2 research outputs found

    The role of peripheral NMDA receptors in nerve growth factor-induced muscle pain

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    Intramuscular injections of nerve growth factor (NGF) into human masseter muscle induce a local mechanical sensitization that mimics the symptoms of myofascial pain in patients with temporomandibular disorders. I hypothesize that NGF induces the myofascial mechanical sensitization in part by increasing the expression of N-methyl-D-aspartate (NMDA) receptors in primary afferent neurons. In behavioral experiments, injection of NGF into rat masseter muscle induced a prolonged local mechanical sensitization that was greater in female rats than in male rats. This NGF-induced sensitization was partly attenuated by a local injection of the NMDA receptor antagonist APV at 3 days post NGF injection in the male rats but not in the female rats. Immunohistochemical studies found that this NGF-induced mechanical sensitization was accompanied by the increased expression of NMDA receptor subtype 2B (NR2B) in trigeminal ganglion neurons innervating the masseter muscle in both sexes, as well as an increase in the average soma size of NR2B-expressing neurons. An increase in the expression of neuropeptides (CGRP/SP) was also observed in the female rats but not in the male rats. In in vivo extracellular recordings of masseter trigeminal ganglion neurons, NGF increased NMDA-induced mechanical sensitization in the male rats but not in the female rats. However, in the female rats, this effect was greater in slow Aδ fibers (2-7 m/s) than fast Aδ fibers (>7-12 m/s). My results suggest that NGF-induced mechanical sensitization is mediated, in part, through an effect on peripheral NMDA receptors in a sexually dimorphic manner.Medicine, Faculty ofGraduat

    DNA-triggered release liposomes : a pharmaceutical strategy for improving the tumor exposure of chemotherapeutic agents

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    Long circulating liposomes have been demonstrated to be an attractive delivery system for anticancer agents with favorable tumor drug accumulation. However, the slow rate of drug release from these liposomes may limit the level of drug exposure in the tumor available for cell uptake and one strategy to address this problem is to develop long circulating liposomes with selective drug release at the tumor. With the well-known propensity of fusogenic cationic liposomes to associate with DNA and strong evidences indicating selective localization of extracellular DNA in solid tumors, it is hypothesized that a fusogenic cationic liposome formulation containing DOTAP and DOPE would exhibit selective drug release in the tumor. This thesis presents a stepwise approach to the design of such liposomes. In order to develop a triggered release liposome that selectively targets the extracellular DNA in the tumor, the characteristic features of these DNA are first studied. In vivo results in Chapter 2 demonstrate an elevated level of extracellular DNA in the tumor in comparison with other organs and that they are in the size range of 200-3000 bp. Secondly, it is essential for an optimum triggered release liposome to remain stable in the circulation before reaching the tumor. Results from Chapter 3 demonstrate that the incorporation of DSPE-PEG 350 into DOTAP/DOPE liposomes prevents their characteristic salt-induced aggregations in physiological solutions while retaining the capacity to be triggered by extracellular DNA to release its entrapped contents. The in vivo results from Chapter 4 demonstrate the prolonged circulation time of DOTAP/DOPE/DSPE-350 (50:35:15) liposomes in H460 tumor bearing mice. These liposomes were stable in the circulation with selective tumor release of the entrapped contents. The results from these studies provide the basis for developing DNA triggered release liposomes that can selectively release their entrapped therapeutic agents in the tumor.Pharmaceutical Sciences, Faculty ofGraduat