A crucial question in drug addiction research concerns whether the varying reports of dopamine-independent and dopamine-dependent motivation can be integrated. According to one theory, the prior drug history of a subject — that is to say, whether they have received minimal or chronic drug exposure — determines whether opiate motivation is dependent upon the brainstem tegmental pedunculopontine nucleus (TPP) or dopamine neurotransmission. The biological analogue of this change is thought to be a switch in the signalling properties (from hyperpolarizing to depolarizing) of ventral tegmental area (VTA) gamma-aminobutyric acid subtype-A (GABAA) receptors. In this thesis, I demonstrate that the mechanisms underlying opiate motivation can be selected artificially by manipulating the signalling properties of VTA GABAA receptors, irrespective of the past drug history of the subject. Furthermore, I suggest that these same VTA GABAA receptors also play a similar role in controlling ethanol motivation. Indeed, the mechanisms underlying ethanol motivation can be doubly dissociated in a manner similar to that observed with opiates. However, whereas opiate motivation is TPP-dependent in the drug-naive state, I found that ethanol motivation was dependent on dopamine neurotransmission (via the D2 receptor) in drug-naive animals. Conversely, ethanol motivation was TPP-dependent in ethanol-deprived mice (as opposed to opiate motivation being dopamine-dependent in opiate-deprived animals). These effects are consistent with a VTA GABAA receptor switching mechanism identical to the one seen in the case of opiate motivation.

Angiogenesis is a fundamental process in reproduction and wound healing. Angiogenesis is also indispensable for solid tumor growth and metastasis, and also associated with angiogenic diseases. Beta-endorphin (£]-EP), derived from its precursor pro-opiomelancortin (POMC), is well known for its role in nociception and immune regulation. However, the function of morphine and £]-EP during angiogenesis remains characterization. One previous study indicated that morphine inhibited the proliferation and hypoxia-induced vascular endothelial growth factor (VEGF) release of endothelial cells. Contrastingly, another report found that morphine via Ras/PI3k/MAPK/ERK signaling promotes the survival and angiogenesis in endothelial cells. Besides, endogenous opioid peptides stimulated angiogenesis in chicken allantoic membrane assay through opioid receptors. Thus, the function and mechanism of £]-EP and opioid receptors in angiogenesis are controversial. This study evaluated the culture effects of £]-EP and morphine on angiogenesis . It was found that £]-EP stimulated the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Morphine at a high dose inhibited the proliferation, migration, and tube formation of endothelial cells. In the ex vivo rat aortic ring assay, £]-EP enhanced, whereas morphine perturbed, the microvessel sprouting. We also confirmed the expression of MOR¡ADOR¡AKOR opioid receptor in endothelial cells. Application of naloxone, a selective opioid antagonist, and neutralizing antibodies of MOR abolished the angiogenic effect of £]-EP and morphine. Thus £]-EP and morphine exert the pro- and anti-angiogenic effect via MOR, respectively .Besides, £]-EP can be regarded as a novel angiogenic factor.

Reproduction de : Thèse d'exercice : Médecine vétérinaire : Toulouse 3 : 2007. / Titre provenant de l'écran titre. Bibliogr. p. 59-64.

Thesis (Ph. D.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains vi, 85 p. : ill. Includes abstract. Includes bibliographical references (p. 78-85).

Thesis (Ph. D.)--University of Hong Kong, 1967. / Typewritten.

published_or_final_version / Biochemistry / Master / Master of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

No description available.

Recently we have begun to investigate a novel role of EphB receptors in opiate-dependant analgesia. EphB2-β-galactosidase knockins demonstrate that EphB2 is persistently expressed within a number of neural pathways involved in MOR-mediated nociception in vivo and that EphB2 colocalizes with markers of the MOR at the cellular level in the spinal cord and dorsal root ganglia. Despite demonstrating wild-type levels of sensory and motor activity, EphB2 null mice exhibit a significantly altered analgesic response to repeated (but not naive) opiate exposure compared to controls. Investigation of EphB2 null mice and wild type animals revealed no differences in MOR protein levels or affinity. Analysis of this opiate-mediated tolerance suggests that associative phenomena play a substantial role in mediating the analgesic effects observed, possibly due to defeciencies in CA1-mediated learning. Therefore, loss of EphB2 may diminish context-dependent learning and that such learning plays a substantial role in regulating morphine-dependent tolerance.

Approximately two-thirds of patients will experience pain following spinal cord injury (SCI). This pain can arise as an immediate consequence of SCI, or can develop over time into chronic, neuropathic pain. Individuals are frequently prescribed opioid analgesics, including morphine, for the treatment of pain in both the acute and chronic phases of SCI. Yet, despite the prevalence of opioid use, no studies have examined the addictive potential of opioids, or their secondary effects, following spinal injury. These experiments used a clinically relevant self-administration paradigm to examine both addiction and functional recovery after morphine administration. To assess morphine administration in the acute phase of SCI, animals were placed in operant chambers 24-hours following spinal injury. In the chambers, depression of a reinforced lever resulted in an intravenous infusion of morphine (or vehicle). Animals were placed in the chambers for 7, 12-hour sessions and could administer up to 30 mg of morphine per session. Morphine self-administration was also examined in the chronic phase of injury. Animals were placed into operant chambers for 7, 12-hour sessions beginning 14 or 35 days after injury. The amount of morphine administered, as well as recovery of locomotor function and general health, was compared across subjects with SCI and sham (no injury) controls. In the acute phase of injury, SCI significantly reduced self-administration of morphine, but administration led to decreased recovery of locomotor function and weight loss. In the chronic phase of injury, self-administration did not differ between contused and sham animals. All subjects administered the full amount of morphine available each day. In this phase of injury, morphine administration led to significant weight loss, but did not attenuate recovery of locomotor function. These studies suggest that spinal injury reduced the addictive potential of morphine in the acute, but not the chronic, phase of SCI. However, acute administration of high doses of morphine decreased recovery of locomotor function. Morphine should not be used in this phase of injury for the clinical treatment of pain. In the chronic phase, opioid use must be closely monitored as use may result in addictive behavior.