Thesis (M.S.)--Northern Michigan University, 2009. / Bibliography: leaves 101-114.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 7 uppsatser.

The chronotropic and inotropic responses to isoprenaline and salbutamol were determined in the chloralose anaesthetized dog. The myocardium was denervated, sympathetically and parasympathetically to prevent direct neural influence on the heart rate and myocardial contractility. The heart rate was determined from the E.C.G. Myocardial contractility was indicated by the change in the maximum rate of rise of left ventricular pressure (dP/dt max) at a constant electrically paced heart rate. The structure-activity relationships for salbutamol and isoprenaline were determined from dose-response curves and by plotting the change in contractility (ΔdP/dt max) against the change in heart rate (ΔHR). The data obtained from this series of experiments indicated that the only difference between the effects of the agonists on the inotropic and chronotropic responses of the myocardium was the lower affinity of salbutamol for the adrenergic receptor as indicated by the 100 times greater concentration required to produce the same response level. Previously reported in vitro studies with the guinea pig atrium and dog papillary muscle had indicated that a smaller inotropic response to salbutamol should have been expected. To test this discrepancy between the present in vivo experimentation, and the previous in vitro work, studies were designed to test the guinea pig atrium and the dog papillary muscle in vitro. The effects of the agonists were studied on the isolated guinea pig atrium in a manner that paralleled the in vivo dog study. With the organ bath at 25°C, the chronotropic response, measured by the change in free contraction rate (ΔR), and the inotropic response, determined from the change in peak tension developed (ΔT) during electrical stimulation at 2 Hz, to a single randomly ordered dose of salbutamol or isoprenaline were determined. Salbutamol acted as a partial agonist, that is, had a lower efficacy than isoprenaline. However, the relative effect of each drug on the inotropic and chronotropic responses was almost identical. In the isolated dog papillary muscle, salbutamol displayed a much lower efficacy, producing only 20% of the maximum isoprenaline increase in peak tension developed to the cummulative addition of agonist. The affinity of salbutamol for the adrenergic receptor in this preparation was much lower than that observed in vivo when compared with isoprenaline, 5,000:1 and 100:1 respectively. The structure-activity relationships for salbutamol and isoprenaline showed that the relative effects of these agonists on the in vivo denervated dog myocardial inotropic and chronotropic responses were similar. This observation indicates that the adrenergic receptors of the dog myocardium mediating the inotropic and chronotropic responses are structurally similar at a site complementary to the phenyl ring of the agonist molecule. However,, a definite conclusion regarding the adrenergic receptors responsible for the inotropic response cannot be made because of the unexplained difference in inotropic response observed with ventricular muscle in vivo and in vitro. Examination of the structure-activity relationships for salbutamol and isoprenaline in the in vitro guinea pig atrium indicates that, in this preparation also, the adrenergic receptors involved in the two measured responses are probably structurally similar. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Clinical evidence has demonstrated that the anxiolytic effects produced by the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist, gepirone, increase progressively over one to three weeks of treatment.

Digital averaging and analysis of miniature endplate currents (MEPCs) from mouse diaphragm was used to characterize the normal MEPC and its modification by a variety of drugs. Under normal conditions the decay of MEPCs showed consistent deviations from a simple exponential consisting in a progressive increase of rate constant, followed by a slow tail. Receptor blockade by d-tubocurarine (dTC), a-bungarotoxin, and other agents thought to occupy ACh-binding sites reduced MEPC amplitude, accelerated MEPC decay by about 30% (making it about equal to decay rate of channels opened by exogenous acetylcholine), and eliminated the early deviations from an exponential decay; dTC also abolished the late tail. Examination of the interaction of acetylcholinesterase (AChE) poisoning and receptor blockade on MEPC height and time course indicated that normally most quantal ACh is captured by receptors and, as predicted by theoretical consideration, a rather large degree of receptor blockade is necessary to reduce MEPC height. MEPC tails were exaggerated by AChE poisoning and exogenous ACh or carba-chol. The latter agents reduced MEPC height in a fashion inconsistent with blockade of ACh binding and concurrent modulation of the tail suggested an important role of desensitized receptors in tail generation. A number of other drug actions are also described quantitatively: (a) channel prolongation, typical of alcohols but also found with ketones and some amines; (b) 'channel plugging', typical of local anaesthetics but also found with many other agents, including long chain alcohols, and (c) an action to reduce MEPC size without reducing net response to exogenous agonist typical of volatile anaesthetics, associated with increase rather than decrease of ACh binding to receptor. Criteria for distinguishing different modes of modification of receptor function are discussed. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Evidências clínicas e experimentais têm sugerido a existência de diferenças na sensação de dor e na resposta a fármacos analgésicos entre machos e fêmeas. A crotalfina (CRF), um peptídeo inicialmente isolado e caracterizado no veneno de serpentes Crotalus durissus terrificus, apresenta efeito antinociceptivo, quando avaliado em diferentes modelos experimentais de dor aguda e crônica. O efeito deste peptídeo é de longa duração e mediado pela ativação de receptores opióides periféricos do tipo <font face=\"Symbol\">k e <font face=\"Symbol\">d. Contudo, os estudos com a crotalfina foram sempre realizados utilizando roedores machos. Assim, o presente projeto de pesquisa teve por objetivo avaliar a diferença na sensibilidade dolorosa e no efeito antinociceptivo da crotalfina, entre ratos machos e fêmeas. Os resultados mostraram que fêmeas apresentam menor limiar nociceptivo e maior sensibilidade à dor. A crotalfina apresentou maior potência antinociceptiva em fêmeas. A diferença na sensibilidade dolorosa e na resposta a analgésicos pode ser decorrente da presença de hormônios esteroidais gonadais. / Several clinical and experimental evidence have suggested the existence of sex differences in pain sensation and in the analgesic effect of opioid drugs in human and rodents. Crotalphine (CRP), a peptide first characterized in the venom of the South American rattlesnake Crotalus durissus terrificus, displays potent and long-lasting opioid (peripheral <font face=\"Symbol\">k and <font face=\"Symbol\">d opioid receptors) analgesic activity in experimental models of acute and chronic pain. Due to its potent and long-lasting analgesic effect, pre-clinical trials with the synthetic peptide and analogues are now in progress. However, the experimental studies with CRP have always been developed in male animals. This study aims to evaluate the differences in pain sensation and in the analgesic response to CRP between male and female Wistar rats. Sex differences could be observed between male and female rats in relation to pain threshold. However, despite displaying opioid activity, the new analgesic peptide CRP is more effective in females than males. These differences could be related with sex hormones.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvii, 271 p.; also includes graphics. Includes bibliographical references (p. 245-269). Available online via OhioLINK's ETD Center

Evidências clínicas e experimentais têm sugerido a existência de diferenças na sensação de dor e na resposta a fármacos analgésicos entre machos e fêmeas. A crotalfina (CRF), um peptídeo inicialmente isolado e caracterizado no veneno de serpentes Crotalus durissus terrificus, apresenta efeito antinociceptivo, quando avaliado em diferentes modelos experimentais de dor aguda e crônica. O efeito deste peptídeo é de longa duração e mediado pela ativação de receptores opióides periféricos do tipo <font face=\"Symbol\">k e <font face=\"Symbol\">d. Contudo, os estudos com a crotalfina foram sempre realizados utilizando roedores machos. Assim, o presente projeto de pesquisa teve por objetivo avaliar a diferença na sensibilidade dolorosa e no efeito antinociceptivo da crotalfina, entre ratos machos e fêmeas. Os resultados mostraram que fêmeas apresentam menor limiar nociceptivo e maior sensibilidade à dor. A crotalfina apresentou maior potência antinociceptiva em fêmeas. A diferença na sensibilidade dolorosa e na resposta a analgésicos pode ser decorrente da presença de hormônios esteroidais gonadais. / Several clinical and experimental evidence have suggested the existence of sex differences in pain sensation and in the analgesic effect of opioid drugs in human and rodents. Crotalphine (CRP), a peptide first characterized in the venom of the South American rattlesnake Crotalus durissus terrificus, displays potent and long-lasting opioid (peripheral <font face=\"Symbol\">k and <font face=\"Symbol\">d opioid receptors) analgesic activity in experimental models of acute and chronic pain. Due to its potent and long-lasting analgesic effect, pre-clinical trials with the synthetic peptide and analogues are now in progress. However, the experimental studies with CRP have always been developed in male animals. This study aims to evaluate the differences in pain sensation and in the analgesic response to CRP between male and female Wistar rats. Sex differences could be observed between male and female rats in relation to pain threshold. However, despite displaying opioid activity, the new analgesic peptide CRP is more effective in females than males. These differences could be related with sex hormones.

The effects of the kappa opioid agonist U-50,488 on morphine-induced condtioned place preference (CPP), locomotor activity and Fos immunoreactivity and assessed in 10-, 17- and 35-day old rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by morhine (a mu opioid receptor agonist).

Indiana University-Purdue University Indianapolis (IUPUI) / It has been proposed that the GABAB receptor subtype plays a role in alcoholism and alcohol use disorders (AUDs) (Cousins et al., 2002; Agabio et al., 2012). Specifically, the GABAB agonist baclofen has been looked at extensively in clinical and pre-clinical studies. In various animal models of chronic and intermittent consumption, baclofen has been shown to both increase (Petry, 1997; Smith et al., 1999; Czachowski et al., 2006; Moore et al., 2007) and decrease (Colombo et al., 2000; 2002; 2005; Stromberg, 2004; Moore et al., 2009) drinking. A critical issue in determining pharmacological effects of a drug is using the appropriate animal model. The drinking-in-the-dark (DID) model, developed by Rhodes et al. (2005, 2007), produces high levels of drinking in a binge-like paradigm and has been used to assess many pharmacological targets (e.g. Kamdar et al., 2007; Gupta et al., 2008; Moore et al., 2007; 2009). While DID produces high-levels of binge drinking, it is unclear what areas of the brain are involved in this behavior. A direct way to target areas that are believed to be involved in the circuitry of particular behaviors is through microinjection of drugs (Kiianmaa et al., 2003). Of particular recent interest involving motivated behaviors and addiction is the nucleus accumbens (Acb) (Everitt & Robbins, 2005); specifically the accumbens shell (AcbSh) (e.g. Rewal et al., 2009, 2012; Nie et al., 2011; Leriche et al., 2008). The current study aimed to investigate the role of GABAB receptors in the AcbSh by examining the ability of two different enantiomers of baclofen to alter ethanol and saccharin intake in male C57BL/6J (B6) mice. B6 mice underwent bilateral cannulation surgery targeting the AcbSh. After 48 hours of recovery time, animals began a five day Drinking-in-the-Dark (DID) procedure where they received 20% ethanol or 0.2% saccharin for two hours, three hours into the dark cycle, each day. Throughout the five drinking sessions, animals were kept in home-cage locomotor activity chambers to monitor activity throughout the drinking cycle. Day 4 drinking was immediately preceded by a mock microinjection, whereas Day 5 drinking was immediately preceded by a drug microinjection. Microinjection of one of five doses of baclofen was given in ng/side dissolved in 200 µl of aCSF (aCSF alone, 0.02 R(+)-, 0.04 R(+)-, 0.08 S(-)-, or 0,16 S(-)-). Intake was recorded every twenty minutes on Days 4 and 5. Retro-orbital sinus blood samples were taken from ethanol animals immediately following the Day 5 drinking period to determine blood ethanol concentrations (BECs). A one-way ANOVA on total Day 4 ethanol consumption revealed no baseline differences between dose groups. A one-way ANOVA on total Day 5 ethanol consumption revealed that the 0.04 R(+)- baclofen dose reduced total drinking, but the 0.16 S(-)- baclofen dose increased total drinking (p’s<0.05). This pattern was reflected in the BECs; 0.04 R(+)- baclofen reduced BECs, whereas 0.16 S(-)- baclofen increased BECs (p’s<0.05). These results were also time-dependent, with R(+)-baclofen reducing drinking in the first 20 minutes of the session and S(-)- increasing drinking in the last 40 minutes of the session. There were no effects on saccharin intake. An issue with the locomotor activity boxes led to unreliable locomotor activity counts. However, because there were no drug effects on saccharin consumption, it was concluded that locomotor effects did not contribute to the decreases or increases in ethanol consumption. These results further implicate the role of GABAB receptors in modulating ethanol intake. The bidirectional effects shown highlight the importance of considering enantioselective drug effects when interpreting data. Finally, these results also support previous conclusions that the AcbSh plays an important role in modulating use of drugs of abuse, but not other reinforcers.