Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline

Aceves, Miriam; Terminel, Mabel N.; Okoreeh, Andre; Aceves, Alejandro R.; Gong, Yan Ming; Polanco, Alan F.; Sohrabji, Farida

doi:10.1016/j.bbi.2019.01.023

Cited by 31 publications

(35 citation statements)

References 92 publications

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“…9,10 Insomnia is associated with increased chronic pain, partially mediated by depressive and anxiety symptoms. 11,12 Mechanistically, opioids and metabolites promote cellular inflammation through opioid 13 and toll-like receptor 4 14 receptor agonism resulting in tissue pathology, reduced recovery, and impaired function. Nonselective or selective cyclo-oxygenase-2 (Cox-2) inhibitors (eg, the nonsteroidal anti-inflammatory drugs ketorolac or celecoxib) reduce production of inflammatory prostaglandins but suppress glucocorticoid release and disinhibit the innate immune inflammatory response.…”

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confidence: 99%

Self‐Reported Prescription Drug Use for Pain and for Sleep and Incident Frailty

Cil

Park

Bergen

2019

J American Geriatrics Society

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OBJECTIVES We aimed to estimate incident frailty risks of prescription drugs for pain and for sleep in older US adults. DESIGN Longitudinal cohort. SETTING Health and Retirement Study. PARTICIPANTS Community‐living respondents aged 65 years and older, excluding individuals who received recent treatment for cancer (N = 14 208). Our longitudinal analysis sample included respondents who were not frail at baseline and had at least one follow‐up wave with complete information on both prescription drug use and frailty, or date of death (N = 7201). MEASUREMENTS Prescription drug use for pain and sleep, sociodemographics, other drug and substance use, and Burden frailty model components. Multivariable drug use stratified hazard models with death as a competing risk evaluated frailty risks associated with co‐use and single use of prescription drugs for pain and for sleep. RESULTS Proportions endorsing prescription drug use were 22.1% for pain only, 6.8% for sleep only, and 7.7% for both indications. Burden frailty model prevalence was 41.0% and varied significantly by drug use. Among non‐frail individuals at baseline, proportions endorsing prescription drug use were 14.9%, 5.6%, and 2.2% for the three indications. Prescription drug use was associated with increased risk of frailty (co‐use adjusted subhazard ratio [sHR] = 1.95; 95% confidence interval [CI] = 1.6‐2.4; pain only adjusted sHR = 1.58; CI = 1.4‐1.8; sleep‐only adjusted sHR = 1.35; CI = 1.1‐1.6; no use = reference group). Cumulative incidence of frailty over 8 years for the four groups was 60.6%, 50.9%, 45.8%, and 34.1%. Sensitivity analyses controlling for chronic diseases associated with persistent pain resulted in minor risk reductions. CONCLUSION Prescription pain and sleep drug use is significantly associated with increased incidence of frailty. Research to estimate effects of pain and sleep indications and of drug class–specific dosage and duration on incident frailty is indicated before advocating deprescribing based on these findings. J Am Geriatr Soc 67:2474–2481, 2019

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confidence: 99%

Self‐Reported Prescription Drug Use for Pain and for Sleep and Incident Frailty

Cil

Park

Bergen

2019

J American Geriatrics Society

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“…Although these data were derived from control animals from a series of experiments, the surgery was carried out by the same investigators who had trained in the same laboratory and the experiments followed sequentially during a period from 2017 to 2019. Kruskal-Wallis testing did not detect difference in day 21 scores ( H = 3.39; P = 0.50) between the animal groups created for the original experiments [including data published in ( 15 – 17 )].…”

Section: Resultsmentioning

confidence: 98%

Variability in Open-Field Locomotor Scoring Following Force-Defined Spinal Cord Injury in Rats: Quantification and Implications

et al. 2020

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Spinal cord injury research in experimental animals aims to define mechanisms of tissue damage and identify interventions that can be translated into effective clinical therapies. Highly reliable models of injury and outcome measurement are essential to achieve these aims and avoid problems with reproducibility. Functional scoring is a critical component of outcome assessment and is currently commonly focused on open field locomotion (the “BBB score”). Here we analyze variability of observed locomotor outcome after a highly regulated spinal cord contusion in a large group of rats that had not received any therapeutic intervention. Our data indicate that, despite tight regulation of the injury severity, there is considerable variability in open-field score of individual rats at 21 days after injury, when the group as a whole reaches a functional plateau. The bootstrapped reference interval (that defines boundaries that contain 95% scores in the population without regard for data distributional character) for the score at 21 days was calculated to range from 2.3 to 15.9 on the 22-point scale. Further analysis indicated that the mean day 21 score of random groups of 10 individuals drawn by bootstrap sampling from the whole study population varies between 9.5 and 13.5. Wide variability between individuals implies that detection of small magnitude group-level treatment effects will likely be unreliable, especially if using small experimental group sizes. To minimize this problem in intervention studies, consideration should be given to assessing treatment effects by comparing proportions of animals in comparator groups that attain pre-specified criterion scores.

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“…However, the chronic use of morphine leads to tolerance and hyperalgesia due to its pro-inflammatory potential. There have been many studies performed over the years showing the pro-inflammatory mechanisms of morphine and the µ opioid receptor agonists in humans, rodents, and cells, including the microglia [13][14][15][16][17][18]. Contrary to the actions of the µ opioid receptor agonists, the agonists of δ and κ opioid receptors suppress inflammatory responses [20][21][22][23].…”

Section: Discussionmentioning

confidence: 99%

“…Despite morphine long being known to have immunosuppressive properties in vivo, a chronic morphine infusion causes neuroinflammation [12,13]. In vitro, both microglia and macrophages respond to morphine by releasing pro-inflammatory cytokines [14][15][16][17][18]. Because the well-known effects of morphine are mediated specifically by the µ opioid receptor subtype, the activation of the µ opioid receptor is closely linked with neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

Chang

Shih

et al. 2020

IJMS

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Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the μ opioid receptor antagonist β-funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-γ)-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague–Dawley rats, β-funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. β-funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by β-funaltrexamine was accompanied by the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of β-funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of β-funaltrexamine in combating neurodegenerative diseases, such as stroke.

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Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline

Cited by 31 publications

References 92 publications

Self‐Reported Prescription Drug Use for Pain and for Sleep and Incident Frailty

Self‐Reported Prescription Drug Use for Pain and for Sleep and Incident Frailty

Variability in Open-Field Locomotor Scoring Following Force-Defined Spinal Cord Injury in Rats: Quantification and Implications

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

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