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.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Pharmacology & Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 131-159.

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.

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.

The central hypothesis of the dissertation is that “the design and synthesis of a codrug of an opiate and a cannabinoid can be achieved which is stable in the gastrointestinal tract and shows a superior pharmacological and pharmacokinetic profile when compared to a physical mixture of the two parent drugs.” To prove the hypothesis, a series of novel codrugs were prepared by conjugation of the opiate drug codeine with Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, abn-cannabidiol and an opiate prodrug 3-O-acetylmorphine with Δ9-THC. Codeine-cannabinoid codrugs were evaluated for analgesic activity in the rat after oral administration. The Cod-THC codrug showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. The stability of Cod-THC codrug in aqueous solutions from pH 1-9, in simulated gastrointestinal fluids, in brain homogenate and the hydrolysis of the carbonate ester linkage in rat plasma suggested that after oral administration, the codrug would be absorbed intact from the GI tract and then hydrolyze in the plasma to generate both parent drugs. The enzymes present in rat brain homogenate were incapable of cleaving the codrug into the parent drugs. The pharmacokinetic profiles of the Cod-THC codrug and an equimolar physical mixture of the parent drugs were evaluated in rats. The plasma concentrations of codeine and Δ9-THC were much higher after codrug administration compared to the plasma concentrations of these drugs after oral administration of an equimolar physical mixture. The parent drugs were also present in the plasma for longer period of time compared to the physical mixture, probably due to the sustained release of the parent drugs from codrug in the plasma. The concentrations of codeine and Δ9-THC were much higher in rat brain after oral administration of the Cod-THC codrug as compared to brain concentrations of these drugs after oral administration of the physical mixture. Thus, the design and synthesis of an opiate and a cannabinoid codrug was achieved which was stable in the gastrointestinal tract, showed enhanced analgesic effects as compared to the parent drugs, and also showed a superior pharmacokinetic profile when compared to a physical mixture or the two parent drugs.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.)--Murdoch University, 2004. / Thesis submitted to the Division of Health Sciences. Bibliography: leaves 351-376.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references.

Thesis (M.H.P.A.)--Washington State University, May 2010. / Title from PDF title page (viewed on July 22, 2010). "Department of Health Policy and Administration." Includes bibliographical references (p. 42-51).

OBJECTIVE: To study the association between benzodiazepine prescribing patterns including dose, type and dosing schedule and the risk of drug overdose death among US veterans receiving opioid analgesics. DESIGN: Case-cohort study SETTING: Veterans Health Administration (VHA), 2004 through 2009. PARTICIPANTS: US veterans, primarily male, who received opioid analgesics between 2004 and 2009. All veterans who died of a drug overdose (n = 2,400) while receiving opioid analgesics and a random sample of veterans (n = 420,386) who received VHA medical services and opioid analgesics were included in the study. Main outcome measure: Drug overdose death, defined as any intentional, unintentional or indeterminate poisoning death caused by any medication or drug, determined by cause of death information from the National Death Index. RESULTS: Twenty seven percent of veterans who received opioid analgesics also received benzodiazepines during the study period. Approximately half of the drug overdose deaths (n=1,185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of drug overdose death increased based on benzodiazepine prescription history: formerly prescribed vs. not prescribed (adjusted hazard ratio [HR]=2.33, 95% confidence interval [CI]: 2.05-2.64); currently prescribed vs. not prescribed (HR=3.86, CI:3.49-4.26). Risk of drug overdose death increased as daily benzodiazepine dose increased. When compared to clonazepam, temazepam was associated with a decreased drug overdose death risk (HR=0.63, CI: 0.48-0.82). Benzodiazepine dosing schedule was not associated with drug overdose death risk. CONCLUSIONS: Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of drug overdose death in a dose-response fashion.