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3 results on '"Opioid induced tolerance"'

1. A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review.

Author

Varrassi, Giustino, Fusco, Mariella, Skaper, Stephen D., Battelli, Daniele, Zis, Panagiotis, Coaccioli, Stefano, Pace, Maria Caterina, and Paladini, Antonella

Subjects
*PAIN management, *CHRONIC pain, *HYPERALGESIA, *MEDICAL care, *MAST cells
Abstract

Chronic pain is an important health and social problem. Misuse and abuse of opioids in chronic non-cancer pain management seem to be a huge problem, in some countries. This could probably affect the normal use of such analgesics in patients in need of them. Basic and clinical researches should find the solution to mitigate the potential damage. Dysregulation of mast cell and microglia activation plays an important role in the pathogenesis and management of chronic pain. Persistent mast cell activation sensitizes nociceptors and initiates central nervous system inflammatory processes, involving microglial cell activation and sensitization of spinal somatosensory neurons. Exposure of mast cells and microglia to opioids is well known to provoke activation of these non-neuronal immune cell populations, thereby contributing to an exacerbation of pro-inflammatory and pro-nociceptive processes and promoting, over the long-term, opioid-induced hyperalgesia and tolerance. This review is intended to provide the reader with an overview of the role for these non-neuronal cells in opioid-induced chronic pain and tolerance as a consequence of prolonged exposure to these drugs. In addition, we will examine a potential strategy with the aim to modulate opioid-induced over-activation of glia and mast cells, based on endogenous defense mechanisms and fatty acid amide signaling molecules. [ABSTRACT FROM AUTHOR]

Published
2018
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2. 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

Author

Okerman, Travis

Subjects
Analgesia, Morphine, nociception, Opioid Induced Tolerance, PIK3/AKT Intracellular Signaling Pathway, Spinal Nerve Ligation
Abstract

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.

Published
2019

3. DESIGN, SYNTHESIS, NMR CONFORMATIONAL ANALYSIS AND DOCKING ANALYSIS OF NOVEL MULTIFUNCTIONAL MOLECULES FOR PAIN

Author

Hruby, Victor J., Glass, Richard, Mash, Eugene, McEvoy, Megan, Vanderah, Todd, Kumarasinghe, Isuru Ransiri, Hruby, Victor J., Glass, Richard, Mash, Eugene, McEvoy, Megan, Vanderah, Todd, and Kumarasinghe, Isuru Ransiri

Abstract

Currently, opioids are extensively used in clinical practices in order to treat pain in patients. However, prolonged administration of opioids are not feasible due to the development of side effects especially tolerance, constipation, addiction and dependence. Our drug design is mainly aimed to reduce opioid induce side effects such as development of tolerance. The first strategy examined involves design and synthesis of peptide based single molecules that have a mu agonist and delta agonist pharmacophore in combination with a COX2 inhibitory pharmacophore. A new molecule, 3-17 having good delta agonist activity, partial COX2 inhibitory activity and weak mu agonist activity was produced. Moreover, Investigation of the bioactivities of the synthesized ligands including 3-17 in terms of their ligand receptor interactions were probed using NMR conformational analysis along with docking analysis to the respective homology modeled mu and delta opioid receptors as well as the COX2 enzyme. As a further continuation of this work, instead of peptide based mu agonist and delta agonist type pharmacophore, the highly mu selective fentanyl pharmacophore was used in combination with a pyrazole based and a pyrazolone based COX pharmacophore. Based on the SAR study and docking analysis of synthesized ligands to the homology modeled mu opioid receptor, an ideal tolerant position without significant loss of mu opioid agonist activity for fentanyl were found. The second strategy involves design and synthesis of a peptide based single molecule that has a mu agonist and a delta antagonist pharmacophore in combination with a NK1 antagonist pharmacophore. A novel molecule (4-2) containing delta antagonist activity, weak mu agonist activity and NK1 antagonist activity was identified. Its homology modeled mu opioid receptor bound conformation was compared with that of reference ligands. Docking analysis of modified 4-2 to the homology modeled mu opioid receptor revealed that it can be furth

Published
2010

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