Reduction of capture-induced hyperthermia and respiratory depression in ungulates

When wild animals are captured they often develop capture-related side-effects that may result in morbidity and mortality. During chemical capture of wild ungulates, capture-induced hyperthermia and opioid-induced respiratory depression occur commonly. Little is known about the mechanisms of capture-induced hyperthermia, and the effects of opioid drugs on respiratory function still need to be clarified. Also, current methods of reversing opioid-induced respiratory depression are inadequate. I therefore investigated the mechanisms and patterns of capture-induced hyperthermia, by continuously measuring body temperatures of impala during different capture procedures. I also investigated the effects of opioid drugs on respiratory function and pulmonary performance by examining the changes of cardiorespiratory variables before and during opioid immobilization of goats and impala. Concurrently, I investigated whether serotonergic ligands could be used to reverse the opioid-induced respiratory depression that occurred in these animals. I found stress to be the major factor associated with capture-induced hyperthermia, with exercise playing a minor role. I also found that environmental thermal conditions and the pharmacological effects of the capture drugs played no role in inducing capture-induced hyperthermia. I found that the opioid drug etorphine, which is commonly used to chemically capture wild animals, not only causes depression in respiratory rhythm and ventilation, but also a decrease in alveolar-arterial oxygen exchange. I demonstrated that serotonergic ligands with agonist effects at 5-HT1A and 5-HT4 receptors partially reversed opioid-induced respiratory depression and hypoxia, predominantly by improving alveolar-arterial oxygen exchange, presumably by increasing pulmonary perfusion and improving ventilation perfusion ratios, but also, in some cases, by improving ventilation. I advise that to limit the morbidity and mortality associated with capture-induced hyperthermia, procedures that cause the least stress should be used and animals should be exposed to stressors for the shortest time possible. The use of anxiolytic drugs to reduce stress may also be considered. If animals are captured by chemical immobilization with opioid drugs their respiratory function should be monitored closely. Counting breaths does not adequately monitor respiratory function and methods to assess carbon dioxide and oxygen levels in arterial blood should be used. If respiratory depression occurs, efforts to reverse this depression should not focus only on improving ventilation but also should aim at improving gas exchange in the lungs. Serotonergic ligands with agonist effects at 5-HT1A and 5-HT4 receptors could be used to achieve these aims. Although some of these ligands can cause arousal in immobilized animals, if they are administered with the opioid they enhance the induction of catatonic-immobilization, and their use in a dart may not only improve knock down times, thereby minimising stress and capture-induced hyperthermia, but they may also prevent opioid-induced respiratory depression

Natural born weight gainers: The mechanisms of obesity in transgenic mice overexpressing neuropeptide Y

Neuropeptide Y (NPY) is a neurotransmitter promoting energy storage by activating Y-receptors and thus affecting food intake, thermogenesis and adipose tissue metabolism. NPY is expressed both in the central and sympathetic nervous system. Hypothalamic NPY is known to stimulate feeding, but the effects of noradrenergic neuron NPY are more ambiguous. Chronic stress stimulates fat accumulation via NPY release from noradrenergic neurons. Furthermore, polymorphism in the human Npy gene has been associated with metabolic disturbances and increased NPY secretion after sympathetic stimulation. The main objective of this study was to clarify the mechanisms of noradrenergic neuron NPY in the development of obesity. The metabolic phenotype of a homozygous mouse overexpressing NPY in the brain noradrenergic neurons and sympathetic nervous system (OE-NPYDβH mouse) was characterized. OE-NPYDβH mice had an increased fat mass and body weight, which caused impairments of glucose metabolism and hyperinsulinaemia with age. There were no differences in energy intake or expenditure, but the sympathetic tone was down-regulated and the endocannabinoid system activated. Furthermore, peripheral Y2-receptors in energy-rich conditions played an important role in mediating the fat-accumulating effect of NPY. These results indicate that noradrenergic neuron NPY promotes obesity via direct effects in the periphery and by modulating the sympatho-adrenal and endocannabinoid systems. Additionally, NPY in the central noradrenergic neurons is believed to possess many important roles. The phenotype of the OE-NPYDβH mouse resembles the situations of chronic stress and Npy gene polymorphism and thus these mice may be exploited in testing novel drug candidates for the treatment of obesity.Luontaiset painon kerryttäjät: Lihavuuden mekanismit siirtogeenisella NPY:tä yli-ilmentävällä hiirellä Neuropeptidi Y (NPY) on hermovälittäjäaine, joka Y-reseptorien välityksellä edistää energian varastointia. NPY vaikuttaa useisiin energiatasapainon osa-alueisiin kuten syömiseen, lämmöntuottoon ja rasva-aineenvaihduntaan. NPY:tä ilmennetään sekä keskus- että sympaattisessa ääreishermostossa. Hypotalaamisen NPY:n tiedetään olevan voimakkain keskushermoston syömistä lisäävä hermovälittäjäaine. Sen sijaan no radrenergisissa hermoissa ilmennettävän NPY:n tehtävät ovat vielä tuntemattomampia. Krooninen stressi vapauttaa NPY:tä noradrenergisista hermoista ja näin lisää rasvan kertymistä. Lisäksi ihmisellä on havaittu metabolisiin häiriöihin assosioituva Npy-geenin polymorfia, jossa NPY:n vapautuminen on lisääntynyt sympaattisen aktivaation aikana. Tämän tutkimuksen tavoitteena oli tutkia tarkemmin mekanismeja, joilla noradrenergisten hermojen NPY osallistuu lihavuuden kehittymiseen. Ensin selvitettiin siirtogeenisen homotsygootisti NPY:tä aivojen noradrenergisissa hermoissa ja sympaattisessa hermostossa yli-ilmentävän hiirimallin (OE-NPYDβH hiiri) metabolinen ilmiasu. OE-NPYDβH-hiirten ruumiin paino ja rasvamassan määrä olivat lisääntyneet, mikä myöhemmällä iällä johti huonontuneeseen glukoosiaineenvaihduntaan ja kohonneeseen veren insuliinipitoisuuteen. Syömisessä ja energiankulutuksessa ei havaittu eroja. Sen sijaan sympaattinen aktiivisuus oli madaltunut ja endokannabinoidijärjestelmä aktivoitunut OE-NPYDβH-hiirellä. Lisäksi perifeerisilla Y2-reseptoreilla on energiapitoisen ruokavalion yhteydessä tärkeä rooli NPY:n aiheuttamassa lisääntyneessä rasvamassan määrässä. Tämä tutkimus osoittaa, että noradrenergisten hermojen NPY edistää lihavuuden syntyä suorien periferisten vaikutusten kautta sekä muokkaamalla sympaattisen hermoston ja endokannabinoidijärjestelmän toimintaa. Näiden lisäksi aivojen noradrenergisella NPY:llä on osuutensa lihavuuden kehittymisessä. OE-NPYDβH-hiirten ilmiasu muistuttaa kroonisen stressin sekä Npy-geenin polymorfian aiheuttamaa metabolista tilaa ja OE-NPYDβH-hiirtä voidaankin hyödyntää testattaessa uusia lääkekandidaatteja lihavuuden ja metabolisen oireyhtymän hoitoon.Siirretty Doriast

An assessment of the effects of neurokinin₁ receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A ‘broad-spectrum’ anti-vomiting effect of neurokinin1 receptor antagonists (NK1RA), shown in preclinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for ‘anti-emetics’. The stimulus-independent effects of NK1RAs against vomiting are explicable by actions within the central pattern generator (CPG; ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The CPG and NTS neurones are multifunctional so the notable lack of obvious effects of NK1RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1RAs to inhibit nausea emphasises (a) our inadequate understanding of the mechanisms of nausea and (b) that classification of a drug as an “anti-emetic” may give a false impression of efficacy against nausea versus vomiting. We discuss the potential mechanisms for the differential efficacy of NK1RA and the implications for future development of drugs which can effectively treat nausea, an area of unmet clinical need

Neurochemical Investigation of Locally Induced Epilepsy and Subsequent Oxidative Damage Using Microdialysis Sampling

The goal of this research was to develop and understand an anesthetized, multiple-seizure rat model for local epilepsy. Local seizures are not as well understood as global seizures due to their specificity and unpredictability. Furthermore, patients are diagnosed with epilepsy after experiencing two or more unprovoked seizures. In this model, two separate seizure episodes were induced by locally administering the epileptic agent 3-mercaptopropionic acid through a microdialysis probe to the CA1 region of the hippocampus. Upon development of the model, attenuation in glutamate release was observed in the second seizure stimulation. To investigate neurochemical and biochemical pathways which may be responsible for the glutamate diminution, the perfusion fluid was spiked with either glucose, lactate, or dihydrokainic acid. Additionally, as it is well known that high levels of extracellular glutamate can result in excitotoxicity, neuronal staining was performed to determine the neuronal viability after the induction of the first seizure. It was determined that the attenuation in glutamate release in the second seizure episode was primarily due to a combination of mitochondrial starvation and cell damage. The local seizure model was then used to correlate local seizure induction to oxidative damage. Glutathione (GSH) and malondialdehyde (MDA) were selected as biomarkers of oxidative stress. Intracellular levels GSH were up regulated and down regulated in hopes of modifying the amount of seizure induced oxidative damage. There was no statistically significant change in MDA formation with changing GSH levels; however, GSH did appear to serve as a release modifier of the redox cycle. Extracellular GSH increased significantly during the seizure induction and returned to basal after the seizure ended. This increase in extracellular GSH concentration can be accounted for by astrocytes and glial cells releasing GSH to counteract reactive oxygen species produced during the seizure. Additional experiments need to be done in order to make further conclusions; however, it is evident that there is a correlation between seizures and oxidative stress. Finally, Appendix I describes a small in vitro pharmacokinetic project using microdialysis sampling to measure plasma protein binding values of commercially available drugs with the ultimate goal of applying the technique for in vivo studies