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  • 1.
    Bivehed, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strömvall, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry2017In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 87, 20-27 p.Article in journal (Refereed)
    Abstract [en]

    Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites. Conversion and degradation products of Dynorphin B as model neuropeptide and effects of peptidase inhibitors applied to native brain tissue sections were analyzed at different brain locations. Synthetic dynorphin B (2 pmol) was found to be converted to the N-terminal fragments on brain sections whereas fewer C-terminal fragments were detected. N-ethylmaleimide (NEM), a non-selective inhibitor of cysteine peptidases, almost completely blocked the conversion of dynorphin B to dynorphin B(1-6; Leu-Enk-Arg), (1-9), (2-13), and (7-13). Proteinase inhibitor cocktail, and also incubation with acetic acid displayed similar results. Bioconversion of synthetic dynorphin B was region-specific producing dynorphin B(1-7) in the cortex and dynorphin B (2-13) in the striatum. Enzyme inhibitors showed region-and enzyme-specific inhibition of dynorphin bioconversion. Both phosphoramidon (inhibitor of the known dynorphin converting enzyme neprilysin) and opiorphin (inhibitor of neprilysin and aminopeptidase N) blocked cortical bioconversion to dynorphin B(1-7), wheras only opiorphin blocked striatal bioconversion to dynorphin B(2-13). This method may impact the development of novel therapies with aim to strengthen the effects of endogenous neuropeptides under pathological conditions such as chronic pain. Combining histochemistry and MALDI imaging MS is a powerful and sensitive tool for the study of inhibition of enzyme activity directly in native tissue sections. (C) 2016 The Authors. Published by Elsevier Inc.

  • 2.
    Botros, Milad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Johansson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tömblöy, Csaba
    Toth, Geza
    Le Greves, Pierre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Hallberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Endomorphins interact with the substance P (SP) aminoterminal SP (1-7) binding in the ventral tegmental area of the rat brain2008In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 29, no 10, 1820-1824 p.Article in journal (Refereed)
    Abstract [en]

    We have recently identified a specific binding site for the tachykinin peptide substance P (SP) fragment SP1-7 in the rat spinal cord. This site appeared very specific for SP1-7 as the binding affinity of this compound highly exceeded those of other SP fragments. We also observed that endomorphin-2 (EM-2) exhibited high potency in displacing SP1-7 from this site. In the present work using a [H-3]-labeled derivative of the heptapeptide we have identified and characterized [H-3]-SP1-7 binding in the rat ventral tegmental area (VTA). Similarly to the [H-3]-SP1-7 binding in the spinal cord the affinity of unlabeled SP1-7 to the specific site in VTA was significantly higher than those of other SP fragments. Further, the tachykinin receptor NK-1, NK-2 and NK-3 ligands showed no or negligible binding to the identified site. However, the mu-opioid peptide (MOP) receptor agonists DAMGO, EM-1 and EM-2 did, and significant difference was observed in the binding affinity between the two endomorphins. As recorded from displacement curves the affinity of EM-2 for the SP1-7 site was 4-5 times weaker than that for SP1-7 but about 5 times higher than that of EM-1. The opioid receptor antagonists naloxone and naloxonazine showed weak or negligible binding. it was concluded that the specific site identified for SP1-7 binding in the rat VTA is distinct from the MOP receptor although it exhibits high affinity for EM-2.

  • 3. Carlini, Valeria P
    et al.
    Ghersi, Marisa
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Barioglio, Susana R
    Ghrelin and memory: differential effects on acquisition and retrieval2010In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 31, no 6, 1190-1193 p.Article in journal (Refereed)
    Abstract [en]

    In a previous paper we have demonstrated that the orexigenic peptide Ghrelin (Ghr), increases memory retention in rats and mice. In the present work we evaluated the Ghr effect when it was administered previous the training session or previous the test session (24h after training) on the memory performance, using step-down test. The results showed that the intra-hippocampal Ghr administration previous the training session improved the long-term memory in this task, but did not modify the short-term memory. Nevertheless, when the Ghr was administrated previous the test session, no changes were observed in the memory performance. Taking into account these results and other previously published by our group, we could hypothesizes that Ghr may modulate specific molecular intermediates involved in memory acquisition/consolidation but not in the retrieval.

  • 4. Carlini, Valeria P.
    et al.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Barioglio, Susana R.
    Melanin-concentrating hormone (MCH) reverts the behavioral effects induced by inescapable stress2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 9, 2300-2306 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to investigate if MCH modifies the feeding and freezing responses in rats exposed to stressful stimuli. We used a basic version of contextual fear, where one group of rats were placed in a novel environment and two different groups were exposed to footshock paradigms, one of them escapable and the other one inescapable. At the end of each treatment, freezing and feeding were measured. Only the animals exposed to inescapable footshock paradigm showed significant increase in the food intake and freezing behavior in comparison to the control animals. The MCH administration (intra-hippocampal or intra-amygdaline) reverted these effects elicited by inescapable footshock. Results presented in this paper lead us to the assumption that the anxiolytic effect of the peptide is responsible for the reversion of the IS effects.

  • 5.
    Ghersi, Marisa Soledad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Casas, Sebastian M.
    Escudero, Carla
    Carlini, Valeria P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Buteler, Florencia
    Cabrera, Ricardo J.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Barioglio, Susana R.
    Ghrelin inhibited serotonin release from hippocampal slices2011In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 11, 2367-2371 p.Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Ghr) is a peptide produced peripherally and centrally. It participates in the modulation of different biological processes. In our laboratory we have shown that (a) Ghr administration, either intracerebroventricular or directly into the hippocampus enhanced memory consolidation in a step down test in rats (b) the effect of Ghr upon memory decreases in animals pretreated with a serotonin (5-HT) reuptake inhibitor, Fluoxetine, suggesting that Ghr effects in the hippocampus could be related to the availability of 5-HT. It has been demonstrated that Ghr inhibits 5-HT release from rat hypothalamic synaptosomes. Taking in mint these evidences, we studied the release of radioactive 5-HT to the superfusion medium from hippocampal slices treated with two doses of Ghr (0.3 and 3 nm/mu l). Ghr inhibited significantly the 5-HT release in relation to those superfused with artificial cerebrospinal fluid (ACSF) (H = 9.48, df = 2, p <= 0.05). In another set of experiments. Ghr was infused into the CA1 area of hippocampus of the rats immediately after training in the step down test and the 5-HT release from slices was studied 24 h after Ghr injection showing that in this condition also the 5-HT release was inhibited (H = 11.72, df = 1, p < 0.05). In conclusion, results provide additional evidence about the neurobiological bases of Ghr action in hippocampus.

  • 6. Gibbons, Catherine
    et al.
    Finlayson, Graham
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Blundell, John E
    Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 77, 3-8 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited.

    OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size).

    PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180min before an ad libitum lunch was provided.

    RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size.

    CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.

  • 7. Gonzalez, Patricia Verónica
    et al.
    Cragnolini, Andrea Beatriz
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Scimonelli, Teresa Nieves
    Interleukin-1 beta-induced anorexia is reversed by ghrelin2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 12, 3220-3225 p.Article in journal (Refereed)
    Abstract [en]

    Interleukins, in particular interleukin-1β (IL-1β), reduce food intake after peripheral and central administration, which suggests that they contribute to anorexia during various infectious, neoplastic, and autoimmune diseases. On the other hand, ghrelin stimulates food intake by acting on the central nervous system (CNS) and is considered an important regulator of food intake in both rodents and humans. In the present study, we investigated if ghrelin could reverse IL-1β-induced anorexia. Intracerebroventricular (i.c.v.) injection of 15, 30 or 45 ng/μl of IL-1β caused significant suppression of food intake in 20 h fasting animals. This effect lasted for a 24 h period. Ghrelin (0.15 nmol or 1.5 nmol/μl) produced a significant increase in cumulative food intake in normally fed animals. However, it did not alter food intake in 20 h fasting animals. Central administration of ghrelin reduced the anorexic effect of IL-1β (15 ng/μl). The effect was observed 30 min after injection and lasted for the next 24 h. This study provides evidence that ghrelin is an orexigenic peptide capable of antagonizing IL-1β-induced anorexia.

  • 8.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Takahashi, Akiyoshi
    Holmén, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Enberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Further evidence for ancient role of ACTH peptides at melanocortin (MC) receptors; pharmacology of dogfish and lamprey peptides at dogfish MC receptors2007In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, no 4, 798-805 p.Article in journal (Refereed)
    Abstract [en]

    The cloning of melanocortin (MC) receptors in distant species has provided us tools to get insight in how the ligand–receptors interactions in the MC system have evolved. We have however lacked studies on pharmacology of native ancient melanocortin peptides at the ancient MC receptors. In this paper we synthesized melanocortin peptides from both the sea lamprey (Petromyzon marinus) and spiny dogfish (Squalus acanthias) and tested them on the MC3 and MC4 receptors from spiny dogfish. The results show that both the dogfish and lamprey ACTH peptides have similar or higher affinity than the dogfish α-, β- and γ-MSH peptides to the dogfish MC3 and MC4 receptors. Moreover, both the dogfish and lamprey ACTH peptides have more than 10-fold higher affinity than α-MSH to the dogfish MC4 receptor. We also show that dogfish δ-MSH is able to bind to MC receptors and its potency is higher than of dogfish β-MSH, which is considered to be its precursor. Our results provide the first evidence that native ACTH ligands from dogfish and lamprey have a preference above native MSH peptides to ancient version of the MC3 and MC4 receptors. This further strengthens the hypotheses that the ligand contributing to the first version of the melanocortin ligand-receptor system resembled ACTH.

  • 9.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Anabolic-androgenic steroids affect the content of substance P and substance P(1-7) in the rat brain2000In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 21, no 6, 845-852 p.Article in journal (Refereed)
    Abstract [en]

    The effects of intramuscular (i.m.) injections of nandrolone decanoate (15 mg/kg/day), an anabolic-androgenic steroid, on the levels of substance P (SP) and on its N-terminal fragment SP(1-7) were examined in the male rat brain by radioimmunoassay. The results demonstrated that the SP immunoreactivity in amygdala, hypothalamus, striatum, and periaqueductal gray was significantly enhanced, whereas the concentration of the N-terminal fragment SP(1-7) was enhanced in the nucleus accumbens and in periaqueductal gray. In the striatum the steroid induced a decrease in the content of SP(1-7). The relevance of these peptides in connection with anabolic-androgenic steroid-induced aggression is discussed.

  • 10.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of chronic nandrolone decanoate administration on the expression of the NK1 receptor density in rat brain as determined by autoradiography2005In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 7, 1228-1234 p.Article in journal (Refereed)
    Abstract [en]

    Adult male Sprague–Dawley rats were treated with the anabolic androgenic steroid nandrolone decanoate (15 mg/kg day) or oil vehicle (sterile arachidis oleum) during 14 days. The effect on the densities of the neurokinin NK1 receptor in brain was examined with autoradiography. An overall tendency of attenuation of NK1 receptor density was observed after completed treatment with nandrolone decanoate. The density of the NK1 receptor was found to be significantly lower compared to control animals in the nucleus accumbens core (37% density reduction), in dentate gyrus (26%), in basolateral amygdaloid nucleus (23%), in ventromedial hypothalamic nucleus (36%), in dorsomedial hypothalamic nucleus (43%) and finally in the periaqueductal gray (PAG) (24%). In the cortex region, no structures exhibited any significant reduction of NK1 receptor density. This result provides additional support to the hypothesis that substance P and the NK1 receptor may be involved as important components that participate in mediating physiological responses including the adverse behaviors often associated with chronically administrated anabolic androgenic steroids in human.

  • 11.
    Jackson, Graham E
    et al.
    Dept. Chemistry, Cape Town, South Africa.
    Mabula, Andre N
    Dept. Chemistry, Cape Town, South Africa.
    Stone, Shane R
    Dept. Chemistry, Cape Town, South Africa.
    Gäde, Gerd
    Dept. Chemistry, Cape Town, South Africa.
    Kövér, Katalin E
    Hungary.
    Szilágyi, László
    Hungary.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Solution conformations of an insect neuropeptide: crustacean cardioactive peptide (CCAP)2009In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, no 3, 557-564 p.Article in journal (Refereed)
    Abstract [en]

    The solution structure of crustacean cardioactive peptide (CCAP), a cyclic amidated nonapeptide neurohormone, was studied using molecular dynamics techniques, with constraints derived from NMR studies in water and water/dodecylphosphocholine micellar medium. This peptide, found in various invertebrates, has the primary sequence Pro(1) Phe(2) Cys(3) Asn(4) Ala(5) Phe(6) Thr(7) Gly(8) Cys(9) NH(2), with an intramolecular disulfide bridge between the two cysteine residues. In aqueous solution the peptide was found to have a type(IV) beta-turn between residues 5-8. In a water/decane biphasic medium a type(IV) beta-turn between residues 3 and 6 and two classic gamma-turns between residues 4-6 and 7-9, were found. Analysis of the (1)H and (13)C NMR chemical shifts data showed that the model free S(2) order parameter of the residues varied between 0.65 and 0.9. The molecular dynamic root mean square fluctuations of structural ensembles of the backbone varied between 0.5 and 2.2 with the central residues showing the least fluctuations.

  • 12.
    Johansson, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Winnergren, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hulting, Anna-Lena
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The relative impact of chronic food restriction and acute food deprivation on plasma hormone levels and hypothalamic neuropeptide expression2008In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 29, no 9, 1588-1595 p.Article in journal (Refereed)
    Abstract [en]

    Our understanding of the central regulation of food intake and body weight has increased tremendously through implication of a high number of neuropeptides. However, lack of all-embracing studies have made comparison difficult in the past. The objective of this study was to demonstrate the relative importance of the different neuropeptides in terms of involvement in appetite regulatory mechanisms. We quantified expression levels of 21 hypothalamic neuropeptides and circulating levels of leptin, insulin, corticosterone, adrenocorticotropic hormone, ghrelin and adiponectin in rats after acute food deprivation and chronic food restriction using validated quantitative real-time PCR and hormone measurements. Body weight, insulin and leptin were reduced whereas corticosterone was increased by both acute food deprivation and chronic food restriction. Our results confirmed the relative importance in body weight homeostasis of neuropeptide Y and proopiomelanocortin, which were increased and decreased as predicted. The expression of other neuropeptides previously attributed central roles in body weight homeostasis, e.g. melanin-concentrating hormone and orexin, appeared to be less affected by the treatments. Moreover, the expression of dynorphin, galanin-like peptide and neuropeptide B was dramatically reduced after both treatments. This suggests that the latter neuropeptides--although previously known to be involved in body weight homeostasis--may be of unexpected importance in states of negative energy balance.

  • 13.
    Larsson, Tomas A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larson, Earl T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Conlon, J Michael
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Characterization of NPY receptor subtypes Y2 and Y7 in rainbow trout Oncorhynchus mykiss2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 6, 1320-1327 p.Article in journal (Refereed)
    Abstract [en]

    We report the cloning and pharmacological characterization of two neuropeptide Y (NPY) receptor subtypes, Y2 and Y7, in rainbow trout (Oncorhynchus mykiss). These subtypes are approximately 50% identical to each other and belong to the Y2 subfamily of NPY receptors. The binding properties of the receptors were investigated after expression in human HEK-293 EBNA cells. Both receptors bound the three zebrafish peptides NPY, PYYa, and PYYb, as well as porcine NPY and PYY, with affinities in the nanomolar range that are similar to mammalian Y2. The affinity of the truncated porcine NPY fragments, NPY 13-36 and NPY 18-36 was markedly lower compared to mammalian and chicken Y2. This suggests that mammalian and chicken Y2 are unique among NPY receptors in their ability to bind truncated peptide fragments. The antagonist BIIE0246, developed for mammalian Y2, did not bind either of the two rainbow trout receptors. Our results support the proposed expansion of this gene family by duplications before the gnathostome radiation. They also reveal appreciable differences in the repertoire and characteristics of NPY receptors between fish and tetrapods stressing the importance of lineage-specific gene loss as well as sequence divergence after duplication.

  • 14. Machado, Ivana
    et al.
    González, Patricia
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lasaga, Mercedes
    Scimonelli, Teresa Nieves
    α-Melanocyte-stimulating hormone (α-MSH) reverses impairment of memory reconsolidation induced by interleukin-1 beta (IL-1 beta) hippocampal infusions2010In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 31, no 11, 2141-2144 p.Article in journal (Refereed)
    Abstract [en]

    Interleukin-1 beta (IL-1β) significantly influences cognitive processes. Treatments which raise the level of IL-1β in the brain impair memory consolidation in contextual fear conditioning. However, the effect of IL-1β on memory reconsolidation has not yet been established. The melanocortin α-melanocyte-stimulating hormone (α-MSH) exerts potent anti-inflammatory actions by antagonizing the effect of proinflammatory cytokines. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, of which MC3R and MC4R are predominant in the central nervous system. The present experiments show that the injection of IL-1β (5 ng/0.25 μl) in dorsal hippocampus up to 30 min after re-exposition to the context decreases freezing during the contextual fear test. Impairment of memory reconsolidation was reversed by treatment with α-MSH (0.05 μg/0.25 μl). Administration of the MC4 receptor antagonist HS014 (0.5 μg/0.25 μl) blocked the effect of α-MSH. These results suggest that IL-1β may influence memory reconsolidation and that activation of central MC4R could lead to improve cognitive performance.

  • 15.
    Magnusson, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Enzymatic conversion of dynorphin A in the rat brain is affected by administration of nandrolone decanoate2007In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, no 4, 851-858 p.Article in journal (Refereed)
    Abstract [en]

    The misuse of anabolic androgenic steroids (AAS) seems to produce profound effects on the central nervous system, leading to aggressive behavior and increased sensitivity to other drugs of abuse. The present study addresses the effect on the enzymatic transformation, here called dynorphin converting enzyme-like activity. The formation of the mu/delta opioid peptide receptor-preferring Leu-enkephalin-Arg6 from the kappa opioid peptide receptor-preferring dynorphin A was measured in rats treated with nandrolone decanoate. Significant variations in enzymatic transformation were observed in several brain regions. An altered receptor activation profile in these regions may be one contributory factor behind AAS-induced personality changes.

  • 16.
    Mitra, Anaya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gosnell, Blake A
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Grace, Martha K
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S
    Chronic sugar intake dampens feeding-related activity of neurons synthesizing a satiety mediator, oxytocin2010In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 31, no 7, 1346-1352 p.Article in journal (Refereed)
    Abstract [en]

    Increased tone of orexigens mediating reward occurs upon repeated consumption of sweet foods. Interestingly, some of these reward orexigens, such as opioids, diminish activity of neurons synthesizing oxytocin, a nonapeptide that promotes satiety and feeding termination. It is not known, however, whether consumption-related activity of the central oxytocin system is modified under chronic sugar feeding reward itself. Therefore, we examined how chronic consumption of a rewarding high-sucrose (HS) vs. bland cornstarch (CS) diet affected the activity of oxytocin cells in the hypothalamus at the time of meal termination. Schedule-fed (2h/day) rats received either a HS or CS powdered diet for 20 days. On the 21st day, they were given the same or the opposite diet, and food was removed after the main consummatory activity was completed. Animals were perfused 60 min after feeding termination and brains were immunostained for oxytocin and the marker of neuronal activity, c-Fos. The percentage of c-Fos-positive oxytocin cells in the hypothalamic paraventricular nucleus was significantly lower in rats chronically exposed to the HS than to the CS diet, regardless of which diet they received on the final day. A similar pattern was observed in the supraoptic nucleus. We conclude that the chronic rather than acute sucrose intake reduces activity of the anorexigenic oxytocin system. These findings indicate that chronic consumption of sugar blunts activity of pathways that mediate satiety. We speculate that a reduction in central satiety signaling precipitated by regular intake of foods high in sugar may lead to generalized overeating.

  • 17.
    Muceniece, Ruta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Zvejniece, Liga
    Liepinsh, Edgars
    Kirjanova, Olga
    Baumane, Larisa
    Petrovska, Ramona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Mutulis, Felikss
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Mutule, Ilze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kalvinsh, Ivars
    Wikberg, Jarl E S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Dambrova, Maija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 6, 1443-1450 p.Article in journal (Refereed)
    Abstract [en]

    Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH, alpha-MSH, MS05, Ac-MS06 and Ac-[Ser12]MS06 caused dose dependent inhibition of the lipopolysaccharide (LPS)-induced increase of NO overproduction in the mice forebrain whereas MSH core modified peptides Ac-[Asp9,Ser12]MS06, [Asp9]alpha-MSH and [Asp16]beta-MSH were devoid of this effect in doses up to 10 nmol per mouse. When the minimal effective dose required for inhibition of NO production was correlated with the in vitro binding activity to MC receptor subtypes a strong and significant correlation was found for the MC3 receptor (r = 0.90; p = 0.0008), whereas weak correlation was present for the other receptors. Our results suggest that the MC3 receptor is the major player in mediating the anti-inflammatory activity of MCs in the central nervous system.

  • 18. Mugumbate, Grace
    et al.
    Jackson, Graham E.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Open conformation of adipokinetic hormone receptor from the malaria mosquito facilitates hormone binding2011In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 3, 553-559 p.Article in journal (Refereed)
    Abstract [en]

    Insect flight requires rapid mobilization of energy reserves during flight, which is mediated and regulated by hormonal control via adipokinetic hormones. The structure of the G-protein receptors to which these hormones bind, are crucial in understanding many of the physiological processes in which they play a central role. To date no 3D structure of an insect G-protein coupled receptor (GPCR) is available. Here, the first models of the 3D structures of a GPCR from the malaria mosquito are presented. Homology modeling of the receptor identified from the genome of Anopheles gambiae was used to construct two models of the receptor. The 7 transmembrane helical bundles of these two models are based on the crystal structures of beta2-adrenergic receptor and rhodopsin. The flexible loop regions were modeled using high temperature simulated annealing and constrained molecular dynamic simulations. The two receptor models differ in a number of critical features, the most important of which is that the rhodopsin-based model has a 'closed' structure while the beta2-based structure is 'open'. The 'open' conformation provides easy access of the hormone to the binding pocket. Docking calculations with the insect adipokinetic hormones, AKH-1 (pGlu-Leu-Thr-Phe-Thr-Pro-Ala-Trp-NH2) from the malaria mosquito and Del-CC (pGlu-Lys-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2) from the blister beetle showed that while the binding motif of the two is similar. AKH-1 has more than 30 times higher affinity than Del-CC, which strongly suggests that the binding is specific, and that the correct binding site was identified. Using these models it is possible to design antagonists, which block the binding site and are thus species-specific insecticides.

  • 19. Mugumbate, Grace
    et al.
    Jackson, Graham E.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Kövér, Katalin E.
    Szilágyi, Laszlo
    Anopheles gambiae, Anoga-HrTH hormone, free and bound structure: A nuclear magnetic resonance experiment2013In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 41, 94-100 p.Article in journal (Refereed)
    Abstract [en]

    The spread of malaria by the female mosquito, Anopheles gambiae, is dependent, amongst other things, on its ability to fly. This in turn, is dependent on the adipokinetic hormone, Anoga-HrTH (pGlu-Leu-Thr-Phe-Thr-Pro-Ala-Trp-NH2). No crystal structure of this important neuropeptide is available and hence NMR restrained molecular dynamics was used to investigate its conformational space in aqueous solution and when bound to a membrane surface. The results showed that Anoga-HrTH has an almost cyclic conformation that is stabilized by a hydrogen bond between the C-terminus and Thr3. Upon docking of the agonist to its receptor, this H-bond is broken and the molecule adopts a more extended structure. Preliminary AKHR docking calculations give the free energy of binding to be -47.30 kJ/mol. There is a close correspondence between the structure of the docked ligand and literature structure-activity studies. Information about the 3D structure and binding mode of Anoga-HrTH to its receptor is vital for the design of suitable mimetics which can act as insecticides. 

  • 20.
    Mutulis, Felikss
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Mutule, Ilze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Liepinsh, Edvards
    Yahorau, Aleh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Lapinsh, Maris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kopantshuk, Sergei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Veiksina, Santa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Rinken, Ago
    Wikberg, Jarl E S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    N-alkylated dipeptide amides and related structures as imitations of the melanocortins' active core2005In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 10, 1997-2016 p.Article in journal (Refereed)
    Abstract [en]

    Thirty-three low molecular mass structures combining both peptide and peptoid features were prepared and tested on human melanocortin receptors MC1,3-5R. Most of them displayed low micromolar activity with preference for diamines, guanidino and 2-naphthyl derivatives compared to monoacetylated, amino and 3-indolyl counterparts. Some contained L- or D-histidine residues, but the change did not influence affinity. QSAR modelling yielded excellent models for the MC3-5 receptors explaining R2Y=0.89-0.91 and predicting Q2=0.77-0.80 of the affinity variations. One compound displayed MC1R selectivity (13-fold and more). An NMR study of showed that it exists as a mixture of four rotamers at its tertiary amide bonds. Comparisons with earlier data for melanocortin core tetrapeptide analogues indicate that the novel peptide-peptoids interact with the melanocortin receptors in a different way.

  • 21. Ohsawa, Masahiro
    et al.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Asato, Megumi
    Koizumi, Takayuki
    Nakanishi, Yuki
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamei, Junzo
    The effect of substance P1-7 amide on nociceptive threshold in diabetic mice2011In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 1, 93-98 p.Article in journal (Refereed)
    Abstract [en]

    We previously demonstrated that intrathecal treatment with substance P metabolite substance P1-7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1-7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1-7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1-7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1-7. The antinociceptive effect of substance P1-7 amide was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the mu-, delta- or kappa-opioid receptor, respectively. In addition, the antinociceptive effect induced by substance P1-7 amide was partly reversed by the sigma(1) receptor agonist (+)-pentazocine, suggesting a possible involvement of the sigma(1) receptor for the action of this peptide. These results suggest that the actions of substance P1-7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the sigma(1) receptor system.

  • 22.
    Olinski, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Dahlberg, Carl
    Thorndyke, Mike
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Three insulin-relaxin-like genes in Ciona intestinalis2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 11, 2535-2546 p.Article in journal (Refereed)
    Abstract [en]

    The Ciona intestinalis genome harbors three insulin-like genes: INS-L1, -L2 and -L3. Conserved synteny between the Ciona-human genomes predicts that Ciona INS-Ls are orthologous to the vertebrate insulin-relaxin family, but this relation cannot be inferred from molecular phylogeny. A conserved protein core with six cysteines; typical arrangement of B-, C- and A-protein domains; pro-protein maturation mode; and putative insulin receptor-binding sites were identified in Ciona INS-L proteins. ESTs used to assemble exonic sequences of INS-Ls combined with qRT-PCR analysis provided evidence that the predicted genes are expressed in the developing and adult Ciona. Our results support that Ciona INS-L1 is orthologous to the vertebrate insulin-like/relaxin genes, INS-L2 to insulin genies and INS-L3 to IGF genes. Our analysis also implies that the insulin-like/relaxin ancestor switched receptor type from tyrosine kinase- to GPCR-type, whereas insulin-IGF subfamily retained the tyrosine kinase-type of receptor. We propose that this receptor-switch occurred after the time when urochordates branched from the common chordate lineage, but before the two genome-duplications at the root of the vertebrates.

  • 23.
    Olszewski, Pawel K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bomberg, Eric M.
    Grace, Martha K.
    Levine, Allen S.
    Alpha-melanocyte stimulating hormone and ghrelin: central interaction in feeding control2007In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, no 10, 2084-2089 p.Article in journal (Refereed)
    Abstract [en]

    Alpha-melanocyte stimulating hormone (alpha-MSH) and ghrelin play significant yet opposite roles in the regulation of feeding: alpha-MSH inhibits, whereas ghrelin stimulates consumption. The two peptidergic systems may interact in the process of food intake control. A single report published thus far has shown that a synthetic agonist of the melanocortin receptors, MTII, injected in the hypothalamic paraventricular nucleus (PVN) decreases feeding generated by ghrelin. We found that very low doses of alpha-MSH and MTII administered ICV significantly reduced ghrelin-dependent hyperphagia. However, an endogenous molecule, alpha-MSH, infused in the PVN did not exert an inhibitory effect on ghrelin-induced consumption, whereas the effective dose of PVN MTII exceeded that necessary to decrease short-term deprivation-induced feeding. We conclude that it is likely that in feeding regulation alpha-MSH and ghrelin "interact" at the central nervous system level, but the involvement of the PVN in this interaction appears questionable.

  • 24.
    Olszewski, Pawel K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Shaw, Timothy J
    Grace, Martha K
    Höglund, Catherine E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S
    Complexity of neural mechanisms underlying overconsumption of sugar in scheduled feeding: involvement of opioids, orexin, oxytocin and NPY2009In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, no 2, 226-233 p.Article in journal (Refereed)
    Abstract [en]

    A regular daily meal regimen, as opposed to ad libitum consumption, enforces eating at a predefined time and within a short timeframe. Hence, it is important to study food intake regulation in animal feeding models that somewhat reflect this pattern. We investigated the effect of scheduled feeding on the intake of a palatable, high-sugar diet in rats and attempted to define central mechanisms - especially those related to opioid signaling--responsible for overeating sweet foods under such conditions. We found that scheduled access to food, even as challenging as 20 min per day, does not prevent overconsumption of a high-sucrose diet compared to a standard one. An opioid receptor antagonist, naloxone, at 0.3-1 mg/kg b. wt., decreased the intake of the sweet diet, whereas higher doses were required to reduce bland food consumption. Real-time PCR analysis revealed that expression of hypothalamic and brainstem genes encoding opioid peptides and receptors did not differ in sucrose versus regular diet-fed rats, which suggests that scheduled intake of sweet food produces only a transient change in the opioid tone. Intake of sugar was also associated with upregulation of orexin and oxytocin genes in the hypothalamus and NPY in the brainstem. We conclude that scheduled consumption of sugar diets is associated with activity of a complex network of neuroregulators involving opioids, orexin, oxytocin and NPY.

  • 25.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differences in basal and ethanol-induced levels of opioid peptides in Wistar rats from five different suppliers2012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 36, no 1, 1-8 p.Article in journal (Refereed)
    Abstract [en]

    One major cause for discrepancies in results from animal experimental studies is the use of different animal strains and suppliers. We have previously reported that Wistar rats from five different suppliers display profound differences in ethanol intake and behavior. One of the neurobiological processes that could be underlying these differences is the endogenous opioid system, which has been implicated in the rewarding and reinforcing effects of alcohol. We therefore hypothesized that the differences between the supplier groups would also be evident in the endogenous opioid system. Radioimmunoassay was used to determine the levels of the opioid peptides Met-enkephalin-Arg(6)Phe(7) and dynorphin B in several brain areas of ethanol-drinking and ethanol naive Wistar rats from five different suppliers. In the ethanol naive animals, differences between the supplier groups were found in the pituitary gland, hypothalamus, frontal cortex, dorsal striatum and hippocampus. In the ethanol-drinking rats, differences were found in the same structures, with the addition of medial prefrontal cortex and substantia nigra. Correlations between ethanol intake and peptide levels were also found in several of the areas examined. The structures in which differences were found have all been implicated in the transition from drug use to addiction and these differences may lead to different propensities and vulnerability to this transition. Because the endogenous opioids have been suggested to be involved in a number of neurobiological disorders the results do not only have implications for research on alcohol or drug addiction, but many other fields as well.

  • 26.
    Paola Carlini, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Machado, Daniele Guilhermano
    Buteler, Florencia
    Ghersi, Marisa
    Ponzio, Marina F.
    Carolina Martini, Ana
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fiol de Cuneo, Marta
    Rodrigues, Ana Lucia S.
    de Barioglio, Susana R.
    Acute ghrelin administration reverses depressive-like behavior induced by bilateral olfactory bulbectomy in mice2012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 35, no 2, 160-165 p.Article in journal (Refereed)
    Abstract [en]

    This study aims to examine the antidepressant-like action of Ghrelin (Ghr), a hormone synthesized predominantly by gastrointestinal endocrine cells and released during periods of negative energy balance, in two behavioral models: tail suspension test (TST), a predictive model of antidepressant activity, and the olfactory bulbectomy (OB), an established animal model of depression. The reduction in the immobility time in the TST was the parameter used to assess antidepressant-like effect of Ghr. The depressive-like behavior in olfactory bulbectomized mice was inferred through the increase in the immobility time in the TST and the hyperlocomotor activity in the open-field test. Ghr produced antidepressant-like effect in TST (0.3 nmol/mu l, i.c.v.), and reversed OB-induced depressive-like behavior. In conclusion, these results provide clear evidence that an acute administration of ghrelin produce antidepressant-like effect in the TST and OB.

  • 27.
    Pickering, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Avesson, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Liljequist, Sture
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The role of hypothalamic peptide gene expression in alcohol self-administration behavior.2007In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, no 12, 2361-2371 p.Article in journal (Refereed)
    Abstract [en]

    Self-administration of ethanol and food share many common features and Richter hypothesized that an increase in ethanol consumption would decrease feeding to balance the excess calories contained in the ethanol. Previously, we have shown that individual alcohol consumption correlates with neurotransmitter gene expression, especially in the prefrontal cortex. To test the hypothesis of Richter, we measured hypothalamic gene expression of receptors or neuropeptides of known relevance for the regulation of food intake using qPCR and correlated this to individual ethanol consumption in Wistar rats. For validation, gene expression was first correlated with body weight. We found a correlation of dynorphin, somatostatin, melanocortin-4 receptor and serotonin 5-HT2C with body weight and trends to correlation for CART, thus confirming the established role of the hypothalamus in the regulation of weight. For ethanol consumption, correlations were found for CRH receptors I and 2 and vasopressin while strong trends were observed for galanin receptor 1, orexin receptor 1, MCH and adrenoceptor alpha(1B). Therefore, alcohol consumption does seem to involve several hypothalamic systems which also mediate feeding responses and suggests that the hypothalamus, together with the prefrontal cortex, may determine the 'stopping point' of an individual.

  • 28. Righard, Lennart
    et al.
    Carlsson-Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Enhanced levels of immunoreactive beta-casomorphin-8 in milk of breastfeeding women with mastitis2014In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 51, 54-58 p.Article in journal (Refereed)
    Abstract [en]

    An incorrect, superficial suckling technique in breastfeeding frequently leads to milk congestion and sometimes mastitis. In the present study we have examined whether milk congestion may affect levels of the atypical opioid beta-casomorphin-8 in milk and in plasma. We also investigated whether the rate of acute psychosis during the first half year after parturition has declined in Sweden over the years. Milk and plasma samples were collected for peptide analysis from 14 women with mastitis and 10 controls. We found that in a group of 14 late cases of mastitis (median 48 days post partum) the detected mean level of beta-casomorphin-8 in milk was significantly higher and somewhat higher in plasma at the acute stage compared with 2-3 weeks later, after recovery when the symptoms had disappeared, as well as compared to the control subjects. Swedish official statistics show that the incidence of acute psychosis in the first month and in the first half year after birth has declined by a half during the last 30 years. A relationship between postpartum psychosis and elevated beta-casomorphin-8 levels in CSF has been suggested from earlier studies. In this study, milk congestion led to enhanced levels of beta-casomorphin-8 in milk, which may be related to postpartum psychosis and probably also to the postnatal blues'.

  • 29. Samgina, Tatyana Yu.
    et al.
    Gorshkov, Vladimir A.
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vorontsov, Egor A.
    Klykov, Oleg V.
    Ogourtsov, Sergey V.
    Zubarev, Roman A.
    Lebedev, Albert T.
    LC-MS/MS with 2D mass mapping of skin secretions' peptides as a reliable tool for interspecies identification inside Rana esculenta complex2012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 34, no 2, 296-302 p.Article in journal (Refereed)
    Abstract [en]

    Identification of species constituting Rana esculenta complex represents a certain problem as two parental species Rana ridibunda and Rana lessonae form their hybrid R. esculenta, while external signs and sizes of the members of this complex are intersected. However the composition of skin secretion consisting mainly of peptides is different for the species of the complex. LC-MS/MS is an ideal analytical tool for the quantitative and qualitative analysis of these peptides. The results covering elemental composition of these peptides, their levels in the secretion, as well as their belonging to a certain family of peptides may be visualized by means of 2D mass maps. The proposed approach proved itself to be a perspective tool for the reliable identification of all 3 species constituting R. esculenta complex. Easy distinguishing between the species may be achieved using 2D maps as fingerprints. Besides this approach may be used to study hybridogenesis and mechanisms of hemiclonal transfer of genetic information, when rapid and reliable identification of species involved in the process is required.

  • 30. Sandin, Johan
    et al.
    Tan No, Koichi
    Kasakov, Lubomir
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Winter, Anders
    Silberring, Jerzy
    Terenius, Lars
    Differential metabolism of dynorphins in substantia nigra, striatum and hippocampus1997In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 18, no 7, 949-956 p.Article in journal (Refereed)
    Abstract [en]

    To map the proteolytic enzymes metabolizing dynorphins in brain structures, size-exclusion chromatography linked to electrospray ionization mass spectrometry was used. Enzymes extracted from rat hippocampus, striatum, and substantia nigra were tested for their capability of converting dynorphin-related peptides. Dynorphin A was the most resistant to proteolytic conversion, whereas Big dynorphin and dynorphin B-29 were slowly converted to dynorphin A and dynorphins A and B, respectively. Dynorphin B and alpha-neoendorphin were the least resistant. Dynorphin B was rapidly converted to Leu-enkephalin in the striatum and hippocampus but to Leu-enkephalin-Arg6 in the substantia nigra. alpha-Neoendorphin was converted to Leu-enkephalin in all tissues investigated.

  • 31.
    Schiöth, Helgi B
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Haitina, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ling, Maria K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ringholm, Aneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cerda-Reverter, J M
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes2005In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 10, 1886-1900 p.Article in journal (Refereed)
    Abstract [en]

    We have cloned melanocortin receptors (MCRs) from several species of fish. The MC4R and MC5R subtypes arose early in vertebrate evolution and their primary structure is remarkably conserved. Expression and pharmacological characterization of the MCRs in fish has revealed that they bind and respond to melanocortin peptides with high potency. Detailed characterization of the binding properties of the different subtypes suggests that MCRs in early vertebrates had preference for adrenocorticotropic hormone (ACTH) peptides, while the high sensitivity for the shorter proopiomelanocortin (POMC) products, such as the α-, β-, and γ-melanocyte-stimulating hormone (MSH), has appeared later, perhaps as the MCR subtypes gained more specialized functions. The MCR repertoire shows in general high similarities in their primary structures, while they are however not similar in terms of functional roles. The MCRs serve therefore as an interesting model family to understand the molecular mechanisms of how functions of the genes can diverge during evolution. In this review, we provide an overview of our recent studies on the cloning, expression, pharmacology, 3D modeling, and genomic studies of the MCRs in non-mammalian species.

  • 32. Silberring, Jerzy
    et al.
    Li, Yi-Ming
    Terenius, Lars
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Characterization of immunoreactive dynorphin B and beta-endorphin in human plasma1998In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 19, no 8, 1329-1337 p.Article in journal (Refereed)
    Abstract [en]

    Dynorphins and beta-endorphin in human plasma were characterized and studied quantitatively using radioimmunoassay, high-performance liquid chromatography (HPLC), and mass spectrometry. Most immunoreactive (ir) dynorphin B and beta-endorphin in human plasma coeluted with authentic peptides in analysis. Dynorphin A was not detected. Added to human plasma it was rapidly converted into Leu-enkephalin-Arg6 followed by elimination of the C-terminal arginine after prolonged incubation. The rate of dynorphin A conversion was estimated at 40 pmol/min/microl plasma. This process was inhibited by the thiol protease inhibitor, PHMB and by EDTA. Dynorphin B, alpha-neoendorphin and big dynorphin were virtually not metabolized by plasma proteases under the same conditions. beta-endorphin was processed into beta-endorphin(1-19) and the corresponding C-terminal counterpart beta-endorphin(20-31) at a rate of about 25 pmol/min/microl of plasma. Based on the above data, a reliable strategy was established to measure dynorphin B- and beta-endorphin-ir in human plasma samples. The basal levels in a male control group were 0.99 +/- 0.11 (n = 11) and 16.3 +/- 1.5 (n = 11) fmol/ml plasma, respectively.

  • 33.
    Sjögren, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Johnson, Ann-Louise
    Hedner, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dahlström, Mia
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Shirani, Hamid
    Bergman, Jan
    Jonsson, Per R.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Antifouling activity of synthesized peptide analogs of the sponge metabolite barettin2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 9, 2058-2064 p.Article in journal (Refereed)
    Abstract [en]

    Barettin (cyclo [(6-bromo-8-en-tryptophan) arginine]), a diketopiperazine isolated from the marine sponge Geodia barretti, is a potent inhibitor of barnacle larvae settlement with an EC50-value of 0.9 mu M. In the present study, 14 analogs of barettin and its structural congener dipodazine were synthezised and tested for their ability to inhibit larval settlement. Two of the analogs have an intact barettin skeleton. The remaining analogs have a dipodazine skeleton (a diketopiperazine where arginine is replaced with glycine). Six of the tested synthetic analogs displayed significant settlement inhibition with the most potent inhibitor being benzo[g]dipodazine, which displayed even stronger activity than barettin (EC50-value 0.034 mu M). The effect of benzo[g]dipodazine was also shown to be readily reversible, when cyprids were transferred to filtered seawater (FSW).

  • 34.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mizoguchi, Hirokazu
    Verbeek, Dineke S.
    Kuzmin, Alexander
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krishtal, Oleg
    Sakurada, Shinobu
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 232012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 35, no 2, 306-310 p.Article in journal (Refereed)
    Abstract [en]

    We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23.

  • 35.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Kuraku, Shigehiro
    RIKEN Center for Developmental Biology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus2013In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 39, 64-70 p.Article in journal (Refereed)
    Abstract [en]

    The neuropeptide Y system is known to have expanded in early vertebrate evolution. Three neuropeptide Y receptors have been proposed to have existed before the two basal vertebrate tetraploidizations, namely a VI-like, a Y2-like, and a Y5-like receptor, with their genes in the same chromosomal region. Previously we have described a VI-subfamily and a Y2-subfamily receptor in the river lamprey, Lampetra fluviatilis. Here we report the identification of a Y5 receptor in the genome of the sea lamprey, Petromyzon marinus. In phylogenetic analyses, the Y5 receptor clusters together with gnathostome Y5 receptors with high bootstrap value and shares the long intracellular loop 3. This lamprey receptor has an even longer loop 3 than the gnathostome Y5 receptors described so far, with the expansion of amino acid repeats. Functional expression in a human cell line, co-transfected with a modified human G-protein, resulted in inositol phosphate turnover in response to the three lamprey NPY-family peptides NPY, PYY and PMY at nanomolar concentrations. Our results confirm that the Y1-Y2-Y5 receptor gene triplet arose before the cyclostome-gnathostome divergence. However, it is not clear from the NPY receptors whether cyclostomes diverged from the gnathostome lineage after the first or the second tetraploidization. Duplicates resulting from the tetraploidizations exist for both Y1 and Y2 in gnathostomes, but only a single copy of Y5 has survived in all vertebrates characterized to date, making the physiological roles of Y5 interesting to explore.

  • 36.
    Zhou, Qin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hallberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats2009In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, no 12, 2418-2422 p.Article in journal (Refereed)
    Abstract [en]

    We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.

  • 37.
    Zhou, Qin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Substance P N-terminal fragment SP(1-7) attenuates chronic morphine tolerance and affects dynorphin B and nociceptin in rats2011In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 8, 1661-1665 p.Article in journal (Refereed)
    Abstract [en]

    The N-terminal substance P fragment SP(1-7) is known to modulate hyperalgesia and opioid withdrawal in animal models. This study examined the effects of intraperitoneal (i.p.) injections of SP(1-7) on chronic morphine tolerance and on the levels of dynorphin B (DYN B) and nociceptin/orphanin FQ(N/OFQ) in various brain areas of male Sprague Dawley rats. Morphine tolerance was induced by subcutaneous injections of the opioid (10 mg/kg) twice daily for 7 days. SP(1-7) injected i.p. (185 nmol/kg) 30 min prior to morphine reduced the development of morphine tolerance. Immunoreactive (it) DYN B and N/OFQ peptide levels were measured in several areas of the central nervous system. Levels of ir DYN B in rats treated with SP(1-7) and morphine were decreased in the nucleus accumbens. substantia nigra and ventral tegmental area and increased in the frontal cortex. The ir N/OFQ levels were increased in the periaqueductal gray and decreased in the nucleus accumbens. Since the concentration profiles of the two peptides were altered by SP(1-7) in the areas that are implicated in the modulation of opioid tolerance and analgesia, it is suggested that DYN B and N/OFQ systems may be involved in the effects of SP(1-7) on opioid tolerance.

  • 38.
    Zhou, Qin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The substance P (SP) heptapeptide fragment SP1-7 alters the density of dopamine receptors in rat brain mesocorticolimbic structures during morphine withdrawal2004In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 25, no 11, 1951-1957 p.Article in journal (Refereed)
    Abstract [en]

    The aminoterminal fragment of substance P (SP), SP(1-7), has been suggested to modulate the expression of opiate tolerance and withdrawal behaviors in rodents. However, the mechanism of this effect is not yet clarified. Using a rat model we have previously demonstrated that SP(1-7) affects dopamine transmission and the expression of the dopamine D2-receptor gene transcript in the nucleus accumbens during naloxone precipitated morphine withdrawal. In the present study, we have applied autoradiography to investigate the effect of the heptapeptide on the binding of dopamine D1- and D2-receptors in mesocorticolimbic brain areas of male rats during morphine withdrawal. Morphine dependent animals were treated with an injection of SP(1-7) into the ventral tegmental area prior to naloxone challenge. The result indicated that the SP fragment elicited a significant decrease in specific binding to D1-like receptors in the caudate putamen, nucleus accumbens shell, nucleus accumbens core, substantia nigra and medial globus pallidus. Radioligand binding to dopamine D2-like receptors was also altered by SP(1-7). The heptapeptide induced a decreased density of these sites in the ventral tegmental area but an increased binding in the substantia nigra and the frontal cortex. The observed alterations in the D1- and D2-like receptor density could reflect activations in dopamine pathways associated with the above-mentioned brain regions. The result provides further evidence for the modulatory effect of SP(1-7) on dopamine systems during opioid withdrawal, suggesting the possible role for the heptapeptide to regulate morphine withdrawal reactions.

  • 39.
    Åkerberg, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sallander, Marie
    Lagerstedt, Anne-Sofie
    Hedhammar, Åke
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Peripheral administration of pancreatic polypeptide inhibits components of food- intake behavior in dogs2010In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 31, no 6, 1055-1061 p.Article in journal (Refereed)
    Abstract [en]

    Pancreatic polypeptide (PP) belongs to the neuropeptide Y (NPY) family of peptides and is released from pancreatic F cells postprandially. PP functions as a peptide hormone and has been associated with decreased food intake in humans and rodents. Our study describes the effects of PP on feeding behavior in dogs, whose mammalian order (Carnivora) is more distantly related to primates and rodents than these are to each other. Furthermore, obesity is becoming more prevalent in dogs which makes knowledge about their appetite regulation highly relevant. Repeated peripheral administration of physiological doses of PP (three injections of 30 pmol/kg each that were administered within 30 min) to six male beagle dogs prolonged the median time spent eating three servings of food by 19% but resulted in no reduction of food intake. In addition, PP decreased the duration of food-seeking behavior after the first serving by 71%. Thus, a physiological dose of PP seems to decrease both the appetitive and the consummatory drive in dogs.

1 - 39 of 39
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