum or epididymides of these rats. These observations suggest that endogenous testicular opiates modulate testosterone secretion by Leydig cells. PMID:6541122

  5. Impact of opiate addiction on neuroinflammation in HIV.

    PubMed

    Byrd, Desiree; Murray, Jacinta; Safdieh, Gabriella; Morgello, Susan

    2012-10-01

    To investigate the independent and interactive effects of opiate addiction and HIV on neuroinflammation, we measured microglial/macrophage activation and astrogliosis in multiple regions of human brain. Samples of thalamus, frontal gray matter, and frontal white matter were obtained from 46 individuals categorized as: HIV negatives, HIV-negative opiate addicts, HIV positives, HIV-positive opiate addicts, HIV encephalitis (HIVE), and HIVE opiate addicts. Activated brain microglia/macrophages and astrocytosis were quantified by morphometric analysis of immunohistochemical stains for CD68, HLA-D, CD163, and GFAP. The effects of HIV grouping, opiate addiction, and their interaction on expression of the markers were examined in a series of two-way ANOVAs. In opiate addicts, there was generally higher baseline expression of CD68 and HLA-D in HIV negatives, and lower expression in HIV and HIVE, compared to individuals without opiate abuse. Thus, for these markers, and for GFAP in frontal gray, opiates were associated with attenuated HIV effect. In contrast, for CD163, opiates did not significantly alter responses to HIV, and HIV effects were variably absent in individuals without opiate abuse. The divergent impact that opiate addiction displays on these markers may suggest a generally immunosuppressive role in the CNS, with decreased HIV-associated activation of markers CD68 and HLA-D that potentially reflect neurotoxic pathways, and preservation of CD163, thought to be an indicator of neuroprotective scavenger systems. These results suggest a complex impact of opiates on neuroinflammation in baseline and virally stimulated states.

  6. Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats.

    PubMed

    Cavalla, David; Chianelli, Fabio; Korsak, Alla; Hosford, Patrick S; Gourine, Alexander V; Marina, Nephtali

    2015-08-15

    Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates.

  7. Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats.

    PubMed

    Cavalla, David; Chianelli, Fabio; Korsak, Alla; Hosford, Patrick S; Gourine, Alexander V; Marina, Nephtali

    2015-08-15

    Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates. PMID:26068549

  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. Expression of MHC class I receptors confers functional intraclonal heterogeneity to a reactive expansion of gammadelta T cells.

    PubMed

    Lafarge, Xavier; Pitard, Vincent; Ravet, Sophie; Roumanes, David; Halary, Franck; Dromer, Claire; Vivier, Eric; Paul, Pascale; Moreau, Jean-François; Déchanet-Merville, Julie

    2005-06-01

    NK cell receptors for MHC class I molecules (MHC-NKR) can be expressed by T cell subsets. The restricted repertoire and phenotypic characteristics of MHC-NKR(+) T cells indicate that expression of MHC-NKR is acquired upon antigenic challenge and might promote expansion of T cells. Previous studies performed on in vitro generated alphabeta T cell clones concluded that MHC-NKR expression was not a clonal attribute. Here, we examined a massive monoclonal expansion of a non-leukemic gammadelta T cell population found in the peripheral blood of a lung-transplanted patient who suffered from a cytomegalovirus infection. Despite their monoclonality, these T cells displayed a heterogeneous and stable in vivo Ig- and lectin-like MHC-NKR phenotype. Twenty percent of the cells displayed a CD94(+)NKG2A(+) phenotype, and 10% were labeled with an anti-CD158b1/b2/j monoclonal antibody. A CD158b/j(+) gammadelta T cell clone derived in vitro from patient's peripheral blood lymphocytes was shown to express the activating form CD158j (KIR2DS2), which once cross-linked stimulated the clone cytolytic function and costimulated the TCR-induced production of cytokines, independently of the killer-activating receptor-associated protein (KARAP). In conclusion, heterogeneity of MHC-NKR expression confers a functional intraclonal diversity that may participate to induction of specific gammadelta T cell effector functions or proliferation upon pathogen challenge.

  10. Heterogeneity of angiotensin II receptors in membranes of developing rat metanephros.

    PubMed

    Uva, B; Vallarino, M; Ghiani, P

    1985-10-01

    Specific and high affinity binding sites for angiotensin II were demonstrated in the membranes of the developing rat metanephros during the second half of pregnancy and in the newborn by binding studies with 125I angiotensin II. Only one type of angiotensin receptor was found during intrauterine life while after birth two classes of angiotensin receptors were present in the membranes of the cortical renal tissue.

  11. Affective temperaments in alcohol and opiate addictions.

    PubMed

    Khazaal, Yasser; Gex-Fabry, Marianne; Nallet, Audrey; Weber, Béatrice; Favre, Sophie; Voide, Raphael; Zullino, Daniele; Aubry, Jean-Michel

    2013-12-01

    Temperament is considered as a biological disposition reflected by relatively stable features related to mood and reactivity to external and internal stimuli, including variability in emotional reactions. The aim of the present study is to test the hypothesis that affective temperaments might differ according to co-occurring mood disorders among patients with alcohol and/or opiate dependence; to explore the relationship between temperaments and dual substance use disorders (SUDs, alcohol and other drugs). Ninety-two patients attending an alcohol addiction treatment facility and 47 patients in an opiate addiction treatment facility were assessed for SUDs, mood disorders and affective temperaments using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego 39-item auto-questionnaire. Comparison of patients with bipolar disorder, depressive unipolar disorder and no (or substance-induced) mood disorder revealed significant differences for the cyclothymic subscale, with highest scores among patients with bipolar disorder. No difference was observed for the depressive, irritable, hyperthymic and anxious subscales. After adjustment for age, gender and bipolar disorder, irritable temperament was a significant risk factor for past or present history of drug use disorders in patients treated for alcohol addiction (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.05-1.93). Anxious temperament was a significant risk factor for history of alcohol use disorders in patients treated for opiate addiction (OR 3.30, 95% CI 1.36-7.99), whereas the hyperthymic subscale appeared as a significant protective factor (OR 0.65, 95% CI 0.42-0.99). The results highlight the need to consider temperamental aspects in further research to improve the long-term outcome of patient with addictive disorders, who often present complex comorbidity patterns.

  12. 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

  13. T-cell receptor heterogeneity of gamma delta T-cell clones from human female reproductive tissues.

    PubMed

    Christmas, S E; Brew, R; Deniz, G; Taylor, J J

    1993-03-01

    gamma delta T cells were isolated from human decidua parietalis, decidua basalis and cervix and cloned in the presence of interleukin-2 (IL-2). T-cell receptor (TcR) expression was then analysed and compared with that of a panel of gamma delta T-cell clones from peripheral blood. Only 17/40 (42.5%) clones from decidua parietalis were V gamma 9+/V delta 2+ as compared to 68/94 (72%) of peripheral blood clones (P < 0.005). Conversely, 50% of clones from decidua parietalis but only 15% of clones from peripheral blood were V delta 1+ (P < 0.001). At least seven distinct TcR types were identified among the panel of clones from decidua parietalis and at least six different types were expressed by the panel of 17 clones from cervix. This receptor heterogeneity was not a result of interdonor variation as in all instances where more than one clone was obtained from a single sample, individual clones having between two and five receptor types were identified. However, 23/24 (95.8%) of clones from decidua basalis were V gamma 9+/V delta 2+. Most clones from decidua parietalis and cervix, whether V gamma 9+/V delta 2+ or V delta 1+, were positive for the mucosal lymphocyte marker, HML-1, but expression was often heterogeneous within a single clone. In contrast, almost all gamma delta T-cell clones from peripheral blood were HML-1-. Thus, unlike the mouse, gamma delta T cells within these human female reproductive tissues have a diverse TcR repertoire which, in decidua parietalis, is distinct from that of peripheral blood.

  14. 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

  15. 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.

  16. Heterogeneous distribution of AMPA glutamate receptor subunits at the photoreceptor synapses of rodent retina.

    PubMed

    Hack, I; Frech, M; Dick, O; Peichl, L; Brandstätter, J H

    2001-01-01

    In the retina the segregation of different aspects of visual information starts at the first synapse in signal transfer from the photoreceptors to the second-order neurons, via the neurotransmitter glutamate. We examined the distribution of the four AMPA glutamate receptor subunits GluR1-GluR4 at the photoreceptor synapses in mouse and rat retinae by light and immunoelectron microscopy and serial section reconstructions. On the dendrites of OFF-cone bipolar cells, which make flat, noninvaginating contacts postsynaptic at cone synaptic terminals, the subunits GluR1 and GluR2 were predominantly found. Horizontal cell processes postsynaptic at both rod and cone synaptic terminals preferentially expressed the subunits GluR2, GluR2/3 and GluR4. An intriguing finding was the presence of GluR2/3 and GluR4 subunits on dendrites of putative rod bipolar cells, which are thought to signal through the sign-inverting metabotropic glutamate receptor 6, mGluR6. Furthermore, at the rod terminals, horizontal cell processes and rod bipolar cell dendrites showed labelling for the AMPA receptor subunits at the ribbon synaptic site or perisynaptically at their site of invagination into the rod terminal. The wide distribution of AMPA receptor subunits at the photoreceptor synapses suggests that AMPA receptors play an important role in visual signal transfer from the photoreceptors to their postsynaptic partners.

  17. Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression.

    PubMed

    Anderson, Sarah Ann R; Michaelides, Michael; Zarnegar, Parisa; Ren, Yanhua; Fagergren, Pernilla; Thanos, Panayotis K; Wang, Gene-Jack; Bannon, Michael; Neumaier, John F; Keller, Eva; Volkow, Nora D; Hurd, Yasmin L

    2013-12-01

    Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.

  18. Is the cutaneous silent period an opiate-sensitive nociceptive reflex?

    PubMed

    Inghilleri, Maurizio; Conte, Antonella; Frasca, Vittorio; Berardelli, Alfredo; Manfredi, Mario; Cruccu, Giorgio

    2002-05-01

    In humans, high-intensity electrical stimuli delivered to the fingers induce an inhibitory effect on C7-T1 motoneurons. This inhibitory reflex, called the cutaneous silent period (CSP) is considered a defense response specific for the human upper limbs. It is not clear whether the CSP-like other defense responses such as the corneal reflex and the R III reflex-is an opiate-sensitive nociceptive reflex. Because opiates suppress some, but not all, nociceptive reflexes, we studied the effect of the narcotic-analgesic drug fentanyl on the CSP and the R III reflex. The CSP was recorded from the first dorsal interosseous (FDI) muscle in seven normal subjects during voluntary contraction, before and 10 and 20 min after fentanyl injection. To assess possible fentanyl-induced changes, we also tested the effect of finger stimulation on motor evoked potentials (MEPs) elicited in the FDI muscle by transcranial magnetic stimulation before and after fentanyl injection. Fentanyl-induced changes were also studied on the R III reflex recorded from the biceps femoris muscle. Fentanyl, as expected, suppressed the R III reflex but failed to change the inhibitory effect of finger stimulation on FDI motoneurons. Finger stimulation reduced the size of MEPs in the FDI, and fentanyl injection left this inhibitory effect unchanged. The differential fentanyl-induced modulation of the CSP and R III reflex provides evidence that the CSP circuit is devoid of mu-opiate receptors and is therefore an opiate-insensitive nociceptive reflex, which may be useful in the assessment of central-acting, non-opioid drugs.

  19. Heterogeneous expression of melatonin receptor MT1 mRNA in the rat intestine under control and fasting conditions.

    PubMed

    Soták, Matús; Mrnka, Libor; Pácha, Jirí

    2006-09-01

    Melatonin is found in mammalian central nervous system and various peripheral tissues including gastrointestinal tract (GIT) where it participates in the regulation of intestinal motility, blood flow, immunomodulation, ion transport, cell proliferation and scavenging of free radicals. Some of these effects are achieved via melatonin binding to specific receptors, MT1 and MT2. As no thorough study on the expression of these receptors in the GIT has yet been done, the aim of this study was to determine the MT1 mRNA expression in the rat intestine under both control and fasting conditions. Our results suggest that MT1 mRNA is present in epithelial as well as subepithelial layer, with higher expression in the latter in all intestinal segments studied. The highest signal of the MT1 transcript along the rostro-caudal intestinal axis was found both in epithelial and subepithelial layers of the duodenum. Nevertheless, duodenal MT1 mRNA expression did not reach the level found in pituitary gland. In a 12:12-hr light:dark cycle a MT1 receptor expression in the subepithelial layer of rat distal colon did not manifest a significant diurnal rhythm. Short-term fasting increased the expression of MT1 transcript in the subepithelial layer of both the small and large intestine. During long-term fasting the increase persisted only in distal colon while a return to control levels was observed in small intestinal segments. In conclusion we demonstrated heterogeneous expression of MT1 receptor in the rat intestine and showed that its expression is up-regulated by nutritional deprivation.

  20. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal

    PubMed Central

    Scavone, J.L.; Sterling, R.C.; Van Bockstaele, E.J.

    2013-01-01

    Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids on the opioid system. Evidence from both animal and clinical studies point towards an interaction between these two systems, and suggest that targeting the endocannabinoid system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids system on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in management of opiate dependence and withdrawal. PMID:23624062

  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

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

    PubMed Central

    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.

    2016-01-01

    Abstract 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

  4. Opiate reinforcement processes: re-assembling multiple mechanisms.

    PubMed

    Bozarth, M A

    1994-11-01

    Opiate reinforcement processes can be described within the context of operant conditioning theory. Both positive and negative reinforcing effects may motivate drug-taking behavior, although the strongest evidence attributes drug-taking to a simple positive reinforcement process. Empirical research has focused largely on a positive reinforcement mechanism involving the ventral tegmental dopamine system, but three additional reinforcement mechanisms can be argued on logical grounds. These other mechanisms involve neuroadaptive changes produced by chronic opiate administration and may contribute to the strong motivational impact of opiates following long-term drug use.

  5. Opiate analgesics' dual role in firefly luciferase activity.

    PubMed

    Sudhaharan, T; Reddy, A R

    1998-03-31

    The effects of three opiate analgesics, isolated from opium, on the firefly luciferase enzyme have been studied. Morphine (MN), 6-acetylmorphine (MAM), and diacetylmorphine (DAM) inhibited the enzyme activity at different levels. At lower concentrations, MN and MAM enhanced enzyme activity, effecting inhibition at higher concentrations. However, DAM inhibited the enzyme activity at all concentrations investigated. The stimulating activity of MN and MAM is attributed to the hydrophilic interaction of the proton donor-acceptor type with the polar regions of the luciferase located outside the binding pocket of the active site. The inhibition at higher concentrations of MN and MAM and at all concentrations of DAM is found to be competitive in nature, with the analgesics competing for the binding of the enzyme's natural substrate luciferin. The binding site of the luciferase could accommodate only one analgesic molecule. Binding constants determined from bioluminescence studies showed that the inhibitor binding site is hydrophobic in nature. The inhibition constants of analgesics are in the order MN > MAM > DAM. The greater binding of DAM to luciferase is attributed to its ability to form a ground state complex with ATP and greater hydrophobicity. At higher concentrations of ATP, the binding constants increased. The results obtained are explained assuming that the firefly luciferase acts as a subtype mu-opioid receptor model.

  6. 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.

  7. Adhesion and receptor clustering stabilizes lateral heterogeneity in cell plasma membranes

    NASA Astrophysics Data System (ADS)

    Veatch, Sarah

    2013-03-01

    The thermodynamic properties of plasma membrane lipids play a vital role in many functions that initiate at the mammalian cell surface. Some functions are thought to occur, at least in part, because plasma membrane lipids have a tendency to separate into two distinct liquid phases, called liquid-ordered and liquid-disordered. We find that isolated cell plasma membranes are poised near a miscibility critical point separating these two liquid phases, and postulate that critical composition fluctuations provide the physical basis of functional membrane heterogeneity in intact cells. In this talk I will describe several possible mechanisms through which dynamic fluctuations can be stabilized in super-critical membranes, and will present some preliminary evidence suggesting that these structures can be visualized in intact cells using quantitative super-resolution fluorescence localization imaging.

  8. Structural heterogeneity of the alpha subunits of the nicotinic acetylcholine receptor in relation to agonist affinity alkylation and antagonist binding.

    PubMed

    Ratnam, M; Gullick, W; Spiess, J; Wan, K; Criado, M; Lindstrom, J

    1986-07-29

    The structural basis for the heterogeneity of the two agonist binding sites of the Torpedo californica acetylcholine receptor with respect to antagonist binding and reactivity toward affinity alkylating reagents was investigated. There is one agonist binding site on each of the two alpha subunits in a receptor monomer. One of these sites is easily affinity labeled with bromoacetylcholine, while more extreme conditions are required to label the other. Evidence is presented that the site which is easily labeled with bromoacetylcholine is the site with higher affinity for the antagonist d-tubocurarine. Digestion of purified alpha subunits with staphylococcal V8 protease gave two limit fragments with apparent molecular weights of 17K and 19K. Both of these fragments began at residue 46 of the alpha sequence, and both reacted with monoclonal antibodies specific for the sequence alpha 152-159 but not with antibodies specific for alpha 235-242. Their tryptic peptide maps and reactivity with a number of monoclonal antibodies were virtually identical. Only the 17-kilodalton (17-kDa) fragments stained heavily for sugars with Schiff's reagent. However, both fragments bound 125I-labeled concanavalin A. Complete removal of carbohydrate detectable with concanavalin A from V8 protease digests of alpha subunits resulted in two fragments of lower apparent molecular weights, indicating that these fragments differed not only in carbohydrate content but also in their C-termini or by another covalent modification. Covalent labeling of one of the two agonist sites of the intact receptor with bromo[3H]acetylcholine followed by digestion with V8 protease resulted in labeling of only the 19-kDa fragment.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. 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.

  10. 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.

  11. 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.

  12. Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man.

    PubMed

    Veldhuis, J D; Rogol, A D; Johnson, M L

    1983-12-01

    We studied the secretion of physiological pools of immunoreactive and biologically active luteinizing hormone in response to endogenous pulses of gonadotropin-releasing hormone (GNRH) in eugonadal men. Concentrations of immunoactive and bioactive luteinizing hormone (LH) were determined in blood drawn at 20-min intervals for 8 h in eight normal men under two conditions: (a) after placebo, in order to evaluate spontaneous LH pulsations in the basal state, and (b) after administration of the opiate-receptor antagonist, naltrexone, which is believed to amplify the pulsatile release of endogenous GNRH. Spontaneous and naltrexone-stimulated secretion of LH occurred in pulses of high biological activity, as measured in the RICT (rat interstitial cell testosterone bioassay), i.e., bioactive:immunoactive LH ratios within both spontaneous and naltrexone-stimulated LH pulses were higher than corresponding interpulse ratios (P less than 0.001). Quantitative characterization of the pulsatile release of bioactive LH revealed the following specific effects of opiate-receptor blockade: increased 8-h mean and integrated serum concentrations of bioactive LH (P less than 0.002), enhanced pulse frequency of bioactive LH release (P less than 0.001), and augmented peak amplitude of bio-LH pulses (P less than 0.01). Moreover, this increase in episodic secretion of bioactive LH was associated with increased 8-h mean and integrated serum testosterone concentrations in these men (P less than 0.05). We conclude the following: (a) LH is normally released in spontaneous pulses of high biological activity in men; (b) when the endogenous GNRH signal is amplified by opiate-receptor blockade, the pituitary gland releases more frequent bioactive LH pulses, which are of high amplitude and contain a high bioactive:immunoactive LH ratio. This increase in pulsatile release of bioactive LH quantitated in the RICT assay in vitro is reflected by acutely increased serum testosterone concentrations in vivo

  13. The endocrinology of the opiates and opioid peptides.

    PubMed

    Morley, J E

    1981-02-01

    Since the isolation of the enkephalins five yr ago, there has been an explosive increase in knowledge concerning the effects of the opiates and opioid peptides. This review deals with the interactions of opiates with the endocrine system in rat and man. The opioid peptides have been demonstrated to exert a variety of effects on pituitary hormone secretion in rat and man. In the rat, opiates stimulate growth hormone, prolactin and ACTH release and inhibit the release of the glycoprotein hormones. In man, the physiologic role of the endogenous opiates appears to be involved predominantly in ACTH and gonadotrophin regulation. Opiate effects are mainly exerted at the level of the hypothalamus but further modulating effects may occur at the pituitary and at end-organs. Opiate-induced hormonal effects appear to be mediated through dopaminergic and/or serotonergic mechanisms. Recent studies have also suggested a possible local neuromodulatory role for the opioid peptides in the control of carbohydrate metabolism and reproductive processes.

  14. 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.

  15. TetraMabs: simultaneous targeting of four oncogenic receptor tyrosine kinases for tumor growth inhibition in heterogeneous tumor cell populations

    PubMed Central

    Castoldi, Raffaella; Schanzer, Jürgen; Panke, Christian; Jucknischke, Ute; Neubert, Natalie J.; Croasdale, Rebecca; Scheuer, Werner; Auer, Johannes; Klein, Christian; Niederfellner, Gerhard; Kobold, Sebastian; Sustmann, Claudio

    2016-01-01

    Monoclonal antibody-based targeted tumor therapy has greatly improved treatment options for patients. Antibodies against oncogenic receptor tyrosine kinases (RTKs), especially the ErbB receptor family, are prominent examples. However, long-term efficacy of such antibodies is limited by resistance mechanisms. Tumor evasion by a priori or acquired activation of other kinases is often causative for this phenomenon. These findings led to an increasing number of combination approaches either within a protein family, e.g. the ErbB family or by targeting RTKs of different phylogenetic origin like HER1 and cMet or HER1 and IGF1R. Progress in antibody engineering technology enabled generation of clinical grade bispecific antibodies (BsAbs) to design drugs inherently addressing such resistance mechanisms. Limited data are available on multi-specific antibodies targeting three or more RTKs. In the present study, we have evaluated the cloning, eukaryotic expression and purification of tetraspecific, tetravalent Fc-containing antibodies targeting HER3, cMet, HER1 and IGF1R. The antibodies are based on the combination of single-chain Fab and Fv fragments in an IgG1 antibody format enhanced by the knob-into-hole technology. They are non-agonistic and inhibit tumor cell growth comparable to the combination of four parental antibodies. Importantly, TetraMabs show improved apoptosis induction and tumor growth inhibition over individual monospecific or BsAbs in cellular assays. In addition, a mimicry assay to reflect heterogeneous expression of antigens in a tumor mass was established. With this novel in vitro assay, we can demonstrate the superiority of a tetraspecific antibody to bispecific tumor antigen-binding antibodies in early pre-clinical development. PMID:27578890

  16. Migraine and possible etiologic heterogeneity for hormone-receptor-negative breast cancer.

    PubMed

    Shi, Min; DeRoo, Lisa A; Sandler, Dale P; Weinberg, Clarice R

    2015-01-01

    Migraine headache is often timed with the menstrual cycle. Some studies have reported reduced risk of breast cancer in migraineurs but most of those did not distinguish menstrually-related from non-menstrually-related migraine. To examine the possible associations between breast cancer and migraine overall and between cancer subcategories and the two migraine subtypes, we used a cohort study of 50,884 women whose sister had breast cancer and a sister-matched case-control study including 1,418 young-onset (<50 years) breast cancer cases. We analyzed the two studies individually and also in tandem via a hybrid Cox model, examining subcategories of breast cancer in relation to menstrually-related and non-menstrually-related migraine. History of migraine was not associated with breast cancer overall. Migraine showed an inverse association with ductal carcinoma in situ (HR = 0.77; 95% CI (0.62,0.96)). Also, women with non-menstrually-related migraine had increased risk (HR = 1.30, 95% CI (0.93,1.81)) while women with menstrually-related migraine had decreased risk (HR = 0.63, 95% CI (0.42,0.96)) of hormone-receptor-negative (ER-/PR-) cancer, with a significant contrast in estimated effects (P = 0.005). While replication of these subset-based findings will be needed, effect specificity could suggest that while migraine has little overall association with breast cancer, menstrual migraine may be associated with reduced risk of ER-/PR- breast cancer.

  17. Opiate sensitivity test in patients with stereotypic movement disorder and trichotillomania.

    PubMed

    Frecska, Ede; Arato, Mihaly

    2002-06-01

    Preliminary data about the therapeutic effect of opiate receptor manipulation in self-injurious behavior (SIB) suggest that endogenous opioid mechanisms may have a pathophysiological role in that condition and their involvement may be dependent on the severity of the SIB. The aim of this study was to use fentanyl-induced prolactin response as an opiate receptor sensitivity test in patients with stereotypic movement disorder (SMD) manifesting SIB (skin picking). Healthy volunteers and trichotillomanic patients were enrolled as comparison subjects. Individuals with trichotillomania (TTM) manifest repetitive, less serious self-mutilation (hair pulling) and are classified under different DSM-IV category than SMD. Therefore, they were considered as patient controls. Ten healthy subjects received 0.05 mg/70 kg and another 10 were given 0.1 mg/70 kg dose of fentanyl intravenously in the AM hours. Five of them had placebo trials. A dose of 0.05 mg/70 kg fentanyl was administered to patients with SMD (n = 10) and TTM (n = 12). Serial blood sampling was performed for prolactin measurements. Fentanyl elevated plasma prolactin in a dose-dependent manner. Patients with skin picking, but not with hair pulling, showed significantly increased responses. This finding supports the involvement of endogenous opioids in the pathomechanism of serious SIB.

  18. 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

  19. 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.

  20. 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.

  1. Testosterone does not influence opiate binding sites in the male rat brain.

    PubMed

    Cicero, T J; Newman, K S; Meyer, E R

    1983-09-26

    It has been reported previously that castration produces testosterone-reversible increases in the density of 3H-naltrexone binding sites in the male rat brain. Unfortunately, we were unable to replicate these observations in a comprehensive series of studies. Specifically, we found that castration failed to produce changes in the Kd or Bmax of opiate binding sites in whole male rat brain, or in the hypothalamus, utilizing 3H-dihydromorphine (a mu receptor ligand), 3H-D-alanine, D-leucine enkephalin (delta) or 3H-naltrexone (ubiquitous). Furthermore, we found that the relative proportion of mu and delta binding sites in brain was unchanged by castration. The reasons for the discrepancy between the present results and those previously reported are unclear, but it appears that the provocative hypothesis that testosterone influences opioid receptors in brain must be carefully reevaluated. PMID:6310295

  2. Neurotransmitter Receptor Binding in Bovine Cerebral Microvessels

    NASA Astrophysics Data System (ADS)

    Peroutka, Stephen J.; Moskowitz, Michael A.; Reinhard, John F.; Synder, Solomon H.

    1980-05-01

    Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

  3. 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

  4. 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

  5. Current and historical concepts of opiate treatment in psychiatric disorders.

    PubMed

    Weber, M M; Emrich, H M

    1988-07-01

    In recent years psychiatric research has rediscovered the theoretical and clinical importance of opiates, especially for the understanding of depressive disorders. However, opiate treatment is not a new therapeutic concept in psychiatry. The use of opium for "melancholia" and "mania" may be traced to ancient classical medicine. After Paracelsus and Sydenham, the psychiatry of the German Romantic Era widely discussed therapeutic opium use with the Engelken family going on to develop a structured opium treatment of depression in the first half of the nineteenth century. Although the underlying scientific problems of psychiatric opium therapy were never solved, it gained an outstanding position as a practical treatment for over 100 years.

  6. 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

  7. Thin layer chromatographic screening for methaqualone, phenothiazines, opiates and benzodiazepines.

    PubMed

    Breiter, J; Helger, R; Interschick, E; Wüst, H

    1978-02-01

    A method is described which permits the simultaneous detection of methaqualone, phenothiazines, opiates and benzodiazepines in urine. Its diagnostic application is discussed. After cleavage of conjugates with hydrochloric acid, the substances are extracted and identified by thin-layer chromatography. In most cases analysis can be carried out using 2 solvent systems, phenothiazines, methaqualone and opiates being visualised using a three stage spray sequence. Since phenothiazines can interfere with the detection of methaqualone, a specific eluant is used to ensure reliable detection of the latter. Methaqualone can be positively identified by its characteristic metabolite pattern, whereas phenothiazines can only be detected as a group.

  8. 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.

  9. Opiate Pharmacology and Relief of Pain

    PubMed Central

    Pasternak, Gavril W.

    2014-01-01

    Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned. PMID:24799496

  10. Role of endogenous opiates in pubertal maturation: opposing actions of naltrexone in prepubertal and late pubertal boys.

    PubMed

    Mauras, N; Veldhuis, J D; Rogol, A D

    1986-06-01

    Despite the acute enhancement of gonadotropin output that occurs in the presence of opiate blockade in sexually immature rats and adult men, studies thus far have not demonstrated a role for endogenous opioid peptides during pubertal development in the human. We studied 15 normal boys, 5 sexually developed (Tanner stages IV-V) and 10 sexually infantile, before and after chronic (1-month) administration of a selective micromicron-opiate-receptor antagonist (naltrexone). Gonadotropin secretion was assessed by repetitive venous sampling for 24 h to appraise the pulsatile features of LH release as well as by graded serum LH responses to GnRH. Using an objective pulse detection method, we found that 1) in response to naltrexone, pubertal boys had significantly higher LH pulse frequency (P = 0.044), mean LH concentration (P = 0.0325), and area under the LH vs. time curve (P = 0.0325) compared to those in the basal state; and 2) in sexually immature individuals, naltrexone significantly decreased LH pulse frequency (P = 0.014), mean LH concentration (P = 0.049), and absolute LH peak concentration (P = 0.039) compared to those in the basal state. We suggest that the paradoxical inhibitory response to naltrexone in prepubertal boys represents an agonist-like effect of chronic naltrexone administration. This consideration implies that opiate neural pathways are responsive if not highly sensitive to the agonist effect of opiate substances in the prepubertal male. Accordingly, physiological pubertal progression may be accompanied by decreased sensitivity of the hypothalamic gonadostat to the inhibitory effects of opioid peptides. PMID:3517031

  11. Contingent methadone delivery: effects on illicit-opiate use.

    PubMed

    Higgins, S T; Stitzer, M L; Bigelow, G E; Liebson, I A

    1986-07-01

    This study examined the effects of contingent vs. non-contingent delivery of a methadone dose supplement on relapse to illicit opiate use in the context of a methadone outpatient detoxification program. Following a 3-week methadone stabilization period on 30 mg, patients (N = 39) were randomly assigned to a contingent, a non-contingent, or a control treatment group. All patients received identical gradual reductions in their assigned methadone dose. During the dose reduction period (weeks 4-11), members of the contingent (N = 13) and non-contingent groups (N = 13) could obtain daily methadone-dose supplements up to 20 mg, but contingent group members could obtain supplements only if their most recent urinalysis results were opiate negative. Control subjects (N = 13) did not have dose increases available. The contingent group presented significantly lower opiate-positive urines during weeks 8-11 (14% positive) of the detox than the non-contingent (38% positive) or control (50% positive) groups. Additionally, the availability of extra methadone improved treatment retention and increased clinic attendance above levels observed in the control group. The potential for further use of methadone's reinforcing properties in the treatment of opiate dependence is discussed.

  12. Contingent methadone delivery: effects on illicit-opiate use.

    PubMed

    Higgins, S T; Stitzer, M L; Bigelow, G E; Liebson, I A

    1986-07-01

    This study examined the effects of contingent vs. non-contingent delivery of a methadone dose supplement on relapse to illicit opiate use in the context of a methadone outpatient detoxification program. Following a 3-week methadone stabilization period on 30 mg, patients (N = 39) were randomly assigned to a contingent, a non-contingent, or a control treatment group. All patients received identical gradual reductions in their assigned methadone dose. During the dose reduction period (weeks 4-11), members of the contingent (N = 13) and non-contingent groups (N = 13) could obtain daily methadone-dose supplements up to 20 mg, but contingent group members could obtain supplements only if their most recent urinalysis results were opiate negative. Control subjects (N = 13) did not have dose increases available. The contingent group presented significantly lower opiate-positive urines during weeks 8-11 (14% positive) of the detox than the non-contingent (38% positive) or control (50% positive) groups. Additionally, the availability of extra methadone improved treatment retention and increased clinic attendance above levels observed in the control group. The potential for further use of methadone's reinforcing properties in the treatment of opiate dependence is discussed. PMID:3757767

  13. 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 DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  14. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man.

    PubMed

    Veldhuis, J D; Rogol, A D; Samojlik, E; Ertel, N H

    1984-07-01

    We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co

  15. 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.

  16. 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.

  17. sigma opiates and certain antipsychotic drugs mutually inhibit (+)-(/sup 3/H)SKF 10,047 and (/sup 3/H)haloperidol binding in guinea pig brain membranes

    SciTech Connect

    Tam, S.W.; Cook, L.

    1984-09-01

    The relationship between binding of antipsychotic drugs and sigma psychotomimetic opiates to binding sites for the sigma agonist (+)-(/sup 3/H)SKF 10,047 (N-allylnormetazocine) and to dopamine D/sub 2/ sites was investigated. In guinea pig brain membranes, (+)-(/sup 3/H)SKF 10,047 bound to single class of sites with a K/sub d/ of 4 x 10/sup -8/ M and a B/sub max/ of 333 fmol/mg of protein. This binding was different from ..mu.., kappa, or delta opiate receptor binding. It was inhibited by opiates that produce psychotomimetic activities but not by opiates that lack such activities. Some antipsychotic drugs inhibited (+)-(/sup 3/H)SKF 10,047 binding with high to moderate affinities in the following order of potency: haloperidol > perphenazine > fluphenazine > acetophenazine > trifluoperazine > molindone greater than or equal to pimozide greater than or equal to thioridazine greater than or equal to chlorpromazine greater than or equal to triflupromazine. However, there were other antipsychotic drugs such as spiperone and clozapine that showed low affinity for the (+)-(/sup 3/H)SKF 10,047 binding sites. Affinities of antipsychotic drugs for (+)-(/sup 3/H)SKF 10,047 binding sites did not correlate with those for (/sup 3/H)spiperone (dopamine D/sub 2/) sites. (/sup 3/H)-Haloperidol binding in whole brain membranes was also inhibited by the sigma opiates pentazocine, cyclazocine, and (+)-(/sup 3/H)SKF 10,047. In the striatum, about half of the saturable (/sup 3/H)haloperidol binding was to (/sup 3/H)spiperone (D/sub 2/) sites and the other half was to sites similar to (+)-(/sup 3/H)SKF 10,047 binding sites. 15 references, 4 figures, 1 table.

  18. 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

  19. 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.

  20. Opiate versus psychostimulant addiction: the differences do matter.

    PubMed

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

    2011-10-05

    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.

  1. 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

  2. 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

  3. 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

    2016-02-05

    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.

  4. 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

  5. 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

  6. Drinking, but not feeding, is opiate-sensitive in hamsters.

    PubMed

    Lowy, M T; Yim, G K

    1982-05-10

    The long-lasting opiate antagonist, naltrexone (NTX), was examined for its effects on various types of consummatory behavior in male golden hamsters and rats. Rat, but not hamster, 24 hr food and water intakes were significantly decreased by four daily NTX (10.0 mg/kg) injections. Hamsters displayed a minimal night to day feeding ratio compared to rats. Hamsters increased food intake following insulin (50 U/kg) administration, but not after 24 hr food deprivation (FD) or 2-deoxy-D-glucose (2-DG; 800 mg/kg) injections. NTX (1.0 and 10 mg/kg) had no effect on feeding, but markedly attenuated hamster drinking induced by 48 hr water deprivation or hypertonic saline injection. Dexamethasone (DEX), a glucocorticoid which depletes pituitary beta-endorphin and produces anorexia in rats, had no effect on daily hamster intake. Since the normal feeding profile of the hamster is similar to that of naloxone and DEX-treated rats, hamsters appear to lack an opiate-sensitive feeding system. In contrast, stimulated drinking behavior of hamsters operates through an opiate-sensitive mechanism. Thus, there are marked species differences concerning the involvement of endogenous opioids in consummatory behavior.

  7. Determination of opiates in serum, saliva and hair addicted persons.

    PubMed

    Piekoszewski, W; Janowska, E; Stanaszek, R; Pach, J; Winnik, L; Karakiewicz, B; Kozielec, T

    2001-01-01

    In the last ten years advances in analytical methods have enabled the determination of xenobiotics in alternative material such as sweat, saliva, and hair. The aim of this study was to develop an analytical method and measure the concentration of the main opiates in serum saliva and hair of subjects from a detoxification and methadone treatment programme. The analytical strategy in the presented study, based on enzymoimmunoassay screening of opiates in urine and GC/MS confirmation, meets the needs of forensic and clinical toxicology. Blood and saliva samples from thirty seven patients and hair from twenty three with a history of intravenous opiate use were collected for analysis. The ranges of morphine in serum and saliva were 0-2081 and 0-208 ng/ml respectively; corresponding concentrations of codeine were 0-580 and 0-428 ng/ml respectively. The concentration of morphine, codeine and 6-MAM in hair of addicts ranged respectively from 0-32.4, 0-12.5 and 0-2.8 ng/mg. From the clinical toxicology point of view, hair analysis is supplementary to urine, serum or saliva determination, but in drug testing at the workplace it can play a crucial role.

  8. Maternal deprivation specifically enhances vulnerability to opiate dependence.

    PubMed

    Vazquez, Vincent; Giros, Bruno; Daugé, Valérie

    2006-12-01

    Maternal deprivation has been shown to increase vulnerability to morphine dependence and to disturb the enkephalinergic system in adulthood. To study whether or not this vulnerability to opiates is a specific feature, we examined oral self-administration behaviour of various reinforcing substances. Experiments were performed with morphine (25 mg/l), ethanol (10%), amphetamine (25 mg/l) and cocaine (100 mg/l). Drugs were available in a continuous free choice paradigm during 3 months. Cocaine and ethanol consumption and preference were similar in both deprived and control rats. Deprived rats greatly increased their morphine consumption and 78% of them showed a progressive decrease in morphine aversion. Only a slight, but significant, increase in oral amphetamine consumption was observed in deprived rats when compared with control rats. The difference in amphetamine self-administration in control and deprived rats cannot be explained by a modification of dopamine transporter expression measured by immunoautoradiography. Altogether, we conclude that maternal deprivation worsens inherent susceptibility to dependence, specifically for opiates, and therefore represents a highly valuable model to study environmentally triggered interindividual vulnerability to opiate addiction. PMID:17110797

  9. Loss of striatal Mu/sub 1/ opiate binding by substantia nigra lesions in the rat

    SciTech Connect

    Bodnar, R.J.; Clark, J.A.; Cooper, M.L.; Pasternak, G.W.

    1988-01-01

    Opiate receptors have been identified within the striatum and some have been localized presynaptically to nigrostriatal neurons. Using unilateral ablative lesion of the substantia nigra, the authors examined binding in the ipsilateral and contralateral striata. Lesions significantly lowered both /sup 3/H(D-Ala/sup 2/, MePhe/sup 4/, Gly(ol)/sup 5/) enkephalin (DAGO) and /sup 3/H(D-Ala/sup 2/,Leu/sup 5/) enkephalin (DADL) binding. The inclusion of competitors in these assays revealed a decrease in both mu/sub 1/ and mu/sub 2/ receptors. Mu/sub 1/ binding was slightly more sensitive to the lesioning than mu/sub 2/ binding. Selective mu/sub 1/ and mu/sub 2/ binding assays supported these observations. No change in delta binding was observed in the lesioned striata. These studies raise the possibility that both mu/sub 1/ and mu/sub 2/, but not delta, receptors are localized presynaptically on nigrostriatal neurons.

  10. Asymmetric dimethylarginine (ADMA)--a modulator of nociception in opiate tolerance and addiction?

    PubMed

    Kielstein, Anousheh; Tsikas, Dimitrios; Galloway, Gantt P; Mendelson, John E

    2007-09-01

    Nitric oxide (NO) is generated from l-arginine by NO synthases, of which three forms have been identified: endothelial, inducible and neuronal (eNOS, iNOS and nNOS, respectively). The l-arginine metabolite asymmetric dimethylarginine (ADMA) is a potent, noncompetitive inhibitor of nNOS, while its congener N(G)-monomethyl-l-arginine (l-NMMA) is a less potent, competitive inhibitor. In rat neurons large amounts of ADMA are found, suggesting its importance in modulating neuronal activity. Humans generate approximately 300mumol ( approximately 60mg) ADMA per day. It is released from myelin basic proteins that are highly expressed in neuronal tissue. ADMA is mainly degraded by the action of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which exists in two isoforms. DDAH1 is highly expressed in brain, suggesting specific function in this area. The presence of nNOS and DDAH1 in brain suggests that ADMA may have specific CNS activity and be more than an unregulated metabolite. Increased NO production-either prior to or concurrently with opioid administration-results in an enhanced rate and extent of development of tolerance to morphine in mice. NO produces an alteration in the mu-opioid receptor that increases constitutive receptor activity. It thereby reduces the ability of a selective mu-opioid agonist to activate the mu-opioid receptor; these in vitro molecular effects occur in a time course consistent with the in vivo development of antinociceptive tolerance in mice. Amongst many other synthetic NOS inhibitors of varying specificity, 7-nitroindazole (7-NI) has been shown to have a high affinity (IC(50) 0.71 microM) to nNOS. Selective blockade of nNOS by 7-NI attenuated morphine withdrawal in opiate dependent rats, suggesting nNOS as a viable target for development of pharmacotherapies. We hypothesize that, by inhibiting nNOS and reducing NO levels, ADMA may decrease mu-opiate receptor constitutive activity, resulting in alteration of the analgesic dose

  11. Heterogeneity of alpha1 receptors associated with vascular smooth muscle: evidence from functional and ligand binding studies

    SciTech Connect

    Babich, M.; Pedigo, N.W.; Butler, B.T.; Piascik, M.T.

    1987-08-10

    The nature of the alpha1 receptor associated with rabbit aorta has been examined in functional and receptor binding studies. In isolated aortic rings the dose-response curve for (-)metaraminol was not parallel to that of (-)epinephrine, (-)norepinephrine or (-)phenylephrine. Following inactivation of a portion of the alpha receptors with phenoxybenzamine, the occupancy versus response relationship for metaraminol, in contrast to the other test agonists, was biphasic. In microsomes prepared from aorta, metaraminol bound to two classes of sites labelled by the selective alpha1 antagonist (TH) prazosin. Norepinephrine also bound to two sites on the alpha receptor in all three preparations tested. The Scatchard plot of (TH)prazosin binding to microsomes prepared from frozen aorta was curvilinear. Estimates of the affinities and site densities were 49.6 +/- 15.3 pM and 44.8 +/- 11.8 pmol/gm protein and 1.0 +/- 0.2 nM and 43.8 +/- 17.4 pmol/gm for the high and low affinity sites, respectively. These data are consistent with the idea that there are subtypes of the alpha1 receptor. 33 references, 5 figures.

  12. More mysteries of opium reveal'd: 300 years of opiates.

    PubMed

    Miller, R J; Tran, P B

    2000-08-01

    This year is the 300th anniversary of the publication of one of the first books written about opiates and their subjective effects. Since that time the influence of opiates in Western society has grown enormously, as has our knowledge of the mechanisms by which these drugs produce their effects. Wars have been fought over the use of opiates and the economies of several countries depend on their production. In this article, some aspects of the history and effects of opiates on the arts in particular are explored.

  13. More mysteries of opium reveal'd: 300 years of opiates.

    PubMed

    Miller, R J; Tran, P B

    2000-08-01

    This year is the 300th anniversary of the publication of one of the first books written about opiates and their subjective effects. Since that time the influence of opiates in Western society has grown enormously, as has our knowledge of the mechanisms by which these drugs produce their effects. Wars have been fought over the use of opiates and the economies of several countries depend on their production. In this article, some aspects of the history and effects of opiates on the arts in particular are explored. PMID:10918635

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. Impaired emotional facial expression recognition in alcoholics, opiate dependence subjects, methadone maintained subjects and mixed alcohol-opiate antecedents subjects compared with normal controls.

    PubMed

    Kornreich, Charles; Foisy, Marie-Line; Philippot, Pierre; Dan, Bernard; Tecco, Juan; Noël, Xavier; Hess, Ursula; Pelc, Isidore; Verbanck, Paul

    2003-08-01

    The present study aims to explore whether an impairment in emotional facial expressions (EFE) decoding is specific to alcoholism compared with opiate dependence. An EFE decoding test consisting of 16 photographs of EFE portraying happiness, anger, sadness and disgust was administered to five different groups of 30 subjects each: recently detoxified alcoholics (RA); opiate addicts under methadone maintenance treatment (OM); detoxified opiate addicts (OA); detoxified subjects with both alcohol and opiate dependence antecedents (DAO); and normal controls (NC). Repeated measures analysis of variance using a multivariate approach was conducted on EFE decoding accuracy scores with group as the between-subjects factor. Accuracy scores were significantly lower in RA and DAO than in OM and OA, which had significantly lower scores than NC. Low accuracy scores in RA and DAO confirm previous results indicating that alcoholism is associated with impaired EFE recognition. Results in OM and OA indicate that opiate dependence is also associated with an impaired EFE decoding but less than in alcoholism. Alcohol and opiate chronic consumption could both exercise a deleterious effect on EFE-decoding brain function, alcohol having the most severe impact. Alternatively, EFE-decoding problems could be present before the development of alcohol and opiate dependence, with an additional effect of chronic alcohol consumption on EFE decoding. In this context, EFE-decoding impairment could reflect a more general emotional intelligence deficit in addicted populations.

  19. 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.

  20. Mechanisms of calcium influx into hippocampal spines: heterogeneity among spines, coincidence detection by NMDA receptors, and optical quantal analysis.

    PubMed

    Yuste, R; Majewska, A; Cash, S S; Denk, W

    1999-03-15

    Dendritic spines receive most excitatory inputs in the vertebrate brain, but their function is still poorly understood. Using two-photon calcium imaging of CA1 pyramidal neurons in rat hippocampal slices, we investigated the mechanisms by which calcium enters into individual spines in the stratum radiatum. We find three different pathways for calcium influx: high-threshold voltage-sensitive calcium channels, NMDA receptors, and an APV-resistant influx consistent with calcium-permeable AMPA or kainate receptors. These pathways vary among different populations of spines and are engaged under different stimulation conditions, with peak calcium concentrations reaching >10 microM. Furthermore, as a result of the biophysical properties of the NMDA receptor, the calcium dynamics of spines are exquisitely sensitive to the temporal coincidence of the input and output of the neuron. Our results confirm that individual spines are chemical compartments that can perform coincidence detection. Finally, we demonstrate that functional studies and optical quantal analysis of single, identified synapses is feasible in mammalian CNS neurons in brain slices.

  1. Knowledge of Medical Students, Residents, and Attending Physicians About Opiate Abuse.

    ERIC Educational Resources Information Center

    Shine, Daniel, Demas, Penelope

    1984-01-01

    A questionnaire concerning knowledge of opiate abuse and attitudes about abusers was administered to 94 randomly selected physicians and medical students at Montefiore Medical Center in New York City. The results indicated that physicians might benefit from improved teaching in the area of opiate abuse. (Author/MLW)

  2. Selective activation of T cells in newly diagnosed insulin-dependent diabetic patients: evidence for heterogeneity of T cell receptor usage.

    PubMed Central

    Kontiainen, S; Toomath, R; Lowder, J; Feldmann, M

    1991-01-01

    Cell surface phenotyping of 58 newly diagnosed diabetic children and 25 controls confirmed the presence of activated T cells, expressing HLA class II antigens or receptors for interleukin-2 (IL-2R, CD25) in the majority of the patients. Some of these cells putatively include those involved in islet cell destruction, as reported previously. Monoclonal antibodies recognizing three families of the variable regions of the beta chain (V beta) of the T cell receptor were used to determine the percentage of peripheral blood cells expressing those specific gene segment products. The number of the activated T cells from each V beta family was compared with that of the resting T cells of the same family in the patients and the controls. In 18 out of 58 (31%) of these patients there was evidence of oligoclonal proliferation of activated T cells as judged by marked increases in cells expressing a V beta family in the IL-2R+ T cell pool, compared with the total T cell pool. However, different V beta families were augmented in individual patients, indicating considerable heterogeneity of T cell activation in different patients. These results are in contrast to murine models of autoimmunity, where virtually monoclonal T cell activation, restricted to a single V beta family has been reported. PMID:1825939

  3. Human Leukocyte Antigen and Cytokine Receptor Gene Polymorphisms Associated With Heterogeneous Immune Responses to Mumps Viral Vaccine

    PubMed Central

    Ovsyannikova, Inna G.; Jacobson, Robert M.; Dhiman, Neelam; Vierkant, Robert A.; Pankratz, V. Shane; Poland, Gregory A.

    2009-01-01

    OBJECTIVES Mumps outbreaks continue to occur throughout the world, including in highly vaccinated populations. Vaccination against mumps has been successful; however, humoral and cellular immune responses to mumps vaccines vary significantly from person to person. We set out to assess whether HLA and cytokine gene polymorphisms are associated with variations in the immune response to mumps viral vaccine. METHODS To identify genetic factors that might contribute to variations in mumps vaccine–induced immune responses, we performed HLA genotyping in a group of 346 healthy schoolchildren (12–18 years of age) who previously received 2 doses of live mumps vaccine. Single-nucleotide polymorphisms (minor allele frequency of >5%) in cytokine and cytokine receptor genes were genotyped for a subset of 118 children. RESULTS Median values for mumps-specific antibody titers and lymphoproliferative stimulation indices were 729 IU/mL and 4.8, respectively. Girls demonstrated significantly higher mumps antibody titers than boys, indicating gender-linked genetic differences in humoral immune response. Significant associations were found between the HLA-DQB1*0303 alleles and lower mumps-specific antibody titers. An interesting finding was the association of several HLA class II alleles with mumps-specific lymphoproliferation. Alleles of the DRB1 (*0101, *0301, *0801, *1001, *1201, and *1302), DQA1 (*0101, *0105, *0401, and *0501), and DQB1 (*0201, *0402, and *0501) loci were associated with significant variations in lymphoproliferative immune responses to mumps vaccine. Additional associations were observed with single-nucleotide polymorphisms in the interleukin-10RA, interleukin-12RB1, and interleukin-12RB2 cytokine receptor genes. Minor alleles for 4 single-nucleotide polymorphisms within interleukin-10RA and interleukin-12RB genes were associated with variations in humoral and cellular immune responses to mumps vaccination. CONCLUSIONS These data suggest the important role of

  4. Intimate associations between the endogenous opiate systems and the growth hormone-releasing hormone system in the human hypothalamus.

    PubMed

    Olsen, J; Peroski, M; Kiczek, M; Grignol, G; Merchenthaler, I; Dudas, B

    2014-01-31

    Although it is a general consensus that opioids modulate growth, the mechanism of this phenomenon is largely unknown. Since endogenous opiates use the same receptor family as morphine, these peptides may be one of the key regulators of growth in humans by impacting growth hormone (GH) secretion, either directly, or indirectly, via growth hormone-releasing hormone (GHRH) release. However, the exact mechanism of this regulation has not been elucidated yet. In the present study we identified close juxtapositions between the enkephalinergic/endorphinergic/dynorphinergic axonal varicosities and GHRH-immunoreactive (IR) perikarya in the human hypothalamus. Due to the long post mortem period electron microscopy could not be utilized to detect the presence of synapses between the enkephalinergic/endorphinergic/dynorphinergic and GHRH neurons. Therefore, we used light microscopic double-label immunocytochemistry to identify putative juxtapositions between these systems. Our findings revealed that the majority of the GHRH-IR perikarya formed intimate associations with enkephalinergic axonal varicosities in the infundibular nucleus/median eminence, while endorphinergic-GHRH juxtapositions were much less frequent. In contrast, no significant dynorphinergic-GHRH associations were detected. The density of the abutting enkephalinergic fibers on the surface of the GHRH perikarya suggests that these juxtapositions may be functional synapses and may represent the morphological substrate of the impact of enkephalin on growth. The small number of GHRH neurons innervated by the endorphin and dynorphin systems indicates significant differences between the regulatory roles of endogenous opiates on growth in humans. PMID:24239719

  5. 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

  6. 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

  7. 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).

  8. GCD quantitation of opiates as propionyl derivatives in blood.

    PubMed

    Mykkänen, S; Seppälä, J; Ariniemi, K; Lillsunde, P

    2000-03-01

    We describe a method using a gas chromatograph with electron ionization detection (GCD) for the simultaneous determination of morphine, codeine, 6-monoacetylmorphine, ethylmorphine, and dihydrocodeine in blood. The method employs propionic anhydride in the presence of triethylamine to propionylate free hydroxyl groups of the opiates in blood. The quantitation is achieved by using GCD with selected ion monitoring of the two most characteristic ions for each analyte. The quantitation limit was 0.01 mg/L and the linearity was 0.01-10 mg/L for dihydrocodeine, ethylmorphine, and 6-monoacetylmorphine. For the other investigated opiates, the quantitation limit was 0.025 mg/L and linearity was 0.025-10 mg/L. The intraday relative standard deviation (RSD) varied from 7.2 to 10% at the 0.5 mg/L level, and the day-to-day RSDs varied from 7.5 to 11% at the 0.85 mg/L level.

  9. Heterogeneity of neuronal nicotinic acetylcholine receptors in 5-HT-containing chemoreceptor cells of the chicken aorta

    PubMed Central

    Ito, Shigeo; Ohta, Toshio; Kasai, Yohei; Yonekubo, Kazuki; Nakazato, Yoshikazu

    2001-01-01

    The effects of nicotinic agonists and antagonists on whole-cell currents and 5-hydroxytryptamine (5-HT) release were studied in order to characterize nicotinic ACh receptors on the 5-HT-containing chemoreceptor cells of the chicken aorta.ACh, nicotine and dimethylphenylpiperazinium (DMPP) evoked concentration-dependent inward currents accompanied by increases in current noise at a holding potential of −70 mV. The peak amplitude of the current response to DMPP was 50% larger than that to either nicotine or ACh.Hexamethonium, α – bungarotoxin (α – BTX) and methyllycaconitine decreased nicotine-induced inward currents in a concentration-dependent manner. Although hexamethonium (0.1 mM) abolished the current response to nicotine (30 μM), a high concentration (1 μM) of α – BTX decreased it only by about 30% of the control response. Methyllycaconitine (0.1 μM) decreased the current response to nicotine to the same extent as did α – BTX whilst a high concentration (10 μM) abolished the response.ACh, nicotine and DMPP caused concentration-dependent increases in 5-HT output from the thoracic aorta which effect was blocked by hexamethonium (0.1 mM). Pre-treatment with α – BTX (1 μM) for 30 min reduced the output of 5-HT induced by ACh to 70% of the control response.It is suggested that neuronal nicotinic ACh receptors, sensitive and insensitive to α – BTX, are present on the chemoreceptor cells of the chicken aorta, the activation of which causes the release of 5-HT. PMID:11309266

  10. Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor.

    PubMed

    Vrolix, Kathleen; Fraussen, Judith; Losen, Mario; Stevens, Jo; Lazaridis, Konstantinos; Molenaar, Peter C; Somers, Veerle; Bracho, Maria Alma; Le Panse, Rozen; Stinissen, Piet; Berrih-Aknin, Sonia; Maessen, Jos G; Van Garsse, Leen; Buurman, Wim A; Tzartos, Socrates J; De Baets, Marc H; Martinez-Martinez, Pilar

    2014-08-01

    Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR-MG) is considered as a prototypic autoimmune disease. The thymus is important in the pathophysiology of the disease since thymus hyperplasia is a characteristic of early-onset AChR-MG and patients often improve after thymectomy. We hypothesized that thymic B cell and antibody repertoires of AChR-MG patients differ intrinsically from those of control individuals. Using immortalization with Epstein-Barr Virus and Toll-like receptor 9 activation, we isolated and characterized monoclonal B cell lines from 5 MG patients and 8 controls. Only 2 of 570 immortalized B cell clones from MG patients produced antibodies against the AChR (both clones were from the same patient), suggesting that AChR-specific B cells are not enriched in the thymus. Surprisingly, many B cell lines from both AChR-MG and control thymus samples displayed reactivity against striated muscle proteins. Striational antibodies were produced by 15% of B cell clones from AChR-MG versus 6% in control thymus. The IgVH gene sequence analysis showed remarkable similarities, concerning VH family gene distribution, mutation frequency and CDR3 composition, between B cells of AChR-MG patients and controls. MG patients showed clear evidence of clonal B cell expansion in contrast to controls. In this latter aspect, MG resembles multiple sclerosis and clinically isolated syndrome, but differs from systemic lupus erythematosus. Our results support an antigen driven immune response in the MG thymus, but the paucity of AChR-specific B cells, in combination with the observed polyclonal expansions suggest a more diverse immune response than expected.

  11. Forensic drug testing for opiates. V. Urine testing for heroin, morphine, and codeine with commercial opiate immunoassays.

    PubMed

    Cone, E J; Dickerson, S; Paul, B D; Mitchell, J M

    1993-01-01

    Urine specimens collected after heroin, morphine, and codeine administration were tested by four commercial opiate immunoassays (TDx, CAC, ABUS, and EMIT) and GC/MS. Quantitative immunoassay results (morphine equivalents) were compared with results by GC/MS for total morphine, free morphine, or total codeine. Mean detection times for the broadly cross-reacting immunoassays (TDx, ABUS, and EMIT, 300 ng/mL cutoff) ranged from 15-44 hours following heroin and morphine administration and 33-54 hours following codeine administration. Detection times obtained with CAC (25 ng/mL cutoff) tended to be somewhat shorter as a result of the high selectivity of the antibody for free morphine. High correlations over a wide concentration range were obtained for TDx, CAC, and ABUS versus GC/MS, with specimens collected after heroin and morphine administration. EMIT showed a high correlation over a narrow concentration range (0-1000 ng/mL) with heroin and morphine specimens, but responses plateaued at higher concentrations. There was substantial variability in immunoassay responses with specimens collected after codeine administration. Generally, this study demonstrated that immunoassay responses for opiate urine testing can be used as a semi-quantitative guide for GC/MS confirmation; however, the presence of codeine increased variability and diminished the accuracy of the immunoassay response.

  12. 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.

  13. Forensic drug testing for opiates. VI. Urine testing for hydromorphone, hydrocodone, oxymorphone, and oxycodone with commercial opiate immunoassays and gas chromatography-mass spectrometry.

    PubMed

    Smith, M L; Hughes, R O; Levine, B; Dickerson, S; Darwin, W D; Cone, E J

    1995-01-01

    Opiate testing for morphine and codeine is performed routinely in forensic urine drug-testing laboratories in an effort to identify illicit opiate abusers. In addition to heroin, the 6-keto-opioids, including hydromorphone, hydrocodone, oxymorphone, and oxycodone, have high abuse liability and are self-administered by opiate abusers, but only limited information is available on detection of these compounds by current immunoassay and gas chromatographic-mass spectrometric (GC-MS) methods. In this study, single doses of hydromorphone, hydrocodone, oxymorphone, and oxycodone were administered to human subjects, and urine samples were collected before and periodically after dosing. Opiate levels were determined in a quantitative mode with four commercial immunoassays, TDx opiates (TDx), Abuscreen radioimmunoassay (ABUS), Coat-A-Count morphine in urine (CAC), and EMIT d.a.u. opiate assay (EMIT), and by GC-MS. GC-MS assay results indicated that hydromorphone, hydrocodone, oxymorphone, and oxycodone administration resulted in rapid excretion of parent drug and O-demethylated metabolites in urine. Peak concentrations occurred within 8 h after drug administration and declined below 300 ng/mL within 24-48 h. Immunoassay testing indicated that hydromorphone, hydrocodone, and oxycodone, but not oxymorphone, were detectable in urine by TDx and EMIT (300-ng/mL cutoff) for 6-24 h. ABUS detected only hydrocodone, and CAC failed to detect any of the four 6-keto-opioid analgesics. Generally, immunoassays for opiates in urine displayed substantially lower sensitivities for 6-keto-opioids compared with GC-MS. Consequently, urine samples containing low to moderate concentrations of hydromorphone, hydrocodone, oxymorphone, and oxycodone will likely go undetected when tested by conventional immunoassays.

  14. Phenotypic variation resulting from a deficiency of epidermal growth factor receptor in mice is caused by extensive genetic heterogeneity that can be genetically and molecularly partitioned.

    PubMed Central

    Strunk, Karen E; Amann, Vicky; Threadgill, David W

    2004-01-01

    The timing of lethality caused by homozygosity for a null allele of the epidermal growth factor receptor (Egfrtm1Mag) in mice is strongly dependent on genetic background. Initial attempts to genetically map background modifiers using Swiss-derived, outbred CD-1 mice were unsuccessful. To investigate the genetic architecture contributing to survival of Egfrtm1Mag homozygous embryos, the genetic variability segregating within the outbred population was partitioned by surveying viability of Egfrtm1Mag mutants using intercrosses between 129S6/SvEvTAC-Egfrtm1Mag and nine Swiss-derived, inbred strains: ALR/LtJ, ALS/LtJ, APN, APS, ICR/HaRos, NOD/LtJ, NON/LtJ, SJL/J, and SWR/J. The observations showed that these strains support varying levels of survival of Egfrtm1Mag homozygous embryos, suggesting that genetic heterogeneity within the CD-1 stock contributed to the original lack of Egfrtm1Mag modifier detection. Similar to the Swiss-derived intercrosses, nine congenic strains, derived from 129S6/SvEvTAC, AKR/J, APN, BALB/cJ, BTBR-T+ tf/tf, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ inbred backgrounds, also supported varying levels of survival of Egfrtm1Mag mutants. By intercrossing the congenic lines to create hybrid F1 embryos, different genetic backgrounds were found to have complementary modifiers. Analysis of the congenic lines argues against heterosis of outbred backgrounds contributing to Egfrtm1Mag phenotypic variability. A detailed analysis of the crosses suggests that modifiers function at three distinct stages of development. One class of modifiers supports survival of Egfrtm1Mag homozygous embryos to mid-gestation, another class supports development through the mid-gestation transition from yolk-sac to placental-derived nutrient sources, and a third class supports survival through later stages of gestation. Data from microarray analysis using RNA from wild-type and Egfrtm1Mag mutant placentas support the existence of extensive genetic heterogeneity and suggest that

  15. Opiates selectively increase intracellular calcium in developing type-1 astrocytes: role of calcium in morphine-induced morphologic differentiation.

    PubMed

    Stiene-Martin, A; Mattson, M P; Hauser, K F

    1993-12-17

    Endogenous opioids and opiate drugs inhibit nervous system maturation, in part, by affecting the growth of astrocytes. Opiates inhibit astrocyte proliferation and cause premature differentiation. The emerging importance of Ca2+ in astrocyte function prompted us to explore whether opiates might affect astrocyte development by altering Ca2+ homeostasis. Astrocyte-enriched cultures were derived from newborn ICR mouse cerebra. Quantitative fluorescent measurements of intracellular free Ca2+ ([Ca2+]i) using Fura-2 as well as fluo-3 and computer-aided image analysis showed that 1 microM morphine significantly increased [Ca2+]i in flat, polyhedral, glial fibrillary acidic protein (GFAP) immunoreactive astrocytes at 2 and 6 min, and at 72 h. Co-administration of 3 microM naloxone blocked morphine-dependent increases in [Ca2+]i. Treatment with 1 microM concentrations of the kappa-opioid receptor agonist, U69,593, but not equimolar amounts of mu ([D-Ala2,MePhe4,Gly(ol)5]enkephalin)- or delta ([D-Pen2,D-Pen5]enkephalin)-opioid receptor agonists, significantly increased [Ca2+]i in astrocytes. To assess the role of Ca2+ in morphine-induced astrocyte differentiation, untreated and 1 microM morphine-treated astrocyte cultures were incubated for 5 days in < 0.01, 0.3, 1.0, or 3.0 mM extracellular Ca2+ ([Ca2+]o), or incubated with 1.0 mM [Ca2+]o in the presence of 1 microM of the Ca2+ ionophore, A23187. The areas of single astrocytes were measured and there was a positive correlation between astrocyte area and [Ca2+]o. Morphine had an additive effect on area and form factor measures when [Ca2+]o was 1.0 mM. High [Ca2+]o (3.0 mM) alone mimicked the action of morphine. Morphine alone had no effect on astrocyte area in the presence of 3.0 mM Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    PubMed

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

    2016-02-01

    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 (18)F-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.

  17. Behavioral naltrexone therapy: an integrated treatment for opiate dependence.

    PubMed

    Rothenberg, Jami L; Sullivan, Maria A; Church, Sarah H; Seracini, Angela; Collins, Eric; Kleber, Herbert D; Nunes, Edward V

    2002-12-01

    Treatment of opiate dependence with naltrexone has been limited by poor compliance. Behavioral Naltrexone Therapy (BNT) was developed to promote adherence to naltrexone and lifestyle changes supportive of abstinence, by incorporating components from empirically validated treatments, including Network Therapy with a significant other to monitor medication compliance, the Community Reinforcement Approach, and voucher incentives. An overview is presented of the BNT treatment manual. In an uncontrolled Stage I trial (N = 47), 19% completed the 6-month course of treatment. Retention was especially poor in the subsample of patients who were using methadone at baseline (N = 18; 39% completed 1 month, none completed 6 months), and more encouraging among heroin-dependent patients (N = 29; 65% completed 1 month, 31% completed 6 months). Thus, attrition continues to be a serious problem for naltrexone maintenance, although further efforts to develop interventions such as BNT are warranted. PMID:12495797

  18. 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.

  19. 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

  20. 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

  1. 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)

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. Simultaneous liquid chromatography-mass spectrometry quantification of urinary opiates, cocaine, and metabolites in opiate-dependent pregnant women in methadone-maintenance treatment.

    PubMed

    Shakleya, Diaa M; Dams, Riet; Choo, Robin E; Jones, Hendree; Huestis, Marilyn A

    2010-01-01

    Opiates, cocaine, and metabolites were quantified by liquid chromatography-mass spectrometry (LC-MS) in 284 urine specimens, collected thrice weekly, to monitor possible drug relapse in 15 pregnant heroin-dependent women. Opiates were detected in 149 urine specimens (52%) with limits of quantification (LOQ) of 10-50 microg/L. Morphine, morphine-3-glucuronide, and/or morphine-6-glucuronide were positive in 121 specimens; 6-acetylmorphine, a biomarker of heroin ingestion, was quantifiable in only 7. No heroin, 6-acetylcodeine, papaverine, or noscapine were detected. One hundred and sixty-five urine specimens (58%) from all 15 participants were positive for one or more cocaine analytes (LOQ 10-100 microg/L). Ecgonine methylester (EME) and/or benzoylecgonine were the major cocaine biomarkers in 142. Anhydroecgonine methylester, a biomarker of smoked cocaine, was positive in six; cocaethylene and/or ecgonine ethylester, biomarkers of cocaine and ethanol co-ingestion, were found in 25. At the current Substance Abuse Mental Health Services Administration cutoffs for total morphine (2000 microg/L), codeine (2000 microg/L), 6-acetylmorphine (10 microg/L), and benzoylecgonine (100 microg/L), 16 opiate- and 29 cocaine-positive specimens were identified. Considering 100 microg/L EME as an additional urinary cocaine biomarker would identify 51 more positive cocaine specimens. Of interest is the differential pattern of opiate and cocaine biomarkers observed after LC-MS as compared to gas chromatography-mass spectrometry analysis. PMID:20109298

  14. Sequence of onset of different drug use among opiate addicts.

    PubMed

    Navaratnam, V; Foong, K

    1989-01-01

    The temporal sequence of drug use should reveal which drugs are precursors to heroin and which drugs are used subsequent to the establishment of heroin addiction as adjunctive drugs. This temporal sequence was examined in an epidemiological study. Out of 249 opiate addicts interviewed in the area of Penang, Malaysia, this sequence of drugs could be obtained in 248 cases. The mean (median) age for first use of nicotine is 15.5 (15) years, alcohol 18.4 (18) years, cannabis 17.8 (17) years, heroin 21.8 (21) years, opium 22.8 (22) years, and benzodiazepines 25.8 (25) years. The age of first use of different drug types is presented in some detail. The patterns of sequence of drug use was analyzed for the five major and most frequently reported drugs, i.e. alcohol, cannabis, heroin, opium and benzodiazepines. Nicotine, used as first drug in almost all cases, was omitted in this analysis. A clear trend to multiple drug abuse emerges from this analysis; the biggest number of cases were users of 4 drugs (81 cases), followed by 3 drugs (59 cases) and 5 drugs (58 cases). Thus, nicotine, alcohol and cannabis are precursors of heroin addiction. Other adjunctive drugs become important only after heroin addiction. Among these substances, opium and benzodiazepines are numerically preponderant.

  15. 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

  16. 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

  17. Effects of opiate antagonists on hormones and behavior of male and female rhesus monkeys.

    PubMed

    Abbott, D H; Holman, S D; Berman, M; Neff, D A; Goy, R W

    1984-02-01

    Opiate antagonists, naloxone (100 micrograms/kg) and naltrexone (1 mg/kg) were given to singly housed adult male or female rhesus prior to a 20-minute behavioral test with an oppositely sexed stimulus monkey. Four of the intact adult males were socially and sexually experienced. The remaining two intact males and two castrated males had been reared in socially restricted conditions and were psychosexually deficient. Adult females were ovariectomized, and the effects of opiate antagonists were examined with or without concurrent estradiol treatment. Both antagonists inhibited sexual behavior of the socially reared, sexually active, intact males. No stimulatory effects on sexual behavior were observed for sexually deficient males, whether intact or castrated. Females showed little change in sexual behavior following opiate antagonist treatment, regardless of endocrine status. The proportion of approaches of the female to the male was increased when naloxone, but not naltrexone, was given. Specific endocrine effects of the opiate antagonists were only found in intact males. Naltrexone significantly increased LH concentrations in the two males tested, while the increase in LH in the four males receiving naloxone was not significant. In all intact males, increases in LH were accompanied by statistically significant increases in circulating concentrations of testosterone following naloxone and naltrexone. The gonadotropic stimulating effect of the opiate antagonists was specific to LH, and no changes were observed in circulating concentrations of FSH in either sex. PMID:6424632

  18. Effect of poppy seed consummation on the positive results of opiates screening in biological samples.

    PubMed

    Jankovicová, Katarína; Ulbrich, Pavol; Fuknová, Mária

    2009-04-01

    Poppy seed is a popular substance of many traditional Slovak cakes. We can eat quite great amount of it, sometimes more than 50 g. Existing problem in interpreting the results of opiate urine analysis in case of drug abuse arises from the natural occurrence of opiate alkaloids in poppy seed. Interpretation of morphine presence in urine sample is in some cases a problem because morphine present in the urine sample may come from different "sources". The presence of additional, respectively, other opiate in urine sample is significant help when interpreting the presence of morphine. We used poppy seed bought in supermarket for our experiment. Presence of morphine and codeine was determined in poppy seed extracts, whereas the concentration of majority opiate-morphine was 0.9 mg/100 g (9 ppm). This poppy seed was used for two series of experiment-poppy seed consummation, where four persons consumed 100g of poppy seed in the first series and 50 g in the second series. Urine samples were taken in regular 1h intervals where first urine sample was given for testing 3 h after consummation. Concentrations of total opiates were determined in each urine sample by screening examination. Morphine concentrations were determined in selected urine samples using GC/MS with internal standard.

  19. Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.

    PubMed

    Fitting, Sylvia; Zou, Shiping; El-Hage, 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.

  20. 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

  1. 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

  2. The effect of opiates on the activity of human placental aromatase/CYP19.

    PubMed

    Zharikova, Olga L; Deshmukh, Sujal V; Kumar, Meena; Vargas, Ricardo; Nanovskaya, Tatiana N; Hankins, Gary D V; Ahmed, Mahmoud S

    2007-01-15

    Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time. PMID:17118343

  3. 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

  4. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.

    PubMed

    Ogitani, Yusuke; Hagihara, Katsunobu; Oitate, Masataka; Naito, Hiroyuki; Agatsuma, Toshinori

    2016-07-01

    Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1. PMID:27166974

  5. 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…

  6. 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…

  7. Differentiating Violent and Nonviolent Opiate-Addicted Reformatory Inmates with the MMPI.

    ERIC Educational Resources Information Center

    Chick, Garry E.; And Others

    1984-01-01

    Discriminated among four groups of male opiate-addicted reformatory inmates (N=193) according to degree of criminal violence using the Minnesota Multiphasic Personality Inventory (MMPI). Results showed that discriminant analysis was moderately successful for classifying Bodily Violent and Nonbodily Violent groups on the basis of their MMPI scores.…

  8. 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…

  9. 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...

  10. 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...

  11. 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... 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...

  12. 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.…

  13. 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)

  14. 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.

  15. 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

  16. Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha.

    PubMed Central

    Krauss, A. H.; Woodward, D. F.; Gibson, L. L.; Protzman, C. E.; Williams, L. S.; Burk, R. M.; Gac, T. S.; Roof, M. B.; Abbas, F.; Marshall, K.; Senior, J.

    1996-01-01

    1. The pharmacological activity of a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha (PGF2 alpha) was investigated in various isolated smooth muscle preparations possessing different prostanoid receptor subtypes as well as in human platelets. Since subdivision of thromboxane (TP-) receptors into vascular/smooth muscle and platelet subtypes is a controversial subject, our studies included a human smooth muscle preparation (myometrium) in addition to the widely used rat aorta and human platelets as TP-receptor preparations. 2. Two members of that series, AGN191976 and AGN192093 were found to be highly potent and selective thromboxane-mimetics. AGN191976 and AGN192093 contracted isolated tissues of the rat thoracic aorta with EC50 values of 0.32 +/- 0.08 and 1.30 +/- 0.53 nM, respectively. Both agonists were at least 10 times more potent than the benchmark TP-agonist, U-46619, in this preparation, whilst being at least 500 times less potent at other prostanoid receptors (DP, EP1, EP3, FP, IP) in vitro. 3. In human myometrial strips from pregnant and non-pregnant donors, both AGN191976 and AGN192093 were potent contractile agonists. The rank order of potency in myometrium of AGN191976 > AGN192093 > U-46619 correlated well with that in the rat aorta. In human platelet-rich plasma (PRP), however, AGN191976 had potent proaggregatory activity (EC50 = 16.3 +/- 1.4 nM), which is a TP-receptor-mediated event, whereas AGN192093 was a much weaker agonist (EC50 = 37.9 +/- 2.0 microM). AGN192093 did not behave as an antagonist in the platelets, since it did not antagonize platelet aggregation induced by ADP, arachidonic acid, U-46619 or AGN191976. In human washed platelets, the activity profile of AGN191976 (EC50 = 4.15 +/- 0.52 nM) and AGN192093 (no aggregation up to 10 microM) was similar to that obtained in PRP. 4. The involvement of TP-receptors was verified with the potent TP-antagonist, SQ29548. SQ29548 (0.1 microM in myometrium; 1 microM in

  17. Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content.

    PubMed

    Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; LoDico, Charles; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

    2014-08-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45 g oral poppy seed doses 8 h apart, each containing 15.7 mg morphine and 3mg codeine. Urine was collected ad libitum up to 32 h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2000 and 300 μg/L cutoffs, and the ThermoFisher CEDIA(®) heroin metabolite (6-acetylmorphine, 6-AM) and Lin-Zhi 6-AM immunoassays with 10 μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32 h following dosing; 26.6% and 83.4% were positive for morphine at 2000 and 300 μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7522 μg/L with a median peak concentration of 5239 μg/L. The median first morphine-positive urine sample at 2000 μg/L cutoff concentration occurred at 6.6 h (1.2-12.1), with the last positive from 2.6 to 18 h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2000 μg/L, but 20.2% exceeded 300 μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300 μg/L cutoffs. The CEDIA 6-AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results.

  18. Morphine and Codeine Concentrations in Human Urine following Controlled Poppy Seeds Administration of Known Opiate Content

    PubMed Central

    Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; LoDico, Charles; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45g oral poppy seed doses 8h apart, each containing 15.7mg morphine and 3mg codeine. Urine was collected ad libitum up to 32h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2,000 and 300μg/L cutoffs, and the ThermoFisher CEDIA® Heroin Metabolite (6-acetylmorphine, 6AM) and Lin-Zhi 6AM immunoassays with 10μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32h following dosing; 26.6% and 83.4% were positive for morphine at 2,000 and 300μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7,522μg/L with a median peak concentration of 5,239μg/L. The median first morphine-positive urine sample at 2,000μg/L cutoff concentration occurred at 6.6h (1.2-12.1), with the last positive from 2.6 to 18h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2,000μg/L, but 20.2% exceeded 300μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300μg/L cutoffs. The CEDIA 6AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. PMID:24887324

  19. The action of trimebutine maleate on gastrointestinal motility is mediated by opiate receptors in human subjects.

    PubMed

    Valori, R; Shannon, S; Reddy, N; Daniel, E E; Collins, S M

    1987-01-01

    The effects of trimebutine on interdigestive motor activity of the small intestine and the colon were studied in healthy volunteers. Trimebutine induced in all subjects phase III-like motor complexes, which were similar to spontaneously occurring phase III complexes of the interdigestive cycle in antrum and duodenum. Trimebutine-induced complexes were suppressed by naloxone. Trimebutine and/or naloxone had no consistent effect on interdigestive contractile activity in the colon. PMID:3038649

  20. Individual differences in initial morphine sensitivity as a predictor for the development of opiate addiction in rats.

    PubMed

    Nishida, Kevin S; Park, Thomas Y; Lee, Bong Hyo; Ursano, Robert J; Choi, Kwang H

    2016-10-15

    Individuals report a wide range of analgesia to similar doses of opiates, and not all opiate users become addicted. This suggests that there may be certain predispositions that influence one to develop opiate addiction. We investigated the relationship between the individual differences in initial morphine sensitivity and the subsequent development of opiate addiction-like behavior using a hot plate test and an intravenous morphine self-administration (MSA) paradigm in rats. Using a median split of initial morphine antinociception, animals were defined as low antinociception (LA) and high antinociception (HA) groups. Thus, the LA group represents the animals that were less sensitive to initial morphine antinociception as compared to those of the HA group. The animals were allowed to self-administer either saline or morphine (0.5mg/kg/infusion, 4hr/day) 5days per week for 3 weeks. Spontaneous locomotor activity was measured on self-administration days 10 and 15. Individual differences in initial morphine sensitivity were not correlated with the amount of morphine self-administered by the animals on day 1. In the second-week of MSA, the LA group exhibited increased morphine intake and locomotor hyperactivity as compared to those of the HA group. Therefore, certain animals that are less sensitive to initial morphine antinociception may be susceptible to developing opiate addiction. The current findings may have clinical implications for future research on the biological mechanisms of opiate addiction and preclinical medication development. PMID:27457135

  1. Individual differences in initial morphine sensitivity as a predictor for the development of opiate addiction in rats.

    PubMed

    Nishida, Kevin S; Park, Thomas Y; Lee, Bong Hyo; Ursano, Robert J; Choi, Kwang H

    2016-10-15

    Individuals report a wide range of analgesia to similar doses of opiates, and not all opiate users become addicted. This suggests that there may be certain predispositions that influence one to develop opiate addiction. We investigated the relationship between the individual differences in initial morphine sensitivity and the subsequent development of opiate addiction-like behavior using a hot plate test and an intravenous morphine self-administration (MSA) paradigm in rats. Using a median split of initial morphine antinociception, animals were defined as low antinociception (LA) and high antinociception (HA) groups. Thus, the LA group represents the animals that were less sensitive to initial morphine antinociception as compared to those of the HA group. The animals were allowed to self-administer either saline or morphine (0.5mg/kg/infusion, 4hr/day) 5days per week for 3 weeks. Spontaneous locomotor activity was measured on self-administration days 10 and 15. Individual differences in initial morphine sensitivity were not correlated with the amount of morphine self-administered by the animals on day 1. In the second-week of MSA, the LA group exhibited increased morphine intake and locomotor hyperactivity as compared to those of the HA group. Therefore, certain animals that are less sensitive to initial morphine antinociception may be susceptible to developing opiate addiction. The current findings may have clinical implications for future research on the biological mechanisms of opiate addiction and preclinical medication development.

  2. Impact of substance abuse treatment on arrests among opiate users in Washington State.

    PubMed

    Campbell, Kevin M; Deck, Dennis; Krupski, Antoinette

    2007-01-01

    Administrative data from Washington State's Division of Alcohol and Substance Abuse drive this three-year prospective study of the impact of substance abuse treatment on arrests among 12,962 opiate users receiving publicly funded substance abuse services. Using survival analysis, the risk of arrest among opiate users who receive substance abuse treatment is compared to those who do not receive treatment. Propensity scores control for client characteristics associated with admission to substance abuse treatment. Overall, a reduction in the risk of arrest was found among subjects in treatment (Hazard Ratio = 0.59-0.78, p < .05) and subjects successfully completing treatment (Hazard Ratio = 0.75, p < .05). Risk of arrest was elevated among those with a negative outcome to treatment (Hazard Ratio = 1.23, p < .05).

  3. Psychiatric disorders and impairment in the children of opiate addicts: prevalances and distribution by ethnicity.

    PubMed

    Nunes, E V; Weissman, M M; Goldstein, R; McAvay, G; Beckford, C; Seracini, A; Verdeli, H; Wickramaratne, P

    2000-01-01

    This study examined rates of psychiatric disorders and impairment in 283 children, aged 6 to 17, of 69 Caucasian, 45 African-American, and 47 Hispanic-American methadone maintenance patients. Children were evaluated by direct and/or parental interview with the K-SADS-E. Final DSM-III-R diagnoses and Global Assessment Scale (C-GAS) were assigned by best estimate. Substantial lifetime prevalences of mood (21%), anxiety (24%) and disruptive disorders (30%), school problems (37%), and global impairment (C-GAS < 61) (25%) were observed in the children of opiate-dependent patients. There were few differences between ethnic groups. Effects of proband gender and major depression and their interactions with ethnicity on risk for childhood psychopathology were also examined. The results suggest children of patients in treatment for opiate dependence from diverse ethnic groups are at risk for psychopathology. Programs for early detection and intervention should be devised and evaluated. PMID:11000919

  4. LC-MS-MS Method for Analysis of Opiates in Wastewater During Football Games II.

    PubMed

    Gul, Waseem; Stamper, Brandon; Godfrey, Murrell; Gul, Shahbaz W; ElSohly, Mahmoud A

    2016-06-01

    Continuing our previous studies analyzing drugs of abuse in municipal wastewater, a method was developed for the analysis of opiates in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). Eight opiate drugs and metabolites were analyzed including codeine, hydrocodone, hydromorphone, 6-monoacetylmorphine (6-MAM, the primary urinary metabolite of heroin), morphine, norhydrocodone (the primary urinary metabolite of hydrocodone), oxycodone and oxymorphone. These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Waste Water Treatment Plant in Oxford, Mississippi (MS) and the University Wastewater Treatment Plant in University, MS. These wastewater samples were collected on weekends in which the Ole Miss Rebel football team held home games (Vaught-Hemingway Stadium, University, MS 38677). The collected samples were analyzed using a validated method and found to contain codeine, hydrocodone, hydromorphone, morphine, norhydrocodone, oxycodone and oxymorphone. None of the samples contained 6-MAM. PMID:27052850

  5. Heterogeneity of neuronal and smooth muscle receptors involved in the VIP- and PACAP-induced relaxations of the pig intravesical ureter

    PubMed Central

    Hernández, Medardo; Barahona, María Victoria; Recio, Paz; Rivera, Luis; Benedito, Sara; Martínez, Ana Cristina; García-Sacristán, Albino; Orensanz, Luis M; Prieto, Dolores

    2003-01-01

    The mechanisms and receptors involved in the vasoactive intestinal peptide (VIP)- and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced relaxations of the pig intravesical ureter were investigated.VIP, PACAP 38 and PACAP 27 concentration-dependently relaxed U46619-contracted ureteral strips with a similar potency. [Ala11,22,28]-VIP, a VPAC1 agonist, showed inconsistent relaxations.The neuronal voltage-gated Ca2+ channel inhibitor, ω-conotoxin GVIA (ω-CgTX, 1 μM), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin-sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 μM), NG-nitro-L-arginine (L-NOARG, 100 μM) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 μM), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by ω-CgTX, capsaicin, L-NOARG and ODQ.The VIP and VIP/PACAP receptor antagonists, [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP (1 μM) and PACAP (6–38) (0.4 μM), inhibited VIP and VIP and PACAP 38, respectively, relaxations.The nonselective and large-conductance Ca2-activated K+ channel blockers, tetraethylammonium (3 mM) and charybdotoxin (0.1 μM), respectively, and neuropeptide Y (0.1 μM) did not modify the VIP relaxations. The small-conductance Ca2-activated K+ channel blocker apamin (1 μM) did not change the PACAP 27 relaxations.The cAMP-dependent protein kinase A (PKA) blocker, 8-(4-chlorophenylthio)adenosine-3′,5′-cyclic monophosphorothioate (Rp-8-CPT-cAMPS, 100 μM), reduced VIP relaxations. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin relaxed ureteral preparations. The rolipram relaxations were reduced by Rp-8-CPT-cAMPS. Forskolin (30 nM) evoked a potentiation of VIP relaxations.These results suggest that VIP and PACAP relax the pig ureter through smooth muscle receptors, probably of the VPAC2 subtype, linked to a cAMP-PKA pathway. Neuronal VPAC receptors localized at

  6. Decreased spinal cord opioid receptor mRNA expression and antinociception in a Theiler’s murine encephalomyelitis virus model of multiple sclerosis

    PubMed Central

    Lynch, Jessica L.; Alley, Jeremy F.; Wellman, Lori; Beitz, Alvin J.

    2008-01-01

    Multiple sclerosis patients typically experience increased pain that is relatively insensitive to opiate treatment. The mechanistic basis for this increased nociception is currently poorly understood. In the present study, we utilized the Theiler’s murine encephalomyelitis virus (TMEV) model of MS to examine possible changes in spinal cord opioid receptor mRNA over the course of disease progression. TMEV infection led to significantly decreased mu, delta and kappa opioid receptor mRNA expression as analyzed by quantitative Real-Time PCR in both male and female mice at days 90, 150 and 180 post-infection (PI). Since opioid receptor mRNA expression decreased in TMEV mice, we examined whether opiate analgesia is also altered. TMEV infected female mice had significantly decreased opiate analgesia in thermal nociceptive tests beginning at day 90 PI, while TMEV-infected male mice did not display significantly decreased opiate analgesia until day 120 PI. The novel finding that opioid receptor expression is significantly decreased in the spinal cord of TMEV mice could explain the increased nociception and loss of opiate analgesia observed in both TMEV mice and multiple sclerosis patients. PMID:18096140

  7. Neurofeedback training for opiate addiction: improvement of mental health and craving.

    PubMed

    Dehghani-Arani, Fateme; Rostami, Reza; Nadali, Hosein

    2013-06-01

    Psychological improvements in patients with substance use disorders have been reported after neurofeedback treatment. However, neurofeedback has not been commonly accepted as a treatment for substance dependence. This study was carried out to examine the effectiveness of this therapeutic method for opiate dependence disorder. The specific aim was to investigate whether treatment leads to any changes in mental health and substance craving. In this experimental study with a pre-post test design, 20 opiate dependent patients undergoing Methadone or Buprenorphine maintenance treatment were examined and matched and randomized into two groups. While both experimental and control groups received their usual maintenance treatment, the experimental group received 30 sessions of neurofeedback treatment in addition. The neurofeedback treatment consisted of sensory motor rhythm training on Cz, followed by an alpha-theta protocol on Pz. Data from the general health questionnaire and a heroin craving questionnaire were collected before and after treatment. Multivariate analysis of covariance showed that the experimental group achieved improvement in somatic symptoms, depression, and total score in general mental health; and in anticipation of positive outcome, desire to use opioid, and relief from withdrawal of craving in comparison with the control group. The study supports the effectiveness of neurofeedback training as a therapeutic method in opiate dependence disorder, in supplement to pharmacotherapy.

  8. Poppy seed foods and opiate drug testing--where are we today?

    PubMed

    Lachenmeier, Dirk W; Sproll, Constanze; Musshoff, Frank

    2010-02-01

    Seeds of the opium poppy plant are legally sold and widely consumed as food. Due to contamination during harvesting, the seeds can contain morphine and other opiate alkaloids. The objective of this study is to review the toxicology of poppy seed foods regarding influence on opiate drug tests. Computer-assisted literature review resulted in 95 identified references. Normal poppy seed consumption is generally regarded as safe. During food processing, the morphine content is considerably reduced (up to 90%). The possibility of false-positive opiate drug tests after poppy food ingestion exists. There are no unambiguous markers available to differentiate poppy food ingestion from heroin or pharmaceutical morphine use. This is also a problem in heroin-assisted maintenance programs. A basic requirement in such substitution programs is the patients' abstinence from any other drugs, including additional illicit heroin. Also a lack of forensic ingestion trials was detected that consider all factors influencing the morphine content in biologic matrices after consumption. Most studies did not control for the losses during food processing, so that the initial morphine dosage was overestimated. The large reduction of the morphine content during past years raises questions about the validity of the "poppy seed defence." However, a threshold of food use that would not lead to positive drug tests with certainty is currently unavailable. Research is needed to prove if the morphine contents in today's foods still pose the possibility of influencing drug tests. Future trials should consider processing-related morphine losses. PMID:19901868

  9. Opiates do not violate the viability and proliferative activity of human articular chondrocytes.

    PubMed

    Chechik, Ofir; Arbel, Ron; Salai, Moshe; Gigi, Roy; Beilin, Mark; Flaishon, Ron; Sever, Ronen; Khashan, Morsi; Ben-Tov, Tomer; Gal-Levy, Ronit; Yayon, Avner; Blumenstein, Sara

    2014-09-01

    Articular cartilage injuries present a challenge for the clinician. Autologous chondrocyte implantation embedded in scaffolds are used to treat cartilage defects with favorable outcomes. Autologous serum is often used as a medium for chondrocyte cell culture during the proliferation phase of the process of such products. A previous report showed that opiate analgesics (fentanyl, alfentanil and diamorphine) in the sera have a significant inhibitory effect on chondrocyte proliferation. In order to determine if opiates in serum inhibit chondrocyte proliferation, twenty two patients who underwent knee arthroscopy and were anesthetized with either fentanyl or remifentanil were studied. Blood was drawn before and during opiate administration and up to 2 h after its discontinuation. The sera were used as medium for in vitro proliferation of both cryopreserved and freshly isolated chondrocytes, and the number and viability of cells were measured. There was no difference in the yield or cell viability between the serum samples of patients anesthetized with fentanyl when either fresh or cryopreserved human articular chondrocytes (hACs) were used. Some non-significant reduction in the yield of cells was observed in the serum samples of patients anesthetized with remifentanil when fresh hAC were used. We conclude that Fentanyl in human autologous serum does not inhibit in vitro hAC proliferation. Remifentanil may show minimal inhibitory effect on in vitro fresh hAC proliferation.

  10. ACTH-like peptides increase pain sensitivity and antagonize opiate analgesia

    NASA Technical Reports Server (NTRS)

    Heybach, J. P.; Vernikos, J.

    1981-01-01

    The role of the pituitary and of ACTH in pain sensitivity was investigated in the rat. Pain sensitivity was assessed by measuring paw-lick and jump latencies in response to being placed on a grid at 55 C. Hypophysectomy reduced pain sensitivity, and this effect was reversed by the intracerebroventricular (ICV) injection of the opiate antagonist naloxone. Similarly, the analgesia produced by a dose of morphine was antagonized by the administration of ACTH or alpha-MSH. The peripheral injection of ACTH or alpha-MSH in normal rats did not increase pain sensitivity. However, ACTH administered ICV increased pain sensivity within 10 min. The results indicate that the pituitary is the source of an endogenous opiate antagonist and hyperalgesic factor and that this factor is ACTH or an ACTH-like peptide. This activity resides in the N-terminal portion of the ACTH molecule since ACTH sub 4-10 is not active in this respect, nor does this activity require a free N-terminal serine since alpha-MSH appears to be almost as potent as the ACTH sub 1-24 peptide. It is concluded that ACTH-like peptides of pituitary origin act as endogenous hyperalgesic and opiate antagonistic factors.

  11. Poppy seed foods and opiate drug testing--where are we today?

    PubMed

    Lachenmeier, Dirk W; Sproll, Constanze; Musshoff, Frank

    2010-02-01

    Seeds of the opium poppy plant are legally sold and widely consumed as food. Due to contamination during harvesting, the seeds can contain morphine and other opiate alkaloids. The objective of this study is to review the toxicology of poppy seed foods regarding influence on opiate drug tests. Computer-assisted literature review resulted in 95 identified references. Normal poppy seed consumption is generally regarded as safe. During food processing, the morphine content is considerably reduced (up to 90%). The possibility of false-positive opiate drug tests after poppy food ingestion exists. There are no unambiguous markers available to differentiate poppy food ingestion from heroin or pharmaceutical morphine use. This is also a problem in heroin-assisted maintenance programs. A basic requirement in such substitution programs is the patients' abstinence from any other drugs, including additional illicit heroin. Also a lack of forensic ingestion trials was detected that consider all factors influencing the morphine content in biologic matrices after consumption. Most studies did not control for the losses during food processing, so that the initial morphine dosage was overestimated. The large reduction of the morphine content during past years raises questions about the validity of the "poppy seed defence." However, a threshold of food use that would not lead to positive drug tests with certainty is currently unavailable. Research is needed to prove if the morphine contents in today's foods still pose the possibility of influencing drug tests. Future trials should consider processing-related morphine losses.

  12. An Anadysplasia-Like, Spontaneously Remitting Spondylometaphyseal Dysplasia Secondary to Lamin B Receptor (LBR) Gene Mutations: Further Definition of the Phenotypic Heterogeneity of LBR-Bone Dysplasias

    PubMed Central

    Sobreira, Nara; Modaff, Peggy; Steel, Gary; You, Jing; Nanda, Sonia; Hoover-Fong, Julie; Valle, David; Pauli, Richard M

    2014-01-01

    We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia. PMID:25348816

  13. An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.

    PubMed

    Sobreira, Nara; Modaff, Peggy; Steel, Gary; You, Jing; Nanda, Sonia; Hoover-Fong, Julie; Valle, David; Pauli, Richard M

    2015-01-01

    We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia. PMID:25348816

  14. Economic evaluation of interventions to treat opiate dependence : a review of the evidence.

    PubMed

    Doran, Christopher M

    2008-01-01

    Opiate dependence imposes a significant economic burden on society in terms of treatment-related costs and prevention services, other healthcare costs, the work absenteeism of patients, productivity loss arising from premature death of patients, costs associated with crime, and social welfare expenditure. The objective of this research is to review the literature on economic evaluation of treatment of opiate dependence (including detoxification, maintenance and psychosocial support).A literature review was performed on several electronic databases, including MEDLINE (Ovid), Cochrane Database of Systematic Reviews, NHS Economic Evaluation Library Database (via Cochrane Library), Web of Science, Social Science Citations Index, EMBASE and PsycINFO. A sensitive approach was used in order to maximize the number of articles retrieved; no language or publication year limitations were applied to the searches. A combination of subject heading term searches and natural word searches were used. The Drummond checklist was applied to assess the quality of economic evaluations.A total of 259 articles were considered relevant, with eight review studies identified. The treatment spectrum ranged from detoxification to maintenance treatments involving the use of agonist and/or antagonist treatments. The evidence suggests that, although the quality of economic evaluations is reasonably good, there is a dearth of knowledge about the cost effectiveness of treatments for opiate dependence. The majority of the literature reporting the results of cost-effectiveness analyses used surrogate outcome measures and adopted a narrow treatment provider perspective. Studies that have conducted cost-benefit analyses, in spite of methodological divergences, generally adopted a societal perspective and consistently demonstrated positive economic returns from opiate treatment. A paucity of research examined the extent to which psychosocial or behavioural interventions support or replace conventional

  15. GSK3β-Activation is a Point of Convergence for HIV-1 and Opiate-Mediated Interactive Neurotoxicity

    PubMed Central

    Masvekar, Ruturaj R.; El-Hage, Nazira; Hauser, Kurt F.; Knapp, Pamela E.

    2015-01-01

    Infection of the CNS with HIV-1 occurs rapidly after primary peripheral infection. HIV-1 can induce a wide range of neurological deficits, collectively known as HIV-1-associated neurocognitive disorders. Our previous work has shown that the selected neurotoxic effects induced by individual viral proteins, Tat and gp120, and by HIV+ supernatant are enhanced by co-exposure to morphine. This mimics co-morbid neurological effects observed in opiate-abusing HIV+ patients. Although there is a correlation between opiate drug abuse and progression of HIV-1-associated neurocognitive disorders, the mechanisms underlie interactions between HIV-1 and opiates remain obscure. Previous studies have shown that HIV-1 induces neurotoxic effects through abnormal activation of GSK3β. Interestingly, expression of GSK3β has shown to be elevated in brains of young opiate abusers indicating that GSK3β is also linked to neuropathology seen with opiate abusing patients. Thus, we hypothesize that GSK3β activation is a point of convergence for HIV- and opiate-mediated interactive neurotoxic effects. Neuronal cultures were treated with supernatant from HIV-1SF162-infected THP-1 cells, in the presence or absence of morphine and GSK3β inhibitors. Our results show that GSK3β inhibitors, including valproate and small molecule inhibitors, significantly reduce HIV-1-mediated neurotoxic outcomes, and also negate interactions with morphine that result in cell death, suggesting that GSK3β-activation is an important point of convergence and a potential therapeutic target for HIV- and opiate-mediated neurocognitive deficits. PMID:25616162

  16. Employment-based abstinence reinforcement promotes opiate and cocaine abstinence in out-of-treatment injection drug users.

    PubMed

    Holtyn, August F; Koffarnus, Mikhail N; DeFulio, Anthony; Sigurdsson, Sigurdur O; Strain, Eric C; Schwartz, Robert P; Silverman, Kenneth

    2014-01-01

    We examined the use of employment-based abstinence reinforcement in out-of-treatment injection drug users, in this secondary analysis of a previously reported trial. Participants (N = 33) could work in the therapeutic workplace, a model employment-based program for drug addiction, for 30 weeks and could earn approximately $10 per hr. During a 4-week induction, participants only had to work to earn pay. After induction, access to the workplace was contingent on enrollment in methadone treatment. After participants met the methadone contingency for 3 weeks, they had to provide opiate-negative urine samples to maintain maximum pay. After participants met those contingencies for 3 weeks, they had to provide opiate- and cocaine-negative urine samples to maintain maximum pay. The percentage of drug-negative urine samples remained stable until the abstinence reinforcement contingency for each drug was applied. The percentage of opiate- and cocaine-negative urine samples increased abruptly and significantly after the opiate- and cocaine-abstinence contingencies, respectively, were applied. These results demonstrate that the sequential administration of employment-based abstinence reinforcement can increase opiate and cocaine abstinence among out-of-treatment injection drug users.

  17. Employment-based abstinence reinforcement promotes opiate and cocaine abstinence in out-of-treatment injection drug users.

    PubMed

    Holtyn, August F; Koffarnus, Mikhail N; DeFulio, Anthony; Sigurdsson, Sigurdur O; Strain, Eric C; Schwartz, Robert P; Silverman, Kenneth

    2014-01-01

    We examined the use of employment-based abstinence reinforcement in out-of-treatment injection drug users, in this secondary analysis of a previously reported trial. Participants (N = 33) could work in the therapeutic workplace, a model employment-based program for drug addiction, for 30 weeks and could earn approximately $10 per hr. During a 4-week induction, participants only had to work to earn pay. After induction, access to the workplace was contingent on enrollment in methadone treatment. After participants met the methadone contingency for 3 weeks, they had to provide opiate-negative urine samples to maintain maximum pay. After participants met those contingencies for 3 weeks, they had to provide opiate- and cocaine-negative urine samples to maintain maximum pay. The percentage of drug-negative urine samples remained stable until the abstinence reinforcement contingency for each drug was applied. The percentage of opiate- and cocaine-negative urine samples increased abruptly and significantly after the opiate- and cocaine-abstinence contingencies, respectively, were applied. These results demonstrate that the sequential administration of employment-based abstinence reinforcement can increase opiate and cocaine abstinence among out-of-treatment injection drug users. PMID:25292399

  18. Estrogen response of MCF-7 cells grown on diverse substrates and in suspension culture: promotion of morphological heterogeneity, modulation of progestin receptor induction; cell-substrate interactions on collagen gels.

    PubMed

    Pourreau-Schneider, N; Berthois, Y; Mittre, H; Charpin, C; Jacquemier, J; Martin, P M

    1984-12-01

    In this study we observed the incidence of hormone sensitivity in the response of MCF-7 cells to estrogen stimulation when the cells were cultured in different contact environments (hydrophilic plastic, bovine corneal extracellular matrix, type I collagen and in suspension culture). The major purpose was to describe the influence of cell to cell and cell to substrate contacts on the morphological response to estrogen treatment. However, other parameters including growth and induction of progestin receptor were also explored, keeping in mind that the MCF-7 cell line, although representative of normal mammary epithelium in that it contains a similar hormone receptivity, was selected in vitro from a metastatic population in a pleural effusion. Although substrate conditions did not modify growth enhancement by estrogens, progestin receptor levels were significantly higher in three-dimensional spheroid cultures in which cell to cell contacts were optimal due to elimination of basal contact. A careful morphological survey of large surfaces lead to an objective opinion of the overall effect of the hormone treatment on the non-cloned cell line in which a marked heterogeneity in the response of individual cells was observed. In terms of morphofunctional differentiation, the edification of acini with dense microvillus coating was best in suspension culture. When sections were made perpendicular to the plane of cultures on collagen gel rafts two other phenomena were noted: decrease in intercellular junctions, resulting in reduced cell to cell cohesion, and accumulation biodegradation products in the collagen lattice. This suggested a hormone-mediated interaction between the metastatic cells and the fibrillar substrate, collagen I, one of the major constituents of tissue stroma. This estrogen response might be related to the metastatic phenotype and must be distinct from their hormone sensitivity in terms of growth and differentiation since hormone receptivity is generally

  19. Auditory sensitivity in opiate addicts with and without a history of noise exposure.

    PubMed

    Rawool, Vishakha; Dluhy, Carrie

    2011-01-01

    Several case reports suggest that some individuals are susceptible to hearing loss from opioids. A combination of noise and opium exposure is possible in either occupational setting such as military service or recreational settings. According to the Drug Enforcement Agency of the U.S. Department of Justice, prescriptions for opiate-based drugs have skyrocketed in the past decade. Since both opium and noise independently can cause hearing loss, it is important to know the prevalence of hearing loss among individuals who are exposed to opium or both opium and noise. The purpose of this research was to evaluate auditory sensitivity in individuals with a history of opium abuse and/or occupational or nonoccupational noise exposure. Twenty-three men who reported opiate abuse served as participants in the study. Four of the individuals reported no history of noise exposure, 12 reported hobby-related noise exposure, 7 reported occupational noise exposure including 2 who also reported hobby-related noise exposure. Fifty percent (2/4) of the individuals without any noise exposure had a hearing loss confirming previous reports that some of the population is vulnerable to the ototoxic effects of opioids. The percentage of population with hearing loss increased with hobby-related (58%) and occupational noise exposure (100%). Mixed MANOVA revealed a significant ear, frequency, and noise exposure interaction. Health professionals need to be aware of the possible ototoxic effects of opioids, since early detection of hearing loss from opium abuse may lead to cessation of abuse and further progression of hearing loss. The possibility that opium abuse may interact with noise exposure in determining auditory thresholds needs to be considered in noise exposed individuals who are addicted to opiates. Possible mechanisms of cochlear damage from opium abuse, possible reasons for individual susceptibility, and recommendations for future studies are presented in the article.

  20. The effects of opiate antagonism on gonadotropin secretion in children and in women with hypothalamic amenorrhea.

    PubMed

    Sauder, S E; Case, G D; Hopwood, N J; Kelch, R P; Marshall, J C

    1984-04-01

    The effects of opiate antagonism [naloxone infusion, 1 mg/(m2 X h)] on gonadotropin secretion were examined in four children (one female and three males: two late prepubertal and two pubertal; chronologic age, range 11.8-15.9 yr; bone age, range 8.5-13.5 yr) and in four women with hypothalamic amenorrhea (two at normal body weight and two at low body weight). Naloxone had no effect on daytime gonadotropin secretion in three children who were biologically the youngest in the group, two late prepubertal and one early pubertal [plasma luteinizing hormone (LH) means +/- SE: control day, 1.2 +/- 0.1; control night, 4.5 +/- 0.4; and naloxone day, 1.3 +/- 0.1 mIU/ml]. In contrast, opiate blockade produced a slight but discernible increase in plasma LH in the child whose hypothalamic-pituitary-gonadal axis was the most mature, a boy at mid-puberty. Naloxone produced a striking increase in plasma LH in the amenorrheic women at normal body weight (LH, means +/- SE: control day, 3.4 +/- 0.3; control night, 7.0 +/- 1.0; and naloxone day, 7.4 +/- 0.7 mIU/ml) as well as in those at low body weight (LH, means +/- SE: control day, 3.5 +/- 0.3; control night, 2.8 +/- 0.2; naloxone day, 4.9 +/- 0.4; and naloxone night, 6.7 +/- 0.5 mIU/ml). Antagonism of endogenous opiate activity increased LH pulse frequency in all four women.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Frontal Metabolite Concentration Deficits in Opiate Dependence Relate to Substance Use, Cognition, and Self-Regulation

    PubMed Central

    Murray, Donna E; Durazzo, Timothy C; Schmidt, Thomas P; Abé, Christoph; Guydish, Joseph; Meyerhoff, Dieter J

    2016-01-01

    Objective Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment. PMID:27695638

  2. Frontal Metabolite Concentration Deficits in Opiate Dependence Relate to Substance Use, Cognition, and Self-Regulation

    PubMed Central

    Murray, Donna E; Durazzo, Timothy C; Schmidt, Thomas P; Abé, Christoph; Guydish, Joseph; Meyerhoff, Dieter J

    2016-01-01

    Objective Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment.

  3. Anatomically heterogeneous populations of CB1 cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics.

    PubMed

    Szabó, Gergely G; Papp, Orsolya I; Máté, Zoltán; Szabó, Gábor; Hájos, Norbert

    2014-12-01

    A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells.

  4. A Label-Free Porous Silicon Immunosensor for Broad Detection of Opiates in a Blind Clinical Study and Result Comparison to Commercial Analytical Chemistry Techniques

    PubMed Central

    Bonanno, Lisa M.; Kwong, Tai C.; DeLouise, Lisa A.

    2010-01-01

    In this work we evaluate for the first time the performance of a label-free porous silicon (PSi) immunosensor assay in a blind clinical study designed to screen authentic patient urine specimens for a broad range of opiates. The PSi opiate immunosensor achieved 96% concordance with liquid chromatography-mass spectrometry/tandem mass spectrometry (LC-MS/MS) results on samples that underwent standard opiate testing (n=50). In addition, successful detection of a commonly abused opiate, oxycodone, resulted in 100% qualitative agreement between the PSi opiate sensor and LC-MS/MS. In contrast, a commercial broad opiate immunoassay technique (CEDIA®) achieved 65% qualitative concordance with LC-MS/MS. Evaluation of important performance attributes including precision, accuracy, and recovery was completed on blank urine specimens spiked with test analytes. Variability of morphine detection as a model opiate target was < 9% both within-run and between-day at and above the cutoff limit of 300 ng ml−1. This study validates the analytical screening capability of label-free PSi opiate immunosensors in authentic patient samples and is the first semi-quantitative demonstration of the technology’s successful clinical use. These results motivate future development of PSi technology to reduce complexity and cost of diagnostic testing particularly in a point-of-care setting. PMID:21062030

  5. Receptor binding properties of amperozide.

    PubMed

    Svartengren, J; Simonsson, P

    1990-01-01

    The receptor pharmacology of amperozide was investigated with in vitro radioligand binding technique. Amperozide possessed a high affinity to the 5-HT2 receptors (Ki = 16.5 +/- 2.1 nM) and a moderate affinity to alpha 1-adrenergic receptors of rat cerebral cortical membranes (Ki = 172 +/- 14 nM). The affinity of amperozide for striatal and limbic dopamine D2 receptors was low and not significantly different (Ki +/- S.E.M. = 540 +/- 59 nM vs 403 +/- 42 nM; p less than 0.11, n = 4). The affinity for striatal and limbic 5-HT2 receptors was measured as well and found to be very close to the affinity to the cerebral cortical 5-HT2 receptor. The drug affinity for D2 and 5-HT2 receptors seems thus not to be influenced by the location of the receptor moiety. The affinity for several other rat brain receptors such as 5-HT1A, alpha 2-adrenergic, dopamine D1, muscarinic M1 and M2, opiate sigma and beta 2-adrenergic was low. The pseudo-Hill coefficient of the amperozide competition binding curve was consistently higher than one indicating antagonistic and complex interactions with the 5-HT2 receptor or with alpha 1-adrenergic and dopamine D2 receptors. The antagonistic properties of amperozide were investigated by its ability to antagonize the serotonin-induced formation of inositol-1-phosphate in human blood platelets. Amperozide inhibited this 5-HT2 receptor-mediated intracellular response with similar potency as ketanserin. These results suggest that amperozide is a selective 5-HT2 receptor antagonist.

  6. Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review.

    PubMed

    Angarita, Gustavo A; Emadi, Nazli; Hodges, Sarah; Morgan, Peter T

    2016-04-26

    Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders.

  7. Involvement of endogenous opiates in regulation of gastric emptying of fat test meals in mice

    SciTech Connect

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

    1988-08-01

    The role of endogenous opioids and cholecystokinin (CCK) in gastric emptying was investigated in mice killed 30 min after gavage with /sup 51/Cr-radiolabeled liquid meals. The meals consisted of 0.5 ml of milk or one of five synthetic meals containing arabic gum, glucose and/or arachis oil and/or casein. Naloxone (0.1 mg/kg sc) significantly (P less than 0.01) accelerated gastric emptying of milk and meals containing fat but did not modify gastric emptying of nonfat meals. The CCK antagonist asperlicin (0.1 mg/kg ip) increased by 25% gastric emptying of milk. The gastric emptying of meals containing glucose and casein but not fat was reduced after administration of the COOH-terminal octapeptide of cholecystokinin (CCK-8, 4 micrograms/kg ip). This decrease was antagonized by both asperlicin (10 mg/kg ip) and naloxone (0.1 mg/kg sc). Intracerebroventricular (icv) administration of an opiate antagonist that poorly crosses the blood-brain barrier, methyl levallorphan (10 micrograms/kg), did not modify gastric emptying of milk but accelerated it when peripherally administered (0.1 mg/kg sc). Similarly, asperlicin (icv) administered at a dose of 1 mg/kg did not affect milk emptying. These results indicate that endogenous opiates are involved at peripheral levels in the regulation of gastric emptying of fat meals only and that such regulation involves release of CCK.

  8. [The opiate pharmacopeia in France from its origins to the 19th century].

    PubMed

    Warolin, Christian

    2010-04-01

    For thousands of years, opium was the main remedy against pain. Its analgesic properties have been known since antiquity, as well as its stupefacient, narcotic and addictive effects. A countless number of opiate galenical preparations had already been formulated by the beginning of our era. The best-known were electuaries, complex drugs combining multiple active substances, essentially plant-based, used to obtain beneficial effects for different aliments. These universal remedies were panaceas. Sonne opium--or opiate--based electuaries were recommended as antidotes to poison or snake venom. The best-known, Mithridate and Theriac Andromache (Venice Treacle), the latter also containing viper flesh, combined up to a hundred or so ingredients. However, this polypharmacy was criticized and it was an English doctor, Thomas Sydenham, to whom we owe the preparation of a liquid laudanum which was easier to administer than an electuary. Sydenham's laudanum (1683) was adopted by ail the pharmacopeias. Later, based on a traditional research approach, pharmacists attempted to isolate the active principles of opium. Seguin, but above ail the German pharmacist Sertürner (in 1805 and 1817) isolated morphine. Organic chemists took over from the analysts, and morphine derivatives were obtained by hemi-synthesis (heroin), and then central analgesics, or opioids, by total synthesis. Opium is no longer seen as the only supreme remedy for painful disorders, and its galenic forms have gradually disappeared from pharmacopeias.

  9. For lack of wanting: Discourses of desire in Ukrainian opiate substitution therapy programs.

    PubMed

    Carroll, Jennifer J

    2016-04-01

    Available treatments for addiction and substance abuse in Ukraine have been shaped by the economic, political, and social shifts that have followed the country's independence. The introduction of methadone-based opiate substitution therapy (OST) for opiate addicts is especially representative of this. Biomedical paradigms of addiction, its etiology, and its treatment, promoted and paid for by international donors and elite global health entities, are being met by Ukrainian notions of personhood and psychology in both public discourse and clinical settings. Ukrainian physicians who work in OST programs frequently reference desire (желание) as the most significant factor in determining the success or failure of treatment. They refer to a desire to be treated, desire to get better, desire to live. The moralized imperative to possess this desire to get better is, in many ways, a reflection of how addiction and the addicted psyche is constructed and understood in the Ukrainian context. By exploring discourses of desire in narratives of addiction and treatment, I examine how notions of psychology, will, and self-control intersect, shaping the subjectivity, agency, and daily experiences of this vulnerable population.

  10. Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors.

    PubMed

    Massaly, Nicolas; Dahan, Lionel; Baudonnat, Mathieu; Hovnanian, Caroline; Rekik, Khaoula; Solinas, Marcello; David, Vincent; Pech, Stéphane; Zajac, Jean-Marie; Roullet, Pascal; Mouledous, Lionel; Frances, Bernard

    2013-03-01

    Plastic changes in the nucleus accumbens (NAcc), a structure occupying a key position in the neural circuitry related to motivation, are among the critical cellular processes responsible for drug addiction. During the last decade, it has been shown that memory formation and related neuronal plasticity may rely not only on protein synthesis but also on protein degradation by the ubiquitin proteasome system (UPS). In this study, we assess the role of protein degradation in the NAcc in opiate-related behaviors. For this purpose, we coupled behavioral experiments to intra-accumbens injections of lactacystin, an inhibitor of the UPS. We show that protein degradation in the NAcc is mandatory for a full range of animal models of opiate addiction including morphine locomotor sensitization, morphine conditioned place preference, intra-ventral tegmental area morphine self-administration and intra-venous heroin self-administration but not for discrimination learning rewarded by highly palatable food. This study provides the first evidence of a specific role of protein degradation by the UPS in addiction.

  11. Functional imaging of emotion reactivity in opiate-dependent borderline personality disorder.

    PubMed

    Smoski, Moria J; Salsman, Nicholas; Wang, Lihong; Smith, Veronica; Lynch, Thomas R; Dager, Stephen R; LaBar, Kevin S; Linehan, Marsha M

    2011-07-01

    Opiate dependence (OD) and borderline personality disorder (BPD), separately and together, are significant public health problems with poor treatment outcomes. BPD is associated with difficulties in emotion regulation, and brain-imaging studies in BPD individuals indicate differential activation in prefrontal cingulate cortices and their interactions with limbic regions. Likewise, a similar network is implicated in drug cue responsivity in substance abusers. The present, preliminary study used functional MRI to examine activation of this network in comorbid OD/BPD participants when engaged in an "oddball" task that required attention to a target in the context of emotionally negative distractors. Twelve male OD/BPD participants and 12 male healthy controls participated. All OD/BPD participants were taking the opiate replacement medication Suboxone, and a subset of participants was positive for substances of abuse on scan day. Relative to controls, OD/BPD participants demonstrated reduced activation to negative stimuli in the amygdala and anterior cingulate. Unlike previous studies that demonstrated hyperresponsivity in neural regions associated with affective processing in individuals with BPD versus healthy controls, comorbid OD/BPD participants were hyporesponsive to emotional cues. Future studies that also include BPD-only and OD-only groups are necessary to help clarify the individual and potentially synergistic effects of these two conditions. PMID:22448769

  12. Opiate use, treatment, and harm reduction in Afghanistan: recent changes and future directions.

    PubMed

    Todd, Catherine S; Macdonald, David; Khoshnood, Kaveh; Mansoor, G Farooq; Eggerman, Mark; Panter-Brick, Catherine

    2012-09-01

    Afghanistan leads global opium and cannabis production, amidst concerted efforts to improve the country's infrastructure. In this commentary, the evidence base for drivers of increased drug use in the context of deteriorating security is presented, government, donor, and civil society responses to date are described, and key areas for health policy response are summarized. Opiate use in Afghanistan shows disturbing trends: multiple substances are accessible at low cost and frequently used in combination, and injecting use has become more common. Pressures from both donor and governmental sectors have compromised innovations in programming. Further, civil unrest and resultant displacement have created challenges for programme implementation. Afghanistan urgently needs a well-funded, sustainable, comprehensive, and inclusive programme of drug dependency treatment, aftercare, and harm reduction services, as well as realistic, effective, and culturally salient primary prevention programmes. To date, drug dependence is not a prioritised issue, current programmes are under-resourced, and the continuum of care has a narrow scope generally limited to treatment. Unless this issue is addressed, the next generation of Afghans is poised to become a casualty of the opiate industry. PMID:22717389

  13. Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib

    PubMed Central

    Berry, Donald A.; Cirrincione, Constance T.; Barry, William T.; Pitcher, Brandelyn N.; Harris, Lyndsay N.; Ollila, David W.; Krop, Ian E.; Henry, Norah Lynn; Weckstein, Douglas J.; Anders, Carey K.; Singh, Baljit; Hoadley, Katherine A.; Iglesia, Michael; Cheang, Maggie Chon U.; Perou, Charles M.; Winer, Eric P.; Hudis, Clifford A.

    2016-01-01

    Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression–based assays. Results Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor–positive subset but a significant increase in pCR with dual therapy in those with hormone receptor–negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%). Conclusion pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when

  14. Randomized Trial Comparing Two Treatment Strategies Using Prize-Based Reinforcement of Abstinence in Cocaine and Opiate Users

    ERIC Educational Resources Information Center

    Preston, Kenzie L.; Ghitza, Udi E.; Schmittner, John P.; Schroeder, Jennifer R.; Epstein, David H.

    2008-01-01

    We compared two strategies of prize-based contingency management (CM) in methadone-maintained outpatients. Urine was tested thrice weekly for 5 weeks pre-CM, 12 weeks CM, and 8 weeks post-CM. Participants were randomly assigned to a cocaine contingency (four prize draws for each cocaine-negative urine, N = 29) or an opiate-cocaine contingency (one…

  15. Current quality of life and its determinants among opiate-dependent individuals five years after starting methadone treatment

    PubMed Central

    Vanderplasschen, Wouter; Lammertyn, Jan; van Nieuwenhuizen, Chijs; Sabbe, Bernard; Broekaert, Eric

    2010-01-01

    Purpose This study explores the current QoL of opiate-dependent individuals who started outpatient methadone treatment at least 5 years ago and assesses the influence of demographic, psychosocial, drug and health-related variables on individuals’ QoL. Methods Participants (n = 159) were interviewed about their current QoL, psychological distress and severity of drug-related problems, using the Lancashire Quality of Life Profile, the Brief Symptom Inventory and the Addiction Severity Index. Potential determinants of QoL were assessed in a multiple linear regression analysis. Results Five years after the start of methadone treatment, opiate-dependent individuals report low QoL scores on various domains. No association was found between drug-related variables and QoL, but a significant negative impact of psychological distress was identified. Severity of psychological distress, taking medication for psychological problems and the inability to change one’s living situation were associated with lower QoL. Having at least one good friend and a structured daily activity had a significant, positive impact on QoL. Conclusions Opiate-dependent individuals’ QoL is mainly determined by their psychological well-being and a number of psychosocial variables. These findings highlight the importance of a holistic approach to treatment and support in methadone maintenance treatment, which goes beyond fixing the negative physical consequences of opiate dependence. PMID:20740316

  16. Sensitivity of an opiate immunoassay for detecting hydrocodone and hydromorphone in urine from a clinical population: analysis of subthreshold results.

    PubMed

    Bertholf, Roger L; Johannsen, Laura M; Reisfield, Gary M

    2015-01-01

    Urine drug testing (UDT) is an emerging standard of care in the evaluation and treatment of chronic non-cancer pain patients with opioid analgesics. UDT may be used both to verify adherence with the opioid analgesic regimen and to monitor abstinence from non-prescribed or illicit controlled substances. In the former scenario, it is vital to determine whether the drug is present in the urine, even at low concentrations, because failure to detect the drug may lead to accusations of opioid abuse or diversion. Opiate immunoassays typically are developed to detect morphine and are most sensitive to morphine and codeine. Although many opiate immunoassays also detect hydrocodone (HC) and/or hydromorphone (HM), sensitivities for these analytes are often much lower, increasing the possibility of negative screening results when the drug is present in the urine. We selected 112 urine specimens from patients who had been prescribed HC or hydromorphone but were presumptive negative by the Roche Online DAT Opiate II™ urine drug screening assay, which is calibrated to 300 ng/mL morphine. Using a GC/MS confirmatory method with a detection limit of 50 ng/mL both for HC and for HM, one or both of these opiates were detected in 81 (72.3%) of the urine specimens. Examination of the raw data from these presumptive negative opiate screens revealed that, in many cases, the turbidity signal was greater than the signal obtained for the negative control, but less than the signal for the 300 ng/mL (morphine) threshold calibrator. A receiver operating characteristic curve generated for the reciprocal of the ratio of turbidity measurements in the patient specimens and negative (drug-free) controls, against the presence or absence of HC and/or HM by confirmatory analyses, produced an area under the curve of 0.910. We conclude that this opiate immunoassay has sufficient sensitivity to detect HC and/or HM in some urine specimens that screen presumptive negative for these commonly prescribed

  17. Heterogeneous distribution of the serotonin 5-HT(1A) receptor mRNA in chemically identified neurons of the mouse rostral brainstem: Implications for the role of serotonin in the regulation of wakefulness and REM sleep.

    PubMed

    Bonnavion, Patricia; Bernard, Jean-François; Hamon, Michel; Adrien, Joëlle; Fabre, Veronique

    2010-07-15

    The 5-HT(1A) receptor (5-HT(1A)R) plays a key role in the inhibitory influence of serotonin (5-HT) on rapid eye movement (REM) sleep in rodents. However, the neuronal networks mediating such influence are mostly unknown, notably in the mouse. This led us to map 5-HT(1A)R mRNA, by in situ hybridization histochemistry (ISHH), and to characterize the neuronal phenotype of 5-HT(1A)R mRNA-positive neurons by dual ISHH and ISHH combined with immunohistochemistry, throughout the mouse rostral brainstem, a pivotal region for the generation of REM sleep and cortical activation. 5-HT(1A)R mRNA was found in most 5-HT neurons in the dorsal raphe (DR), the median raphe (MnR), the B9, and the interpeduncular (IP) nuclei. 5-HT(1A)R mRNA-positive neurons were also identified in individualized clusters of gamma-aminobutyric acid (GABA)ergic neurons in the DR and in neurons of an undetermined phenotype in the MnR. In addition, 1) GABAergic neurons of the ventral portion of Gudden's dorsal tegmental nucleus (DTg), the IP, and the caudal portion of the deep mesencephalic nucleus (DpMe), and 2) glutamatergic neurons scattered in the caudal pontine reticular nucleus (PnC) and densely packed in the internal lateral parabrachial subnucleus (PBil) also expressed 5-HT(1A)R mRNA. In contrast, no specific 5-HT(1A)R-related ISHH signal was generally detected in brainstem cholinergic and catecholaminergic neurons. These results emphasize the role of 5-HT(1A)R as an autoreceptor and the phenotypical heterogeneity of 5-HT(1A)R-expressing neurons within the DR and the MnR in the mouse brain. They also provide a neuroanatomical basis for understanding the influence of 5-HT(1A)R on REM sleep and wakefulness.

  18. Blood-Borne Hepatitis in Opiate Users in Iran: A Poor Outlook and Urgent Need to Change Nationwide Screening Policy

    PubMed Central

    Honarvar, Behnam; Odoomi, Neda; Moghadami, Mohsen; Afsar Kazerooni, Parvin; Hassanabadi, Alireza; Zare Dolatabadi, Parvin; Farzanfar, Ehsan; Bagheri Lankarani, Kamran

    2013-01-01

    Objective Iran has the highest rate of opiate use worldwide. However, most opiate users are not screened for hepatitis virus infections. This study aimed to provide accurate, detailed data on the size of the opiate user population at risk of developing these infections. Method This seroprevalence study was conducted in the city of Shiraz, southern Iran. All participants were screened for HBV, HCV and HIV infection. The data were analyzed with SPSS. Result Among 569 participants, 233 (40.9%) were injection drug users (IDU), 369 (64.8%) were heterosexual, 84 (14.7%) were bisexual and 15 (2.6%) were homosexual. One hundred nine (19.1%) were HCV antibody-positive, 18 (3.1%) were HBS antigen-positive, 72 (12.6%) were HBc antibody-positive and 23 (4%) were HIV-positive. Among IDU compared to non-IDU, positivity rates for HBS antigen (5.5 vs 1.4%), HBc antibody (22.7 vs 5.6%), HCV antibody (40.3 vs 4.4%) and HIV (7.7 vs 1.4%) were higher (P < 0.05). Most patients with HBV (80.7%) and HCV infection (83.4%) were HIV-negative. In the cumulative analysis, only history of imprisonment was a statistically significant determinant of infection by HCV or HBV in opiate users. Conclusion The current policy of screening only HIV-positive drug users for HBV and HCV in Iran misses most cases of HBV and HCV infection. We therefore recommend urgent revision of the nationwide protocol by the Ministry of Health in Iran to implement routine screening of all opiate users and especially IDU for these viruses, regardless of their HIV status. PMID:24312645

  19. Molecular and neuronal plasticity mechanisms in the amygdala-prefrontal cortical circuit: implications for opiate addiction memory formation.

    PubMed

    Rosen, Laura G; Sun, Ninglei; Rushlow, Walter; Laviolette, Steven R

    2015-01-01

    The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related "trigger" memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca(2+)/calmodulin-dependent protein

  20. Three patients and their drugs: A parallel case paper on paediatric opiate use and withdrawal

    PubMed Central

    Siden, Harold B; Collin, Kathleen

    2005-01-01

    Clinicians are increasingly aware of the important role that opioids play in the management of a variety of paediatric conditions. Frequently, clinicians encounter challenges in initiating opioid therapy and, then, in weaning paediatric patients off opioids. In the present article, three different cases (an infant and two adolescents) are used to illustrate why and how opiates may be used in paediatrics and how they can be discontinued. The presentations include neonatal abstinence syndrome, chronic headache and cystic fibrosis. The cases are meant to emphasize the distinctions rather than the similarities among the cases, which is why this is called a case parallel, rather than a case series. The article downplays the use of rigid rules in managing patients on opioids, and emphasizes a flexible and patient-centred approach. PMID:19675829

  1. An examination of sex differences in the effects of early-life opiate and alcohol exposure.

    PubMed

    Terasaki, Laurne S; Gomez, Julie; Schwarz, Jaclyn M

    2016-02-19

    Early-life exposure to drugs and alcohol is one of the most preventable causes of developmental, behavioural and learning disorders in children. Thus a significant amount of basic, animal and human research has focused on understanding the behavioural consequences and the associated neural effects of exposure to drugs and alcohol during early brain development. Despite this, much of the previous research that has been done on this topic has used predominantly male subjects or rodents. While many of the findings from these male-specific studies may ultimately apply to females, the purpose of this review is to highlight the research that has also examined sex as a factor and found striking differences between the sexes in their response to early-life opiate and alcohol exposure. Finally, we will also provide a framework for scientists interested in examining sex as a factor in future experiments that specifically examine the consequences of early-life drug and alcohol exposure. PMID:26833841

  2. Nutritional status of the opiate dependent persons after 4 years of methadone maintenance treatment.

    PubMed

    Kolarzyk, Emilia; Pach, Dorota; Wojtowicz, Barbara; Szpanowska-Wohn, Agnieszka; Szurkowska, Magdalena

    2005-01-01

    The aim of the study was to evaluate the nutritional status of opiate dependent patients before and after 4 years of participation in the methadone maintenance treatment. The examinations were performed in 30 opiates addicted persons (7 women and 23 men). The initial examination (exam 1) was done during the patients qualification for the methadone program, preceding methadone administration and final examination (exam 2) after 4 years of the treatment. In order to estimate the nutritional status body mass, the height, the arm circumference and the thickness of the triceps and subscapular fat-skin folds were measured. On the basis of them the BMI and mid arm muscle circumference (MAMC) were counted. The measurements of the body composition (using the bioimpedance method) were performed. The changes between the results of subsequent examination were tested using the t-Student test. In the examination that took place after 4 years of follow-up, body weight loss in the group of women was observed (mean--1.7 kg). It was followed by the decrease of BMI value (from 20.3 to 19.8 kg/m2). In both examinations the percentage of fatty tissue in general body mass was significantly below recommended values (10.7% in both examinations--the recommended values are 20%-22%). In the group of men an increase in body weight (mean--8.8 kg) and BMI value (from 23.3 to 25.9 kg/m2) was noticed. Arm circumference, muscle arm circumference and fat-skin folds values were increased. The analysis of particular body components showed increased fatty body mass (11.9% in the first and 18.5% in the second examination--the recommended values 16-19%) together with the decrease of lean body mass and body water.

  3. Simultaneous quantification of cocaine, amphetamines, opiates and cannabinoids in vitreous humor.

    PubMed

    Peres, Mariana Dadalto; Pelição, Fabrício Souza; Caleffi, Bruno; De Martinis, Bruno Spinosa

    2014-01-01

    A GC-MS method for simultaneous analysis of cocaine (COC), amphetamines (AMPs), opiates, cannabinoids and their metabolites in vitreous humor (VH) was developed and fully validated. VH samples were extracted using solid phase extraction and injected into the GC-MS, using a selected ion monitoring mode. Linearity ranged from 10 to 1000 ng/mL; the exception was anhydroecgonine methyl ester (AEME), for which linearity ranged from 10 to 750 ng/mL. Inter-assay imprecision lay from 1.2 to 10.0%, intra-assay imprecision was <10.4% for all the analytes and accuracy ranged from 95.6 to 104.0%. An limit of quantitation for all drugs was 10 ng/mL and recoveries ranged from 70.4 to 100.1% for basic and neutral compounds; the acid compounds had poor recovery--<40%. The validated method was applied to 10 VH samples taken from individuals whose blood had screened positive for drugs of abuse. All the individuals screened positive for COC in the blood (seven samples) also had positive results in VH; COC concentration ranged from 30.81 to 283.97 ng/mL (mean 186.98 ng/mL) and benzoylecgonine concentration ranged from 11.47 to 460.98 ng/mL (mean 133.91 ng/mL). It was also noticed that, in five cases, cocaethylene was detected. AEME was also quantified in one case. The use of AMP detected by blood analysis was confirmed in the VH of one individual (24.31 ng/mL). However, samples taken from three individuals whose blood tested positive for carboxy-tetrahydrocannabinol presented negative results. The results demonstrated that VH is a suitable alternative biological sample to determine COC, AMPs, opiates and their metabolites. PMID:24225634

  4. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial

    PubMed Central

    2014-01-01

    Background To evaluate if an opiate sparing multimodal regimen of dexamethasone, gabapentin, ibuprofen and paracetamol had better analgesic effect, less side effects and was safe compared to a traditional morphine and paracetamol regimen after cardiac surgery. Methods Open-label, prospective randomized controlled trial. 180 patients undergoing cardiac procedures through median sternotomy, were included in the period march 2007- August 2009. 151 patients were available for analysis. Pain was assessed with the 11-numeric rating scale (11-NRS). Results Patients in the multimodal group demonstrated significantly lower average pain scores from the day of surgery throughout the third postoperative day. Extensive nausea and vomiting, was found in no patient in the multimodal group but in 13 patients in the morphine group, p < 0.001. Postoperative rise in individual creatinine levels demonstrated a non-significant rise in the multimodal group, 33.0±53.4 vs. 19.9±48.5, p = 0.133. Patients in the multimodal group suffered less major in-hospital events in crude numbers: myocardial infarction (MI) (1 vs. 2, p = 0.54), stroke (0 vs. 3, p = 0.075), dialysis (1 vs. 2, p = 0.54), and gastrointestinal (GI) bleeding (0 vs. 1, p = 0.31). 30-day mortality was 1 vs. 2, p = 0.54. Conclusions In patients undergoing cardiac surgery, a multimodal regimen offered significantly better analgesia than a traditional opiate regimen. Nausea and vomiting complaints were significantly reduced. No safety issues were observed with the multimodal regimen. Trial registration Clinicaltrials.gov identifier: NCT01966172 PMID:24650125

  5. Deficit of circulating stem – progenitor cells in opiate addiction: a pilot study

    PubMed Central

    Reece, Albert S; Davidson, Peter

    2007-01-01

    A substantial literature describes the capacity of all addictive drugs to slow cell growth and potentiate apoptosis. Flow cytometry was used as a means to compare two lineages of circulating progenitor cells in addicted patients. Buprenorphine treated opiate addicts were compared with medical patients. Peripheral venous blood CD34+ CD45+ double positive cells were counted as haemopoietic stem cells (HSC's), and CD34+ KDR+ (VEGFR2+) cells were taken as endothelial progenitor cells (EPC's). 10 opiate dependent patients with substance use disorder (SUD) and 11 non-addicted (N-SUD) were studied. The ages were (mean + S.D.) 36.2 + 8.6 and 56.4 + 18.6 respectively (P <0.01). HSC's were not different in the SUD (2.38 + 1.09 Vs. 3.40 + 4.56 cells/mcl). EPC's were however significantly lower in the SUD (0.09 + 0.14 Vs. 0.26 + 0.20 cells/mcl; No. > 0.15, OR = 0.09, 95% C.I. 0.01–0.97), a finding of some interest given the substantially older age of the N-SUD group. These laboratory data are thus consistent with clinical data suggesting accelerated ageing in addicted humans and implicate the important stem cell pool in both addiction toxicology and ageing. They carry important policy implications for understanding the fundamental toxicology of addiction, and suggest that the toxicity both of addiction itself and of indefinite agonist maintenance therapies may have been seriously underestimated. PMID:17615060

  6. Group III metabotropic glutamate receptors and drug addiction

    PubMed Central

    Mao, Limin; Guo, Minglei; Jin, Daozhong; Xue, Bing; Wang, John Q.

    2014-01-01

    Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction. Accumulating data have demonstrated roles of ionotropic glutamate receptors and group I and II metabotropic glutamate receptors (mGluRs) in this event. Emerging evidence also identifies Gαi/o-coupled group III mGluRs (mGluR4/7/8 subtypes enriched in the limbic system) as direct substrates of drugs of abuse and active regulators of drug action. Auto- and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways, respectively. These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis. In response to operant administration of common addictive drugs, such as psychostimulants (cocaine and amphetamine), alcohol and opiates, limbic group III mGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior. As a result, a loss-of-function mutation (knockout) of individual group III receptor subtypes often promotes drug seeking. This review summarizes the data from recent studies on three group III receptor subtypes (mGluR4/7/8) expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs (psychostimulants, alcohol, and opiates). PMID:24078068

  7. [Mode of action of trimebutine: involvement if opioid receptors].

    PubMed

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

    1989-02-15

    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 the drug and its N-desmethyl metabolite (NDTMB) to displace mu, delta and kappa specific ligands from their receptors using guinea-pig whole brain membranes and ileum myenteric plexus synaptosomes membranes. The activity of both compounds on the twitch response induced by transmural stimulation of the guinea-pig ileum and of the mouse and rabbit vas deferens was also investigated. These preparations have been claimed 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. The decreasing order of IC50 (50 per cent inhibitory concentration)'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 agonistic 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:2537972

  8. Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

    PubMed

    Karlsen, Morten; Liu, Huiling; Johansen, Jon Eigill; Hoff, Bård Helge

    2015-01-01

    The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.

  9. Effects of opiate agonists and an antagonist on food intake and brain neurotransmitters in normophagic and obese "cafeteria" rats.

    PubMed

    Robert, J J; Orosco, M; Rouch, C; Jacquot, C; Cohen, Y

    1989-11-01

    The relationship between the effects of opiates on food intake and on central monoamines in various brain areas was investigated in normophagic and obese "cafeteria" rats. Three agonists, beta-endorphin, dynorphin, and D-Ser2-Leu-Enk-Thr6 (DSLET) and an antagonist, naltrexone, were used. The three agonists enhanced feeling in normophagic rats but had different dopaminergic effects. Serotonergic metabolism increased concomitantly with the enhancement of feeding by the agonists, whereas it decreased following treatment with the antagonist naltrexone. In the cafeteria rats, although the feeding effects of dynorphin and DSLET occurred earlier, there was a complete lack of monoaminergic effects. beta-Endorphin was completely devoid of effects in this model. There would, thus, appear to be a positive correlation between the behavioural effects of these opiates and serotonergic metabolism in normophagic rats, while stimulated feeding situations ("cafeteria" rats) the disruption of a monoaminergic modulation does not prohibit a direct effect on feeding.

  10. A Pilot Study of a Distress Tolerance Treatment for Opiate Dependent Patients Initiating Buprenorphine: Rationale, Methodology, and Outcomes

    PubMed Central

    Brown, Richard A.; Bloom, Erika Litvin; Hecht, Jacki; Moitra, Ethan; Herman, Debra S.; Stein, Michael D.

    2016-01-01

    Buprenorphine, an opioid that is a long-acting partial opiate agonist, is an efficacious treatment for opiate dependence that is growing in popularity. Nevertheless, evidence suggests that many patients will lapse within the first week of treatment, and that lapses are often associated with withdrawal-related or emotional distress. Recent research suggests that individuals’ reactions to this distress may represent an important treatment target. In the current study, we describe the development and outcomes from a preliminary pilot evaluation (N = 5) of a novel distress tolerance treatment for individuals initiating buprenorphine. This treatment incorporates exposure-based and acceptance-based treatment approaches that we have previously applied to the treatment of tobacco dependence. Results from this pilot study establish the feasibility and acceptability of this approach. We are now conducting a randomized controlled trial of this treatment that we hope will yield clinically significant findings and offer clinicians an efficacious behavioral treatment to complement the effects of buprenorphine. PMID:24973401

  11. Separation of Opiate Isomers Using Electrospray Ionization and Paper Spray Coupled to High-Field Asymmetric Waveform Ion Mobility Spectrometry

    NASA Astrophysics Data System (ADS)

    Manicke, Nicholas E.; Belford, Michael

    2015-05-01

    One limitation in the growing field of ambient or direct analysis methods is reduced selectivity caused by the elimination of chromatographic separations prior to mass spectrometric analysis. We explored the use of high-field asymmetric waveform ion mobility spectrometry (FAIMS), an ambient pressure ion mobility technique, to separate the closely related opiate isomers of morphine, hydromorphone, and norcodeine. These isomers cannot be distinguished by tandem mass spectrometry. Separation prior to MS analysis is, therefore, required to distinguish these compounds, which are important in clinical chemistry and toxicology. FAIMS was coupled to a triple quadrupole mass spectrometer, and ionization was performed using either a pneumatically assisted heated electrospray ionization source (H-ESI) or paper spray, a direct analysis method that has been applied to the direct analysis of dried blood spots and other complex samples. We found that FAIMS was capable of separating the three opiate structural isomers using both H-ESI and paper spray as the ionization source.

  12. Separation of opiate alkaloids by electrokinetic chromatography with sulfated-cyclodextrin as a pseudo-stationary phase.

    PubMed

    Zakaria, Philip; Macka, Miroslav; Haddad, Paul R

    2003-01-24

    The separation of six related opiate alkaloids (morphine, thebaine, 10-hydroxythebaine, codeine, oripavine and laudanine) was studied using sulfated-cyclodextrin (s-CD) as a cation-exchange pseudo-stationary phase. Cation-exchange interactions between the cationic analytes and the anionic s-CD (7-11 mol of sulfate groups per mole CD) were found to bethe predominant mechanism, allowing the separations to be performed at low pH where the opiates are protonated and exhibit very similar mobilities. The concentrations of the s-CD and the competing ion (Na+ or Mg2+) in the electrolyte were used to govern the extent of the ion-exchange interactions. Interactions with the sulfated-cyclodextrin differed for each analyte, with oripavine exhibiting the strongest interaction and 10-thebaine and laudanine showing the weakest interactions. Despite the very similar structures of the analytes, these differences resulted in significant changes in separation selectivity. The separation was modelled using a migration equation derived from first principles and based on ion-exchange interactions between the s-CD and the opiates. Constants within the model were obtained by non-linear regression using a small subset of experimentally determined migration times. These constants related to the ion-exchange affinities of the s-CD for the various opiates. When the model was used to predict migration times under other experimental conditions, a very good correlation was obtained between observed and predicted mobilities (r2=0.996). Optimisation of the system was performed using the normalised resolution product and minimum resolution criteria and this process provided two optimised separations, each exhibiting a different separation selectivity.

  13. Comparative Study of the Activity of Brain Behavioral Systems in Methamphetamine and Opiate Dependents

    PubMed Central

    Alemikhah, Marjan; Faridhosseini, Farhad; Kordi, Hassan; Rasouli-Azad, Morad; Shahini, Najmeh

    2016-01-01

    Background: Substance dependency is a major problem for the general health of a society. Different approaches have investigated the substance dependency in order to explain it. Gray’s reinforcement sensitivity theory (RST) is an advanced and important neuropsychological theory in this area. Objectives: The aim of this study was to compare three systems of the revised reinforcement sensitivity theory the behavioral activation system (r-BAS), the revised behavioral inhibition system (r-BIS), and the revised fight/flight/freezing system (r-FFFS) between patients dependent on methamphetamine and opiates, and a group of controls. Patients and Methods: This research was a causal-comparative study that was conducted in the first six months of 2012. The population of the study was males of Mashhad city, who were dependent on methamphetamine or opiates, and ruling out psychotic disorders and prominent Axis II. Twenty-five people were selected by the convenient sampling method. Also, 25 non-dependent people from the patients’ relatives were selected and matched for the variables of age, gender, and education to participate in this study. Participants were evaluated using a structured clinical interview (SCID) for DSM-IV, demographic questionnaire information, and a Jackson-5 questionnaire (2009). Data were analyzed by Chi-square, K-S, and independent t-test. Results: The methamphetamine dependent group had a higher sensitivity in the r-BAS, r-BIS, and the r-Fight and r-Freezing systems compared to the control group (P < 0.05). However, there was no significant difference in r-Flight between the two groups (P > 0.05). “The scores of r-BIS were also significantly higher in the methamphetamine-dependent group than the opioid-dependent and control groups. For the r-Fight variable, the methamphetamine-dependent group was higher than the opioid-dependent group”. Conclusions: The personality patterns of patients dependent on methamphetamines were different from the controls

  14. Influence of the histaminergic system on opiate-induced neurosecretion and behaviour.

    PubMed

    Duka, T; Hoehe, M; Doenicke, A; Stephan, U; Matussek, N

    1987-01-01

    The influence of the histaminergic system on fentanyl (Fe)-induced growth hormone (GH) and prolactin (PRL) release as well as on Fe-induced increase of noradrenaline (NA) plasma levels has been studied in male volunteers. These volunteers received, according to a randomized block design, different pretreatments: the H1-antagonist dimethindene (Di) (0.1 mg/kg i.v.), or the H2-antagonist cimetidine (Ci)(5 mg/kg i.v.), or a combination of dimethindene and cimetidine (Di + Ci), or saline. The PRL increase caused by Fe (0.2 mg/70 kg) was not altered by pretreatment with the H1-antagonist Di, the H2-antagonist Ci, or the combination of both. The increase of NA plasma levels after Fe also was not modified by the histamine antagonists. In contrast, the maximum GH increase after Fe was blunted by the combination of Ci and Di, but not by either Ci or Di alone. These results suggest an involvement of the histaminergic system in opiate-induced GH-release.

  15. Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

    SciTech Connect

    Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. )

    1991-05-01

    Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.

  16. Single cell heterogeneity

    PubMed Central

    Abdallah, Batoul Y; Horne, Steven D; Stevens, Joshua B; Liu, Guo; Ying, Andrew Y; Vanderhyden, Barbara; Krawetz, Stephen A; Gorelick, Root; Heng, Henry HQ

    2013-01-01

    Multi-level heterogeneity is a fundamental but underappreciated feature of cancer. Most technical and analytical methods either completely ignore heterogeneity or do not fully account for it, as heterogeneity has been considered noise that needs to be eliminated. We have used single-cell and population-based assays to describe an instability-mediated mechanism where genome heterogeneity drastically affects cell growth and cannot be accurately measured using conventional averages. First, we show that most unstable cancer cell populations exhibit high levels of karyotype heterogeneity, where it is difficult, if not impossible, to karyotypically clone cells. Second, by comparing stable and unstable cell populations, we show that instability-mediated karyotype heterogeneity leads to growth heterogeneity, where outliers dominantly contribute to population growth and exhibit shorter cell cycles. Predictability of population growth is more difficult for heterogeneous cell populations than for homogenous cell populations. Since “outliers” play an important role in cancer evolution, where genome instability is the key feature, averaging methods used to characterize cell populations are misleading. Variances quantify heterogeneity; means (averages) smooth heterogeneity, invariably hiding it. Cell populations of pathological conditions with high genome instability, like cancer, behave differently than karyotypically homogeneous cell populations. Single-cell analysis is thus needed when cells are not genomically identical. Despite increased attention given to single-cell variation mediated heterogeneity of cancer cells, continued use of average-based methods is not only inaccurate but deceptive, as the “average” cancer cell clearly does not exist. Genome-level heterogeneity also may explain population heterogeneity, drug resistance, and cancer evolution. PMID:24091732

  17. Different levels in orexin concentrations and risk factors associated with higher orexin levels: comparison between detoxified opiate and methamphetamine addicts in 5 Chinese cities.

    PubMed

    Zhang, Haoran; Lian, Zhi; Yan, Shiyan; Bao, Yanping; Liu, Zhimin

    2013-01-01

    This study sought to explore the degree of orexin levels in Chinese opiate and methamphetamine addicts and the differences between them. The cross-sectional study was conducted among detoxified drug addicts from Mandatory Detoxification Center (MDC) in five Chinese cities. Orexin levels were assayed with radioimmunoassay (RIA). Mann-Whitney U test and Kruskal-Wallis test were used to detect differences across groups, and logistic regression was used to explore the association between orexin levels and characteristics of demographic and drug abuse. Between November 2009 and January 2011, 285 opiates addicts, 112 methamphetamine addicts, and 79 healthy controls were enrolled. At drug withdrawal period, both opiate and methamphetamine addicts had lower median orexin levels than controls, and median orexin levels in opiate addicts were higher than those in methamphetamine addicts (all above P < 0.05). Adjusted odds of the above median concentration of orexin were higher for injection than "chasing the dragon" (AOR = 3.1, 95% CI = 1.2-7.9). No significant factors associated with orexin levels of methamphetamine addicts were found. Development of intervention method on orexin system by different administration routes especially for injected opiate addicts at detoxification phase may be significant and was welcome. PMID:24102051

  18. Comparing the Effectiveness of Behavioral Recognition and Group Stress Surmounting Techniques Instructions on Changing University Students' Positive Attitudes towards Opiate Abuse

    PubMed Central

    Akbari, Bahman

    2011-01-01

    Background One of the most important strategies in preventing addiction is changing positive attitudes and stabilizing negative attitudes towards opiate abuse. Current research has been comparing the effectiveness of behavioral recognition and stress surmounting techniques instructions on changing students' positive attitudes towards opiate abuse. Methods To determine the effectiveness of behavioral-recognition and group stress surmounting instructions on changing student’s positive attitudes towards opiate abuse, 90 students (45 boys and 45 girls) who had got good grades in attitude measuring questionnaire were chosen and were randomly assigned in 3 groups (two test groups and the control group) and then, were randomly replaced in 15 person groups with sex distinction. The research data were analyzed using multivariate statistical analysis method. Findings The results of pot-test analyses showed significant improvement compared with pretest analysis in both training methods and in both genders (P < 0.05). Then, the surmounting methods group training and recognition-behavioral group training both significantly improved positive attitudes towards opiate abuse in male and female students. Conclusion Behavioral-recognition and stress surmounting techniques instructions brought about changes in students attitudes towards opiate abuse and these changes were more prominent in female students than in males. PMID:24494119

  19. Visualization of. mu. /sub 1/ opiate receptors in rat brain by using a computerized autoradiographic subtraction technique

    SciTech Connect

    Goodman, R.R.; Pasternak, G.W.

    1985-10-01

    The authors have developed a quantitative computerized subtraction technique to demonstrate in rat brain the regional distribution of ..mu../sub 1/ sites, a common very-high-affinity binding site for both morphine and the enkephalins. Low concentrations of (D-Ala/sup 2/, D-Leu/sup 5/)enkephalin selectively inhibit the ..mu../sub 1/ binding of (/sup 3/H)dihydromorphine, leaving ..mu../sub 2/-sites, while low morphine concentrations eliminate the ..mu../sub 1/ binding of (/sup 3/H)(D-Ala/sup 2/, D-Leu/sub 5/)enkephalin, leaving sigma sites. Thus, quantitative differences between images of sections incubated in the presence and absence of these low concentrations of unlabeled opioid represent ..mu../sub 1/ binding sites. The regional distributions of ..mu../sub 1/ sites labeled with (/sup 3/H)dihydromorphine were quite similar to those determined by using (/sup 3/H)(D-Ala/sup 2/, D-Leu/sup 5/)enkephalin. High levels of ..mu../sub 1/ binding were observed in the periaqueductal gray, medial thalamus, and median raphe, consistent with the previously described role of ..mu../sub 1/ sites in analgesia. Other regions with high levels of ..mu../sub 1/ binding include the nucleus accumbens, the clusters and subcallosal streak of the striatum, hypothalamus, medial habenula, and the medial septum/diagonal band region. The proportion of total specific binding corresponding to ..mu../sub 1/ sites varied among the regions, ranging from 14% to 75% for (/sup 3/H)(D-Ala/sup 2/, D-Leu/sup 5/)enkephalin and 20% to 52% for (/sup 3/H)dihydromorphine.

  20. Phenotypically heterogeneous populations in spatially heterogeneous environments

    NASA Astrophysics Data System (ADS)

    Patra, Pintu; Klumpp, Stefan

    2014-03-01

    The spatial expansion of a population in a nonuniform environment may benefit from phenotypic heterogeneity with interconverting subpopulations using different survival strategies. We analyze the crossing of an antibiotic-containing environment by a bacterial population consisting of rapidly growing normal cells and slow-growing, but antibiotic-tolerant persister cells. The dynamics of crossing is characterized by mean first arrival times and is found to be surprisingly complex. It displays three distinct regimes with different scaling behavior that can be understood based on an analytical approximation. Our results suggest that a phenotypically heterogeneous population has a fitness advantage in nonuniform environments and can spread more rapidly than a homogeneous population.

  1. Measurement of movement is an objective method to assist in assessment of opiate withdrawal in newborns

    PubMed Central

    O'Brien, C; Hunt, R; Jeffery, H

    2004-01-01

    Objective: To develop an objective and reliable method to assess drug withdrawal in newborns by quantitatively estimating the amount of movement rather than scoring individual withdrawal signs. Design: In this cross sectional study, a commercial portable motion detector with computer memory, similar to a wrist watch (the actigraph) was used to measure movement. The measurements were compared with a clinical decision based on the neonatal abstinence syndrome (NAS) score. Movement was analysed, using non-parametric tests, in three groups: a control group of 10 infants, 13 opiate exposed newborns not treated for NAS, and 30 newborns treated for NAS (17 before treatment, eight within 24 hours of treatment, five when stabilised). Results: There were significant differences in the median activity score, expressed as counts per minute (cpm), in the pretreatment group (124 cpm) compared with the control (42 cpm, p < 0.0001), non-treated (74 cpm, p  =  0.001), and stabilised treatment (75 cpm, p  =  0.007) groups. The accuracy of the actigraph in the identification of newborns requiring treatment from those who did not was high compared with the clinical scores; sensitivity 94%; specificity 85%; positive and negative predictive values 88% and 92% respectively. Conclusions: The measure of movement is comparable to the clinical score in the identification of newborns who require treatment and in determining the severity of withdrawal. The clear advantage of this method is its objectivity, reliability, and efficiency as a simple, non-invasive, bedside measure. Further evaluation in a randomised, controlled trial would establish comparative benefits, potential harms, safety, and acceptability. PMID:15210661

  2. Reinforcement-based intensive outpatient treatment for inner city opiate abusers: a short-term evaluation.

    PubMed

    Gruber, K; Chutuape, M A; Stitzer, M L

    2000-01-01

    We evaluated 3-month outcomes for reinforcement-based intensive outpatient treatment (RBT), a new relapse prevention behavior therapy for inner city opiate abusers. The therapy provides abstinence-contingent partial support of housing, food and recreational activities, abstinence-contingent access to social skills and job finding group therapy and non-contingent individual counseling, all in the context of a day treatment program. Heroin abusers (n = 52), contacted at a 3-day detoxification unit, were randomly assigned to RBT (n = 28) or referred to community treatment resources (n = 24) after a staff escort from the detoxification unit. For RBT patients, treatment began on the day of discharge; 61% received partial rent support in a recovery house based on the need for drug-free housing; the remainder were eligible for partial support of utility payments where they lived. Abstinence-based contingencies were in effect for 1 month with three times per week counseling available for an additional 2 months. One month after detoxification, 61% of RBT versus 17% of referral patients were enrolled in outpatient treatment (P < 0.01); RBT patients were significantly less likely than controls to have returned to any drug use; and 50% of RBT versus 21% of controls reported 30 days of abstinence from heroin and cocaine with confirmatory negative urine (P < 0.05). RBT patients had significantly lower scores on the Beck Depression Inventory at 1 month (M = 9.0 versus 17.6 for controls; P < 0.05) and showed evidence of less alcohol use and higher rates of employment. These results establish the short-term efficacy for RBT and support continued development and evaluation of this new outpatient behavioral treatment. PMID:10661672

  3. Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate-Induced Neuropathogenesis and NeuroAIDS

    PubMed Central

    Sagar, Vidya; Pilakka-Kanthikeel, Sudheesh; Atluri, Venkata S. R.; Ding, Hong; Arias, Adriana Y.; Jayant, Rahul D.; Kaushik, Ajeet; Nair, Madhavan

    2015-01-01

    Magnetite (Fe3O4) is the most commonly and extensively explored magnetic nanoparticles (MNPs) for drug-targeting and imaging in the field of biomedicine. Nevertheless, its potential application as safe and effective drug-carrier for CNS (Central Nervous System) anomalies is very limited. Previous studies have shown an entangled epidemic of opioid use and HIV infection and increased neuropathogenesis. Opiate such as morphine, heroine, etc. are used frequently as recreational drugs. Existing treatments to alleviate the action of opioid are less effective at CNS level due to impermeability of therapeutic molecules across brain barriers. Thus, development of an advanced nanomedicine based approach may pave the way for better treatment strategies. We herein report magnetic nanoformulation of a highly selective and potent morphine antagonist, CTOP (D-Pen-Cys-Tyr-DTrp-Orn-Thr-Pen-Thr-NH2), which is impenetrable to the brain. MNPs, synthesized in size range from 25 to 40 nm, were characterized by Transmission electron microscopy and assembly of MNPs-CTOP nanoformulations were confirmed by FTIR spectroscopy and fluorescent detection. Flow-cytometry analysis showed that biological efficacy of this nanoformulation in prevention of morphine induced apoptosis in peripheral blood mononuclear cells remains equivalent to that of free CTOP. Similarly, confocal microscopy reveals comparable efficacy of free and MNPs bound CTOP in protecting modulation of neuronal dendrite and spine morphology during morphine exposure and morphine-treated HIV infection. Further, typical transmigration assay showed increased translocation of MNPs across in vitro blood-brain barrier upon exposure of external magnetic force where barrier integrity remains unaltered. Thus, the developed nanoformulation could be effective in targeting brain by application of external magnetic force to treat morphine addiction in HIV patients. PMID:26502636

  4. Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate-Induced Neuropathogenesis and NeuroAIDS.

    PubMed

    Sagar, Vidya; Pilakka-Kanthikeel, Sudheesh; Atluri, Venkata S R; Ding, Hong; Arias, Adriana Y; Jayant, Rahul D; Kaushik, Ajeet; Nair, Madhavan

    2015-10-01

    Magnetite (Fe3O4) is the most commonly and extensively explored magnetic nanoparticles (MNPs) for drug-targeting and imaging in the field of biomedicine. Nevertheless, its potential application as safe and effective drug-carrier for CNS (Central Nervous System) anomalies is very limited. Previous studies have shown an entangled epidemic of opioid use and HIV infection and increased neuropathogenesis. Opiate such as morphine, heroine, etc. are used frequently as recreational drugs. Existing treatments to alleviate the action of opioid are less effective at CNS level due to impermeability of therapeutic molecules across brain barriers. Thus, development of an advanced nanomedicine based approach may pave the way for better treatment strategies. We herein report magnetic nanoformulation of a highly selective and potent morphine antagonist, CTOP (D-Pen-Cys-Tyr-DTrp-Orn-Thr-Pen-Thr-NH2), which is impenetrable to the brain. MNPs, synthesized in size range from 25 to 40 nm, were characterized by Transmission electron microscopy and assembly of MNPs-CTOP nanoformulations were confirmed by FTIR spectroscopy and fluorescent detection. Flow-cytometry analysis showed that biological efficacy of this nanoformulation in prevention of morphine induced apoptosis in peripheral blood mononuclear cells remains equivalent to that of free CTOP. Similarly, confocal microscopy reveals comparable efficacy of free and MNPs bound CTOP in protecting modulation of neuronal dendrite and spine morphology during morphine exposure and morphine-treated HIV infection. Further, typical transmigration assay showed increased translocation of MNPs across in vitro blood-brain barrier upon exposure of external magnetic force where barrier integrity remains unaltered. Thus, the developed nanoformulation could be effective in targeting brain by application of external magnetic force to treat morphine addiction in HIV patients.

  5. Reversal of ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade.

    PubMed

    Emanuele, M A; LaPaglia, N; Steiner, J; Jabamoni, K; Hansen, M; Kirsteins, L; Emanuele, N V

    1998-09-01

    Teenage drinking is a major problem in the United States, as well as abroad. Besides psychosocial implications, ethanol (EtOH) has detrimental effects on the reproductive system. Clinical problems associated with reduced reproductive hormones include osteoporosis, decreased muscle function, anemia, altered immune function, prostate involution, and decreased reproductive abilities. Education coupled with strategies aimed at preventing these deleterious consequences even in the face of continued EtOH intake is extremely important. We have tested the possibility that naltrexone, a drug currently used in patients to decrease alcohol craving, might also prevent the fall in the male hormone, testosterone, caused by EtOH exposure. Rats aged 35 days old (prepubertal), 45 days old (midpubertal), and 55 days old (late pubertal) were injected (intraperitoneally) with either saline, EtOH, naltrexone, or EtOH plus naltrexone. In the two older age groups, EtOH significantly suppressed testosterone, which was prevented by administration of naltrexone. In the youngest animals, there was no treatment effect presumably due to low basal levels of testosterone. EtOH similarly reduced luteinizing hormone (LH), but this suppression was not prevented by naltrexone. There was no consistent effect of any treatment on hypothalamic concentration of pro-LH releasing hormone (RH) (LHRH), LHRH, or on steady-state levels of LHRH mRNA. We conclude that, as animals progress through puberty, EtOH suppresses LH and testosterone. The testosterone decline can be prevented by opiate blockade with naltrexone, an effect primarily seen at gonadal level. Thus, naltrexone, a drug already used clinically to reduce EtOH intake, also has protective physiological effects on the endocrine system. PMID:9756033

  6. Reversal of chronic ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade.

    PubMed

    Emanuele, N V; LaPaglia, N; Steiner, J; Kirsteins, L; Emanuele, M A

    1999-01-01

    Teenage drinking continues to be a significant problem in the U.S., as well as abroad. We have previously demonstrated that opiate blockade with naltrexone, a drug currently used in patients to diminish alcohol craving, prevented the fall in serum testosterone seen after acute ethanol (EtOH) exposure in young, peripubertal male rats. To follow-up on this reversal, a series of experiments was performed to determine if naltrexone would also prevent the testosterone suppression caused by chronic EtOH exposure. Peripubertal rats either 45 days old (mid-pubertal) or 55 days old (late pubertal) were fed an EtOH-containing liquid diet or pair-fed control diet for 14 days. Each animal was implanted with either a naltrexone containing or placebo pellet before starting the liquid diet. In each age group, EtOH alone significantly suppressed testosterone, whereas naltrexone prevented this fall, although it had no effect alone. Serum luteinizing hormone was also suppressed by EtOH; however, naltrexone did not abrogate this fall. In the 45-day-old animals, beta-luteinizing hormone mRNA levels rose significantly in the EtOH group, but not when naltrexone was coadministered with EtOH. There was no change in hypothalamic luteinizing hormone releasing hormone (LHRH) mRNA, pro-LHRH, or LHRH in any group at either age. Thus, naltrexone is able to partially prevent the EtOH-induced suppression of gonadal testosterone of young, adolescent male rats. This effect appears to be mediated directly at gonadal level, because hypothalamic and pituitary hormone changes were minor and nonsignificant. PMID:10029204

  7. Patterns of Emphysema Heterogeneity

    PubMed Central

    Valipour, Arschang; Shah, Pallav L.; Gesierich, Wolfgang; Eberhardt, Ralf; Snell, Greg; Strange, Charlie; Barry, Robert; Gupta, Avina; Henne, Erik; Bandyopadhyay, Sourish; Raffy, Philippe; Yin, Youbing; Tschirren, Juerg; Herth, Felix J.F.

    2016-01-01

    Background Although lobar patterns of emphysema heterogeneity are indicative of optimal target sites for lung volume reduction (LVR) strategies, the presence of segmental, or sublobar, heterogeneity is often underappreciated. Objective The aim of this study was to understand lobar and segmental patterns of emphysema heterogeneity, which may more precisely indicate optimal target sites for LVR procedures. Methods Patterns of emphysema heterogeneity were evaluated in a representative cohort of 150 severe (GOLD stage III/IV) chronic obstructive pulmonary disease (COPD) patients from the COPDGene study. High-resolution computerized tomography analysis software was used to measure tissue destruction throughout the lungs to compute heterogeneity (≥ 15% difference in tissue destruction) between (inter-) and within (intra-) lobes for each patient. Emphysema tissue destruction was characterized segmentally to define patterns of heterogeneity. Results Segmental tissue destruction revealed interlobar heterogeneity in the left lung (57%) and right lung (52%). Intralobar heterogeneity was observed in at least one lobe of all patients. No patient presented true homogeneity at a segmental level. There was true homogeneity across both lungs in 3% of the cohort when defining heterogeneity as ≥ 30% difference in tissue destruction. Conclusion Many LVR technologies for treatment of emphysema have focused on interlobar heterogeneity and target an entire lobe per procedure. Our observations suggest that a high proportion of patients with emphysema are affected by interlobar as well as intralobar heterogeneity. These findings prompt the need for a segmental approach to LVR in the majority of patients to treat only the most diseased segments and preserve healthier ones. PMID:26430783

  8. Methadone, Cocaine, Opiates and Metabolite Disposition in Umbilical Cord and Correlations to Maternal Methadone Dose and Neonatal Outcomes

    PubMed Central

    de Castro, Ana; Jones, Hendreé E.; Johnson, Rolley E.; Gray, Teresa R; Shakleya, Diaa M; Huestis, Marilyn A

    2011-01-01

    Objectives To explore methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) umbilical cord disposition, correlate with maternal methadone dose and neonatal outcomes, and evaluate the window of drug detection in umbilical cord of in utero illicit drug exposure. Methods Subjects, 19 opioid-dependent pregnant women from two clinical studies, one comparing methadone and buprenorphine pharmacotherapy for opioid-dependence treatment, and the second examining monetary reinforcement schedules to maintain drug abstinence. Correlations were calculated for methadone and EDDP umbilical cord concentrations and maternal methadone dose, and neonatal outcomes. Cocaine- and opiate-positive umbilical cord concentrations were compared to those in placenta and meconium, and urine specimens collected throughout gestation. Results Significant positive correlations were found for umbilical cord methadone concentrations and methadone mean daily dose, mean dose during the 3rd trimester and methadone cumulative daily dose. Umbilical cord EDDP concentrations and EDDP/methadone concentration ratios were positively correlated to newborn length, peak neonatal abstinence syndrome (NAS) score and time-to-peak NAS score. Methadone concentrations and EDDP/methadone ratios in umbilical cord and placenta were positively correlated. Meconium identified many more cocaine and opiate positive specimens than umbilical cord. Conclusion Umbilical cord methadone concentrations were correlated to methadone doses. Also, our results indicate that methadone and EDDP concentrations might help to predict NAS severity. Meconium proved to be more suitable than umbilical cord to detect in utero exposure to cocaine and opiates; however, umbilical cord could be useful when meconium is unavailable due to in utero or delayed expulsion. PMID:21743375

  9. Tumour Cell Heterogeneity

    PubMed Central

    Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

    2016-01-01

    The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

  10. [Opiates do not guarantee an adequate analgesia after large-volume open operations on the abdominal cavity organs].

    PubMed

    Potapov, A L; Kobeliatskiĭ, Iu Iu

    2011-08-01

    Efficacy of systemic application of opiates (promedol) for the pain relief after big open abdominal operations, using visual-analogue scale (VAS), was estimated in 50 patients. During 36-48 h postoperatively analgesia was inadequate (VAS in a rest state more than 3 points and while movement--more than 4 points). Intensive pain (VAS 6 points and more) was noted in 58% of patients, while they are moving, and in 26%--in a rest state. Inadequate anesthesia may constitute one of causes of excessive systemic inflammatory reaction development in patients postoperatively.

  11. [The therapeutic alliance as a main factor of building cooperation during the treatment of patients with opiate addiction].

    PubMed

    Agibalova, T V; Tuchin, P V; Shustov, D I; Buzik, O Zh

    2014-01-01

    Objective. To assess an alliance-centred method of short-term psychotherapy (AP) in the formation of compliance in patients with opiate addiction. Material and methods. Authors studied 100 male inpatients with ICD-10 diagnosis Opioid Dependence (F11.2). Patients were stratified into main (with use of AP) and control groups. The tasks of short-term psychotherapy were to determine mutual goals for the patient and the physician and the interaction between them. Results and Conclusion. Based on some special quantitative psychological tests and correlation analysis, it was identified that AP stimulated compliance behaviour in patients with opioid dependence more effectively than traditional recommendations.

  12. Opiate-like inhibitory effect of trimebutine on the twitch response of the isolated guinea pig ileum.

    PubMed

    Yamasato, T; Takaki, M; Nakayama, S

    1987-02-01

    Trimebutine at low concentrations (6 X 10(-9)-1.4 X 10(-8) M) slightly enhanced the twitch response of isolated guinea pig ileum induced by transmural stimulation. At high concentrations (2 X 10(-8)-2 X 10(-7) M), however, it inhibited the twitch response in a dose dependent manner. This inhibitory effect of trimebutine was reversed by naloxone (8.1 X 10(-9) M). These results suggest that trimebutine has an opiate-like action on the myenteric plexus. PMID:3565073

  13. The Opiate Pain Reliever Epidemic among U.S. Arrestees 2000–2010: Regional and Demographic Variations

    PubMed Central

    GOLUB, ANDREW; ELLIOTT, LUTHER; BROWNSTEIN, HENRY H.

    2013-01-01

    The increasing rate of opiate pain reliever (OPR) use is a pressing concern in the United States. This article uses a drug epidemics framework to examine OPR use among arrestees surveyed by the Arrestee Drug Abuse Monitoring program. Results demonstrate regional and demographic variation in use across nine focal cities. High rates of OPR use on the West Coast illustrate the expansion of use from its initial epicenter. By 2010, OPR use had plateaued in all focal cities. Findings suggest directions for ongoing research into pathways to use and vectors of diffusion and for regionally specific interventions sensitive to age and ethnic diversity. PMID:23480209

  14. Circulating tumour cells: insights into tumour heterogeneity.

    PubMed

    Hayes, D F; Paoletti, C

    2013-08-01

    Tumour heterogeneity is a major barrier to cure breast cancer. It can exist between patients with different intrinsic subtypes of breast cancer or within an individual patient with breast cancer. In the latter case, heterogeneity has been observed between different metastatic sites, between metastatic sites and the original primary tumour, and even within a single tumour at either a metastatic or a primary site. Tumour heterogeneity is a function of two separate, although linked, processes. First, genetic instability is a hallmark of malignancy, and results in 'fixed' genetic changes that are almost certainly carried forward through progression of the cancer over time, with increasingly complex additional genetic changes in new metastases as they arise. The second type of heterogeneity is due to differential but 'plastic' expression of various genes important in the biology and response to various therapies. Together, these processes result in highly variable cancers with differential response, and resistance, to both targeted (e.g. endocrine or anti-human epithelial growth receptor type 2 (HER2) agents) and nontargeted therapies (e.g. chemotherapy). Ideally, tumour heterogeneity would be monitored over time, especially in relation to therapeutic strategies. However, biopsies of metastases require invasive and costly procedures, and biopsies of multiple metastases, or serially over time, are impractical. Circulating tumour cells (CTCs) represent a potential surrogate for tissue-based cancer and therefore might provide the opportunity to monitor serial changes in tumour biology. Recent advances have enabled accurate and reliable quantification and molecular characterization of CTCs with regard to a number of important biomarkers including oestrogen receptor alpha and HER2. Preliminary data have demonstrated that expression of these markers between CTCs in individual patients with metastatic breast cancer reflects the heterogeneity of the underlying tumours. Future

  15. A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action

    PubMed Central

    Bernstein, Robert Root; Dillon, Patrick F

    2014-01-01

    Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, cortico-steroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers. PMID:25174918

  16. Structural basis for bifunctional peptide recognition at human δ-opioid receptor

    DOE PAGESBeta

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; et al

    2015-02-16

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. In summary, the observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics.

  17. Structural basis for bifunctional peptide recognition at human δ-opioid receptor

    SciTech Connect

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C. H.; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J.; Gati, Cornelius; Yefanov, Oleksandr M.; White, Thomas A.; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N.; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W.; Roth, Bryan L.; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C.; Cherezov, Vadim

    2015-02-16

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. In summary, the observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics.

  18. Structural basis for bifunctional peptide recognition at human δ-Opioid receptor

    PubMed Central

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C.H.; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J.; Gati, Cornelius; Yefanov, Oleksandr M.; White, Thomas A.; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N.; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W.; Roth, Bryan L.; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C.; Cherezov, Vadim

    2015-01-01

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt(1)-Tic(2)-Phe(3)-Phe(4)-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt(1) and Tic(2). The observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics. PMID:25686086

  19. Structural basis for bifunctional peptide recognition at human δ-opioid receptor.

    PubMed

    Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C H; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J; Gati, Cornelius; Yefanov, Oleksandr M; White, Thomas A; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W; Roth, Bryan L; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C; Cherezov, Vadim

    2015-03-01

    Bifunctional μ- and δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human δ-OR bound to the bifunctional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics.

  20. Structural basis for bifunctional peptide recognition at human δ-opioid receptor.

    PubMed

    Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C H; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J; Gati, Cornelius; Yefanov, Oleksandr M; White, Thomas A; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W; Roth, Bryan L; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C; Cherezov, Vadim

    2015-03-01

    Bifunctional μ- and δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human δ-OR bound to the bifunctional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics. PMID:25686086

  1. The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders.

    PubMed

    Toll, Lawrence

    2013-01-01

    The NOP receptor, the fourth receptor in the opioid receptor family, is found throughout the brain and is involved in a variety of CNS systems and pathways. The endogenous ligand for NOP receptors, nociceptin/orphanin FQ (now called N/OFQ), was originally thought to increase a painful stimulus since intracerebroventricular (i.c.v.) administration of this heptadecapeptide led to a decrease in tail-flick and hot-plate latency in mice. Further studies suggested that N/OFQ blocks opiate analgesia when administered i.c.v. but potentiates opiate analgesia and has antinociceptive activity when administered intrathecally. I.c.v. administration of N/OFQ has other beneficial actions including inhibition of reward induced by several different abused drugs, as well as anti-anxiety activity. Recent work has demonstrated that individual small molecules that activate both NOP and mu receptors possess mu-mediated antinociceptive activity with reduced reward, as determined by conditioned place preference tests. Furthermore, selective NOP receptor agonists appear to be active in certain chronic pain models and reduce both drug craving and anxiety. NOP receptor antagonists may also have therapeutic benefits since both peptide and small molecule antagonists have anti-depressant activity in two different animal models. Therefore, both selective NOP receptor compounds and non-selective compounds, with both NOP receptor and mu opioid receptor activity, appear to have potential for clinical use for several neurological and psychiatric disorders including acute and chronic pain, drug abuse, anxiety and depression.

  2. Comparison of the Microgenics CEDIA heroin metabolite (6-AM) and the Roche Abuscreen ONLINE opiate immunoassays for the detection of heroin use in forensic urine samples.

    PubMed

    Holler, Justin M; Bosy, Thomas Z; Klette, Kevin L; Wiegand, Russel; Jemionek, John; Jacobs, Aaron

    2004-09-01

    Current Department of Defense (DoD) and Department of Health and Human Services (HHS) procedures for the detection of heroin abuse by testing urine utilize an initial opiate (codeine/morphine) immunoassay (IA) screen followed by gas chromatography-mass spectrometry (GC-MS) confirmation of 6-acetylmorphine (6-AM), if the morphine concentration is above established cutoff. An alternative to the current opiates screen for heroin abuse is the direct IA for the metabolite of heroin, 6-acetylmorphine. In this regard, the performance of the Microgenics CEDIA heroin metabolite (6-AM) screening reagent was assessed. This evaluation was conducted on the P module of a Hitachi Modular automated IA analyzer calibrated using 6-AM at 10 ng/mL. Reproducibility, linearity, accuracy, sensitivity, and interferences associated with use of the 6-AM IA reagent were evaluated. The IA reagent precision (percent coefficient of variation (%CV)) around each of seven standards was less than 0.63%, with a linearity (r(2)) value of 0.9951. A total of 37,713 active duty service members' urine samples were analyzed simultaneously using the CEDIA heroin metabolite (6-AM) reagent and the Roche Abuscreen ONLINE opiate reagent to evaluate both the prevalence rate of 6-AM in the demographic group and the sensitivity and specificity of the reagents for the detection of heroin use. Of the 37,713 samples tested using the CEDIA heroin metabolite (6-AM) reagent, three samples screened positive at the DoD and HHS cutoff of 10 ng/mL. One of the three samples confirmed positive for 6-AM by GC-MS above the cutoff of 10 ng/mL, the two remaining samples confirmed negative for 6-AM at a GC-MS limit of detection (LOD) of 2.1 ng/mL. In contrast, the Roche Abuscreen ONLINE opiate IA produced 74 opiate-positive results for codeine/morphine, with 6 of the 74 specimens confirming positive for morphine above the DoD cutoff concentration of 4000 ng/mL (8% DoD morphine confirmation rate), only one of the 74 opiate

  3. Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

    PubMed

    Karlsen, Morten; Liu, Huiling; Johansen, Jon Eigill; Hoff, Bård Helge

    2015-01-01

    The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products. PMID:25816077

  4. Reversal of opiate-induced apoptosis by human recombinant growth hormone in murine foetus primary hippocampal neuronal cell cultures.

    PubMed

    Svensson, Anne-Lie; Bucht, Nora; Hallberg, Mathias; Nyberg, Fred

    2008-05-20

    Previous studies have shown that chronic opiates may inhibit cell growth and trigger apoptosis leading to impaired cognitive capabilities in both humans and other mammals. In contrast, growth hormone (GH) has been demonstrated to stimulate cell growth and counteract apoptosis. GH has also been shown to improve learning and memory in both human and rodents. In this work, we demonstrate that GH may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Primary hippocampal cell cultures derived from 16-day-old fetal mouse neurons were treated with morphine for 7 days during growth in the absence or presence of recombinant human GH (rhGH). The release of lactate dehydrogenase (LDH) into the culture media and the level of cleaved caspase-3 were measured. Results indicate that morphine (15 microM) decreased the cell content in a concentration-dependent manner and increased LDH release and caspase-3 activity. Thus, fetal mouse neurons treated with morphine showed less viability compared with controls. Interestingly, the addition of rhGH (1 microM) counteracted the morphine-induced effect on the cell density. Furthermore, the hormone attenuated the effects on LHD release and caspase-3 activity elicited by morphine. These results suggest that the hormone is capable of preventing or even repairing morphine-induced damage to hippocampal cells.

  5. Heterogeneous atmospheric chemistry

    NASA Technical Reports Server (NTRS)

    Schryer, D. R.

    1982-01-01

    The present conference on heterogeneous atmospheric chemistry considers such topics concerning clusters, particles and microparticles as common problems in nucleation and growth, chemical kinetics, and catalysis, chemical reactions with aerosols, electron beam studies of natural and anthropogenic microparticles, and structural studies employing molecular beam techniques, as well as such gas-solid interaction topics as photoassisted reactions, catalyzed photolysis, and heterogeneous catalysis. Also discussed are sulfur dioxide absorption, oxidation, and oxidation inhibition in falling drops, sulfur dioxide/water equilibria, the evidence for heterogeneous catalysis in the atmosphere, the importance of heterogeneous processes to tropospheric chemistry, soot-catalyzed atmospheric reactions, and the concentrations and mechanisms of formation of sulfate in the atmospheric boundary layer.

  6. Teaching Heterogeneous Classes.

    ERIC Educational Resources Information Center

    Millrood, Radislav

    2002-01-01

    Discusses an approach to teaching heterogeneous English-as-a-Second/Foreign-Language classes. Draws on classroom research data to describe the features of a success-building lesson context. (Author/VWL)

  7. Changes in LH and prolactin levels in diabetic male rats and the role of the opiate system in the control of their secretion.

    PubMed

    Yogev, L; Gottriech, A; Timan, B; Homonnai, Z T; Paz, G F

    1985-09-16

    Diabetic male rat has low serum levels of luteinizing hormone (LH) and testosterone (T), which are accompanied by atrophy of the testes and accessory glands. The present study investigated changes in the serum levels of LH, prolactin (PRL) and glucose, following diabetes induction by streptozotocin. In addition, involvement of the opiate system in the control of LH and PRL secretion was evaluated. There was no difference in PRL levels between diabetic and control animals, except at 8 hours after streptozotocin injection. In contrast, the diabetic animals had consistently lower levels of LH, starting on the second day of diabetes. Blockade of the opiate system by naltrexone caused a sharp increase of LH levels in normoglycemic rats, while only a gradual decrease was observed in hyperglycemic animals. PRL secretion was inhibited by naltrexone, both in diabetic and control groups. It is concluded that, unlike normoglycemic rats, inhibition of LH secretion in diabetes is not under the control of the opiate system, probably as a result of T deficiency. In contrast, PRL secretion in diabetic rats, as in the control group, is under the influence of endogenous opiates. PMID:4033351

  8. Investigating the relationship between sexual and chemical addictions by comparing executive function in subjects with pedophilia or opiate addiction and healthy controls.

    PubMed

    Cohen, Lisa J; Nesci, Cristina; Steinfeld, Matthew; Haeri, Sophia; Galynker, Igor

    2010-11-01

    Disorders of driven sexual behavior have been conceptualized as sexual addictions. In the following study, we compared 51 subjects with pedophilia, 53 subjects with opiate addiction, and 84 healthy control subjects on neuropsychological tests that tap executive functions. The test battery included the Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test, the Matching Familiar Figures Test (MFFT), Porteus Mazes, Controlled Word Association (COWA), and Trailmaking Test. The groups differed on tests of cognitive flexibility and set switching (WCST), sustained attention (Stroop), and impulsivity (MFFT and Porteus Mazes). There were no differences on verbal fluency (COWA). The subjects with pedophilia differed significantly from those with opiate addiction on several tests, with longer latency to response on MFFT and fewer completed mazes but also fewer errors on Porteus Mazes. Thus, while both subjects with pedophilia and those with opiate addiction show executive dysfunction, the nature of that dysfunction may differ between the two groups; specifically, opiate addicted subjects may be more prone to cognitive impulsivity.

  9. The Impact of Take-Home Naloxone Distribution and Training on Opiate Overdose Knowledge and Response: An Evaluation of the THN Project in Wales

    ERIC Educational Resources Information Center

    Bennett, Trevor; Holloway, Katy

    2012-01-01

    Aims: To determine the impact of naloxone training on knowledge of opiate overdose and confidence and willingness to take appropriate action and to examine the use of naloxone and other harm-reduction actions at the time of overdose events. Methods: The evaluation was based on a repeated-measure design, whereby clients were tested before and after…

  10. Characterization of Paper Heterogeneity

    NASA Astrophysics Data System (ADS)

    Considine, John M.

    Paper and paperboard are the most widely-used green materials in the world because they are renewable, recyclable, reusable, and compostable. Continued and expanded use of these materials and their potential use in new products requires a comprehensive understanding of the variability of their mechanical properties. This work develops new methods to characterize the mechanical properties of heterogeneous materials through a combination of techniques in experimental mechanics, materials science and numerical analysis. Current methods to analyze heterogeneous materials focus on crystalline materials or polymer-crystalline composites, where material boundaries are usually distinct. This work creates a methodology to analyze small, continuously-varying stiffness gradients in 100% polymer systems and is especially relevant to paper materials where factors influencing heterogeneity include local mass, fiber orientation, individual pulp fiber properties, local density, and drying restraint. A unique approach was used to understand the effect of heterogeneity on paper tensile strength. Additional variation was intentionally introduced, in the form of different size holes, and their effect on strength was measured. By modifying two strength criteria, an estimate of strength in the absence of heterogeneity was determined. In order to characterize stiffness heterogeneity, a novel load fixture was developed to excite full-field normal and shear strains for anisotropic stiffness determination. Surface strains were measured with digital image correlation and were analyzed with the VFM (Virtual Fields Method). This approach led to VFM-identified stiffnesses that were similar to values determined by conventional tests. The load fixture and VFM analyses were used to measure local stiffness and local stiffness variation on heterogeneous anisotropic materials. The approach was validated on simulated heterogeneous materials and was applied experimentally to three different paperboards

  11. Duration of opioid receptor blockade determines biotherapeutic response.

    PubMed

    McLaughlin, Patricia J; Zagon, Ian S

    2015-10-01

    Historically, studies on endogenous and exogenous opioids and their receptors focused on the mediation of pain, with excess opiate consumption leading to addiction. Opioid antagonists such as naloxone and naltrexone blocked these interactions, and still are widely used to reverse drug and alcohol overdose. Although specific opioid antagonists have been designed for mu, delta, and kappa opioid receptors, the general antagonists remain the most effective. With the discovery of the opioid growth factor (OGF)-OGF receptor (OGFr) axis as a novel biological pathway involved in homeostasis of replicating cells and tissues, the role of opioid receptor antagonists was expanded. An intermittent OGFr blockade by low dosages of naltrexone resulted in depressed cell replication, whereas high (or sustained) dosages of naltrexone that conferred a continuous OGFr blockade resulted in enhanced growth. More than 3 decades of research have confirmed that the duration of opioid receptor blockade, not specifically the dosage, by general opioid antagonists determines the biotherapeutic outcome. Dysregulation of the OGF-OGFr pathway is apparent in a number of human disorders including diabetes, multiple sclerosis, and cancer, and thus opioid antagonist disruption of interaction prevails as a therapeutic intervention. We review evidence that the duration of opioid receptor blockade is correlated with the magnitude and direction of response, and discuss the potential therapeutic effectiveness of continuous receptor blockade for treatment of diabetic complications such as corneal defects and skin wounds, and of intermittent receptor blockade by low dosages of naltrexone for treatment of autoimmune diseases and cancer. PMID:26119823

  12. The imidazoline receptors and ligands in pain modulation

    PubMed Central

    Bektas, Nurcan; Nemutlu, Dilara; Arslan, Rana

    2015-01-01

    Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies. PMID:26600633

  13. Treatment of major depressive disorder and dysthymic disorder with antidepressants in patients with comorbid opiate use disorders enrolled in methadone maintenance therapy: a meta-analysis.

    PubMed

    Pedrelli, Paola; Iovieno, Nadia; Vitali, Mario; Tedeschini, Enrico; Bentley, Kate H; Papakostas, George I

    2011-10-01

    Depression and opiate-use disorders (abuse, dependence) often co-occur, each condition complicating the course and outcome of the other. It has been recommended that clinicians prescribe antidepressant therapy for mood symptoms in patients with active substance-use disorders, but whether antidepressants are effective in this specific population is not entirely clear. Therefore, the aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder (DD) with comorbid opiate-use disorders currently in methadone maintenance treatment (MMT). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the treatment of MDD/DD in patients with comorbid opiate-use disorders currently in MMT. The search was limited to articles published between January 1, 1980, and June 30, 2010 (inclusive). Four manuscripts were found eligible for inclusion in our analysis (n = 317 patients). We found no statistically significant difference in response rates between antidepressant and placebo therapy in trials of MDD/DD patients with comorbid opiate-use disorders currently in MMT (risk ratio for response, 1.182; 95% CI: 0.822-1.700; P = 0.366). These results show no difference in the depressive outcome of patients with comorbid opiate-use disorders on MMT whether they are on medication or placebo. Future studies examining the effectiveness of antidepressants while controlling for several variables such as psychosocial treatment and assessing the specific classes of antidepressants are needed.

  14. Opiates or cocaine: mortality from acute reactions in six major Spanish cities. State Information System on Drug Abuse (SEIT) Working Group.

    PubMed Central

    Sánchez, J; Rodríguez, B; de la Fuente, L; Barrio, G; Vicente, J; Roca, J; Royuela, L

    1995-01-01

    STUDY OBJECTIVE--To describe temporal and geographical variations in mortality from acute reactions to opiates or cocaine and the demographic and toxicological characteristics of persons who died from these in major Spanish cities between 1983 and 1991. DESIGN--Descriptive study. Data were obtained retrospectively from pathologists' reports. SETTING--Cities of Madrid, Barcelona, Valencia, Seville, Zaragoza, and Bilbao. SUBJECTS--Deaths from acute reactions to opiates or cocaine were defined as those in which pathologists' reports did not indicate any other cause of death and in which evidence was found of recent consumption of these drugs. MAIN RESULTS--The mortality rate from acute reactions to opiate/cocaine per 100,000 population in the six cities as a whole rose from 1.2 in 1983 to 8.2 in 1991. Average annual rates for the whole period ranged from 1.7 in Seville to 4.9 in Barcelona. The male/female rates ratio was 5.9:1. The mean age of persons who died rose from 25.1 years in 1983 to 28 years in 1991. In more than 90% of the cases in whom toxicological tests were undertaken opiates were detected, and the proportion in which benzodiazepines or cocaine were detected increased during the period studied. CONCLUSIONS--Between 1983 and 1991 mortality from acute reactions to opiates/cocaine rose dramatically in major Spanish cities and significant differences in mortality between cities were found. Deaths were concentrated among men and young people. Acute drug reactions became one of the leading causes of death in persons 15-39 years of age, representing 11.1% of mortality from all causes in 1988 for this age group. Future studies should examine the relationship between the temporal and geographical variations in this type of mortality and various personal, environmental and social factors. PMID:7707007

  15. Managing Power Heterogeneity

    NASA Astrophysics Data System (ADS)

    Pruhs, Kirk

    A particularly important emergent technology is heterogeneous processors (or cores), which many computer architects believe will be the dominant architectural design in the future. The main advantage of a heterogeneous architecture, relative to an architecture of identical processors, is that it allows for the inclusion of processors whose design is specialized for particular types of jobs, and for jobs to be assigned to a processor best suited for that job. Most notably, it is envisioned that these heterogeneous architectures will consist of a small number of high-power high-performance processors for critical jobs, and a larger number of lower-power lower-performance processors for less critical jobs. Naturally, the lower-power processors would be more energy efficient in terms of the computation performed per unit of energy expended, and would generate less heat per unit of computation. For a given area and power budget, heterogeneous designs can give significantly better performance for standard workloads. Moreover, even processors that were designed to be homogeneous, are increasingly likely to be heterogeneous at run time: the dominant underlying cause is the increasing variability in the fabrication process as the feature size is scaled down (although run time faults will also play a role). Since manufacturing yields would be unacceptably low if every processor/core was required to be perfect, and since there would be significant performance loss from derating the entire chip to the functioning of the least functional processor (which is what would be required in order to attain processor homogeneity), some processor heterogeneity seems inevitable in chips with many processors/cores.

  16. Treatment of idiopathic erectile dysfunction in men with the opiate antagonist naltrexone--a double-blind study.

    PubMed

    Brennemann, W; Stitz, B; Van Ahlen, H; Brensing, K A; Klingmüller, D

    1993-01-01

    Opiate antagonists can indirectly stimulate the secretion of luteinizing hormone (LH) and testosterone, as well as sexual functions in animals and humans. We therefore treated 20 otherwise healthy men with idiopathic erectile dysfunction aged 46.3 +/- 2.7 years (mean +/- SE, range 23.9-63.3) in a double-blind study with an opiate antagonist, naltrexone, or placebo. The erectile dysfunction of these men had persisted for 3.6 +/- 0.5 years despite libido maintenance; standard procedures had excluded any organic causes. Trial duration was 12 weeks overall. After a 4-week forerun, the patients received at first 25 mg naltrexone/day orally or placebo for 4 weeks followed by 4 weeks of a 50-mg dose of naltrexone/day or placebo. Each day the patients filled out a questionnaire detailing libido, degree of erection, frequency of sexual intercourse, and spontaneous morning erections. Serum concentrations of gonadotropins and testosterone were determined radioimmunologically in the initial stage and at the end of each phase. Both patient collectives had similar initial factors. The group treated with naltrexone showed a significant rise in spontaneous early morning erections during the treatment: from 2.8 +/- 0.3 to 4.2 +/- 0.3 a week (P < 0.001). The placebo group showed no significant change in spontaneous erections (2.4 +/- 0.3 and 2.6 +/- 0.3, respectively). The subjective parameters, however, such as libido, degree of erection, and frequency of sexual intercourse showed no significant difference within each group. There was no difference in LH, follicle-stimulating hormone, or testosterone concentrations in both groups. Thus, treatment with naltrexone significantly raises the rate of spontaneous early morning erections when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8294223

  17. Simultaneous determination of opiates, methadone, buprenorphine and metabolites in human urine by superficially porous liquid chromatography tandem mass spectrometry.

    PubMed

    Lin, Huei-Ru; Chen, Chin-Lun; Huang, Chieh-Liang; Chen, Shao-Tsu; Lua, Ahai-Chuang

    2013-04-15

    For monitoring compliance of methadone or buprenorphine maintenance patient, a method for the simultaneous determination of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, opiates (morphine, codeine, 6-monoacetylmorphine) in urine by superficially porous liquid chromatography tandem mass spectrometry was developed and validated. After enzyme digestion and liquid-liquid extraction, reverse-phase separation was achieved in 5.2 min and quantification was performed by multiple reaction monitoring. Chromatographic separation was performed at 40 °C on a reversed phase Poroshell column with gradient elution. The mobile phase consisted of water and methanol, each containing 0.1% formic acid, at a flow rate of 0.32 mL/min. Intra-day and inter-day precision were less than 12.1% and accuracy was between -9.8% and 13.7%. Extraction efficiencies were more than 68%. Although ion suppression was detected, deuterated internal standards compensated for these effects. Carryover was minimal, less than 0.20%. All analytes were stable at room temperature for 16 h, 4 °C for 72 h, and after three freeze-thaw cycles. The assay also fulfilled compound identification criteria in accordance with the European Commission Decision 2002/657/EC. We analyzed 62 urine samples from patients received maintenance therapy and found that 54.8% of the patient samples tested were detected for morphine, codeine, or 6-monoacetylmorphine. This method provides a reliable and simultaneous quantification of opiates, maintenance drugs, and their metabolites in urine samples. It facilitates the routine monitoring in individuals prescribed the drug to ensure compliance and help therapeutic process. PMID:23507455

  18. Specific binding of a ligand of sigma-opioid receptors - N-allylnormetazocine (SKF 10047) - with liver membranes

    SciTech Connect

    Samovilova, N.N.; Yarygin, K.N.; Vinogradov, V.A.

    1986-08-01

    A ligand of the sigma-opioid receptors - N-allylnormetazocine (SKF 10047) -binds specifically and reversible with rat liver membranes. In relation to a number of properties, the sites binding SKF 10047 in the liver are similar to the sigma-opioid receptors of the central nervous system. They do not interact with classical opiates (morphine, naloxone) and with opioid peptides, but bind well benzomorphans (bremazocine, SKF 10047) and a number of compounds of different chemical structures with a pronounced psychtropic action (haloperidol, imipramine, phencyclidine, etc.).

  19. Heterogeneous waste processing

    DOEpatents

    Vanderberg, Laura A.; Sauer, Nancy N.; Brainard, James R.; Foreman, Trudi M.; Hanners, John L.

    2000-01-01

    A combination of treatment methods are provided for treatment of heterogeneous waste including: (1) treatment for any organic compounds present; (2) removal of metals from the waste; and, (3) bulk volume reduction, with at least two of the three treatment methods employed and all three treatment methods emplyed where suitable.

  20. Scales of mantle heterogeneity

    NASA Astrophysics Data System (ADS)

    Moore, J. C.; Akber-Knutson, S.; Konter, J.; Kellogg, J.; Hart, S.; Kellogg, L. H.; Romanowicz, B.

    2004-12-01

    A long-standing question in mantle dynamics concerns the scale of heterogeneity in the mantle. Mantle convection tends to both destroy (through stirring) and create (through melt extraction and subduction) heterogeneity in bulk and trace element composition. Over time, these competing processes create variations in geochemical composition along mid-oceanic ridges and among oceanic islands, spanning a range of scales from extremely long wavelength (for example, the DUPAL anomaly) to very small scale (for example, variations amongst melt inclusions). While geochemical data and seismic observations can be used to constrain the length scales of mantle heterogeneity, dynamical mixing calculations can illustrate the processes and timescales involved in stirring and mixing. At the Summer 2004 CIDER workshop on Relating Geochemical and Seismological Heterogeneity in the Earth's Mantle, an interdisciplinary group evaluated scales of heterogeneity in the Earth's mantle using a combined analysis of geochemical data, seismological data and results of numerical models of mixing. We mined the PetDB database for isotopic data from glass and whole rock analyses for the Mid-Atlantic Ridge (MAR) and the East Pacific Rise (EPR), projecting them along the ridge length. We examined Sr isotope variability along the East Pacific rise by looking at the difference in Sr ratio between adjacent samples as a function of distance between the samples. The East Pacific Rise exhibits an overall bowl shape of normal MORB characteristics, with higher values in the higher latitudes (there is, however, an unfortunate gap in sampling, roughly 2000 km long). These background characteristics are punctuated with spikes in values at various locations, some, but not all of which are associated with off-axis volcanism. A Lomb-Scargle periodogram for unevenly spaced data was utilized to construct a power spectrum of the scale lengths of heterogeneity along both ridges. Using the same isotopic systems (Sr, Nd

  1. Purification and characterization of mu-specific opioid receptor from rat brain

    SciTech Connect

    Hasegawa, J.; Cho, T.M.; Ge, B.L.; Loh, H.H.

    1986-03-05

    A mu-specific opioid receptor was purified to apparent homogeneity from rat brain membranes by 6-succinylmorphine affinity chromatography, Ultrogel filtration, wheat germ agglutinin affinity chromatography, and isoelectric focusing. The purified receptor had a molecular weight of 58,000 as determined by polyacrylamide gel electrophoresis, and was judged to be homogeneous by the following criteria: (1) a single band on the SDS gel; and (2) a specific opioid binding activity of 17,720 pmole/mg protein, close to the theoretical value. In addition, the 58,000 molecular weight value agrees closely with that determined by covalently labelling purified receptor with bromoacetyl-/sup 3/H-dihydromorphine or with /sup 125/I-beta-endorphin and dimethyl suberimidate. To their knowledge, this is the first complete purification of an opioid receptor that retains its ability to bind opiates.

  2. Anti-opioid effects of neuropeptide FF receptors in the ventral tegmental area.

    PubMed

    Kersanté, Flavie; Wang, Jin-Ya; Chen, Jin-Chung; Mollereau, Catherine; Zajac, Jean-Marie

    2011-01-25

    The present study investigates the modulatory effects of neuropeptide FF (NPFF) receptors on the mesolimbic dopaminergic pathway controlled by opioid receptors. A stable NPFF(2) receptor agonist, dNPA, was injected into the ventral tegmental area (VTA) and the release of dopamine and serotonin within the nucleus accumbens (NAc), induced by intraperitoneal injection of morphine, was monitored using the brain microdialysis, in non-constrained rat. dNPA decreased systemic morphine-induced elevation of dopamine and serotonin metabolites within the NAc. Furthermore, co-injected with morphine into the VTA, NPFF inhibited morphine-induced stereotypy 60-120min after the injection. This neurochemical and behavioural anti-opioid effect mediated by NPFF(2) receptors at the level of VTA suggests the involvement of NPFF in the rewarding effects of opiates on the mesolimbic dopamine system.

  3. Suppression of sex behavior by kappa opiates and stress steroids occurs via independent neuroendocrine pathways.

    PubMed

    Lombana, Karla; Middleton, Natalie; Coddington, Emma

    2015-01-01

    Endocannabinoids and their receptors are found throughout the brain of all vertebrates. By virtue of their wide distribution, endocannabinoids have the potential to affect many behaviors. Prior research has shown that cannabinoids inhibit courtship-clasping and mediate behavioral responses to stress in male rough-skinned newts, Taricha granulosa, and cannabinoid signaling is initiated by rapid actions of the steroid corticosterone (CORT) at its specific membrane receptor (mCR). This same mCR also recognizes κ-opioid receptor agonists and antagonists. Prior behavioral studies show that κ-opioid agonists suppress clasping behavior in a dose dependent manner. Combined, these studies suggest that κ-opioid agonists might suppress clasping behavior via the same pathway initiated by CORT: up-regulation of endocannabinoid signaling. We examined whether pretreatment with a CB1 antagonist, AM281, would block κ-opioid-mediated suppression of clasping. We found that the CB1 antagonist did not reverse κ-opioid-induced suppression of clasping, revealing that while endocannabinoids mediate CORT-induced suppression of clasping, endocannabinoids do not mediate the κ-opioid-induced suppression of clasping.

  4. Heterogeneous voter models

    NASA Astrophysics Data System (ADS)

    Masuda, Naoki; Gibert, N.; Redner, S.

    2010-07-01

    We introduce the heterogeneous voter model (HVM), in which each agent has its own intrinsic rate to change state, reflective of the heterogeneity of real people, and the partisan voter model (PVM), in which each agent has an innate and fixed preference for one of two possible opinion states. For the HVM, the time until consensus is reached is much longer than in the classic voter model. For the PVM in the mean-field limit, a population evolves to a preference-based state, where each agent tends to be aligned with its internal preference. For finite populations, discrete fluctuations ultimately lead to consensus being reached in a time that scales exponentially with population size.

  5. Atmospheric Heterogeneous Stereochemistry

    NASA Astrophysics Data System (ADS)

    Stokes, G. Y.; Buchbinder, A. M.; Geiger, F. M.

    2009-12-01

    This paper addresses the timescale and mechanism of heterogeneous interactions of laboratory models of organic-coated mineral dust and ozone. We are particularly interested in investigating the role of stereochemistry in heterogeneous oxidation reactions involving chiral biogenic VOCs. Using the surface-specific nonlinear optical spectroscopy, sum frequency generation, we tracked terpene diastereomers during exposure to 10^11 to 10^13 molecules of ozone per cm^3 in 1 atm helium to model ozone-limited and ozone-rich tropospheric conditions. Our kinetic data indicate that the diastereomers which orient their reactive C=C double bonds towards the gas phase exhibit heterogeneous ozonolysis rate constants that are two times faster than diastereomers that orient their C=C double bonds away from the gas phase. Insofar as our laboratory model studies are representative of real world environments, our studies suggest that the propensity of aerosol particles coated with chiral semivolatile organic compounds to react with ozone may depend on stereochemistry. Implications of these results for chiral markers that would allow for source appointment of anthropogenic versus biogenic carbon emissions will be discussed.

  6. Somatostatin receptors: identification and characterization in rat brain membranes.

    PubMed

    Srikant, C B; Patel, Y C

    1981-06-01

    We have identified and characterized specific receptors for tetradecapeptide somatostatin (SRIF; somatotropin release-inhibiting factor) in rat brain using [125I]Tyr11]SRIF as the radioligand. These receptors are present in membranes obtained from a subfraction of synaptosomes. Membranes derived from cerebral cortex bind SRIF with high affinity (Ka = 1.25 X 10(10) M-1) and have a maximum binding capacity (Bmax) of 0.155 X 10(-12) mol/mg. Neither opiates nor other neuropeptides appear to influence the binding of SRIF to brain membranes. Synthetic analogs with greater biological potency than SRIF--[D-Trp8]SRIF, [D-Cys14]SRIF, and [D-Trp8, D-Cys14]SRIF--bind to the receptors with greater avidity than SRIF, whereas inactive analogs [(2H)Ala3]SRIF and [Ala6]SRIF exhibit low binding. The ratio of receptor density to endogenous somatostatin is high in the cortex, thalamus, and striatum, low in the hypothalamus, and extremely low in the brain stem and cerebellum. Thus, SRIF receptors in the brain appear to be a distinct, new class of receptors with a regional distribution different from that of endogenous somatostatin.

  7. Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn-177Lu is superior to 90Y-177Lu in peptide receptor radiotherapy

    NASA Astrophysics Data System (ADS)

    Walrand, Stephan; Hanin, François-Xavier; Pauwels, Stanislas; Jamar, François

    2012-07-01

    Clinical trials on 177Lu-90Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1-25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for 93Y, 90Y and 125Sn in combination with 177Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75-25% combination of 177Lu and 90Y activity. However, 125Sn-177Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. 125Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125Sn is the best RN for combination with 177Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125Sn-labelled somatostatin analogues.

  8. Effects of kappa opiate agonists, cholecystokinin and bombesin on intake of diets varying in carbohydrate-to-fat ratio in rats.

    PubMed

    Romsos, D R; Gosnell, B A; Morley, J E; Levine, A S

    1987-05-01

    Effects of the dietary carbohydrate-to-fat ratio on opiate-stimulated eating and on naloxone-, cholecystokinin- and bombesin-suppressed eating were examined. Rats were fed either a high carbohydrate (cornstarch) diet (68% of energy from carbohydrate and 12% from fat), an intermediate diet (40% carbohydrate and 40% fat) or a high fat (corn oil and lard) diet (3% carbohydrate and 77% fat). Other rats self-selected from the high carbohydrate and high fat diets. Subcutaneous administration of naloxone, an opiate antagonist, generally suppressed intake of the high fat diet to a greater extent than intake of the high carbohydrate diet. Neither cholecystokinin octapeptide nor bombesin (administered intraperitoneally) exerted preferential suppression of fat intake. The opiate agonists ketocyclazocine and butorphanol tartrate administered subcutaneously at 1000 h preferentially, although not exclusively, stimulated intake of the high fat diet in a dose-dependent manner during the 6-h feeding trial. Repeated daily subcutaneous injections of butorphanol tartrate caused rats to consume more than 50% of their daily intake during the 6-h period postinjection; intake during the normal night feeding period was suppressed to maintain total daily intake equal to that of vehicle-injected rats. We conclude that stimulation of the opioid feeding system contributes to the overeating often associated with consumption of a high fat diet.

  9. Granulocyte defects and opioid receptors in chronic exposure to heroin or methadone in humans.

    PubMed

    Mazzone, A; Mazzucchelli, I; Fossati, G; Gritti, D; Fea, M; Ricevuti, G

    1994-11-01

    In order to elucidate better the immunological effect of opioid abuse in the absence of HIV infection as a confounding factor, granulocyte function was investigated in three groups of HIV-negative subjects, including 20 active parenteral heroin abusers (H), 20 long-term methadone-maintained former opiate abusers (M) and 20 healthy controls (C). Chemotaxis to N-formyl methionyl-leucyl-phenylalanine (fMLP), casein and activated plasma were markedly and similarly reduced (approx. 50%) in both H and M groups, as was true for superoxide production after fMLP and PMA stimulation, 47% decrease of C values. Polymorphonuclear (PMN) of H and M subjects also exhibited a very marked and similar reduction in the expression of CD11b/CD18 integrin receptors after fMLP treatment, with values that were less than 10% of those in controls, as observed by flow cytometry. In parallel, PMN of H and M individuals presented an approximately four-fold increase in opioid receptors numbers compared to controls, a significant inverse correlation existing between the increase in opiate receptors and defective chemotaxis. The possible mechanism underlying the observed changes in PMN of H and M individuals is discussed.

  10. Intratumor Heterogeneity in Breast Cancer.

    PubMed

    Beca, Francisco; Polyak, Kornelia

    2016-01-01

    Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field. PMID:26987535

  11. Unravelling mononuclear phagocyte heterogeneity

    PubMed Central

    Geissmann, Frédéric; Gordon, Siamon; Hume, David A.; Mowat, Allan M.; Randolph, Gwendalyn J.

    2011-01-01

    When Ralph Steinman and Zanvil Cohn first described dendritic cells (DCs) in 1973 it took many years to convince the immunology community that these cells were truly distinct from macrophages. Almost four decades later, the DC is regarded as the key initiator of adaptive immune responses; however, distinguishing DCs from macrophages still leads to confusion and debate in the field. Here, Nature Reviews Immunology asks five experts to discuss the issue of heterogeneity in the mononuclear phagocyte system and to give their opinion on the importance of defining these cells for future research. PMID:20467425

  12. Roles for lipid heterogeneity in immunoreceptor signaling.

    PubMed

    Holowka, David; Baird, Barbara

    2016-08-01

    Immune receptors that specifically recognize foreign antigens to activate leukocytes in adaptive immune responses belong to a family of multichain cell surface proteins. All of these contain immunoreceptor tyrosine-based activation motifs in one or more subunits that initiate signaling cascades following stimulated tyrosine phosphorylation by Src-family kinases. As highlighted in this review, lipids participate in this initial activation step, as well as in more downstream signaling steps. We summarize evidence for cholesterol-dependent ordered lipids serving to regulate the store-operated Ca(2+) channel, Orai1, and we describe the sensitivity of Orai1 coupling to the ER Ca(2+) sensor, STIM1, to inhibition by polyunsaturated fatty acids. Phosphoinositides play key roles in regulating STIM1-Orai1 coupling, as well as in the stimulated Ca(2+) oscillations that are a consequence of IgE receptor signaling in mast cells. They also participate in the coupling between the plasma membrane and the actin cytoskeleton, which regulates immune receptor responses in T cells, B cells, and mast cells, both positively and negatively, depending on the cellular context. Recent studies show that other phospholipids with mostly saturated acylation also participate in coupling between receptors and the actin cytoskeleton. Lipid heterogeneity is a central feature of the intimate relationship between the plasma membrane and the actin cytoskeleton. The detailed nature of these interactions and how they are dynamically regulated to initiate and propagate receptor-mediated cell signaling are challenging questions for further investigation. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID:26995463

  13. Unexpected effects of nalmefene, a new opiate antagonist, on the hypothalamic-pituitary-gonadal axis in the male rat.

    PubMed

    Limonta, P; Bardin, C W; Hahn, E F; Thau, R B

    1985-12-01

    In order to gain additional information on the role of brain opioid peptides in the regulation of the hypothalamic-pituitary-gonadal axis, we studied the effects of nalmefene, a new opiate antagonist, on gonadotropin and testosterone secretion in male rats. The results were compared with those obtained with naloxone, a well-studied antagonist. Acute injections of either nalmefene or naloxone (2 mg/kg) produced 4-fold increases in LH and testosterone secretion. In castrated male rats treated with testosterone propionate (TP), nalmefene (10 mg/kg) reversed the androgen negative feedback on LH secretion; surprisingly, when higher doses (25 and 50 mg/kg) were injected, the compound lost its ability to antagonize the testosterone-induced inhibition of LH levels. In contrast, naloxone was able to increase LH levels in TP-treated castrated rats even at the highest dose tested (50 mg/kg). Chronic administration of these antagonists resulted in suppression of the acute release of LH and T secretion in nalmefene-treated but not in naloxone-injected animals. These data are consistent with previous observations suggesting that opioid peptides a) exert a tonic inhibitory effect on LH and testosterone production and b) participate in the negative androgen-induced feedback control of LH secretion. Our results also show that the antagonistic action of nalmefene, but not naloxone, is reversed when higher doses are used or following chronic administration.

  14. [Possible role of positive reinforcement zones in the mechanisms of pain regulation and their relation to the endogenous opiate system].

    PubMed

    Burov, Iu V; Viglinskaia, I V; Zhukov, V N

    1987-05-01

    The consequences of self-stimulation reaction (RSS) to pain threshold in tail withdrawal test (55 degrees C) and naloxone effect have been investigated in tests, using male rats with chronically implanted electrodes into the hypothalamus (AP = 1.5, L = 1.5, H = 8.5) and suture dorsal nucleus (AP = 7.0, L = 0, H = 7.0) (coordinates according to Fifková atlas). It was established that right after RSS, pain threshold in both zones increased 2-2.5-fold and 30 min later reached the initial level. Naloxone injected before RSS increased pain thresholds and decreased RSS frequency from hypothalamus but failed to change these RSS parameters from suture dorsal nucleus. However, naloxone did not affect the increase in pain thresholds caused by RSS from both zones. Taking into account the fact that analgesia appearing after RSS from the anterior hypothalamus as well as from suture dorsal nucleus is not reversed by naloxone, it is suggested that positive reward zones activation partially realized by opioidergic mechanisms or having no connection with them may lead to the development of non-opiate type analgesia.

  15. Unexpected effects of nalmefene, a new opiate antagonist, on the hypothalamic-pituitary-gonadal axis in the male rat.

    PubMed

    Limonta, P; Bardin, C W; Hahn, E F; Thau, R B

    1985-12-01

    In order to gain additional information on the role of brain opioid peptides in the regulation of the hypothalamic-pituitary-gonadal axis, we studied the effects of nalmefene, a new opiate antagonist, on gonadotropin and testosterone secretion in male rats. The results were compared with those obtained with naloxone, a well-studied antagonist. Acute injections of either nalmefene or naloxone (2 mg/kg) produced 4-fold increases in LH and testosterone secretion. In castrated male rats treated with testosterone propionate (TP), nalmefene (10 mg/kg) reversed the androgen negative feedback on LH secretion; surprisingly, when higher doses (25 and 50 mg/kg) were injected, the compound lost its ability to antagonize the testosterone-induced inhibition of LH levels. In contrast, naloxone was able to increase LH levels in TP-treated castrated rats even at the highest dose tested (50 mg/kg). Chronic administration of these antagonists resulted in suppression of the acute release of LH and T secretion in nalmefene-treated but not in naloxone-injected animals. These data are consistent with previous observations suggesting that opioid peptides a) exert a tonic inhibitory effect on LH and testosterone production and b) participate in the negative androgen-induced feedback control of LH secretion. Our results also show that the antagonistic action of nalmefene, but not naloxone, is reversed when higher doses are used or following chronic administration. PMID:3842024

  16. Opiate-prostaglandin interactions in the regulation of insulin secretion from rat islets of Langerhans in vitro

    SciTech Connect

    Green, I.C.; Tadayyon, M.

    1988-01-01

    The inadequate insulin secretory response to glucose stimulation in non-insulin dependent diabetes has been attributed to many factors including high PGE/sub 2/ levels blunting the secretory response, and to the existence of inhibitory opiate activity in vivo. The purpose of the present work was to see if there was a connection between these two independent theories. Radioimmunoassayable PGE/sub 2/ in islets of Langerhans was found to be proportional to islet number and protein content and was typically 4 to 5pg/..mu..g islet protein. Indomethacin sodium salicylate and chlorpropamide all lowered islet PGE/sub 2/ levels and stimulated insulin release in vitro. Dynorphin stimulated insulin release at a concentration of 6 x 10/sup -9/M, while lowering islet PGE/sub 2/. Conversely, at a higher concentration, dynorphin had no stimulatory effect on insulin secretion and did not lower PGE/sub 2/ levels in islets or in the incubation media. The stimulatory effects of dynorphin and sodium salicylate on insulin secretion were blocked by exogenous PGE/sub 2/. PGE/sub 2/ at a lower concentration did not exert any inhibitory effect on dynorphin- or sodium salicylate-induced insulin release. This concentration of exogenous PGE/sub 2/ stimulated insulin release in the presence of 6mM glucose.

  17. A chance to stop and breathe: participants’ experiences in the North American Opiate Medication Initiative clinical trial

    PubMed Central

    2014-01-01

    Background The North American Opiate Medication Initiative (NAOMI) clinical trial compared the effectiveness of injectable diacetylmorphine (DAM) or hydromorphone (HDM) to oral methadone maintenance treatment (MMT). This study aimed to determine participants’ perceptions of treatment delivered in NAOMI. Methods A qualitative sub-study was conducted with 29 participants (12 female): 18 (62.1%) received injectable DAM or HDM and 11 (37.9%) received MMT. A phenomenological theoretical framework was used. Semi-structured interviews were audio-recorded and transcribed verbatim. A thematic analysis was used over successive phases and was driven by the semantic meanings of the data. Results Participants receiving injectable medications suggested that the supervised delivery model was stringent but provided valuable stability to their lives. Females discussed the adjustment required for the clinical setting, while males focused on the challenging clinic schedule and its impact on employment abilities. Participants receiving MMT described disappointment with being randomized to this treatment; however, positive aspects, including the quick titration time and availability of auxiliary services, were also discussed. Conclusion Treatment with injectable DAM (or HDM) is preferred by participants and considered effective in reducing the burden of opioid dependency. Engaging patients in research regarding their perceptions of treatment provides a comprehensive assessment of treatment needs and barriers. Clinical trial registration NCT00175357 PMID:25262567

  18. Comparison of personality traits in pedophiles, abstinent opiate addicts, and healthy controls: considering pedophilia as an addictive behavior.

    PubMed

    Cohen, Lisa J; Grebchenko, Yuli F; Steinfeld, Matthew; Frenda, Steven J; Galynker, Igor I

    2008-11-01

    To investigate the model of pedophilia as a disorder of addictive behavior, pedophiles and chemically addicted individuals were compared on personality traits potentially associated with impaired behavioral inhibition. Twenty-nine pedophiles, 25 opiate addicts (OA's), and 27 healthy controls were administered the Barratt Impulsivity Scale, Hare Psychopathy Checklist-Revised (PCL-R), and Structured Clinical Interview for DSM-V for Axis-II. OA's scored higher than either pedophiles or controls on the Barratt. Pedophiles and OA's scored higher than controls on all 3 Psychopathy Checklist-Revised scores but OA's scored marginally higher than pedophiles on factor 2 (behavioral) and total scores. On Structured Clinical Interview for DSM-V for Axis-II, pedophiles scored higher than controls on paranoid and schizoid scores whereas OA's did so on paranoid scores. Thus, both pedophiles and OA's may have elevated psychopathic traits and propensity toward cognitive distortions, as reflected in cluster A traits. Such similarities support the conceptualization of pedophilia as a behavioral addiction. Pedophiles may be less impulsive than OA's, however, and more prone toward cognitive distortions.

  19. Heterogeneous broadband network

    NASA Astrophysics Data System (ADS)

    Dittmann, Lars

    1995-11-01

    Although the vision for the future Integrated Broadband Communication Network (IBCN) is an all optical network, it is certain that for a long period to come, the network will remain very heterogeneous, with a mixture of different physical media (fiber, coax and twisted pair), transmission systems (PDH, SDH, ADSL) and transport protocols (TCP/IP, AAL/ATM, frame relay). In the current work towards the IBCN, the ATM concept is considered the generic network protocol for both public and private network, with the ability to use different underlying transmission protocols and, through adaptation protocols, provide the appropriate services (old as well as new) to the customer. One of the major difficulties of heterogeneous network is the restriction that is usually given by the lowest common denominator, e.g. in terms of single channel capacity. A possible way to overcome these limitations is by extending the ATM concept with a multilink capability, that allows us to use separate resources as one common. The improved flexibility obtained by this protocol extension further allows a real time optimization of network and call configuration, without any impact on the quality of service seen from the user. This paper describes an example of an ATM based multilink protocol that has been experimentally implemented within the RACE project 'STRATOSPHERIC'. The paper outlines the complexity of introducing an extra network functionality compared with the added value, such as an improved ability to recover an error due to a malfunctioning network component.

  20. Large epidemic thresholds emerge in heterogeneous networks of heterogeneous nodes

    NASA Astrophysics Data System (ADS)

    Yang, Hui; Tang, Ming; Gross, Thilo

    2015-08-01

    One of the famous results of network science states that networks with heterogeneous connectivity are more susceptible to epidemic spreading than their more homogeneous counterparts. In particular, in networks of identical nodes it has been shown that network heterogeneity, i.e. a broad degree distribution, can lower the epidemic threshold at which epidemics can invade the system. Network heterogeneity can thus allow diseases with lower transmission probabilities to persist and spread. However, it has been pointed out that networks in which the properties of nodes are intrinsically heterogeneous can be very resilient to disease spreading. Heterogeneity in structure can enhance or diminish the resilience of networks with heterogeneous nodes, depending on the correlations between the topological and intrinsic properties. Here, we consider a plausible scenario where people have intrinsic differences in susceptibility and adapt their social network structure to the presence of the disease. We show that the resilience of networks with heterogeneous connectivity can surpass those of networks with homogeneous connectivity. For epidemiology, this implies that network heterogeneity should not be studied in isolation, it is instead the heterogeneity of infection risk that determines the likelihood of outbreaks.

  1. Mu Opioids and Their Receptors: Evolution of a Concept

    PubMed Central

    Pan, Ying-Xian

    2013-01-01

    Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes—primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated. PMID:24076545

  2. Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence.

    PubMed

    Zan, Gui-Ying; Wang, Qian; Wang, Yu-Jun; Liu, Yao; Hang, Ai; Shu, Xiao-Hong; Liu, Jing-Gen

    2015-09-15

    The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/κ opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of κ opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/κ opioid receptor system, and shed light on the κ opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal.

  3. Disordered hyperuniform heterogeneous materials

    NASA Astrophysics Data System (ADS)

    Torquato, Salvatore

    2016-10-01

    Disordered hyperuniform many-body systems are distinguishable states of matter that lie between a crystal and liquid: they are like perfect crystals in the way they suppress large-scale density fluctuations and yet are like liquids or glasses in that they are statistically isotropic with no Bragg peaks. These systems play a vital role in a number of fundamental and applied problems: glass formation, jamming, rigidity, photonic and electronic band structure, localization of waves and excitations, self-organization, fluid dynamics, quantum systems, and pure mathematics. Much of what we know theoretically about disordered hyperuniform states of matter involves many-particle systems. In this paper, we derive new rigorous criteria that disordered hyperuniform two-phase heterogeneous materials must obey and explore their consequences. Two-phase heterogeneous media are ubiquitous; examples include composites and porous media, biological media, foams, polymer blends, granular media, cellular solids, and colloids. We begin by obtaining some results that apply to hyperuniform two-phase media in which one phase is a sphere packing in d-dimensional Euclidean space {{{R}}d} . Among other results, we rigorously establish the requirements for packings of spheres of different sizes to be ‘multihyperuniform’. We then consider hyperuniformity for general two-phase media in {{{R}}d} . Here we apply realizability conditions for an autocovariance function and its associated spectral density of a two-phase medium, and then incorporate hyperuniformity as a constraint in order to derive new conditions. We show that some functional forms can immediately be eliminated from consideration and identify other forms that are allowable. Specific examples and counterexamples are described. Contact is made with well-known microstructural models (e.g. overlapping spheres and checkerboards) as well as irregular phase-separation and Turing-type patterns. We also ascertain a family of

  4. Disordered hyperuniform heterogeneous materials.

    PubMed

    Torquato, Salvatore

    2016-10-19

    Disordered hyperuniform many-body systems are distinguishable states of matter that lie between a crystal and liquid: they are like perfect crystals in the way they suppress large-scale density fluctuations and yet are like liquids or glasses in that they are statistically isotropic with no Bragg peaks. These systems play a vital role in a number of fundamental and applied problems: glass formation, jamming, rigidity, photonic and electronic band structure, localization of waves and excitations, self-organization, fluid dynamics, quantum systems, and pure mathematics. Much of what we know theoretically about disordered hyperuniform states of matter involves many-particle systems. In this paper, we derive new rigorous criteria that disordered hyperuniform two-phase heterogeneous materials must obey and explore their consequences. Two-phase heterogeneous media are ubiquitous; examples include composites and porous media, biological media, foams, polymer blends, granular media, cellular solids, and colloids. We begin by obtaining some results that apply to hyperuniform two-phase media in which one phase is a sphere packing in d-dimensional Euclidean space [Formula: see text]. Among other results, we rigorously establish the requirements for packings of spheres of different sizes to be 'multihyperuniform'. We then consider hyperuniformity for general two-phase media in [Formula: see text]. Here we apply realizability conditions for an autocovariance function and its associated spectral density of a two-phase medium, and then incorporate hyperuniformity as a constraint in order to derive new conditions. We show that some functional forms can immediately be eliminated from consideration and identify other forms that are allowable. Specific examples and counterexamples are described. Contact is made with well-known microstructural models (e.g. overlapping spheres and checkerboards) as well as irregular phase-separation and Turing-type patterns. We also ascertain a family

  5. Heterogeneity in Waardenburg syndrome.

    PubMed Central

    Hageman, M J; Delleman, J W

    1977-01-01

    Heterogeneity of Waardenburg syndrome is demonstrated in a review of 1,285 patients from the literature and 34 previously unreported patients in five families in the Netherlands. The syndrome seems to consist of two genetically distinct entities that can be differentiated clinically: type I, Waardenburg syndrome with dystopia canthorum; and type II, Waardenburg syndrome without dystopia canthorum. Both types have an autosomal dominant mode of inheritance. The incidence of bilateral deafness in the two types of the syndrome was found in one-fourth with type I and about half of the patients with type II. This difference has important consequences for genetic counseling. Images Fig. 7 Fig. 8 Fig. 9 PMID:331943

  6. Multipartite entanglement in heterogeneous systems

    NASA Astrophysics Data System (ADS)

    Goyeneche, Dardo; Bielawski, Jakub; Życzkowski, Karol

    2016-07-01

    Heterogeneous bipartite quantum pure states, composed of two subsystems with a different number of levels, cannot have both reductions maximally mixed. In this work, we demonstrate the existence of a wide range of highly entangled states of heterogeneous multipartite systems consisting of N >2 parties such that every reduction to one and two parties is maximally mixed. Two constructions of generating genuinely multipartite maximally entangled states of heterogeneous systems for an arbitrary number of subsystems are presented. Such states are related to quantum error correction codes over mixed alphabets and mixed orthogonal arrays. Additionally, we show the advantages of considering heterogeneous systems in practical implementations of multipartite steering.

  7. On-line liquid chromatography/tandem mass spectrometry simultaneous determination of opiates, cocainics and amphetamines in dried blood spots.

    PubMed

    Saussereau, E; Lacroix, C; Gaulier, J M; Goulle, J P

    2012-02-15

    A novel approach has been developed for the illicit drugs quantitative determination using dried blood spots (DBS) on filter paper. The illicit drugs tested were opiates (morphine and its 3- and 6-glucuronide metabolites, codeine, 6-monoacetylmorphine), cocainics (ecgonine methylester, benzoylecgonine, cocaine, cocaethylene) and amphetamines (amphetamine, methamphetamine, MDA, MDMA, MDEA). The described method, requiring a small blood volume, is based on high performance liquid chromatography coupled to tandem mass spectrometry using on-line extraction. A Whatman card 903 was spotted with 30μL of whole blood and left overnight to dry at room temperature. A 3-mm diameter disk was removed using a manual punch, suspended in 150μL of water for 10min with ultrasonication, and then 100μL was injected in the on-line LC-MS/MS system. An Oasis HLB was used as an extraction column and a C18 Atlantis as an analytical column. The chromatographic cycle was performed with 20mM ammonium formate buffer (pH 2.8) (solvent A) and acetonitrile/solvent A (90:10, v/v) gradient in 16min. Detection was performed in positive electrospray ionization mode (ESI+) with a Quattro Micro (Waters). Recoveries of all analytes were up to 80%. DBS were stored in duplicate at 4°C and -20°C for up to 6 months. Illicit drugs seemed to be much more stabled at -20°C. Furthermore, it was tested whether analysis of DBS may be as reliable as that of whole blood investigating authentic samples; significant correlations were obtained. This DBS assay has potential as rapid, sensitive and inexpensive option for the illicit drugs determination in small blood volumes, which seems of great interest in suspected cases of driving under the influence of drugs. PMID:22281234

  8. Evidence of anhedonia and differential reward processing in prefrontal cortex among post-withdrawal patients with prescription opiate dependence.

    PubMed

    Huhn, A S; Meyer, R E; Harris, J D; Ayaz, H; Deneke, E; Stankoski, D M; Bunce, S C

    2016-05-01

    Anhedonia is an important but understudied element of a neuroadaptive model underlying vulnerability to relapse in opioid dependence. Previous research using fMRI has shown reduced activation to pleasant stimuli in rostral prefrontal cortex among heroin-dependent patients in early recovery. This study evaluated the presence of anhedonia among recently withdrawn prescription opiate dependent patients (PODP) in residential treatment compared to control subjects. Anhedonia was assessed using self-report, affect-modulated startle response (AMSR), and a cue reactivity task during which participant's rostral prefrontal cortex (RPFC) and ventrolateral prefrontal cortex (VLPFC) was monitored with functional near infrared spectroscopy (fNIRS). The cue reactivity task included three distinct categories of natural reward stimuli: highly palatable food, positive social situations, and intimate (non-erotic) interactions. PODP reported greater anhedonia on self-report (Snaith-Hamilton Pleasure Scale), and showed reduced hedonic response to positive stimuli in the AMSR task relative to controls. PODP also exhibited reduced neural activation in bilateral RPFC and left VLPFC in response to food images and reduced left VLPFC in response to images depicting positive social situations relative to controls. No differences were found for emotionally intimate stimuli. When patients were divided into groups based on the Snaith-Hamilton criteria for the presence or absence of anhedonia, patients endorsing anhedonia showed reduced neural responses to images depicting positive social stimuli and food relative to patients who did not endorse anhedonia. Activations were in areas of RPFC that support the retrieval of episodic memories. The results suggest the presence of anhedonia in a subsample of PODP. PMID:26711857

  9. Auditory cortex of the marmoset monkey - complex responses to tones and vocalizations under opiate anaesthesia in core and belt areas.

    PubMed

    Rajan, Ramesh; Dubaj, Vladimir; Reser, David H; Rosa, Marcello G P

    2013-03-01

    Many anaesthetics commonly used in auditory research severely depress cortical responses, particularly in the supragranular layers of the primary auditory cortex and in non-primary areas. This is particularly true when stimuli other than simple tones are presented. Although awake preparations allow better preservation of the neuronal responses, there is an inherent limitation to this approach whenever the physiological data need to be combined with histological reconstruction or anatomical tracing. Here we tested the efficacy of an opiate-based anaesthetic regime to study physiological responses in the primary auditory cortex and middle lateral belt area. Adult marmosets were anaesthetized using a combination of sufentanil (8 μg/kg/h, i.v.) and N2 O (70%). Unit activity was recorded throughout the cortical layers, in response to auditory stimuli presented binaurally. Stimuli consisted of a battery of tones presented at different intensities, as well as two marmoset calls ('Tsik' and 'Twitter'). In addition to robust monotonic and non-monotonic responses to tones, we found that the neuronal activity reflected various aspects of the calls, including 'on' and 'off' components, and temporal fluctuations. Both phasic and tonic activities, as well as excitatory and inhibitory components, were observed. Furthermore, a late component (100-250 ms post-offset) was apparent. Our results indicate that the sufentanil/N2 O combination allows better preservation of response patterns in both the core and belt auditory cortex, in comparison with anaesthetics usually employed in auditory physiology. This anaesthetic regime holds promise in enabling the physiological study of complex auditory responses in acute preparations, combined with detailed anatomical and histological investigation. PMID:23278961

  10. Simultaneous analysis of buprenorphine, methadone, cocaine, opiates and nicotine metabolites in sweat by liquid chromatography tandem mass spectrometry.

    PubMed

    Concheiro, Marta; Shakleya, Diaa M; Huestis, Marilyn A

    2011-04-01

    A liquid chromatography tandem mass spectrometry method for buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine, ecgonine methyl ester (EME), morphine, codeine, 6-acetylmorphine, heroin, 6-acetylcodeine, cotinine, and trans-3'-hydroxycotinine quantification in sweat was developed and comprehensively validated. Sweat patches were mixed with 6 mL acetate buffer at pH 4.5, and supernatant extracted with Strata-XC-cartridges. Reverse-phase separation was achieved with a gradient mobile phase of 0.1% formic acid and acetonitrile in 15 min. Quantification was achieved by multiple reaction monitoring of two transitions per compound. The assay was a linear 1-1,000 ng/patch, except EME 5-1,000 ng/patch. Intra-, inter-day and total imprecision were <10.1%CV, analytical recovery 87.2-107.7%, extraction efficiency 35.3-160.9%, and process efficiency 25.5-91.7%. Ion suppression was detected for EME (-63.3%) and EDDP (-60.4%), and enhancement for NBUP (42.6%). Deuterated internal standards compensated for these effects. No carryover was detected, and all analytes were stable for 24 h at 22 °C, 72 h at 4 °C, and after three freeze/thaw cycles. The method was applied to weekly sweat patches from an opioid-dependent BUP-maintained pregnant woman; 75.0% of sweat patches were positive for BUP, 93.8% for cocaine, 37.5% for opiates, 6.3% for methadone and all for tobacco biomarkers. This method permits a fast and simultaneous quantification of 14 drugs and metabolites in sweat patches, with good selectivity and sensitivity. PMID:21125263

  11. Simultaneous analysis of buprenorphine, methadone, cocaine, opiates and nicotine metabolites in sweat by liquid chromatography tandem mass spectrometry

    PubMed Central

    Concheiro, Marta; Shakleya, Diaa M.

    2013-01-01

    A liquid chromatography tandem mass spectrometry method for buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine, ecgonine methyl ester (EME), morphine, codeine, 6-acetylmorphine, heroin, 6-acetylcodeine, cotinine, and trans-3′-hydroxycotinine quantification in sweat was developed and comprehensively validated. Sweat patches were mixed with 6 mL acetate buffer at pH 4.5, and supernatant extracted with Strata-XC-cartridges. Reverse-phase separation was achieved with a gradient mobile phase of 0.1% formic acid and acetonitrile in 15 min. Quantification was achieved by multiple reaction monitoring of two transitions per compound. The assay was a linear 1–1,000 ng/patch, except EME 5–1,000 ng/patch. Intra-, inter-day and total imprecision were <10.1%CV, analytical recovery 87.2–107.7%, extraction efficiency 35.3– 160.9%, and process efficiency 25.5–91.7%. Ion suppression was detected for EME (−63.3%) and EDDP (−60.4%), and enhancement for NBUP (42.6%). Deuterated internal standards compensated for these effects. No carryover was detected, and all analytes were stable for 24 h at 22 °C, 72 h at 4 °C, and after three freeze/thaw cycles. The method was applied to weekly sweat patches from an opioid-dependent BUP-maintained pregnant woman; 75.0% of sweat patches were positive for BUP, 93.8% for cocaine, 37.5% for opiates, 6.3% for methadone and all for tobacco biomarkers. This method permits a fast and simultaneous quantification of 14 drugs and metabolites in sweat patches, with good selectivity and sensitivity. PMID:21125263

  12. Unambiguous characterization of analytical markers in complex, seized opiate samples using an enhanced ion mobility trace detector-mass spectrometer.

    PubMed

    Liuni, Peter; Romanov, Vladimir; Binette, Marie-Josée; Zaknoun, Hafid; Tam, Maggie; Pilon, Pierre; Hendrikse, Jan; Wilson, Derek J

    2014-11-01

    Ion mobility spectroscopy (IMS)-based trace-compound detectors (TCDs) are powerful and widely implemented tools for the detection of illicit substances. They combine high sensitivity, reproducibility, rapid analysis time, and resistance to dirt with an acceptable false alarm rate. The analytical specificity of TCD-IMS instruments for a given analyte depends strongly on a detailed knowledge of the ion chemistry involved, as well as the ability to translate this knowledge into field-robust analytical methods. In this work, we introduce an enhanced hybrid TCD-IMS/mass spectrometer (TCD-IMS/MS) that combines the strengths of ion-mobility-based target compound detection with unambiguous identification by tandem MS. Building on earlier efforts along these lines (Kozole et al., Anal. Chem. 2011, 83, 8596-8603), the current instrument is capable of positive and negative-mode analyses with tightly controlled gating between the IMS and MS modules and direct measurement of ion mobility profiles. We demonstrate the unique capabilities of this instrument using four samples of opium seized by the Canada Border Services Agency (CBSA), consisting of a mixture of opioid alkaloids and other naturally occurring compounds typically found in these samples. Although many analytical methods have been developed for analyzing naturally occurring opiates, this is the first detailed ion mobility study on seized opium samples. This work demonstrates all available analytical modes for the new IMS-MS system including "single-gate", "dual-gate", MS/MS, and precursor ion scan methods. Using a combination of these modes, we unambiguously identify all signals in the IMS spectra, including previously uncharacterized minor peaks arising from compounds that are common in raw opium. PMID:25302672

  13. Political Jurisdictions in Heterogeneous Communities.

    ERIC Educational Resources Information Center

    Alesina, Alberto; Baqir, Reza; Hoxby, Caroline

    2004-01-01

    We investigate whether political jurisdictions form in response to the trade-off between economies of scale and the costs of a heterogeneous population. We consider heterogeneity in income, race, ethnicity, and religion, and we test the model using American school districts, school attendance areas, municipalities, and special districts. We find…

  14. Query Expansion Using Heterogeneous Thesauri.

    ERIC Educational Resources Information Center

    Mandala, Rila; Tokunaga, Takenobu; Tanaka, Hozumi

    2000-01-01

    Proposes a method to improve the performance of information retrieval systems by expanding queries using heterogeneous thesauri. Experiments show that using heterogeneous thesauri with an appropriate weighting method results in better retrieval performance than using only one type of thesaurus. (Author/LRW)

  15. Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin.

    PubMed

    Feng, Yue-Mei; Jia, Yun-Fang; Su, Ling-Yan; Wang, Dong; Lv, Li; Xu, Lin; Yao, Yong-Gang

    2013-09-01

    Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin.

  16. Reduced emotional signs of opiate withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake

    PubMed Central

    Radke, Anna K.; Holtz, Nathan A.; Gewirtz, Jonathan C.; Carroll, Marilyn E.

    2013-01-01

    Rationale Rats bred for high (HiS) and low (LoS) saccharin intake exhibit divergent behavioral responses to multiple drugs of abuse, with HiS rats displaying greater vulnerability to drug taking. Previous research indicates that this effect may be due to increased sensitivity to reward in HiS rats and to the aversive effects of acute drug administration in LoS rats. Objective The current study investigated whether HiS and LoS rats also exhibit different behavioral signs of withdrawal following one or repeated opiate exposures. Methods Emotional signs of opiate withdrawal were assessed with potentiation of the acoustic startle reflex and conditioned place aversion (CPA) in male and female HiS and LoS rats. Startle was measured before and 4 h after a 10 mg/kg injection of morphine on days 1, 2, and 7 of opiate exposure. CPA was induced with a two-day, naloxone-precipitated conditioning paradigm. Somatic signs of withdrawal and weight loss were used also measured. Results Male and female LoS rats exhibited lower startle potentiation than HiS rats on the seventh day of morphine exposure. LoS male rats also failed to develop a CPA to morphine withdrawal. No differences in physical withdrawal signs were observed between HiS and LoS rats, but males of both lines had more physical signs of withdrawal than females. Conclusions These results suggest that LoS rats are less vulnerable to the negative emotional effects of morphine withdrawal than HiS rats. A less severe withdrawal syndrome may contribute to decreased levels of drug taking in the LoS line. PMID:23254375

  17. Alpha2C-adrenoceptor Del322-325 polymorphism and risk of psychiatric disorders: significant association with opiate abuse and dependence.

    PubMed

    Rivero, Guadalupe; Martín-Guerrero, Idoia; de Prado, Elena; Gabilondo, Ane M; Callado, Luis F; García-Sevilla, Jesús A; García-Orad, África; Meana, J Javier

    2016-06-01

    Objectives α2C-adrenoceptors (α2C-AR) are involved in behavioural responses relevant to psychiatric disorders and suicide completion. The genetic polymorphism α2CDel322-325-AR confers a loss-of-function phenotype. Functional human studies have associated α2CDel322-325-AR polymorphism with major depression pathophysiology. The aim of this study was to analyse, for the first time, the association of α2CDel322-325-AR polymorphism with suicide completion and with related psychiatric disorders: major depression, schizophrenia, opiate and alcohol abuse and dependence. Methods Post-mortem brain DNA was extracted (n = 516) and genotyping performed by HaeIII restriction endonuclease digestion of PCR products and DNA fragment analysis on capillary sequencer. Amplified products were sequenced to confirm the presence of the polymorphism. Results The frequency of α2CDel322-325-AR in suicide (9%, n = 236) and non-suicide victims (11%, n = 280) was similar. Genotype frequencies for the α2CDel322-325-AR polymorphism in depressed (15%, n = 39) and schizophrenic subjects (18%, n = 39) were higher than in controls (7%, n = 187), but these differences did not reach statistical significance (P = 0.125 and P = 0.063, respectively). A selective and significant association of α2CDel322-325-AR polymorphism with opiate abuse and dependence was found (23%, n = 35, P = 0.011). Conclusions Our results indicate that α2CDel322-325-AR may play a role in the pathophysiology of opiate abuse and dependence and raise the interest for larger genetic associative studies. PMID:27007576

  18. Alpha2C-adrenoceptor Del322-325 polymorphism and risk of psychiatric disorders: significant association with opiate abuse and dependence.

    PubMed

    Rivero, Guadalupe; Martín-Guerrero, Idoia; de Prado, Elena; Gabilondo, Ane M; Callado, Luis F; García-Sevilla, Jesús A; García-Orad, África; Meana, J Javier

    2016-06-01

    Objectives α2C-adrenoceptors (α2C-AR) are involved in behavioural responses relevant to psychiatric disorders and suicide completion. The genetic polymorphism α2CDel322-325-AR confers a loss-of-function phenotype. Functional human studies have associated α2CDel322-325-AR polymorphism with major depression pathophysiology. The aim of this study was to analyse, for the first time, the association of α2CDel322-325-AR polymorphism with suicide completion and with related psychiatric disorders: major depression, schizophrenia, opiate and alcohol abuse and dependence. Methods Post-mortem brain DNA was extracted (n = 516) and genotyping performed by HaeIII restriction endonuclease digestion of PCR products and DNA fragment analysis on capillary sequencer. Amplified products were sequenced to confirm the presence of the polymorphism. Results The frequency of α2CDel322-325-AR in suicide (9%, n = 236) and non-suicide victims (11%, n = 280) was similar. Genotype frequencies for the α2CDel322-325-AR polymorphism in depressed (15%, n = 39) and schizophrenic subjects (18%, n = 39) were higher than in controls (7%, n = 187), but these differences did not reach statistical significance (P = 0.125 and P = 0.063, respectively). A selective and significant association of α2CDel322-325-AR polymorphism with opiate abuse and dependence was found (23%, n = 35, P = 0.011). Conclusions Our results indicate that α2CDel322-325-AR may play a role in the pathophysiology of opiate abuse and dependence and raise the interest for larger genetic associative studies.

  19. Reference Point Heterogeneity.

    PubMed

    Terzi, Ayse; Koedijk, Kees; Noussair, Charles N; Pownall, Rachel

    2016-01-01

    It is well-established that, when confronted with a decision to be taken under risk, individuals use reference payoff levels as important inputs. The purpose of this paper is to study which reference points characterize decisions in a setting in which there are several plausible reference levels of payoff. We report an experiment, in which we investigate which of four potential reference points: (1) a population average payoff level, (2) the announced expected payoff of peers in a similar decision situation, (3) a historical average level of earnings that others have received in the same task, and (4) an announced anticipated individual payoff level, best describes decisions in a decontextualized risky decision making task. We find heterogeneity among individuals in the reference points they employ. The population average payoff level is the modal reference point, followed by experimenter's stated expectation of a participant's individual earnings, followed in turn by the average earnings of other participants in previous sessions of the same experiment. A sizeable share of individuals show multiple reference points simultaneously. The reference point that best fits the choices of the individual is not affected by a shock to her income. PMID:27672374

  20. Reference Point Heterogeneity

    PubMed Central

    Terzi, Ayse; Koedijk, Kees; Noussair, Charles N.; Pownall, Rachel

    2016-01-01

    It is well-established that, when confronted with a decision to be taken under risk, individuals use reference payoff levels as important inputs. The purpose of this paper is to study which reference points characterize decisions in a setting in which there are several plausible reference levels of payoff. We report an experiment, in which we investigate which of four potential reference points: (1) a population average payoff level, (2) the announced expected payoff of peers in a similar decision situation, (3) a historical average level of earnings that others have received in the same task, and (4) an announced anticipated individual payoff level, best describes decisions in a decontextualized risky decision making task. We find heterogeneity among individuals in the reference points they employ. The population average payoff level is the modal reference point, followed by experimenter's stated expectation of a participant's individual earnings, followed in turn by the average earnings of other participants in previous sessions of the same experiment. A sizeable share of individuals show multiple reference points simultaneously. The reference point that best fits the choices of the individual is not affected by a shock to her income. PMID:27672374

  1. Heterogeneous recording media

    NASA Astrophysics Data System (ADS)

    Sukhanov, Vitaly I.

    1991-02-01

    The paper summarizes the results of investigations performed to obtain deep 3-D holograms with 102 i0 mkm physical thickness allowing the postexposure amplification and the a posteriori changing of the grating parameters. This aim has been achieved by developing heterogeneous systems on the basis of porous glass with light-sensitive compositions introduced into it. 1. INTRODUCTION. LIGHT-SENSITIVE MEDIA FOR 3-D HOLOGRAMS RECORDING. The 3-D holograms have many useful properties: very high diffraction efficiency angular and spectral selectivity but low level of noise. It shoud be noted that in this case deep 3-D holograms are dealt with whose physical thickness is as high as 102 -i mkm. Such hologram recording is usually done using homogeneous light-sensitive media for example dyed acid-halide and electrooptical crystals photochrome glass photostructurized polimer compositions and so on. The nature of photophisical and photochemical processes responsible for the light sensitivity of these materials exclude the possibility of post-exposure treatment. This does not allow to enhance the recorded holograms and considerably hampers their fixing or makes it practically impossible. The object of our work is to create the media which are quite suitable for two-stage processes of the deep hologram formation with post-exposure processing. Such material must satisfy the following requirements: a)they must have high permeability for the developing substances in order to make the development duration suitable for practical applications b)they must be shrinkproof to prevent deformation of the

  2. On Heterogeneous Covert Networks

    NASA Astrophysics Data System (ADS)

    Lindelauf, Roy; Borm, Peter; Hamers, Herbert

    Covert organizations are constantly faced with a tradeoff between secrecy and operational efficiency. Lindelauf, Borm and Hamers [13] developed a theoretical framework to determine optimal homogeneous networks taking the above mentioned considerations explicitly into account. In this paper this framework is put to the test by applying it to the 2002 Jemaah Islamiyah Bali bombing. It is found that most aspects of this covert network can be explained by the theoretical framework. Some interactions however provide a higher risk to the network than others. The theoretical framework on covert networks is extended to accommodate for such heterogeneous interactions. Given a network structure the optimal location of one risky interaction is established. It is shown that the pair of individuals in the organization that should conduct the interaction that presents the highest risk to the organization, is the pair that is the least connected to the remainder of the network. Furthermore, optimal networks given a single risky interaction are approximated and compared. When choosing among a path, star and ring graph it is found that for low order graphs the path graph is best. When increasing the order of graphs under consideration a transition occurs such that the star graph becomes best. It is found that the higher the risk a single interaction presents to the covert network the later this transition from path to star graph occurs.

  3. Reference Point Heterogeneity

    PubMed Central

    Terzi, Ayse; Koedijk, Kees; Noussair, Charles N.; Pownall, Rachel

    2016-01-01

    It is well-established that, when confronted with a decision to be taken under risk, individuals use reference payoff levels as important inputs. The purpose of this paper is to study which reference points characterize decisions in a setting in which there are several plausible reference levels of payoff. We report an experiment, in which we investigate which of four potential reference points: (1) a population average payoff level, (2) the announced expected payoff of peers in a similar decision situation, (3) a historical average level of earnings that others have received in the same task, and (4) an announced anticipated individual payoff level, best describes decisions in a decontextualized risky decision making task. We find heterogeneity among individuals in the reference points they employ. The population average payoff level is the modal reference point, followed by experimenter's stated expectation of a participant's individual earnings, followed in turn by the average earnings of other participants in previous sessions of the same experiment. A sizeable share of individuals show multiple reference points simultaneously. The reference point that best fits the choices of the individual is not affected by a shock to her income.

  4. Thermal tolerance reduces hyperthermia-induced disruption of working memory: a role for endogenous opiates?

    PubMed

    Mickley, G A; Cobb, B L

    1998-03-01

    Previous reports indicate that microwave-induced hyperthermia can impair learning and memory. Here, we report that preexposure to a single 20-min period of hyperthermia can produce thermal tolerance and, thereby, attenuate future physiological and behavioral reactions to heating. Because endogenous opioids have been implicated in thermoregulation and reactions to microwave exposure, we also determined how opioid receptor antagonism might modulate these effects. In an initial experiment, rats were exposed daily, over 5 successive days, to 600-MHz microwaves (at a whole-body specific absorption rate of 9.3 W/kg) or sham exposed. In animals exposed to microwaves, thermal tolerance was evidenced by declining rectal temperatures over time. Temperature reductions following microwave exposure were prominent after a single previous exposure. Therefore, in a second study, a single hyperthermic episode was used to induce thermal tolerance. On Day 1, rats were either exposed, over a 20-min period, to 600-MHz microwaves (at a whole-body specific absorption rate of 9.3 W/kg) or sham exposed. Just prior to radiation/sham-radiation treatment, rats received either saline or naltrexone (0.1 or 10 mg/kg, intraperitoneally (i.p.)). The following day (Day 2), rats were either microwave or sham exposed and tested on a task which measures the relative time subjects explore a familiar versus a novel stimulus object. Normothermic rats spend significantly more time in contact with new environmental components and less time with familiar objects. Brain (dura) and rectal temperatures were recorded on both days of the study. Microwave exposure produced a reliable hyperthermia which was significantly lower (on Day 2) in rats receiving repeated treatments (tolerant group). On the behavioral test, rats exposed only once to microwave-induced hyperthermia (nontolerant group) exhibited significantly different patterns of object discrimination than did tolerant or sham-exposed animals. Sham

  5. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells.

    PubMed

    Tomasello, E; Bléry, M; Vély, F; Vivier, E

    2000-04-01

    Despite the absence of antigen-specific receptors at their surface, NK cells can selectively eliminate virus-infected cells, tumor cells and allogenic cells. A dynamic and precisely coordinated balance between activating and inhibitory receptors governs NK cell activation programs. Multiple activating and inhibitory NK cell surface molecules have been described, a group of them acting as receptors for MHC class I molecules. In spite of their heterogeneity, activating NK cell receptors present remarkable structural and functional homologies with T cell- and B cell-antigen receptors. Inhibitory NK cell receptors operate at early stages of activating cascades by recruiting protein tyrosine phosphatases via intra- cytoplasmic motifs (ITIM), a strategy which is widely conserved in hematopoietic and non-hematopoietic cells.

  6. Contusive spinal cord injury up regulates mu-opioid receptor (mor) gene expression in the brain and down regulates its expression in the spinal cord: possible implications in spinal cord injury research.

    PubMed

    Michael, Felicia Mary; Mohapatra, Alok Nath; Venkitasamy, Lavanya; Chandrasekar, Kirubhanand; Seldon, Tenzin; Venkatachalam, Sankar

    2015-09-01

    Traumatic spinal cord injury (SCI) is one of the dreaded neurological conditions and finding a cure for it has been a hot area of research. Naloxone - a mu-opiate receptor (mor) antagonist was considered for SCI treatment based on its positive effects under shock conditions. In contrary to animal studies based reports about the potential benefits of naloxone in treating SCI, a large scale clinical trial [National Acute Spinal Cord Injury Study II (NASCIS II)] conducted in USA failed to witness any effectiveness. The inconsistency noticed was intriguing. Therefore, the objective of the present study was to re-examine the role of naloxone in treating SCI using a highly standardised Multicenter Animal Spinal Cord Injury Study (MASCIS) animal model of contusive SCI. Results indicated that naloxone produced negligible and insignificant neuroprotection. In an attempt to understand the cause for the failure, it was found that mu-opioid receptor (mor) gene expression was upregulated in the brain but was down regulated in the spinal cord after contusive SCI. Given that the beneficial effects of naloxone are through its action on the mor, the results indicate that unlike the brain, spinal cord might not be bracing to utilise the opiate system in the repair process. This could possibly explain the failure of naloxone treatment in NASCIS II. To conclude, opiate antagonists like naloxone may be neuroprotective for treating traumatic brain injuries, but not for traumatic/contusive spinal cord injuries. PMID:26039701

  7. Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents.

    PubMed

    Álvaro-Bartolomé, M; García-Sevilla, J A

    2013-09-01

    The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB1 receptor protein in the prefrontal cortex (PFC) was reduced (-44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB1 receptors and GRK2/3/5 (-26% to -30%) indicated receptor desensitization. CB2 receptor protein was not significantly altered in the PFC of cocacine addicts. Chronic cocaine in mice and rats also reduced CB1 receptor protein (-41% and -80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB1 receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.

  8. Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents.

    PubMed

    Álvaro-Bartolomé, M; García-Sevilla, J A

    2013-09-01

    The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB1 receptor protein in the prefrontal cortex (PFC) was reduced (-44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB1 receptors and GRK2/3/5 (-26% to -30%) indicated receptor desensitization. CB2 receptor protein was not significantly altered in the PFC of cocacine addicts. Chronic cocaine in mice and rats also reduced CB1 receptor protein (-41% and -80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB1 receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts. PMID:23727505

  9. Node assignment in heterogeneous computing

    NASA Technical Reports Server (NTRS)

    Som, Sukhamoy

    1993-01-01

    A number of node assignment schemes, both static and dynamic, are explored for the Algorithm to Architecture Mapping Model (ATAMM). The architecture under consideration consists of heterogeneous processors and implements dataflow models of real-time applications. Terminology is developed for heterogeneous computing. New definitions are added to the ATAMM for token and assignment classifications. It is proved that a periodic execution is possible for dataflow graphs. Assignment algorithms are developed and proved. A design procedure is described for satisfying an objective function in an heterogeneous architecture. Several examples are provided for illustration.

  10. Morphine-induced trafficking of a mu-opioid receptor interacting protein in rat locus coeruleus neurons

    PubMed Central

    Jaremko, Kellie M.; Thompson, Nicholas L.; Reyes, Beverly A. S.; Jin, Jay; Ebersole, Brittany; Jenney, Christopher B.; Grigson, Patricia S.; Levenson, Robert; Berrettini, Wade H.; Van Bockstaele, Elisabeth J.

    2014-01-01

    Opiate addiction is a devastating health problem, with approximately 2 million people currently addicted to heroin or non-medical prescription opiates in the United States alone. In neurons, adaptations in cell signaling cascades develop following opioid actions at the mu opioid receptor (MOR). A novel putative target for intervention involves interacting proteins that may regulate trafficking of MOR. Morphine has been shown to induce a re-distribution of a MOR-interacting protein Wntless (WLS, a transport molecule necessary for secretion of neurotrophic Wnt proteins), from cytoplasmic to membrane compartments in rat striatal neurons. Given its opiate-sensitivity and its well-characterized molecular and cellular adaptations to morphine exposure, we investigated the anatomical distribution of WLS and MOR in the rat locus coeruleus (LC)-norepinephrine (NE) system. Dual immunofluorescence microscopy was used to test the hypothesis that WLS is localized to noradrenergic neurons of the LC and that WLS and MOR co-exist in common LC somatodendritic processes, providing an anatomical substrate for their putative interactions. We also hypothesized that morphine would influence WLS distribution in the LC. Rats received saline, morphine or the opiate agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), and tissue sections through the LC were processed for immunogold-silver detection of WLS and MOR. Statistical analysis showed a significant re-distribution of WLS to the plasma membrane following morphine treatment in addition to an increase in the proximity of gold-silver labels for MOR and WLS. Following DAMGO treatment, MOR and WLS were predominantly localized within the cytoplasmic compartment when compared to morphine and control. In a separate cohort of rats, brains were obtained from saline-treated or heroin self-administering male rats for pulldown co-immunoprecipitation studies. Results showed an increased association of WLS and MOR following heroin exposure. As

  11. Development and validation of a single LC-MS/MS assay following SPE for simultaneous hair analysis of amphetamines, opiates, cocaine and metabolites.

    PubMed

    Imbert, L; Dulaurent, S; Mercerolle, M; Morichon, J; Lachâtre, G; Gaulier, J-M

    2014-01-01

    The two major challenges in hair analysis are the limited amount of samples usually available and the low targeted concentrations. To overcome these limitations, a liquid chromatography-electrospray-tandem mass spectrometry method (LC-ESI-MS/MS) allowing the simultaneous analysis of 17 amphetamines (amphetamine, BDB, m-CPP, dexfenfluramine, DOB, DOM, ephedrine, MBDB, MDA, MDEA, MDMA, methamphetamine, methylphenidate, 4-MTA, norephedrine, norfenfluramine and PMA), 5 opiates (morphine, codeine, heroin, ethylmorphine, and 6AM), cocaine and 5 metabolites [ecgonine methyl ester (EME), benzoylecgonine (BZE), anhydroecgonine methyl ester (AME), cocaethylene, and norcocaine] has been developed. The validation procedure included linearity, intra-day and inter-day variability and accuracy for 5 days (5 replicates at 3 concentration levels). Proficiency studies were used to check the accuracy of the method. As a result, all amphetamines, opiates and cocaine derivatives were satisfactory identified by 2 MRM transitions in 15 min. Calibration curves were performed by a quadratic 1/X weighted regression. The calibration model fits from 0.05 to 10 ng/mg. The limits of detection (LODs) range between 0.005 and 0.030 ng/mg. Precision has been checked by intra-day and inter-day RSD, and associated relative bias, which were lower than 25% for the limits of quantifications (LOQs) and lower than 20% for the other levels tested. This method was routinely applied to hair samples: two positive results of adult drug addicts are presented.

  12. Development and validation of a single LC-MS/MS assay following SPE for simultaneous hair analysis of amphetamines, opiates, cocaine and metabolites.

    PubMed

    Imbert, L; Dulaurent, S; Mercerolle, M; Morichon, J; Lachâtre, G; Gaulier, J-M

    2014-01-01

    The two major challenges in hair analysis are the limited amount of samples usually available and the low targeted concentrations. To overcome these limitations, a liquid chromatography-electrospray-tandem mass spectrometry method (LC-ESI-MS/MS) allowing the simultaneous analysis of 17 amphetamines (amphetamine, BDB, m-CPP, dexfenfluramine, DOB, DOM, ephedrine, MBDB, MDA, MDEA, MDMA, methamphetamine, methylphenidate, 4-MTA, norephedrine, norfenfluramine and PMA), 5 opiates (morphine, codeine, heroin, ethylmorphine, and 6AM), cocaine and 5 metabolites [ecgonine methyl ester (EME), benzoylecgonine (BZE), anhydroecgonine methyl ester (AME), cocaethylene, and norcocaine] has been developed. The validation procedure included linearity, intra-day and inter-day variability and accuracy for 5 days (5 replicates at 3 concentration levels). Proficiency studies were used to check the accuracy of the method. As a result, all amphetamines, opiates and cocaine derivatives were satisfactory identified by 2 MRM transitions in 15 min. Calibration curves were performed by a quadratic 1/X weighted regression. The calibration model fits from 0.05 to 10 ng/mg. The limits of detection (LODs) range between 0.005 and 0.030 ng/mg. Precision has been checked by intra-day and inter-day RSD, and associated relative bias, which were lower than 25% for the limits of quantifications (LOQs) and lower than 20% for the other levels tested. This method was routinely applied to hair samples: two positive results of adult drug addicts are presented. PMID:24378313

  13. Determination of opiates in whole blood and vitreous humor: a study of the matrix effect and an experimental design to optimize conditions for the enzymatic hydrolysis of glucuronides.

    PubMed

    Sanches, Livia Rentas; Seulin, Saskia Carolina; Leyton, Vilma; Paranhos, Beatriz Aparecida Passos Bismara; Pasqualucci, Carlos Augusto; Muñoz, Daniel Romero; Osselton, Michael David; Yonamine, Mauricio

    2012-04-01

    Undoubtedly, whole blood and vitreous humor have been biological samples of great importance in forensic toxicology. The determination of opiates and their metabolites has been essential for better interpretation of toxicological findings. This report describes the application of experimental design and response surface methodology to optimize conditions for enzymatic hydrolysis of morphine-3-glucuronide and morphine-6-glucuronide. The analytes (free morphine, 6-acetylmorphine and codeine) were extracted from the samples using solid-phase extraction on mixed-mode cartridges, followed by derivatization to their trimethylsilyl derivatives. The extracts were analysed by gas chromatography-mass spectrometry with electron ionization and full scan mode. The method was validated for both specimens (whole blood and vitreous humor). A significant matrix effect was found by applying the F-test. Different recovery values were also found (82% on average for whole blood and 100% on average for vitreous humor). The calibration curves were linear for all analytes in the concentration range of 10-1,500 ng/mL. The limits of detection ranged from 2.0 to 5.0 ng/mL. The method was applied to a case in which a victim presented with a previous history of opiate use.

  14. Psychiatric comorbidity differences between women with history of childhood sexual abuse who are methadone-maintained former opiate addicts and non-addicts.

    PubMed

    Peles, Einat; Adelson, Miriam; Seligman, Zivya; Bloch, Miki; Potik, David; Schreiber, Shaul

    2014-09-30

    Following our finding of high rates of obsessive compulsive disorder (OCD) among methadone maintained (MMT) former opiate addict women with a history of childhood sexual abuse, we compared 68 MMT sexually abused women to 48 women from a Sexual Abuse Treatment Center (SATC) without a history of opiate addiction, for clinical-OCD (Yale-Brown Obsessive Compulsive Scale), dissociation (Dissociative Experiences Scale (DES), complex-post-traumatic stress disorder (PTSD) (Structured Interview for Disorders of Extreme Stress - Non-Other Specify), sexual PTSD (the Clinician-Administered PTSD Scale) and trauma events history (Life Event Inventory). MMT patients were treated for longer periods and were older and less educated. Clinical OCD was more prevalent among the MMT patients (66.2% vs. 30.4%, respectively), while complex-PTSD and high dissociation score (DES≥30) were more prevalent among the non-addicts (46.9% vs. 19.1%, and 57.1% vs. 11.8% respectively). The high rate of OCD among sexually abused MMT women was not found in women who are sexually abused non-addicts. As dissociation was rare among the MMT group, it may just be that the opioids (either as street-drugs or as MMT) serve as an external coping mechanism when the access to the internal one is not possible. Future study about OCD and dissociation before entry to MMT are needed.

  15. Rapid determination of methadone and its major metabolite in biological fluids by gas-liquid chromatography with thermionic detection for maintenance treatment of opiate addicts.

    PubMed

    Chikhi-Chorfi, N; Pham-Huy, C; Galons, H; Manuel, N; Lowenstein, W; Warnet, J M; Claude, J R

    1998-11-01

    A rapid gas-liquid chromatographic assay is developed for the quantification of methadone (Mtd) and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in biological fluids of opiate addicts. After alkaline extraction from samples with lidocaine hydrochloride as internal standard, Mtd and EDDP are separated on SP-2250 column at 220 degrees C and detected with a thermionic detector. The chromatographic time is about 6 min. The relative standard deviations (R.S.D.) of Mtd and EDDP standards are between 1.5 and 5.5%. Most drugs of abuse (morphine, codeine, narcotine, cocaine, benzoylecgonine, cocaethylene, dextropropoxyphene etc) are shown not to interfere with this technique. The method has been applied to study the levels of Mtd and EDDP metabolite in serum, saliva and urine of patients under maintenance treatment for opiate dependence. EDDP levels were found higher than those of Mtd in urine samples from four treated patients, but lower in serum and undetectable in saliva. However, Mtd concentrations were higher in saliva than in serum.

  16. Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women.

    PubMed

    Oosterhuis, Bronson E; LaForge, K Steven; Proudnikov, Dmitri; Ho, Ann; Nielsen, David A; Gianotti, Robert; Barral, Sandra; Gordon, Derek; Leal, Suzanne M; Ott, Jurg; Kreek, Mary Jeanne

    2008-09-01

    Catechol-O-methyltransferase (COMT) catalyzes the breakdown of catechol neurotransmitters, including dopamine, which plays a prominent role in drug reward. A common single nucleotide polymorphism (SNP), G472A, codes for a Val158Met substitution and results in a fourfold down regulation of enzyme activity. We sequenced exon IV of COMT gene in search for novel polymorphisms and then genotyped four out of five identified by direct sequencing, using TaqMan assay on 266 opioid-dependent and 173 control subjects. Genotype frequencies of the G472A SNP varied significantly (P = 0.029) among the three main ethnic/cultural groups (Caucasians, Hispanics, and African Americans). Using a genotype test, we found a trend to point-wise association (P = 0.053) of the G472A SNP in Hispanic subjects with opiate addiction. Further analysis of G472A genotypes in Hispanic subjects with data stratified by gender identified a point-wise significant (P = 0.049) association of G/A and A/A genotypes with opiate addiction in women, but not men. These point-wise significant results are not significant experiment-wise (at P < 0.05) after correction for multiple testing. No significant association was found with haplotypes of the three most common SNPs. Linkage disequilibrium patterns were similar for the three ethnic/cultural groups.

  17. Heterogeneous Oxidation of Catechol.

    PubMed

    Pillar, Elizabeth A; Zhou, Ruixin; Guzman, Marcelo I

    2015-10-15

    Natural and anthropogenic emissions of aromatic hydrocarbons from biomass burning, agro-industrial settings, and fossil fuel combustion contribute precursors to secondary aerosol formation (SOA). How these compounds are processed under humid tropospheric conditions is the focus of current attention to understand their environmental fate. This work shows how catechol thin films, a model for oxygenated aromatic hydrocarbons present in biomass burning and combustion aerosols, undergo heterogeneous oxidation at the air-solid interface under variable relative humidity (RH = 0-90%). The maximum reactive uptake coefficient of O3(g) by catechol γO3 = (7.49 ± 0.35) × 10(-6) occurs for 90% RH. Upon exposure of ca. 104-μm thick catechol films to O3(g) mixing ratios between 230 ppbv and 25 ppmv, three main reaction pathways are observed. (1) The cleavage of the 1,2 carbon-carbon bond at the air-solid interface resulting in the formation of cis,cis-muconic acid via primary ozonide and hydroperoxide intermediates. Further direct ozonolysis of cis,cis-muconic yields glyoxylic, oxalic, crotonic, and maleic acids. (2) A second pathway is evidenced by the presence of Baeyer-Villiger oxidation products including glutaconic 4-hydroxy-2-butenoic and 5-oxo-2-pentenoic acids during electrospray ionization mass spectrometry (MS) and ion chromatography MS analyses. (3) Finally, indirect oxidation by in situ produced hydroxyl radical (HO(•)) results in the generation of semiquinone radical intermediates toward the synthesis of polyhydoxylated aromatic rings such as tri-, tetra-, and penta-hydroxybenzene. Remarkably, heavier polyhydroxylated biphenyl and terphenyl products present in the extracted oxidized films result from coupling reactions of semiquinones of catechol and its polyhydroxylated rings. The direct ozonolysis of 1,2,3- and 1,2,4-trihydroxybenezene yields 2- and 3-hydroxy-cis,cis-muconic acid, respectively. The production of 2,4- or 3,4-dihdroxyhex-2-enedioic acid is

  18. Homogeneous, Heterogeneous, and Enzymatic Catalysis.

    ERIC Educational Resources Information Center

    Oyama, S. Ted; Somorjai, Gabor A.

    1988-01-01

    Discusses three areas of catalysis: homegeneous, heterogeneous, and enzymatic. Explains fundamentals and economic impact of catalysis. Lists and discusses common industrial catalysts. Provides a list of 107 references. (MVL)

  19. Heterogeneity in motor driven transport

    NASA Astrophysics Data System (ADS)

    Tabei, Ali

    2015-03-01

    I will discuss quantitative analysis of particle tracking data for motor driven vesicles inside an insulin secreting cell. We use this method to study the dynamical and structural heterogeneity inside the cell. I will discuss our effort to explain the origin of observed heterogeneity in intracellular transport. Finally, I will explain how analyzing directional correlations in transport trajectories reveals self-similarity in the diffusion media.

  20. PUNCH: Population Characterization of Heterogeneity.

    PubMed

    Tunc, Birkan; Ghanbari, Yasser; Smith, Alex R; Pandey, Juhi; Browne, Aaron; Schultz, Robert T; Verma, Ragini

    2014-09-01

    Neuropsychiatric disorders are notoriously heterogeneous in their presentation, which precludes straightforward and objective description of the differences between affected and typical populations that therefore makes finding reliable biomarkers a challenge. This difficulty underlines the need for reliable methods to capture sample characteristics of heterogeneity using a single continuous measure, incorporating the multitude of scores used to describe different aspects of functioning. This study addresses this challenge by proposing a general method of identifying and quantifying the heterogeneity of any clinical population using a severity measure called the PUNCH (Population Characterization of Heterogeneity). PUNCH is a decision level fusion technique to incorporate decisions of various phenotypic scores, while providing interpretable weights for scores. We provide applications of our framework to simulated datasets and to a large sample of youth with Autism Spectrum Disorder (ASD). Next we stratify PUNCH scores in our ASD sample and show how severity moderates findings of group differences in diffusion weighted brain imaging data; more severely affected subgroups of ASD show expanded differences compared to age and gender matched healthy controls. Results demonstrate the ability of our measure in quantifying the underlying heterogeneity of the clinical samples, and suggest its utility in providing researchers with reliable severity assessments incorporating population heterogeneity.

  1. Analysis of active renin heterogeneity.

    PubMed

    Katz, S A; Malvin, R L; Lee, J; Kim, S H; Murray, R D; Opsahl, J A; Abraham, P A

    1991-09-01

    Active renin is a heterogeneous enzyme that can be separated into multiple forms with high-resolution isoelectric focusing. The isoelectric heterogeneity may result from differences in glycosylation between the different forms. In order to determine the relationship between active renin heterogeneity and differences in composition or attachment of oligosaccharides, two separate experiments were performed: (i) Tunicamycin, which interferes with normal glycosylation processing, increased the proportion of relatively basic renin forms secreted into the incubation media by rat renal cortical slices. (ii) Endoglycosidase F, which enzymatically removes carbohydrate from some classes of glycoprotein, similarly increased the proportion of relatively basic forms when incubated with active human recombinant renin. In addition, further studies with inhibitors of human renin activity revealed that the heterogeneous renin forms were similarly inhibited by two separate renin inhibitors. These results are consistent with the hypothesis that renin isoelectric heterogeneity is due in part to differences in carbohydrate moiety attachment and that the heterogeneity of renin does not influence access of direct renin inhibitors to the active site of renin.

  2. Analysis of active renin heterogeneity.

    PubMed

    Katz, S A; Malvin, R L; Lee, J; Kim, S H; Murray, R D; Opsahl, J A; Abraham, P A

    1991-09-01

    Active renin is a heterogeneous enzyme that can be separated into multiple forms with high-resolution isoelectric focusing. The isoelectric heterogeneity may result from differences in glycosylation between the different forms. In order to determine the relationship between active renin heterogeneity and differences in composition or attachment of oligosaccharides, two separate experiments were performed: (i) Tunicamycin, which interferes with normal glycosylation processing, increased the proportion of relatively basic renin forms secreted into the incubation media by rat renal cortical slices. (ii) Endoglycosidase F, which enzymatically removes carbohydrate from some classes of glycoprotein, similarly increased the proportion of relatively basic forms when incubated with active human recombinant renin. In addition, further studies with inhibitors of human renin activity revealed that the heterogeneous renin forms were similarly inhibited by two separate renin inhibitors. These results are consistent with the hypothesis that renin isoelectric heterogeneity is due in part to differences in carbohydrate moiety attachment and that the heterogeneity of renin does not influence access of direct renin inhibitors to the active site of renin. PMID:1908097

  3. Sequence, Structure and Ligand Binding Evolution of Rhodopsin-Like G Protein-Coupled Receptors: A Crystal Structure-Based Phylogenetic Analysis

    PubMed Central

    Wolf, Steffen; Grünewald, Stefan

    2015-01-01

    G protein-coupled receptors (GPCRs) form the largest family of membrane receptors in the human genome. Advances in membrane protein crystallization so far resulted in the determination of 24 receptors available as high-resolution atomic structures. We performed the first phylogenetic analysis of GPCRs based on the available set of GPCR structures. We present a new phylogenetic tree of known human rhodopsin-like GPCR sequences based on this structure set. We can distinguish the three separate classes of small-ligand binding GPCRs, peptide binding GPCRs, and olfactory receptors. Analyzing different structural subdomains, we found that small molecule binding receptors most likely have evolved from peptide receptor precursors, with a rhodopsin/S1PR1 ancestor, most likely an ancestral opsin, forming the link between both classes. A light-activated receptor therefore seems to be the origin of the small molecule hormone receptors of the central nervous system. We find hints for a common evolutionary path of both ligand binding site and central sodium/water binding site. Surprisingly, opioid receptors exhibit both a binding cavity and a central sodium/water binding site similar to the one of biogenic amine receptors instead of peptide receptors, making them seemingly prone to bind small molecule ligands, e.g. opiates. Our results give new insights into the relationship and the pharmacological properties of rhodopsin-like GPCRs. PMID:25881057

  4. Enhanced dendritic availability of mu-opioid receptors in inhibitory neurons of the extended amygdala in mice deficient in the corticotropin-releasing factor-1 receptor

    PubMed Central

    Jaferi, Azra; Zhou, Ping; Pickel, Virginia M.

    2010-01-01

    Activation of the corticotropin-releasing factor-1 (CRF-1) receptor in the anterolateral BNST (BSTal), a key subdivision of the extended amygdala, elicits opiate-seeking behavior exacerbated by stress. However, it is unknown whether the presence of CRF-1 affects expression of the mu-opioid receptor (μ-OR) in the many GABAergic BSTal neurons implicated in the stress response. We hypothesized that deletion of the CRF-1 receptor gene would alter the density and/or subcellular distribution of μ-ORs in GABAergic neurons of the BSTal. We used electron microscopy to quantitatively examine μ-OR immunogold and GABA immunoperoxidase labeling in the BSTal of CRFr-1 knockout (KO) compared to wildtype (WT) mice. To assess regional specificity, we examined μ-OR distribution in dorsal striatum. The μ-ORs in each region were predominantly localized in dendrites, many of which were GABA-immunoreactive. Significantly more cytoplasmic μ-OR gold particles per dendritic area were observed selectively in GABA-containing dendrites of the BSTal, but not of the dorsal striatum, in KO compared to WT mice. In both regions, however, significantly fewer GABA-immunoreactive axon terminals were present in KO compared to WT mice. Our results suggest that absence of CRF-1 results in enhanced expression and/or dendritic trafficking of μ-ORs in inhibitory BSTal neurons. They also suggest that expression of CRF-1 is a critical determinant of the availability of GABA in functionally diverse brain regions. These findings underscore the complex interplay between CRF, opioid and GABA systems in limbic and striatal regions, and have implications for the role of CRF-1 in influencing the pharmacological effects of opiates active at μ-ORs. PMID:20506149

  5. Somatostatin receptors.

    PubMed

    Srikant, C B; Patel, Y C

    1985-01-01

    It is now well established that the biological actions of tetradecapeptide somatostatin (somatostatin-14, S-14) are receptor-mediated. These receptors were first quantified in GH4C pituitary tumor cells using [125I-Tyr1] S-14 as radioligand which was found to exhibit high non-specific binding to membrane receptor preparations from normal tissues. Our studies have shown that [125I-Tyr11] S-14 in which the radiolabel is situated away from the N-terminus exhibits significantly lower non-specific binding and therefore is more suitable for S-14 receptor studies. In the CNS, highest concentration of S-14 receptors was found in the cerebral cortex, followed by thalamus, hypothalamus, striatum, amygdala and hippocampus while medulla-pons, cerebellum and spinal cord exhibited negligible binding. Outside the CNS membrane receptors for S-14 have been characterized in pituitary, adrenal cortex and pancreatic acini. In all these tissues a single class of high affinity binding sites for S-14 were present, the receptors in pancreatic acinar cells exhibiting significantly greater affinity for binding S-14 than in other tissues.

  6. Dealing with spatial heterogeneity

    NASA Astrophysics Data System (ADS)

    Marsily, Gh.; Delay, F.; Gonçalvès, J.; Renard, Ph.; Teles, V.; Violette, S.

    2005-03-01

    Heterogeneity can be dealt with by defining homogeneous equivalent properties, known as averaging, or by trying to describe the spatial variability of the rock properties from geologic observations and local measurements. The techniques available for these descriptions are mostly continuous Geostatistical models, or discontinuous facies models such as the Boolean, Indicator or Gaussian-Threshold models and the Markov chain model. These facies models are better suited to treating issues of rock strata connectivity, e.g. buried high permeability channels or low permeability barriers, which greatly affect flow and, above all, transport in aquifers. Genetic models provide new ways to incorporate more geology into the facies description, an approach that has been well developed in the oil industry, but not enough in hydrogeology. The conclusion is that future work should be focused on improving the facies models, comparing them, and designing new in situ testing procedures (including geophysics) that would help identify the facies geometry and properties. A world-wide catalog of aquifer facies geometry and properties, which could combine site genesis and description with methods used to assess the system, would be of great value for practical applications. On peut aborder le problème de l'hétérogénéité en s'efforçant de définir une perméabilité équivalente homogène, par prise de moyenne, ou au contraire en décrivant la variation dans l'espace des propriétés des roches à partir des observations géologiques et des mesures locales. Les techniques disponibles pour une telle description sont soit continues, comme l'approche Géostatistique, soit discontinues, comme les modèles de faciès, Booléens, ou bien par Indicatrices ou Gaussiennes Seuillées, ou enfin Markoviens. Ces modèles de faciès sont mieux capables de prendre en compte la connectivité des strates géologiques, telles que les chenaux enfouis à forte perméabilité, ou au contraire les faci

  7. Dealing with spatial heterogeneity

    NASA Astrophysics Data System (ADS)

    Marsily, Gh.; Delay, F.; Gonçalvès, J.; Renard, Ph.; Teles, V.; Violette, S.

    2005-03-01

    Heterogeneity can be dealt with by defining homogeneous equivalent properties, known as averaging, or by trying to describe the spatial variability of the rock properties from geologic observations and local measurements. The techniques available for these descriptions are mostly continuous Geostatistical models, or discontinuous facies models such as the Boolean, Indicator or Gaussian-Threshold models and the Markov chain model. These facies models are better suited to treating issues of rock strata connectivity, e.g. buried high permeability channels or low permeability barriers, which greatly affect flow and, above all, transport in aquifers. Genetic models provide new ways to incorporate more geology into the facies description, an approach that has been well developed in the oil industry, but not enough in hydrogeology. The conclusion is that future work should be focused on improving the facies models, comparing them, and designing new in situ testing procedures (including geophysics) that would help identify the facies geometry and properties. A world-wide catalog of aquifer facies geometry and properties, which could combine site genesis and description with methods used to assess the system, would be of great value for practical applications. On peut aborder le problème de l'hétérogénéité en s'efforçant de définir une perméabilité équivalente homogène, par prise de moyenne, ou au contraire en décrivant la variation dans l'espace des propriétés des roches à partir des observations géologiques et des mesures locales. Les techniques disponibles pour une telle description sont soit continues, comme l'approche Géostatistique, soit discontinues, comme les modèles de faciès, Booléens, ou bien par Indicatrices ou Gaussiennes Seuillées, ou enfin Markoviens. Ces modèles de faciès sont mieux capables de prendre en compte la connectivité des strates géologiques, telles que les chenaux enfouis à forte perméabilité, ou au contraire les faci

  8. Subgroups Among Opiate Addicts

    ERIC Educational Resources Information Center

    Berzins, Juris I.; And Others

    1974-01-01

    The principal objective of the present investigation was to delineate homogeneous MMPI profile subgroups (types) through multivariate clustering procedures and to compare the derived (replicable) types on measures of the components of "sociopathy" as well as on other psychometric devices. (Author)

  9. Reaction Selectivity in Heterogeneous Catalysis

    SciTech Connect

    Somorjai, Gabor A.; Kliewer, Christopher J.

    2009-02-02

    The understanding of selectivity in heterogeneous catalysis is of paramount importance to our society today. In this review we outline the current state of the art in research on selectivity in heterogeneous catalysis. Current in-situ surface science techniques have revealed several important features of catalytic selectivity. Sum frequency generation vibrational spectroscopy has shown us the importance of understanding the reaction intermediates and mechanism of a heterogeneous reaction, and can readily yield information as to the effect of temperature, pressure, catalyst geometry, surface promoters, and catalyst composition on the reaction mechanism. DFT calculations are quickly approaching the ability to assist in the interpretation of observed surface spectra, thereby making surface spectroscopy an even more powerful tool. HP-STM has revealed three vitally important parameters in heterogeneous selectivity: adsorbate mobility, catalyst mobility, and selective site-blocking. The development of size controlled nanoparticles from 0.8 to 10 nm, of controlled shape, and of controlled bimetallic composition has revealed several important variables for catalytic selectivity. Lastly, DFT calculations may be paving the way to guiding the composition choice for multi-metallic heterogeneous catalysis for the intelligent design of catalysts incorporating the many factors of selectivity we have learned.

  10. Medically assisted recovery from opiate dependence within the context of the UK drug strategy: methadone and Suboxone (buprenorphine-naloxone) patients compared.

    PubMed

    McKeganey, Neil; Russell, Christopher; Cockayne, Lucinda

    2013-01-01

    The focus of drug policy in the UK has shifted markedly in the past 5 years to move beyond merely emphasising drug abstinence towards maximising individuals' opportunities for recovery. The UK government continues to recognise the prescribing of narcotic medications indicated for opiate dependence as a key element of these individuals' recovery journey. This article describes a small, naturalistic comparison of the efficacy of the two most commonly prescribed opiate substitute medications in the UK--methadone hydrochloride (methadone oral solution) and Suboxone (buprenorphine-naloxone sublingual tablets)--for reducing current heroin users' (n = 34) days of heroin use, and preventing short-term abstainers (n = 37) from relapsing to regular heroin use. All patients had been prescribed either methadone or Suboxone for maintenance for 6 months prior to intake. Results showed that when controlling for a number of patient-level covariates, both methadone and Suboxone significantly reduced current users' days of heroin use between the 90 days prior to intake and at the 8-month follow-up, with Suboxone yielding a significantly larger magnitude reduction in heroin use days than methadone. Methadone and Suboxone were highly and equally effective for preventing relapse to regular heroin use, with all but 3 of 37 (91.9%) patients who were abstinent at intake reporting past 90-day point prevalence heroin abstinence at the 8-month follow-up. Overall, prescribing methadone or Suboxone for eight continuous months was highly effective for initiating abstinence from heroin use, and for converting short-term abstinence to long-term abstinence. However, the study design, which was based on a relatively small sample size and was not able randomise patients to medication and so could not control for the effects of potential prognostic factors inherent within each patient group, means that these conclusions can only be made tentatively. These positive but preliminary indications of the

  11. Rats that binge eat fat-rich food do not show somatic signs or anxiety associated with opiate-like withdrawal: implications for nutrient-specific food addiction behaviors.

    PubMed

    Bocarsly, Miriam E; Berner, Laura A; Hoebel, Bartley G; Avena, Nicole M

    2011-10-24

    Previous studies suggest that binge eating sugar leads to behavioral and neurochemical changes similar to those seen with drug addiction, including signs of opiate-like withdrawal. Studies are emerging that show multiple neurochemical and behavioral indices of addiction when animals overeat a fat-rich diet. The goal of the present study was to utilize liquid and solid diets high in sugar and fat content to determine whether opiate-like withdrawal is seen after binge consumption of these diets in Sprague-Dawley rats. Control groups were given ad libitum access to the sweet-fat food or standard chow. All rats were then given a battery of tests to measure signs of opiate-like withdrawal, which included somatic signs of distress, elevated plus-maze anxiety, and locomotor hypoactivity. Neither naloxone-precipitated (3 mg/kg) nor deprivation-induced withdrawal was observed in rats that were maintained on a nutritionally complete pelleted sweet-fat diet or a sweet, high-fat diet supplemented with standard rodent chow. Naloxone-precipitated withdrawal was also not seen in rats fed a liquid sweet-fat food. Further, body weight reduction to 85%, which is known to potentiate the reinforcing effects of substances of abuse, did not affect naloxone-precipitated signs of opiate-like withdrawal. Thus, unlike previous findings reported regarding rats with binge access to a sucrose solution, rats that binge eat sweet-fat combinations do not show signs of opiate-like withdrawal under the conditions tested. These data support the idea that excessive consumption of different nutrients can induce behaviors associated with addiction in different ways, and that the behaviors that could characterize "food addiction" may be subtyped based on the nutritional composition of the food consumed.

  12. Somatostatin receptors.

    PubMed

    Patel, Y C; Srikant, C B

    1997-12-01

    The diverse biological effects of somatostatin (SRIF) are mediated by a family of G protein-coupled receptors (termed sst) that are encoded by five nonallelic genes located on separate chromosomes. The receptors can be further divided into two subfamilies: sst(2,3,5) react with octapeptide and hexapeptide SRIF analogues and belong to one subclass; sst(1,4) react poorly with these compounds and fall into another subclass. This review focuses on the molecular pharmacology and function of these receptors, with particular emphasis on the ligand-binding domain, subtype-selective analogues, agonist-dependent receptor regulation and desensitization responses, subtype-specific effector coupling, and signal transduction pathways responsible for inhibiting cell secretion and cell growth or induction of apoptosis.

  13. Resource heterogeneity can facilitate cooperation.

    PubMed

    Kun, Ádám; Dieckmann, Ulf

    2013-01-01

    Although social structure is known to promote cooperation, by locally exposing selfish agents to their own deeds, studies to date assumed that all agents have access to the same level of resources. This is clearly unrealistic. Here we find that cooperation can be maintained when some agents have access to more resources than others. Cooperation can then emerge even in populations in which the temptation to defect is so strong that players would act fully selfishly if their resources were distributed uniformly. Resource heterogeneity can thus be crucial for the emergence and maintenance of cooperation. We also show that resource heterogeneity can hinder cooperation once the temptation to defect is significantly lowered. In all cases, the level of cooperation can be maximized by managing resource heterogeneity.

  14. Static heterogeneities in liquid water

    NASA Astrophysics Data System (ADS)

    Stanley, H. Eugene; Buldyrev, Sergey V.; Giovambattista, Nicolas

    2004-10-01

    The thermodynamic behavior of water seems to be closely related to static heterogeneities. These static heterogeneities are related to the local structure of water molecules, and when properly characterized, may offer an economical explanation of thermodynamic data. The key feature of liquid water is not so much that the existence of hydrogen bonds, first pointed out by Linus Pauling, but rather the local geometry of the liquid molecules is not spherical or oblong but tetrahedral. In the consideration of static heterogeneities, this local geometry is critical. Recent experiments suggested more than one phase of amorphous solid water, while simulations suggest that one of these phases is metastable with respect to another, so that in fact there are only two stable phases.

  15. Simulator for heterogeneous dataflow architectures

    NASA Technical Reports Server (NTRS)

    Malekpour, Mahyar R.

    1993-01-01

    A new simulator is developed to simulate the execution of an algorithm graph in accordance with the Algorithm to Architecture Mapping Model (ATAMM) rules. ATAMM is a Petri Net model which describes the periodic execution of large-grained, data-independent dataflow graphs and which provides predictable steady state time-optimized performance. This simulator extends the ATAMM simulation capability from a heterogenous set of resources, or functional units, to a more general heterogenous architecture. Simulation test cases show that the simulator accurately executes the ATAMM rules for both a heterogenous architecture and a homogenous architecture, which is the special case for only one processor type. The simulator forms one tool in an ATAMM Integrated Environment which contains other tools for graph entry, graph modification for performance optimization, and playback of simulations for analysis.

  16. Lipoxin receptors.

    PubMed

    Romano, Mario; Recchia, Irene; Recchiuti, Antonio

    2007-01-01

    Lipoxins (LXs) represent a class of arachidonic acid (AA) metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO) and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2) in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL). In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1). This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed. PMID:17767357

  17. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.

    PubMed

    Ali, S F; Newport, G D; Scallet, A C; Gee, K W; Paule, M G; Brown, R M; Slikker, W

    1989-01-01

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.

  18. The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats.

    PubMed

    Yue, Kai; Ma, Baomiao; Ru, Qin; Chen, Lin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2012-07-01

    Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement. PMID:22741173

  19. Interleukin-1 interaction with neuroregulatory systems: selective enhancement by recombinant human and mouse interleukin-1 of in vitro opioid peptide receptor binding in rat brain

    SciTech Connect

    Wiedermann, C.J.

    1989-02-01

    Interleukin-1 (IL-1) exerts a wide variety of biological effects on various cell types and may be regarded as a pleiotropic peptide hormone. Biological evidence suggests that IL-1 participates in the modulation of central nervous system physiology and behavior in a fashion characteristic of neuroendocrine hormones. In this investigation, recombinant (r) human (h) IL-1 and r mouse (m) IL-1 were examined for their modulation of opioid peptide receptor binding in vitro. Experiments were performed on frozen sections of rat brain. Receptor binding of radiolabeled substance P and of radiolabeled neurotensin were not significantly affected by the presence of rIL-1s. Recombinant IL-1s, however, significantly enhanced specific binding of 125I-beta-endorphin (125I-beta-END) and of D-ala2-(tyrosyl-3,5-3H)enkephalin-(5-D-leucine) (3H-D-ALA), equipotently and in a concentration-dependent manner with maximal activity occurring at a concentration of 10 LAF units/ml. The increased binding of 125I-beta-END and 3H-D-ALA was blocked steroselectively by (-)-naloxone and by etorphine, suggesting detection of opiate receptors. In addition, brain distribution patterns of receptors labeled in the presence of rIL-1s corresponded to patterns previously published for opiate receptors. Autoradiographic visualization of receptors revealed that rIL-1s in the different areas of the brain exert their effect on opioid binding with comparable potencies. The data suggest that certain central nervous system effects of IL-1s may be mediated by their selective interaction with opiatergic systems at the receptor level.

  20. Age-related differences in the sensitivity to opiate-induced perturbations in reproductive endocrinology in the developing and adult male rat.

    PubMed

    Cicero, T J; O'Connor, L; Nock, B; Adams, M L; Miller, B T; Bell, R D; Meyer, E R

    1989-01-01

    The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were left in place to provide the release of morphine during critical phases of puberty and sexual maturation and to prevent an abrupt withdrawal syndrome upon pellet removal which would confound our results. Developing rats were sacrificed at representative intervals after pellet insertion to assess the development of key indices of reproductive endocrinology; adult rats were sacrificed at the same time intervals to permit an evaluation of age-related differences in the sensitivity to opiate-induced endocrine disturbances. Our results showed that morphine markedly influenced a number of endocrine parameters associated with the maturation of the hypothalamic-pituitary-gonadal axis in developing rats for prolonged periods of time, whereas the effects of the opiate in the adult rat were relatively modest and transient. In the developing rat, serum luteinizing hormone (LH), testosterone, the wet tissue weights of the seminal vesicles and testes and hypothalamic LH-releasing hormone (LHRH) levels were substantially depressed immediately after pellet implantation and these effects persisted for up to 4 weeks when compared to placebo-implanted, age-matched controls. In contrast to these results, adult rats showed only transient effects (less than 1 week) of morphine on certain reproductive endocrine parameters (e.g., serum LH, testosterone and the weights of the seminal vesicles) and no effects on others (e.g., testes weights and hypothalamic LHRH).(ABSTRACT TRUNCATED AT 250 WORDS)

  1. The Effect of Methadone-Maintenance Therapy With and Without Interactive Treatment on Improving Emotion-Regulation Strategies and Resilience Among Opiate-Dependent Clients

    PubMed Central

    Hoseiny, Hadis; Jadidi, Mohsen; Habiballah Nataj, Leila; Saberi- Zafarghandi, Mohammad Bagher

    2015-01-01

    Background: Due to the chronic and recurrent nature of addiction, many people who quit drug addiction may slip back into the pattern of using drugs shortly after the detoxification period. Emotion-regulation strategies and resilience play an important role in preventing the recurrences of substance abuse. Objectives: This study aimed to compare the effects of methadone-maintenance therapy (MMT) and interactive therapy (a combination of MMT and cognitive-behavioral therapy) on improving emotion-regulation strategies and resilience among opiate-dependent clients. Patients and Methods: This pretest-posttest quasi-experimental study was performed on 60 patients with substance abuse admitted to Methadone Addiction Treatment Centers and Detox Centers in Sari within three months of therapy for their addiction (from October to December 2013). Then, the participants were randomly assigned to two different groups (n = 30) were examined in two groups of 30 people targeted to be available in the selected population. Participants in all three groups, before and after the intervention, filled out the questionnaires of Schutte emotional intelligence scale and Connor-Davidson resiliency questionnaire. Data were analyzed using the analysis of covariance method. Results: The results showed that an interactive therapy would be significantly more effective than the MMT on improving emotion-regulation strategies and promoting the resilience level among opiate-dependent clients. Moreover, the results showed that cognitive- behavior therapy combined with MMT may improve emotion-regulation strategies, and promote the amount of resiliency and recovery. Conclusions: The cognitive-behavior therapy combined with MMT can improve emotion-regulation strategies and resiliency and thus prevent the substance-abuse relapse. PMID:25821751

  2. Upstream reciprocity in heterogeneous networks.

    PubMed

    Iwagami, Akio; Masuda, Naoki

    2010-08-01

    Many mechanisms for the emergence and maintenance of altruistic behavior in social dilemma situations have been proposed. Indirect reciprocity is one such mechanism, where other-regarding actions of a player are eventually rewarded by other players with whom the original player has not interacted. The upstream reciprocity (also called generalized indirect reciprocity) is a type of indirect reciprocity and represents the concept that those helped by somebody will help other unspecified players. In spite of the evidence for the enhancement of helping behavior by upstream reciprocity in rats and humans, theoretical support for this mechanism is not strong. In the present study, we numerically investigate upstream reciprocity in heterogeneous contact networks, in which the players generally have different number of neighbors. We show that heterogeneous networks considerably enhance cooperation in a game of upstream reciprocity. In heterogeneous networks, the most generous strategy, by which a player helps a neighbor on being helped and in addition initiates helping behavior, first occupies hubs in a network and then disseminates to other players. The scenario to achieve enhanced altruism resembles that seen in the case of the Prisoner's Dilemma game in heterogeneous networks.

  3. Heterogeneous catalytic alcoholysis of benzonitrile

    SciTech Connect

    Kagarlitskii, A.D.; Dmumakaev, K.Kh.; Bekova, N.S.

    1986-04-01

    The authors investigate the possibility of the direct heterogeneous catalytic synthesis of ethylbenzoate from benzonitrile. The catalysts tested were oxides of aluminium, titanium, and vanadium. The main conversion product detected chromatographically was ethylbenzoate; benzaldehyde, benzamide, and benzanilide were also identified. Aluminium oxide was found to be the most effective catalyst.

  4. Heterogeneity in the gingival fibromatoses.

    PubMed

    Takagi, M; Yamamoto, H; Mega, H; Hsieh, K J; Shioda, S; Enomoto, S

    1991-11-15

    Forty-nine cases of isolated familial and idiopathic gingival fibromatoses, consisting of 12 cases from six families and 37 cases of idiopathic gingival fibromatosis, were reviewed. Pedigrees of five families revealed various penetrances and genetic heterogeneity as suggested by the presence of both autosomal dominant and autosomal recessive inheritances. Ultrastructurally, the lesions were composed of fibroblast-like cells and myofibroblast-like cells, with the former being the predominant cell type. The 267 cases of familial and idiopathic gingival fibromatoses were analyzed, and they with or without hypertrichosis, mental retardation, and/or epilepsy. These included 49 cases seen by the authors, 50 cases from the Japanese literature, and 168 cases from non-Japanese literature. Isolated gingival fibromatosis occurred more frequently after age of 12 years (P less than 0.0074). There was no significant difference in age of onset between generalized and localized forms of the idiopathic gingival fibromatosis. Gingival fibromatosis with hypertrichosis and mental retardation and/or epilepsy occurred frequently before 12 years (P less than 0.069). It has been shown that heterogeneity of the gingival fibromatosis is a result of either histologic heterogeneity, genetic heterogeneity, or a combination with other systemic disorders.

  5. Social Capital and Community Heterogeneity

    ERIC Educational Resources Information Center

    Coffe, Hilde

    2009-01-01

    Recent findings indicate that more pronounced community heterogeneity is associated with lower levels of social capital. These studies, however, concentrate on specific aspects in which people differ (such as income inequality or ethnic diversity). In the present paper, we introduce the number of parties in the local party system as a more…

  6. Teaching about Heterogeneous Response Models

    ERIC Educational Resources Information Center

    Murray, Michael P.

    2014-01-01

    Individuals vary in their responses to incentives and opportunities. For example, additional education will affect one person differently than another. In recent years, econometricians have given increased attention to such heterogeneous responses and to the consequences of such responses for interpreting regression estimates, especially…

  7. Flammability of Heterogeneously Combusting Metals

    NASA Technical Reports Server (NTRS)

    Jones, Peter D.

    1998-01-01

    Most engineering materials, including some metals, most notably aluminum, burn in homogeneous combustion. 'Homogeneous' refers to both the fuel and the oxidizer being in the same phase, which is usually gaseous. The fuel and oxidizer are well mixed in the combustion reaction zone, and heat is released according to some relation like q(sub c) = delta H(sub c)c[((rho/rho(sub 0))]exp a)(exp -E(sub c)/RT), Eq. (1) where the pressure exponent a is usually close to unity. As long as there is enough heat released, combustion is sustained. It is useful to conceive of a threshold pressure beyond which there is sufficient heat to keep the temperature high enough to sustain combustion, and beneath which the heat is so low that temperature drains away and the combustion is extinguished. Some materials burn in heterogeneous combustion, in which the fuel and oxidizer are in different phases. These include iron and nickel based alloys, which burn in the liquid phase with gaseous oxygen. Heterogeneous combustion takes place on the surface of the material (fuel). Products of combustion may appear as a solid slag (oxide) which progressively covers the fuel. Propagation of the combustion melts and exposes fresh fuel. Heterogeneous combustion heat release also follows the general form of Eq.(1), except that the pressure exponent a tends to be much less than 1. Therefore, the increase in heat release with increasing pressure is not as dramatic as it is in homogeneous combustion. Although the concept of a threshold pressure still holds in heterogeneous combustion, the threshold is more difficult to identify experimentally, and pressure itself becomes less important relative to the heat transfer paths extant in any specific application. However, the constants C, a, and E(sub c) may still be identified by suitable data reduction from heterogeneous combustion experiments, and may be applied in a heat transfer model to judge the flammability of a material in any particular actual

  8. Magnetic heterogeneity of biological systems.

    PubMed

    Piruzyan, L A; Kuznetsov, A A; Chikov, V M

    1980-01-01

    In biological systems nonuniformity of magnetic susceptibility, magnetic heterogeneity, is a reflection of their physical-chemical and morphological heterogeneity, A characteristic value of heterogeneity is delta K approximately 10(-6)-10(-7) CGS units, a quantitative measurement of susceptibility of cells and other small objects, may give qualitatively new information about their life processes. Patterns and features of movement of small biological objects and liquids affected by magnetic forces were studied. A method was developed for measuring magnetic susceptibility of single microobjects based on observation of movement of the objects in a strong heterogeneous field with parameters (formula: see text) grad H2/2 approximately 10(9)-10(10) Oe2/cm. This method does not require knowing the distribution of the field along the path of movement of the particles, and does not require preliminary calibration. Movement of human erythrocytes, rat hepatocytes, and starch granules in liquids at a point of entry into a gap with the field was observed experimentally. With sufficiently large fields Ho approximately (1-2) x 10(4) Oe, the value of the magnetic force was enough to change the rate of sedimentation movement of the objects appreciably (up to stopping it). This made it possible to compute the value delta K for cells approximately 10(-7)-10(-8) CGS units and to obtain the value of K for starch granules (-0.80 x 10(-6) cGS units). In connection with the fact that sensitivity to gravity in plants is coupled with a disturbance of the intracellular starch granules under the influence of gravity, certain problems of stimulating the effect of gravity on plants by magnetic forces were studied. Noncontact force effect on magnetically heterogeneous biological objects is a promising instrument for biophysical studies.

  9. Opioid binding properties of the purified kappa receptor from human placenta

    SciTech Connect

    Ahmed, M.S.; Zhou, D.; Cavinato, A.G.; Maulik, D.

    1989-01-01

    A glycoprotein with a molecular weight of 63,000 has been purified, in an active form, from human placental villus tissue membranes. The binding properties of this glycoprotein to opioid alkaloids and peptides indicates that it is the kappa opiate receptor of human placenta. The receptor binds the tritiated ligands etorphine, bremazocine, ethylketocyclazocine and naloxone specifically and reversibly with Kd values of 3.3, 4.4, 5.1 and 7.0nM, respectively. The binding of /sup 3/H-Bremazocine to the purified receptor is inhibited by the following compounds with the corresponding Ki values EKC, 1.3 x 10/sup -8/M; Dynorphin 1-8, 3.03 x 10/sup -7/; U50,488H, 4.48 x 10/sup -9/; U69-593,2.28 x 10/sup -8/, morphine, 4.05 x 10/sup -6/ DADLE, 6.47 x 10/sup -6/ and naloxone, 2.64 x 10/sup -8/. The purified receptor binds 8 nmole of /sup 3/H-Etorphine and 1.7 nmole /sup 3/H-BZC per mg protein. The theoretical binding capacity of a protein of this molecular weight is 15.8. Although the iodinated purified receptor appears by autoradiography as one band on SDS-PAGE, yet homogeneity of the preparation is not claimed.

  10. The dangers of heterogeneous network computing: heterogeneous networks considered harmful

    SciTech Connect

    Demmel, J.; Stanley, K.; Dongarra, J.; Hammarling, S.; Osstrouchov, S.

    1996-12-31

    This report addresses the issue of writing reliable numerical software for networks of heterogeneous computers. Much software has been written for distributed memory parallel computers and in principal such software could readily be ported to networks of machines, such as a collection of workstations connected by Ethernet, but if such a network is not homogeneous there are special challenges that need to be addressed. The symptoms can range from erroneous results returned without warning to deadlock. Some of the problems are straightforward to solve, but for others the solutions are not so obvious and indeed in some cases, such as the method of bisection which we shall discuss in the report, we have not yet decided upon a satisfactory solution that does not incur an unacceptable overhead. Making software robust on heterogeneous systems often requires additional communication. In this report we describe and illustrate the problems and, where possible, suggest solutions so that others may be aware of the potential pitfalls and either avoid them or, if that is not possible, ensure that their software is not used on heterogeneous networks.

  11. κ-Opioid receptors within the nucleus accumbens shell mediate pair bond maintenance.

    PubMed

    Resendez, Shanna L; Kuhnmuench, Morgan; Krzywosinski, Tarin; Aragona, Brandon J

    2012-05-16

    The prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transition from general affiliation to aggressive rejection of novel conspecifics. This "selective aggression" is indicative of mate guarding that is necessary to maintain the initial pair bond. In the laboratory, the neurobiology of this behavior is studied using resident-intruder testing. Although it is well established that social behaviors in other species are mediated by endogenous opioid systems, opiate regulation of pair bond maintenance has never been studied. Here, we used resident-intruder testing to determine whether endogenous opioids within brain motivational circuitry mediate selective aggression in prairie voles. We first show that peripheral blockade of κ-opioid receptors with the antagonist norbinaltorphimine (nor-BNI; 100 mg/kg), but not with the preferential μ-opioid receptor antagonist naloxone (1, 10, or 30 mg/kg), decreased selective aggression in males. We then provide the first comprehensive characterization of κ- and μ-opioid receptors in the prairie vole brain. Finally, we demonstrate that blockade of κ-opioid receptors (500 ng nor-BNI) within the nucleus accumbens (NAc) shell abolishes selective aggression in both sexes, but blockade of these receptors within the NAc core enhances this behavior specifically in females. Blockade of κ-opioid receptors within the ventral pallidum or μ-opioid receptors with the specific μ-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (1 ng CTAP) within the NAc shell had no effect in either sex. Thus, κ-opioid receptors within the NAc shell mediate aversive social motivation that is critical for pair bond maintenance. PMID:22593047

  12. Targeting the EGF Receptor for Ovarian Cancer Therapy

    PubMed Central

    Zeineldin, Reema; Muller, Carolyn Y.; Stack, M. Sharon; Hudson, Laurie G.

    2010-01-01

    Ovarian carcinoma is the leading cause of death from gynecologic malignancy in the US. Factors such as the molecular heterogeneity of ovarian tumors and frequent diagnosis at advanced stages hamper effective disease treatment. There is growing emphasis on the identification and development of targeted therapies to disrupt molecular pathways in cancer. The epidermal growth factor (EGF) receptor is one such protein target with potential utility in the management of ovarian cancer. This paper will discuss contributions of EGF receptor activation to ovarian cancer pathogenesis and the status of EGF receptor inhibitors and EGF receptor targeted therapies in ovarian cancer treatment. PMID:20066160

  13. Heterogeneous, weakly coupled map lattices

    NASA Astrophysics Data System (ADS)

    Sotelo Herrera, M.a. Dolores; San Martín, Jesús; Porter, Mason A.

    2016-07-01

    Coupled map lattices (CMLs) are often used to study emergent phenomena in nature. It is typically assumed (unrealistically) that each component is described by the same map, and it is important to relax this assumption. In this paper, we characterize periodic orbits and the laminar regime of type-I intermittency in heterogeneous weakly coupled map lattices (HWCMLs). We show that the period of a cycle in an HWCML is preserved for arbitrarily small coupling strengths even when an associated uncoupled oscillator would experience a period-doubling cascade. Our results characterize periodic orbits both near and far from saddle-node bifurcations, and we thereby provide a key step for examining the bifurcation structure of heterogeneous CMLs.

  14. NASA GSFC Perspective on Heterogeneous Processing

    NASA Technical Reports Server (NTRS)

    Powell, Wesley A.

    2016-01-01

    This presentation provides an overview of NASA GSFC, our onboard processing applications, the applicability heterogeneous processing to these applications, and necessary developments to enable heterogeneous processing to be infused into our missions.

  15. Temperature chaos and quenched heterogeneities

    NASA Astrophysics Data System (ADS)

    Barucca, Paolo; Parisi, Giorgio; Rizzo, Tommaso

    2014-03-01

    We present a treatable generalization of the Sherrington-Kirkpatrick (SK) model which introduces correlations in the elements of the coupling matrix through multiplicative disorder on the single variables and investigate the consequences on the phase diagram. We define a generalized qEA parameter and test the structural stability of the SK results in this correlated case evaluating the de Almeida-Thouless line of the model. As a main result we demonstrate the increase of temperature chaos effects due to heterogeneities.

  16. Analyzing and modeling heterogeneous behavior

    NASA Astrophysics Data System (ADS)

    Lin, Zhiting; Wu, Xiaoqing; He, Dongyue; Zhu, Qiang; Ni, Jixiang

    2016-05-01

    Recently, it was pointed out that the non-Poisson statistics with heavy tail existed in many scenarios of human behaviors. But most of these studies claimed that power-law characterized diverse aspects of human mobility patterns. In this paper, we suggest that human behavior may not be driven by identical mechanisms and can be modeled as a Semi-Markov Modulated Process. To verify our suggestion and model, we analyzed a total of 1,619,934 records of library visitations (including undergraduate and graduate students). It is found that the distribution of visitation intervals is well fitted with three sections of lines instead of the traditional power law distribution in log-log scale. The results confirm that some human behaviors cannot be simply expressed as power law or any other simple functions. At the same time, we divided the data into groups and extracted period bursty events. Through careful analysis in different groups, we drew a conclusion that aggregate behavior might be composed of heterogeneous behaviors, and even the behaviors of the same type tended to be different in different period. The aggregate behavior is supposed to be formed by "heterogeneous groups". We performed a series of experiments. Simulation results showed that we just needed to set up two states Semi-Markov Modulated Process to construct proper representation of heterogeneous behavior.

  17. Heterogeneous nucleation or homogeneous nucleation?

    NASA Astrophysics Data System (ADS)

    Liu, X. Y.

    2000-06-01

    The generic heterogeneous effect of foreign particles on three dimensional nucleation was examined both theoretically and experimentally. It shows that the nucleation observed under normal conditions includes a sequence of progressive heterogeneous processes, characterized by different interfacial correlation function f(m,x)s. At low supersaturations, nucleation will be controlled by the process with a small interfacial correlation function f(m,x), which results from a strong interaction and good structural match between the foreign bodies and the crystallizing phase. At high supersaturations, nucleation on foreign particles having a weak interaction and poor structural match with the crystallizing phase (f(m,x)→1) will govern the kinetics. This frequently leads to the false identification of homogeneous nucleation. Genuine homogeneous nucleation, which is the up-limit of heterogeneous nucleation, may not be easily achievable under gravity. In order to check these results, the prediction is confronted with nucleation experiments of some organic and inorganic crystals. The results are in excellent agreement with the theory.

  18. Investigating Population Heterogeneity With Factor Mixture Models

    ERIC Educational Resources Information Center

    Lubke, Gitta H.; Muthen, Bengt

    2005-01-01

    Sources of population heterogeneity may or may not be observed. If the sources of heterogeneity are observed (e.g., gender), the sample can be split into groups and the data analyzed with methods for multiple groups. If the sources of population heterogeneity are unobserved, the data can be analyzed with latent class models. Factor mixture models…

  19. (99m)Tc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging.

    PubMed

    Li, Dan; Chen, Yuanyuan; Wang, Xia; Deuther-Conrad, Winnie; Chen, Xin; Jia, Bing; Dong, Chengyan; Steinbach, Jörg; Brust, Peter; Liu, Boli; Jia, Hongmei

    2016-02-11

    We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ2 receptor ligands. Rhenium compound 20a possessed low nanomolar σ2 receptor affinity (K(i) = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [(99m)Tc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [(99m)Tc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection.

  20. (99m)Tc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging.

    PubMed

    Li, Dan; Chen, Yuanyuan; Wang, Xia; Deuther-Conrad, Winnie; Chen, Xin; Jia, Bing; Dong, Chengyan; Steinbach, Jörg; Brust, Peter; Liu, Boli; Jia, Hongmei

    2016-02-11

    We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ2 receptor ligands. Rhenium compound 20a possessed low nanomolar σ2 receptor affinity (K(i) = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [(99m)Tc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [(99m)Tc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection. PMID:26741785

  1. Mu opioid receptor up-regulation and participation in excitability of hippocampal pyramidal cell electrophysiology

    SciTech Connect

    Moudy, A.M.

    1988-01-01

    Chronic administration of opiate antagonists to rats results in up-regulation of their brain opioid receptors. Using subcellular fractionation techniques, brain opioid receptors were resolved into two membrane populations, one associated with synaptic plasma membranes (SPM) and the other enriched in smooth endoplasmic reticulum and Golgi (microsomes). This study addressed in part the question of whether an antagonist induces up-regulation uniformly in these two populations. Rats were administered naltrexone by subcutaneously implanted osmotic minipumps. Forebrain mu receptor levels were determined by homologous displacement of ({sup 3}H)D-ala{sup 2}-mePhe{sup 4}-gly-ol{sup 5}-enkephalin (DAGO) followed by computer estimation of binding parameters. Receptor levels in crude membranes rose 77% after treatment. Microsomes displayed a 92% increase, a two-fold greater change than in SPMs (51%). These results establish that naltrexone induces up-regulation of both membrane populations; and that microsomal and SPM receptors represent discrete populations of intracellular and cell surface sites, respectively. Binding experiments on isolated hippocampi also demonstrated up-regulation (71%) of mu receptors. To demonstrate up-regulation of opioid receptors electrophysiologically, hippocampal slices were prepared from rats which had been chronically treated with naltrexone. After superfusion with DAGO, these slices showed a 42% greater population spike output than controls in response to the same EPSP input. Hippocampi from animals treated for two weeks showed an additional increase in sensitivity. The results support a disinhibitory role for opioids in pyramidal cell hyper-excitability. More importantly, they demonstrate a significant physiological correlate to opioid receptor up-regulation.

  2. Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric analysis of opiates and metabolites in rat urine after inhalation of opium.

    PubMed

    Kikura-Hanajiri, R; Kaniwa, N; Ishibashi, M; Makino, Y; Kojima, S

    2003-06-01

    To examine the urinary excretion of opiates and their metabolites following inhalation exposure of rats to opium, analytical procedures for the simultaneous determination of the compounds in opium, the vapor derived by the volatilization of opium and the urine of rats exposed to the opium vapor were developed using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS). Seven compounds were determined in the opium, namely morphine, codeine, thebaine, noscapine, papaverine, meconic acid and meconin. All seven were extracted with 2.5% acetic acid solution and subjected to LC-APCI-MS analysis. The separation was performed on an ODS column in acetonitrile-50 mM ammonium formate buffer (pH 3.0) using a linear gradient program and quantitative analysis was carried out in the selected ion monitoring mode ([M+H](+)). For the analysis of the volatilization of opium, the opium (1 g) was added to a glass pipe, which was then heated at 300 degrees C for 20 min. Negative pressure (air flow-rate; 300 ml/min) was used to draw the vapor through a series of glass wool and methanol traps. The total amount of each compound in the vapor was estimated by measurement of the compounds trapped in the glass wool and methanol. Wister rats (n=3) were exposed to the vapor derived from the volatilization system and the urinary amounts (0-72 h) of the six opiates and metabolites including morphine-3-grucronide (M3G) and morphine-6-grucronide (M6G) were measured after solid-phase extraction. The calibration curves for those compounds in the rat urine were linear over the concentration range 10-500 ng/ml. The recoveries for each analyte from the rat urine sample spiked with standard solution were generally greater than 80%, and the relative standard deviation for the analytical procedure was less than 8% with the exception of meconin. After inhalation exposure of rats to opium, M3G (5.45-14.38 micro g), morphine (2.27-4.65 micro g), meconin (0.54-1.85 micro

  3. Root Patterns in Heterogeneous Soils

    NASA Astrophysics Data System (ADS)

    Dara, A.; Moradi, A. B.; Carminati, A.; Oswald, S. E.

    2010-12-01

    Heterogeneous water availability is a typical characteristic of soils in which plant roots grow. Despite the intrinsic heterogeneity of soil-plant water relations, we know little about the ways how plants respond to local environmental quality. Furthermore, increasing use of soil amendments as partial water reservoirs in agriculture calls for a better understanding of plant response to soil heterogeneity. Neutron radiography is a non-invasive imaging that is highly sensitive to water and root distribution and that has high capability for monitoring spatial and temporal soil-plant water relations in heterogeneous systems. Maize plants were grown in 25 x 30 x 1 cm aluminum slabs filled with sandy soil. On the right side of the compartments a commercial water absorbent (Geohumus) was mixed with the soil. Geohumus was distributed with two patterns: mixed homogeneously with the soil, and arranged as 1-cm diameter aggregates (Fig. 1). Two irrigation treatments were applied: sufficient water irrigation and moderate water stress. Neutron radiography started 10 days after planting and has been performed twice a day for one week. At the end of the experiment, the containers were opened, the root were removed and dry root weight in different soil segments were measured. Neutron radiography showed root growth tendency towards Geohumus treated parts and preferential water uptake from Geohumus aggregates. Number and length of fine lateral roots were lower in treated areas compared to the non-treated zone and to control soil. Although corn plants showed an overall high proliferation towards the soil water sources, they decreased production of branches and fine root when water was more available near the main root parts. However there was 50% higher C allocation in roots grown in Geohumus compartments, as derived by the relative dry weight of root. The preferential C allocation in treated regions was higher when plants grew under water stress. We conclude that in addition to the

  4. Synchronization in growing heterogeneous media

    NASA Astrophysics Data System (ADS)

    Chen, W.; Cheng, S. C.; Avalos, E.; Drugova, O.; Osipov, G.; Lai, Pik-Yin; Chan, C. K.

    2009-04-01

    Synchronization of heterogeneous systems that consist of oscillatory and passive elements are studied in cardiac myocytes/fibroblasts co-cultures. It is found that beating clusters of cardiac myocytes surrounded by fibroblasts will be formed. The beatings of the cardiac myocyte clusters are not correlated at early times, but get synchronized as the cultures mature. This synchronization can be understood by a Kuramoto model with a time-increasing coupling strength. Our findings show that the growth of the coupling strength between clusters is linear, while the overall wave dynamics of the system is controlled by the passive fibroblast in the system which presumably is growing exponentially.

  5. A Heterogeneous Medium Analytical Benchmark

    SciTech Connect

    Ganapol, B.D.

    1999-09-27

    A benchmark, called benchmark BLUE, has been developed for one-group neutral particle (neutron or photon) transport in a one-dimensional sub-critical heterogeneous plane parallel medium with surface illumination. General anisotropic scattering is accommodated through the Green's Function Method (GFM). Numerical Fourier transform inversion is used to generate the required Green's functions which are kernels to coupled integral equations that give the exiting angular fluxes. The interior scalar flux is then obtained through quadrature. A compound iterative procedure for quadrature order and slab surface source convergence provides highly accurate benchmark qualities (4- to 5- places of accuracy) results.

  6. Cellulose conversion under heterogeneous catalysis.

    PubMed

    Dhepe, Paresh L; Fukuoka, Atsushi

    2008-01-01

    In view of current problems such as global warming, high oil prices, food crisis, stricter environmental laws, and other geopolitical scenarios surrounding the use of fossil feedstocks and edible resources, the efficient conversion of cellulose, a non-food biomass, into energy, fuels, and chemicals has received much attention. The application of heterogeneous catalysis could allow researchers to develop environmentally benign processes that lead to selective formation of value-added products from cellulose under relatively mild conditions. This Minireview gives insight into the importance of biomass utilization, the current status of cellulose conversion, and further transformation of the primary products obtained.

  7. [Opioid μ receptors mediate the stress-induced spatial reference memory impairment].

    PubMed

    Cao, Lan-Qin; Wen, Jie; Liu, Zhi-Qiang

    2015-04-25

    Learning/memory impairment is one of the most serious problems induced by stress, and the underlying mechanisms remain unclear. Opiates and opioid receptors are implicated in multiple physiological functions including learning and memory. However, there is no clear evidence whether the endogenous opioid system is involved in the formation of the stress-induced spatial reference memory impairment. The aim of the present study was to evaluate the role of μ opioid receptor in the stress-induced spatial reference memory impairment by means of Morris water maze (MWM) test in a mouse elevated platform stress model. The mice were trained in the MWM for four trials a session for 4 consecutive days after receiving the elevated platform stress, and intracerebroventricular injection of μ opioid receptor agonist DAMGO, antagonist CTAP or saline. Retention of the spatial training was assessed 24 h after the last training session with a 60-s free-swim probe trial using a new starting position. The results showed that intracerebroventricular injection of μ opioid receptor agonist DAMGO but not antagonist CTAP before MWM training impaired the memory retrieval of mice. Elevated platform stress before MWM training also impaired memory retrieval, which could be reversed by pre-injection of CTAP, and aggravated by DAMGO. These results suggest that endogenous opioid system may play a crucial role in the formation of the stress-induced memory impairment.

  8. Chronic exposure to morphine decreases the expression of EAAT3 via opioid receptors in hippocampal neurons.

    PubMed

    Guo, Mingyan; Cao, Dexiong; Zhu, Siyu; Fu, Ganglan; Wu, Qiang; Liang, Jianjun; Cao, Minghui

    2015-12-01

    Alterations in glutamate transporter expression are closely related to opiate addition behavior, but the role of opioid receptors is unclear. In this study, we used primary cultures of hippocampal neurons from neonatal rats to study the effects of chronic exposure to morphine on excitatory amino acid transporter 3 (EAAT3) expression and the roles of µ opioid receptor (MOR), δ opioid receptor (DOR), and κ opioid receptor (KOR) in the morphine-dependent alterations in EAAT3 expression. The results showed that the EAAT3 protein and mRNA expression levels decreased significantly after chronic exposure to morphine (10μmol/L) for 48h, whereas the concentration of extracellular glutamate increased. In addition, we found that both the MOR inhibitor CTOP and the DOR inhibitor naltrindole could reverse the decreased expression of EAAT3 after exposure to morphine, whereas the MOR activator DAMGO and the DOR activator DPDPE significantly decreased EAAT3 expression. The KOR inhibitor had no effect on the expression of EAAT3, whereas its activator increased EAAT3 expression. These results suggest that the down-regulation of morphine-dependent EAAT3 expression in primary rat hippocampal cultures may be mediated by MOR and DOR and that KOR may not contribute significantly to this effect.

  9. Comparison of [(3)H]Glyburide binding with opiate analgesia, tolerance, and dependence in ICR and Swiss-Webster mice.

    PubMed

    Campbell, V C; Dewey, W L; Welch, S P

    2000-12-01

    Our laboratory demonstrated that morphine exhibits a modulatory control over the glyburide-binding site (sulfonylurea receptor) of the ATP-gated K(+) channel. This study evaluated the effect of chronic morphine administration on the sulfonylurea receptor during tolerance and physical dependence. ICR and Swiss-Webster mice were rendered tolerant to morphine by pellet implantation and were withdrawn by pellet removal. Alterations in the B(max) and K(D) were evaluated in mouse spinal cord using the radiolabeled ATP-gated K(+) channel blocker glyburide. The ED(50) for Swiss-Webster mice shifted from 13 to 451 mg/kg and thus they were more tolerant to morphine than ICR mice (ED(50) shift from 12 to 120 mg/kg). Swiss-Webster mice were also dependent to morphine only when the morphine pellet was in place, unlike ICR mice, which were dependent for 48 h after morphine pellet removal. Glyburide binding increased during chronic morphine treatment in Swiss-Webster mice by over 2-fold (from 294 to 635 fmol/mg of protein). This was not observed in ICR mice. In Swiss-Webster mice, chronic morphine treatment also significantly increased the K(D) by 3-fold (from 0.38 to 1.1 nM), whereas there was no change in affinity for ICR mice. Both strains of mice remained tolerant for 2 days after spontaneous withdrawal from morphine. However, the only increases in the B(max) and K(D) of glyburide were observed in Swiss-Webster mice that were highly tolerant to morphine. These results indicate that a high degree of tolerance is needed to alter ATP-gated potassium channels.

  10. Calibration device for heterogeneous immunoassay

    SciTech Connect

    Sizto, N.C.; Roux, C.G.

    1988-12-13

    This patent describes a method for determining the presence in a sample of an analyte, which is a member of a specific binding pair (mip) consisting of ligand and receptor (antiligand). The method consists of contacting with the sample at least one enzyme including an enzyme bound to a mip (''enzyme-bound-mip'') and a solute which is catalytically transformed by an enzyme bound to a mip-containing measurement first surface to produce a change in a detectable signal at the first surface in proportion to the amount of enzyme-bound-mip bound to the first surface. The enzyme-bound-mip binds to the first surface in proportion to the amount of analyte iin the sample. A calibration second surface is also contacted to the sample. The second surface enzyme becomes bound in an amount which provides substantially predetermined ratios to the amount of the enzyme bound to the first surface, whereby the intensity of the signal at the second surface compared to the intensity of signal at the first surface is related to the amount of analyte in the sample. The method then involves determining the signal. The improvement comprises employing on the second surface a receptor for the enzyme-bound-mip, the receptor being capable of specific binding to the enzyme-bound-mip and being substantially incapable of binding to the enzyme or the mip part from the enzyme-bound-mip.

  11. Dispersivity in heterogeneous permeable media

    SciTech Connect

    Chesnut, D.A.

    1994-01-01

    When one fluid displaces another through a one-dimensional porous medium, the composition changes from pure displacing fluid at the inlet to pure displaced fluid some distance downstream. The distance over which an arbitrary percentage of this change occurs is defined as the mixing zone length, which increases with increasing average distance traveled by the displacement front. For continuous injection, the mixing zone size can be determined from a breakthrough curve as the time required for the effluent displacing fluid concentration to change from, say, 10% to 90%. In classical dispersion theory, the mixing zone grows in proportion to the square root of the mean distance traveled, or, equivalently, to the square root of the mean breakthrough time. In a multi-dimensional heterogeneous medium, especially at field scales, the size of the mixing zone grows almost linearly with mean distance or travel time. If an observed breakthrough curve is forced to fit the, clinical theory, the resulting effective dispersivity, instead of being constant, also increases almost linearly with the spatial or temporal scale of the problem. This occurs because the heterogeneity in flow properties creates a corresponding velocity distribution along the different flow pathways from the inlet to the outlet of the system. Mixing occurs mostly at the outlet, or wherever the fluid is sampled, rather than within the medium. In this paper, we consider the effects. of this behavior on radionuclide or other contaminant migration.

  12. Shock Initiation of Heterogeneous Explosives

    SciTech Connect

    Reaugh, J E

    2004-05-10

    The fundamental picture that shock initiation in heterogeneous explosives is caused by the linking of hot spots formed at inhomogeneities was put forward by several researchers in the 1950's and 1960's, and more recently. Our work uses the computer hardware and software developed in the Advanced Simulation and Computing (ASC) program of the U.S. Department of Energy to explicitly include heterogeneities at the s