Browsing by Author "Millington, William R."
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Publication Blockade of a-adrenergic receptors in the preoptic area/anterior hypothalamus prevents lipopolysaccharide evoked hypotension(Federation Amer Soc Exp Biol, 2008-04-01) Myer, Brian S.; Feleder, Carlos; Millington, William R.; Yılmaz, Mustafa Sertaç; YILMAZ, MUSTAFA SERTAÇ; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Kalp ve Damar Cerrahisi Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021Item Choline potentiates the pressor response evoked by glycyl-glutamine or naloxone in haemorrhaged rats(Wiley, 2003-09) Millington, William R.; Gürün, Mine Sibel; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; AAG-8716-2019; D-5340-2015; 55664349700; 70042710861. Severe blood loss initially lowers arterial pressure through a central mechanism that is thought to involve opioid and cholinergic neurons. The present study tested the hypothesis that simultaneous administration of a cholinergic agonist and an opioid receptor antagonist would produce a synergistic effect in the treatment of haemorrhage. Specifically, we tested whether choline, a precursor of acetylcholine, potentiates the pressor effect of the beta-endorphin derived peptide glycylglutamine (Gly-Gln) or the opioid receptor antagonist naloxone following acute haemorrhage. 2. Conscious rats were treated intracerebroventricularly (i.c.v.) with choline chloride ( 180 nmol) alone or combined with Gly-Gln ( 10 nmol) or naloxone ( 10 nmol) 2 min after blood withdrawal (2.5 mL/100 g bodyweight over 20 min) was completed; mean arterial pressure and heart rate were monitored for 30 min. 3. Combined treatment with choline and Gly-Gln elevated mean arterial pressure but did not affect heart rate significantly. Choline and Gly-Gln had no effect on cardiovascular function when administered alone to haemorrhaged rats or when given together to normotensive animals. Choline also potentiated the pressor and tachycardic effect of naloxone in haemorrhaged rats. 4. These data show that choline potentiates the pressor effect of Gly-Gln and naloxone in haemorrhaged rats.Item The effect of Gly-Gln [SS-endorphin(30-31)] on morphine-evoked serotonin and GABA efflux in the nucleus accumbens of conscious rats(Churchill Livingstone, 2016-01-26) Millington, William R.; Basaran, Nesrin F.; Büyükuysal, R. Levent; Yılmaz, M. Sertaç; Aydın, Sami; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; 0000-0002-0076-6554; AAC-9702-2019; AAH-1657-2021; AAH-1571-2021; 36672447000; 6602686612; 56891699900; 7005387015; 6507468595Glycyl-L-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized through the post-translational processing of beta-endorphin(1-31). Central Gly-Gln administration inhibits the rewarding properties of morphine and attenuates morphine tolerance, dependence and withdrawal although it does not interfere with morphine analgesia. In an earlier study, we found that Gly-Gln inhibits morphine-induced dopamine efflux in the nucleus accumbens (NAc), consistent with its ability to inhibit morphine reward. To further investigate the mechanism responsible for its central effects we tested whether i.c.v. Gly-Gln administration influences the rise in extracellular serotonin and GABA concentrations evoked by morphine in the NAc. Conscious rats were treated with Gly-Gln (100 nmol/5 mu l) or saline i.c.v. followed, 2 min later, by morphine (2.5 mg/kg) or saline i.p. and extracellular serotonin and GABA concentrations were analyzed by microdialysis and HPLC. Morphine administration increased extracellular serotonin and GABA concentrations significantly within 20 min, as shown previously. Unexpectedly, Gly-Gln also increased extracellular serotonin concentrations significantly in control animals. Combined treatment with Gly-Gln + morphine also elevated extracellular serotonin concentrations although the magnitude of the response did not differ significantly from the effect of Gly-Gln or morphine, given alone suggesting that Gly-Gin suppressed morphine induced serotonin efflux. Gly-Gln abolished the morphine-induced rise in extracellular GABA concentrations but had no effect on extracellular GABA when given alone to otherwise untreated animals. These data show that Gly-Gln stimulates NAc serotonin efflux and, together with earlier studies, support the hypothesis that Gly-Gln inhibits the rewarding effects of morphine by modulating morphine induced dopamine, GABA and serotonin efflux in the NAc.Item Glycyl-glutamine (β-endorphin30-31) inhibits morphine-induced dopamine efflux in the nucleus accumbens(Springer, 2010-05) Millington, William R.; Filiz, Nesrin Başaran; Büyükuysal, Rıfat Levent; Çavuş, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; AAH-1657-2021; AAC-9702-2019; 36672447000; 6602686612; 6507468595Glycyl-glutamine (Gly-Gln) is an endogenous dipeptide that is synthesized from beta-endorphin post-translationally. Previously, we showed that Gly-Gln prevents acquisition of morphine-conditioned place preference, a behavioral test of morphine reward, but does not interfere with morphine analgesia. In this study, we tested the hypothesis that Gly-Gln inhibits morphine reward by blocking morphine-induced dopamine efflux in the nucleus accumbens (NAc). Extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were sampled by microdialysis and analyzed by high-performance liquid chromatography with electrochemical detection. Guide cannulas were implanted in the right NAc and left lateral ventricle of male Sprague-Dawley rats stereotaxically. Approximately 24 h later, a microdialysis probe was inserted into the NAc and perfused at 1 A mu l/min. Gly-Gln (1, 3, 30, or 100 nmol/5 A mu l) or saline was administered intracerebroventricularly, morphine (2.5 mg/kg) was injected intraperitoneally (i.p.) 2 min later, and extracellular dopamine and DOPAC were sampled at 20-min intervals. Morphine administration increased extracellular dopamine concentrations by approximately 600% within 40 min. Gly-Gln pretreatment inhibited the rise in extracellular dopamine in a dose-related manner; the lowest significantly inhibitory dose was 1 nmol. Gly-Gln also inhibited the morphine-induced rise in extracellular DOPAC concentrations but did not affect extracellular dopamine or DOPAC in control animals. Gly-Gln (100 nmol/5 A mu l) prevented morphine-induced dopamine efflux in rats treated with morphine chronically (10 mg/kg, i.p. twice daily for 6 days), although it did not affect DOPAC concentrations significantly. These data support the hypothesis that Gly-Gln abolishes the rewarding effect of morphine by inhibiting the ability of morphine to stimulate dopamine release in the NAc.Item Glycyl-glutamine, an endogenous beta-endorphin-derived peptide, inhibits morphine-induced conditioned place preference, tolerance, dependence, and withdrawal(Amer Soc Pharmacology Experimental Therapeutics, 2005-11) Göktalay, Gökhan; Millington, William R.; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; AAC-9702-2019; 6507468595Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized from beta-endorphin(1-31). Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and beta-endorphin(1-31), but it does not interfere with opioid analgesia. In this study, we tested whether Gly-Gln administration would influence morphine-induced conditioned place preference, tolerance, dependence, or withdrawal. For place preference experiments, rats were conditioned with morphine sulfate (2.5 mg/kg i.p.) or saline on alternate days for 6 days and tested on day 7. Glycyl-glutamine (1-100 nmol i.c.v.) pretreatment inhibited acquisition of a conditioned place preference to morphine significantly. Glycyl-glutamine (100 nmol i.c.v.) also blocked expression of a pre-established morphine place preference, but it did not interfere with acquisition of a conditioned place preference to palatable food, and it did not produce place preference or aversion when given alone to morphine-naive animals. To induce antinociceptive tolerance, rats were treated with morphine (10 mg/kg i.p.) twice daily for 7 days, and morphine antinociception was evaluated with the tail-flick test. Glycylglutamine (100 nmol i.c.v.) pretreatment delayed the onset of morphine tolerance significantly and partially reversed pre-established tolerance. Morphine dependence and withdrawal were assessed by measuring naloxone-precipitated withdrawal symptoms. Glycyl-glutamine inhibited the development of morphine dependence when given to rats twice daily immediately before they received morphine (10 mg/kg i.p.) and suppressed withdrawal symptoms of rats with subcutaneously implanted morphine pellets when administered 5 min before withdrawal was induced with naloxone. Glycyl-glutamine thus attenuates morphine-induced conditioned place preference, tolerance, dependence, and withdrawal without compromising morphine analgesia.Item Glycyl-L-glutamine [beta-endorphin-(30-31)] attenuates hemorrhagic hypotension in conscious rats(Amer Physiological Soc, 1997) Owen, Medge D.; Zaloga, Galy P.; Millington, William R.; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; AAG-8716-2019; 6506970743The profound hypotension caused by acute hemorrhage is thought to involve opioid peptide neurons. In this study, we tested whether glycyl-L-glutamine [Gly-Gln; beta-endorphin-(30-31)], a nonopioid peptide derived from beta-endorphin processing, prevents the cardiovascular depression induced by hemorrhage in conscious and anesthetized rats. Previously, we found that Gly-GLn inhibits the hypotension and respiratory depression produced by beta-endorphin and morphine but does not affect opioid antinociception. Hemorrhage (2.5 ml/100 g body wt over 20 min) lowered arterial pressure in conscious rats (from 120.1 +/- 2.9 to 56.2 +/- 4.7 mmHg) but did not change heart rate significantly. Intracerebroventricular Gly-Gln (3, 10, or 30 nmol) pretreatment inhibited the fall in arterial pressure and increased heart rate significantly. The response was dose related and tvas sustained during the 35-min posthemorrhage interval. Pentobarbital sodium anesthesia potentiated the hemodynamic response to hemorrhage and attenuated the effect of Gly-Gln. Gig-Gin (10 or 100 nmol icy) did not influence arterial pressure or heart rate in normotensive rats. These data indicate that Gly-Gln is an effective antagonist of hemorrhagic hypotension.Item The hypotension evoked by visceral nociception is mediated by delta opioid receptors in the periaqdeductal gray(Elsevier, 2004-09-03) Millington, William R.; Çavun, Sinan; Göktalay, Gökhan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; AAC-9702-2019; AAH-1448-2021; 6507468595; 6508023759This study tested the hypothesis that the ventrolateral column of the midbrain periaqueductal gray (vlPAG) region mediates the hypotension and bradycardia evoked by visceral nociception. To test this, the local anesthetic lidocaine (2%; 0.5 mul) was microinjected into the vlPAG of halothane-anesthetized rats bilaterally and visceral nociception was induced 2 min later by injecting 5% acetic acid (0.5 ml) intraperitoneally. Acetic acid injection caused an abrupt fall in arterial pressure (-12.2 +/- 2.1 mm Hg) and heart rate (-37 +/- 93 bpm) lasting approximately 15 min. Lidocaine injection into the vlPAG prevented the fall in arterial pressure and heart rate completely. Cobalt chloride (5 mM; 0.2 or 0.5 mul) injection into the vlPAG also prevented nociceptive hypotension but it did not affect the fall in heart rate significantly. Lidocaine pretreatment also inhibited the depressor response caused by intramuscular formalin (5%; 0.2 ml) administration, a model of deep somatic nociception, although it did not prevent the response completely. To determine if opioid receptors mediate the response, selective mu, delta or kappa opioid receptor antagonists were microinjected into the vlPAG 5 min before intraperitoneal (ip) acetic acid administration. Naltrindole, a delta receptor antagonist, inhibited the response significantly but mu and kappa antagonists were completely ineffective. Lidocaine and naltrindole had no effect when injected into the dorsolateral PAG and did not influence cardiovascular function when injected into the vlPAG of saline treated control animals. These data support the hypothesis that the vlPAG mediates the depressor response evoked by visceral nociception and indicate that delta opioid receptors participate in the response.Item Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage(Elsevier, 2016-02-27) Millington, William R.; Göktalay, Gökhan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-6261-4233; AAH-1448-2021; 6508023759This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100 g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 mu l or 0.3 mu l) or cobalt chloride (5 mM; 0.3 mu l) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.Item The initial fall in arterial pressure evoked by endotoxin is mediated by the ventrolateral periaqueductal gray(Wiley, 2016-03-21) Millington, William R.; Feleder, Carlos; Yılmaz, Mustafa Sertaç; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021; 8895544100This study tested the hypothesis that the initial fall in arterial pressure evoked by lipopolysaccharide (LPS) is mediated by the ventrolateral column of the midbrain periaqueductal gray region (vlPAG). To test this hypothesis, the local anaesthetic lidocaine (2%; 0.1L, 0.2L or 1.0L), the delta opioid receptor antagonist naltrindole (2nmol) or saline was microinjected into the vlPAG of isoflurane-anaesthetized rats bilaterally and LPS (1mg/kg) or saline was administered intravenously 2min later. Both lidocaine and naltrindole inhibited LPS-evoked hypotension significantly but did not affect arterial pressure in saline-treated control animals. Neither lidocaine nor naltrindole altered heart rate significantly in either LPS-treated or control animals. Microinjection of lidocaine or naltrindole into the dorsolateral PAG was ineffective. These data indicate that the vlPAG plays an important role in the initiation of endotoxic hypotension and further show that delta opioid receptors in the vlPAG participate in the response.Item Muscimol injection into the lateral hypothalamus inhibits the hypotension and bradycardia caused by somato-visceral nociception(Elsevier, 2004-12-10) Levendusky, Mark C.; Millington, William R.; Göktalay, Gökhan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-6261-4233; AAH-1448-2021; 6508023759This study investigated whether the lateral hypothalamus (LH) contributes to the depressor response evoked by somato-visceral nociception. Lidocame (2%; 0.1, 0.3 or 1.0 mul) or muscimol (0.34 nmol; 0.5 mul) was microinjected into the rostral LH of halothane-anesthetized rats bilaterally and somato-visceral nociception was induced 2 min later by injecting 5% acetic acid (0.5 ml) intraperitoneally. Lidocaine and muscimol inhibited the hypotension and bradycardia caused by somato-visceral nociception significantly without affecting cardiovascular function in normotensive animals.Publication The OVLT initiates the fall in arterial pressure evoked by high dose lipopolysaccharide: Evidence that dichotomous, dose-related mechanisms mediate endotoxic hypotension(Elsevier, 2015-05-27) Feleder, Carlos; Yılmaz, M. Sertaç; Peng, Jianya; Göktalay, Gökhan; Millington, William R.; YILMAZ, MUSTAFA SERTAÇ; GÖKTALAY, GÖKHAN; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; 0000-0002-2617-3626; AAH-1448-2021; AAH-1571-2021This study tested the hypothesis that lipopolysaccharide (LPS) lowers arterial pressure through two different mechanisms depending on the dose. Previously, we found that a low hypotensive dose of LPS (1 mg/kg) lowers arterial pressure by activating vagus nerve afferents. Here we report that hypotension evoked by high dose LPS (15 mg/kg) can be prevented by injecting lidocaine into the OVLT but not by vagotomy or inactivation of the NTS. The hypotension produced by both LPS doses was correlated with elevated extracellular norepinephrine concentrations in the POA and prevented by blocking alpha-adrenergic receptors. Thus, initiation of endotoxic hypotension is dose-related, mechanistically. (C) 2015 Elsevier B.V. All rights reserved.