Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

published_or_final_version / abstract / toc / Zoology / Master / Master of Philosophy

The hypothalamic-pituitary-adrenal (HPA) axis, a system activated by stress, is traditionally considered to affect the susceptibility to chronic pain via effects on peripheral processes. This study investigates whether the HPA axis contributes to the development of chronic pain in an animal model via direct effects on central pain mechanisms. / First, correlations between pain processes and the susceptibility to chronic pain in an animal model that is correlated with HPA-axis function were examined. The results show that, in the Fischer rat, the amount of pain suppression observed during the formalin interphase depression is negatively correlated with susceptibility to polyarthritis. Since the formalin interphase depression mechanisms are within the central nervous system, the results suggest a role for central pain mechanisms in the development of polyarthritis. / Hypophysectomy inhibits the development of adjuvant-induced arthritis. To test whether hypophysectomy inhibits adjuvant-induced polyarthritis via central pain mechanisms, the analgesic effect of hypophysectomy was examined in the formalin test. The results show that hypophysectomy specifically prolongs the formalin interphase depression, further supporting that the underlying central pain suppression mechanisms are associated with resistance to adjuvant-induced polyarthritis. / Corticotropin-releasing factor (CRF) was then investigated as a possible underlying mechanism of the effects of hypophysectomy. Peripheral injection of CRF into inflamed tissue affects pain mechanisms unrelated to the susceptibility to adjuvant-induced polyarthritis. However, central and intravenous administration of CRF preferentially affect the formalin interphase depression mechanisms. The observed dose-response relationships indicate that these effects are due to direct actions of CRF within the central nervous system. / In conclusion, the results strongly suggest that the HPA axis modulates the susceptibility to adjuvant-induced polyarthritis via direct effects on supraspinal pain suppression mechanisms. Thus, the HPA axis may contribute to the development of chronic pain syndromes associated with HPA-axis abnormalities, such as rheumatoid arthritis and fibromyalgia, via effects on pain mechanisms within the central nervous system.

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The acute administration of an analgesic dose (1mg/kg) of morphine sulfate to conscious and hydrated rats produced a pronounced antidiuretic response. This was accompanied by an increase in urine osmolality and a decrease in free water clearance in the normal and Brattleboro rats heterozygous for the diabetes insipidus trait. The response was comparable to that of an exogenous dose of vasopressin. Antidiuresis was also observed in the homozygous D.I. rats. Since these rats are incapable of synthesizing vasopressin, the antidiuresis must be mediated by other mechanism(s). When arterial blood pressure was monitored, it was found that the mean arterial pressure decreased sharply immediately after the morphine injection in all animals. This can account for the antidiuresis in the homozygous D.I. rats. In the normal and heterozygous D.I. animals, it is quite possible that both morphine-mediated release of vasopressin and hypotension are responsible for the decrease in urinary flow. In addition, hypotension per se may act as a stimulus for vasopressin release. To study the chronic effects of morphine, rats were rendered tolerant and physically dependent by two means: multiple injections and pellet implantation of morphine sulfate. In contrast to the antidiuretic effects of acute morphine administration, chronic treatment resulted in polyuria. Using a vasopressin radioimmunoassay (RIA), it was found that rats implanted with a morphine pellet for 3 days had a significantly lower neurohypophyseal store of vasopressin (744.3 ± 27.9 ng, n=6) as compared to the placebo pellet implanted controls (1024. 1 ± 66.0 ng, n=6). This depletion was replenished as the animals developed tolerance to the drug.. abrupt withdrawal of the drug from physically dependent animals also produced a significant depletion of the neurohypophyseal vasopressin stores - from 902.4 ± 37.0 ng (n=6) to 638. 3 ± 36.0 ng (n=6). In contrast to rats implanted with morphine pellets, no significant changes in the neurohypophyseal vasopressin stores were observed in those injected daily with morphine for 2 weeks. Withdrawal from the drug in these animals also did not produce any detectable changes in the vasopressin stores. A withdrawal symptom, reduction in body weight, monitored after 24 hr of abstinence suggested that the degree of physical dependence in these animals is very light. ³H-naloxone binding performed on whole brain homogenate of rats injected with morphine for 2 weeks revealed no significant changes in the number of binding sites (q). The affinity constant (Kd) was augmented from a control value of 5.33 nM to 22.37 nM in the morphine-injected rats. The changes in g and Kd suggested the presence of morphine in the whole brain homogenates. Moreover, the Kd was restored to the control value in animals withdrawn from the drug for 24 hr. Vasopressin or oxytocin iid not have any direct effect on the ³H-naloxone binding. Thus, it is unlikely that the facilitation of morphine tolerance by the neurohypophyseal peptides is mediated by their direct action on the opiate receptor. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2010. / Härtill 5 uppsatser.

The Hypothalamic Pituitary Adrenal (HPA) axis is the coordinator of adaptive responses to physical and psychological stress. The central nervous system plays a key role in modulation of both basal and adaptive HPA axis functions. In fact, since long ago, animal studies have shown that acute and chronic exposure to glucocorticoids (a stress hormone released due to HPA axis activation, cortisol in humans) affects the function and the morphology of brain areas such as the hippocampus and the cingulate cortex. This thesis is based on novel neuroimaging methodologies used to investigate the interactions of psychological stress, cortisol and the brain. It consists of three functional studies and a morphometric one. In the first functional study we show that the hippocampus (where glucocorticoid receptors are most abundant) plays a role in initiation of an HPA axis stress response. In the second study, we provide evidence that besides hippocampus, the neural activity in the so-called "default mode network" (DMN), especially the anterior cingulate cortex (ACC), relates to interindividual variations in HPA axis response to psychological stress. In the third study we have investigated the cortisol-modulation of the DMN. Again, we provide evidence for a role of the ACC and the orbitofrontal cortex in negative feedback inhibition of the HPA axis activity. Finally, we show a morphological link between the ACC and the cortisol response to awakening which is an index of basal HPA axis activity. Overall, our findings confirm the critical role of the ACC and mesolimbic system in HPA axis regulation. These findings also draw attention to the interactions between functional subregions of the medial prefrontal cortex and states of HPA axis function prior to stress onset---suggesting an interplay of the monitoring and the executive planning roles of the medial prefrontal cortex in behavioral adaptation to stress. Beyond stress research, our findings offer a framework for combining neuroimaging and neuroendocrinology to better understand the interindividual variances in behavior, and perhaps to better identify subgroups at risk of psychological disorders.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.