Browsing by Subject "Analgesia"

Now showing 1 - 4 of 4
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    Effects of chronic morphine treatment on tumor angiogenesis and growth.
    (2009-06) Koodie, Lisa
    Morphine is one of the most effective analgesics commonly prescribed for the treatment of severe to moderate cancer pain. To date very little is known regarding the effect of long-term morphine treatment on tumor angiogenesis. At this time, the effect of morphine on tumor growth is contradictory and still inconclusive. As solid tumors grow, the formation of a blood supply or angiogenesis is essential. In previous studies, morphine inhibited vascular endothelial growth factor (VEGF) secretion from mice cardiomyocytes and human umbilical vein endothelial cells. VEGF is a highly potent pro-angiogeneic molecule and we therefore hypothesized morphine would also inhibit angiogenesis associated with tumor growth. In the first part of these studies we show that morphine inhibited the hypoxia-induced tumor cell expression of VEGF to significantly reduce tumor cell angiogenesis, and suppress tumor growth in vivo. Additional investigations supported the view that the effect of morphine was not due to a direct effect on tumor cell apoptosis, but instead indirectly through angiogenesis. Tumor, stromal and inflammatory cells within the tumor microenvironment all contribute to a large pool of chemoattractants that increase the recruitment of myeloid cells from peripheral blood circulation into the tumor tissues. These cells mature and differentiate into neutrophils, and macrophages that eventually result in a pro-inflammatory-like environment to support and maintain tumor growth. Considering that morphine is highly immuno-suppressive, we also hypothesized that morphine will inhibit immune cell recruitment and thus angiogenesis. In an in vivo model of cell migration and recruitment we found that morphine inhibited not only CD11b+ progenitors of inflammatory cells but also the recruitment of Tie2+/CD14+ endothelial cell precursors known to actively participate in vessel formation to tumor sites. These studies have allowed us to further understand the effects of a potent analgesic such as morphine in cancer growth. Our data support the use of morphine for pain associated with cancer. Our results support the view that morphine may not cause any further detriment in the cancer patients' quality of life but further suppress angiogenesis associated with tumor growth and progression.
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    The Effects of Morphine Tolerance on the PI3K/AKT Intracellular Signaling Pathway During Acute and Chronic Pain in the Central and Peripheral Nervous System of Mice
    (2019-09) Okerman, Travis
    The management of chronic pain with opioids can cause opioid-induced analgesic tolerance and hyperalgesia, complicating clinical pain-management treatments. Mu opioid receptors (MOPs) are inhibitory G-protein coupled receptors. MOPs have been studied for years; however, the intracellular signaling pathways triggered by their activation are not well known. Research presented here sought to determine if opioid induced tolerance is linked to a decreased activity in the PI3K/AKT intracellular signaling pathway. To assess gene expression within this pathway and cGMP nucleotide levels, C57Bl/6 wild type male mice were divided into saline , morphine tolerant (MT), and morphine tolerant with spinal nerve ligation (MT+SNL) groups. Injections were given subcutaneously twice a day for a total of five days. MT mice without SNL developed opioid induced tolerance by day 3 and opioid induced hyperalgesia by day 5. MT+SNL mice had lower TPWL responses for the ipsi (injured) side compared to their contra (uninjured) side. Brainstem, spinal cord, dorsal root ganglia, and sciatic nerves were harvested from mice on day 6 of the behavior testing and were used for qPCR gene expression analysis. Genes chosen for qPCR analysis were Akt1, Akt2, Akt3, Pik3cg (splice variants v1-v3), Pten, Abcc8, Abcc9, Kcnj11 (splice variants v1 and v2), Kcnj8, Oprm1, Jnk3, and nNos1. There were few significant gene expression changes of the PI3K/AKT intracellular signaling pathway for MT mice compared to saline mice in both the central and peripheral nervous system. The addition of the MT+SNL model saw larger gene expression increases or decreases in almost all genes, with no clear trend for gene expression changes both between and within the central and peripheral nervous system tissues. Additionally, there was decreased gene expression in all genes except Pten in the MT+SNL spinal cord. The daily administration of PI3K/AKT pathway inhibitors, thalidomide, SP600125, and quercetin to MT+SNL mice attenuated the development of morphine tolerance, suggesting PI3K/AKT pathway activity is positively correlated with morphine tolerance. Thus, our initial hypothesis that stated PI3K/AKT pathway downregulation may contribute to morphine tolerance was not supported by our data collected from this study. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance. Continued research into this pathway, including further protein analysis and studies utilizing knockout mice, will advance understanding of morphine tolerance and potentially contribute to the development of new analgesic drug therapies.
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    Studies of efficacy of sustained-release buprenorphine in Sprague Dawley Rats
    (2023-04-21) Peterson, Cristina, D; Wilcox, George, L; Fairbanks, Carolyn, A; Kitto, Kelley, F; Larson, Christina, M; carfair@umn.edu; Fairbanks, Carolyn A; University of Minnesota Wilcox/Fairbanks Lab
    Buprenorphine in a sustained-release formulation is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine persist in serum once sustained-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of sustained-release buprenorphine in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg sustained-release buprenorphine, analgesic efficacy did not persist to 24 hours. No changes in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally-mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to sustained-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or sustained-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1 – 3 mg/kg). Rats previously given sustained-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in rats after exposure to the sustained-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.