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Opioids and Sepsis: Elucidating the Role of the Microbiome and microRNA-146.
Abu, Y, Vitari, N, Yan, Y, Roy, S
International journal of molecular sciences. 2022;(3)
Abstract
Sepsis has recently been defined as life-threatening organ dysfunction caused by the dysregulated host response to an ongoing or suspected infection. To date, sepsis continues to be a leading cause of morbidity and mortality amongst hospitalized patients. Many risk factors contribute to development of sepsis, including pain-relieving drugs like opioids, which are frequently prescribed post-operatively. In light of the opioid crisis, understanding the interactions between opioid use and the development of sepsis has become extremely relevant, as opioid use is associated with increased risk of infection. Given that the intestinal tract is a major site of origin of sepsis-causing microbes, there has been an increasing focus on how alterations in the gut microbiome may predispose towards sepsis and mediate immune dysregulation. MicroRNAs, in particular, have emerged as key modulators of the inflammatory response during sepsis by tempering the immune response, thereby mediating the interaction between host and microbiome. In this review, we elucidate contributing roles of microRNA 146 in modulating sepsis pathogenesis and end with a discussion of therapeutic targeting of the gut microbiome in controlling immune dysregulation in sepsis.
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New insights into molecular pathways in colorectal cancer: Adiponectin, interleukin-6 and opioid signaling.
Świerczyński, M, Szymaszkiewicz, A, Fichna, J, Zielińska, M
Biochimica et biophysica acta. Reviews on cancer. 2021;(1):188460
Abstract
Colorectal cancer (CRC) is one of the most common cause of death among neoplasms around the world. The environmental factors, like diet and obesity, are crucial in CRC pathogenesis by creating cancer-favorable microenvironment and hormonal changes. Adiponectin, the adipose tissue-specific hormone, is generally considered to negatively correlate with CRC development. The interleukin 6 (IL-6) is one of the most important pro-inflammatory cytokine connected with CRC, which is strongly inflammation-associated. The opioids are variable group substantially correlated with cancers - the endogenous opioids affect immune system and cell cycle including proliferation and cell death whereas exogenous opioids are leading clinically used analgesics in terminal cancer patients. In this review we discuss the involvement of adiponectin, IL-6 and opioids in CRC pathogenesis, their link with obesity, possible cross-talk and potential novel therapeutic approach in CRC treatment.
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3.
Opioids Preconditioning Upon Renal Function and Ischemia-Reperfusion Injury: A Narrative Review.
Palomino, J, Echavarria, R, Franco-Acevedo, A, Moreno-Carranza, B, Melo, Z
Medicina (Kaunas, Lithuania). 2019;(9)
Abstract
Kidneys have an important role in regulating water volume, blood pressure, secretion of hormones and acid-base and electrolyte balance. Kidney dysfunction derived from acute injury can, under certain conditions, progress to chronic kidney disease. In the late stages of kidney disease, treatment is limited to replacement therapy: Dialysis and transplantation. After renal transplant, grafts suffer from activation of immune cells and generation of oxidant molecules. Anesthetic preconditioning has emerged as a promising strategy to ameliorate ischemia reperfusion injury. This review compiles some significant aspects of renal physiology and discusses current understanding of the effects of anesthetic preconditioning upon renal function and ischemia reperfusion injury, focusing on opioids and its properties ameliorating renal injury. According to the available evidence, opioid preconditioning appears to reduce inflammation and reactive oxygen species generation after ischemia reperfusion. Therefore, opioid preconditioning represents a promising strategy to reduce renal ischemia reperfusion injury and, its application on current clinical practice could be beneficial in events such as acute renal injury and kidney transplantation.
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Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications.
Hughes, PA, Costello, SP, Bryant, RV, Andrews, JM
American journal of physiology. Gastrointestinal and liver physiology. 2016;(3):G501-13
Abstract
Opioids are one of the most prescribed drug classes for treating acute pain. However, chronic use is often associated with tolerance as well as debilitating side effects, including nausea and dependence, which are mediated by the central nervous system, as well as constipation emerging from effects on the enteric nervous system. These gastrointestinal (GI) side effects limit the usefulness of opioids in treating pain in many patients. Understanding the mechanism(s) of action of opioids on the nervous system that shows clinical benefit as well as those that have unwanted effects is critical for the improvement of opioid drugs. The opioidergic system comprises three classical receptors (μ, δ, κ) and a nonclassical receptor (nociceptin), and each of these receptors is expressed to varying extents by the enteric and intestinal extrinsic sensory afferent nerves. The purpose of this review is to discuss the role that the opioidergic system has on enteric and extrinsic afferent nerves in the lower GI tract in health and diseases of the lower GI tract, particularly inflammatory bowel disease and irritable bowel syndrome, and the implications of opioid treatment on clinical outcomes. Consideration is also given to emerging developments in our understanding of the immune system as a novel source of endogenous opioids and the mechanisms underlying opioid tolerance, including the potential influence of opioid receptor splice variants and heteromeric complexes.
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Effects of Postoperative Pain Management on Immune Function After Laparoscopic Resection of Colorectal Cancer: A Randomized Study.
Kim, SY, Kim, NK, Baik, SH, Min, BS, Hur, H, Lee, J, Noh, HY, Lee, JH, Koo, BN
Medicine. 2016;(19):e3602
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Abstract
There has been a rising interest in the possible association between perioperative opioid use and postoperative outcomes in cancer patients. Continuous surgical wound infiltration with local anesthetics is a nonopioid analgesic technique that can be used as a postoperative pain management alternative to opioid-based intravenous patient-controlled analgesia (IV PCA). The aim of this study was to compare the effects of an opioid-based analgesic regimen versus a local anesthetic wound infiltration-based analgesic regimen on immune modulation and short-term cancer recurrence or metastasis in patients undergoing laparoscopic resection of colorectal cancer.Sixty patients undergoing laparoscopic resection of colorectal cancer were randomly assigned to either the opioid group or the ON-Q group. For postoperative analgesia during the first 48 hours, the opioid group (n = 30) received fentanyl via IV PCA, whereas the ON-Q group (n = 30) received continuous wound infiltration of 0.5% ropivacaine with an ON-Q pump and tramadol via IV PCA. Pethidine for the opioid group and ketorolac or propacetamol for the ON-Q group were used as rescue analgesics. Anesthesia was induced and maintained with propofol and remifentanil. The primary outcome was postoperative immune function assessed by natural killer cell cytotoxicity (NKCC) and interleukin-2. Secondary outcomes were postoperative complications, cancer recurrence, or metastasis within 1 year after surgery, and postoperative inflammatory responses measured by white blood cell count, neutrophil percentage, and C-reactive protein. Immune function and inflammatory responses were measured before surgery and 24 and 48 hours after surgery.Fifty-nine patients completed the study. In the circumstance of similar pain control efficacy between the opioid group and the ON-Q group, postoperative NKCC and interleukin-2 levels did not differ between the 2 groups. The incidence of postoperative complications and recurrence or metastasis within 1 year after surgery was comparable between the groups. Postoperative inflammatory responses were also similar between the groups.When compared with ropivacaine wound infiltration-based analgesia, fentanyl-based analgesia did not further decrease NKCC or affect short-term cancer recurrence or metastasis. Thus, a fentanyl-based analgesic regimen and a ropivacaine wound infiltration-based analgesic regimen can both be used for postoperative pain management in laparoscopic resection of colorectal cancer.
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Comparison Between the Effects of Intravenous Morphine, Tramadol, and Ketorolac on Stress and Immune Responses in Patients Undergoing Modified Radical Mastectomy.
Bakr, MA, Amr, SA, Mohamed, SA, Hamed, HB, Abd El-Rahman, AM, Mostafa, MA, El Sherif, FA
The Clinical journal of pain. 2016;(10):889-97
Abstract
OBJECTIVES Analgesics had been suspected of impairing various immune functions either directly or indirectly. Our primary objective was to compare the effects of intravenous (IV) morphine, tramadol, and ketorolac on stress and immune responses in patients who underwent modified radical mastectomy. PATIENTS Sixty patients randomly assigned to receive IV morphine 5 mg (group M, n=20), tramadol 100 mg (group T, n=20), or ketorolac 60 mg (group K, n=20) at the end of surgery. METHODS Serum cortisol, prolactin were measured immediately, 40 minutes, and 24 hours postoperatively. Expressions of peripheral T lymphocytes (CD3, CD3CD4, CD3CD8) and natural killer cells (CD3, CD56) were measured as percentages of total lymphocytes by flow cytometry immediately, 90 minutes, and 24 hours postoperatively. RESULTS After 40 minutes, cortisol level increased but prolactin decreased significantly (P=0.001), then both decreased after 24 hours (P=0.001) compared with baseline within the 3 groups. CD3, CD4, CD8, and CD56 significantly decreased at 90 minutes and 24 hours (P≤0.033) compared with baseline in the 3 groups. CD4, CD8, and CD56 significantly decreased in group M, compared with group T and K (P≤0.016) and CD3, CD8, and CD56 in group T compared with group K at 90 minutes (P≤0.024) postoperatively. After 24 hours, CD4, and CD8 decreased in group M compared with group T (P≤0.048) and CD4 and CD56 in groups M and T compared with group K (P≤0.049). CONCLUSIONS IV morphine, tramadol, and ketorolac suppressed stress and immune responses. Ketorolac was the least immunosuppressive among the 3 drugs.
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Opioids modulate constitutive B-lymphocyte secretion.
Vassou, D, Bakogeorgou, E, Kampa, M, Dimitriou, H, Hatzoglou, A, Castanas, E
International immunopharmacology. 2008;(5):634-44
Abstract
The opioid system plays a major role in immunomodulation, while its action on cells of the immune system may be opioid receptor-mediated or not. Opioid effects on B-lymphocytes are considered as indirect, attributed to an interplay between distinct cell populations. The aim of the present study was to investigate whether opioid agonists (morphine, alpha(S1)-casomorphin and ethylketocyclazocine) may have a direct action on the secretion of antibodies and cytokines by multiple myeloma-derived cell lines and normal CD19+ B-lymphocytes. Our results show that opioids modulate antibody and cytokine secretion by multiple myeloma cells in a cell line-dependent and opioid receptor-independent manner, while they decrease antibody secretion by normal B-lymphocytes. Furthermore, they decrease the proliferation rate of multiple myeloma cells through opioid receptor activation. Our data suggest two different mechanisms of action of opioids, mediated by different signaling pathways: an early non-opioid receptor-related effect, modulating the constitutive immunoglobulin and cytokine secretion, and a long-term receptor-mediated action on cell growth. These data suggest a further opioid implication in the control of humoral immunity.