Toll-like Receptor-Dependent Negative Effects of Opioids: A Battle between Analgesia and Hyperalgesia

Shah, Masaud; Choi, Sangdun

doi:10.3389/fimmu.2017.00642

Cited by 21 publications

(19 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The aforementioned results indicate that HMGB1 released from lung cancer cells induces NETs via the TLR4/MAPK signaling pathway. To alleviate cancer-associated pain, patients with lung cancer may be administered morphine, which also binds with TLR4 (17,18). Therefore, neutrophils infiltrated into lung tissues may be stimulated by HMGB1 and morphine.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Lung cancer cells release high mobility group box 1 and promote the formation of neutrophil extracellular traps

Yang

Gan

et al. 2019

Oncol Lett

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer-associated mortality. Tumor-associated neutrophils represent a large portion of inflammatory cells within the lung tumor microenvironment. However, the roles of neutrophil extracellular traps (NETs) in lung cancer remain unclear. In the present study, it was identified that Lewis lung carcinoma cells actively released the danger-associated molecular pattern protein high mobility group box 1 (HMGB1). Furthermore, HMGB1 in lung cancer cell supernatants promoted the formation of neutrophil extracellular traps (NETs), which was dependent on Toll-like receptor 4 (TLR4). The downstream molecules of TLR4, including myeloid differentiation factor 88, TIR-domain-containing adapter-inducing interferon-β, p38 mitogen-activated protein kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs), were activated during the formation of NETs. In addition, inhibition of p38 MAPKs or ERKs significantly decreased NETs. Morphine, an additional ligand for TLR4, aggravated the NETs induced by lung cancer cells. The present study revealed novel mechanisms in tumor-associated NET formation.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Arguably, morphine may stimulate angiogenesis and promote tumor progression (15,16). HGMB1 and morphine are able to bind with TLR4 (17,18). The present study aimed to evaluate the role of HMGB1 from lung cancer cells in the formation of NETs.…”

Section: Introductionmentioning

confidence: 99%

Lung cancer cells release high mobility group box 1 and promote the formation of neutrophil extracellular traps

Yang

Gan

et al. 2019

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…Discovering "off-site" effects of opioids could shed light on the complex mechanisms of neurobiological phenomena, such as hyperalgesia if it were to be determined for example that opioids upregulate the KP leading to the accumulation of the neurotoxic metabolites such as quinolinic acid. To our knowledge, there have been no studies assessing the direct impact of opioids on circulating levels of KP metabolites, however, opioids have been shown to participate in neuroimmune signaling through toll-like receptors that, when activated, can stimulate the KP (34)(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

An Analysis of Biomarkers in Patients with Chronic Pain

Gunn¹

2020

Pain Phys

View full text Add to dashboard Cite

Background: Because of the subjective nature of current pain assessments, limited efficacy of treatment options and risks associated with opioid abuse and diversion, the need for objective data to assist with chronic pain management has never been greater. Successful identification of mechanistic biomarkers would not only improve our understanding and ability to accurately diagnose pain disorders but would also facilitate the development of disease-modifying pain drugs. Objectives: The objective of this study was to determine and evaluate the prevalence of abnormal biomarker findings in a population of patients with chronic pain. Study Design: Retrospective, observational study. Setting: Data analysis of biomarker test results was performed at a single industry site (Ethos Research & Development, Newport, KY) from clinical samples collected and analyzed from July to December 2018. Methods: A novel, pain-specific biomarker test panel that evaluates biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover, and micronutrient status was employed to determine the prevalence of abnormal findings in 17,834 unique patient samples analyzed at a national reference laboratory (Ethos Laboratories, Newport, KY). Patient biomarker results were considered abnormal if they were outside of the 95% confidence interval reference ranges established using a healthy population of donors who had no history of chronic pain or opioid use. Results: A total of 77% of patients with chronic pain exhibited at least one abnormal biomarker result (n = 13,765). The most common abnormal biomarker finding was elevated quinolinic acid, which was observed in 29% of patients (n = 5,107). Elevated pyroglutamate, indicative of glutathione depletion, was observed in 19% of patients (n = 3,314). Elevated xanthurenic acid, indicative of vitamin B6 insufficiency, was observed in 17% of patients (3,025). Elevated levels of the acrolein metabolite 3-hydroxypropyl mercapturic acid were observed in 21% of patients (n = 3,667). Elevated methylmalonic acid, indicative of a vitamin B12 deficiency, was observed in 10% of patients (n = 1,827), whereas abnormally low levels of neurotransmitter metabolites were observed in 8% of patients (n = 1,456). Limitations: Medications and/or conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings. Conclusions: A novel biomarker assay that measures objective correlates to the neurobiological processes underlying chronic pain reveals a high prevalence of atypical biochemistry in a population of patients with pain. Abnormal biomarker findings presented here provide objective support for the role of cytokine-mediated inflammation, oxidative stress, abnormally low production of neurotransmitters, and micronutrient deficiencies in the development or worsening of chronic pain. This unique panel of functional pain biomarkers provides practitioners with novel, objective insight into the underlying causes of pain, which will pave the way for truly personalized pain medicine. Correcting abnormal biomarker findings with targeted, nonopioid therapies to improve patient function and alleviate pain potentially could lessen the opioid burden and drastically reduce health care costs. Key words: Biomarker, pain, inflamation, oxidative stress, neurotransmitter, micronutrient deficiency, Kynurenine Pathway

show abstract

“…It is reported that opioids such as morphine can induce neuroinflammation in the central nervous system (Narita et al, 2006;Yang et al, 2010). Furthermore, this neuroinflammation has been associated with morphine analgesia, dependence, tolerance and withdrawal effects (Eidson and Murphy, 2013;Jacobsen et al, 2014;Mattioli et al, 2014;Eidson et al, 2017;Shah and Choi, 2017). It has been shown that morphine can directly bind to myeloid differentiation protein 2 (MD-2), the accessory receptor of TLR4, and activate TLR4 signaling by inducing the oligomerization of TLR4/MD-2.…”

Section: Evidence Of a Role Of Toll-like Receptor 4 In Opioid Addictionmentioning

confidence: 99%

Toll-Like Receptor 4 Signaling and Drug Addiction

Wü

2020

Front. Pharmacol.

View full text Add to dashboard Cite

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

show abstract

Toll-like Receptor-Dependent Negative Effects of Opioids: A Battle between Analgesia and Hyperalgesia

Cited by 21 publications

References 49 publications

Lung cancer cells release high mobility group box 1 and promote the formation of neutrophil extracellular traps

Lung cancer cells release high mobility group box 1 and promote the formation of neutrophil extracellular traps

An Analysis of Biomarkers in Patients with Chronic Pain

Toll-Like Receptor 4 Signaling and Drug Addiction

Contact Info

Product

Resources

About