Find us on:


Low Dose Naltrexone Reduces In Vitro Endoplasmic Reticulum Stress and Stimulates Wound Healing in Intestinal Epithelial Cells

Low Dose Naltrexone Reduces In Vitro Endoplasmic Reticulum Stress and Stimulates Wound Healing in Intestinal Epithelial Cells
Publication Type
Research Type
Reported as
Clinical Trial
May 01, 2016
Fuhler, G., Lie, M., Dimitrijevic, P., Van Der Woude, C.J., and Peppelenbosch, M.
Erasmus MC University Medical Centre

BACKGROUND: Naltrexone (NTX), a μ-opioid receptor (MOR) antagonist, up regulates MOR and its ligands when used at low doses. Stimulation of MOR in mouse models alleviates intestinal inflammation, and treatment of IBD patients with low-dose NTX can induce remission and mucosal healing. Although NTX reduces immunocyte proliferation and cytokine production, it is unclear whether a direct action of low-dose naltrexone (LDN) on intestinal epithelial cells (IEC) can contribute to its beneficial effects in IBD. In this study, we aimed to investigate the in-vitro effect of NTX on IECs, and confirm these results in IBD patients treated with low-dose NTX.

METHODS: In total, 40 patients (43% male, median age 40y, IQR 28–52 years) were treated with 5 mg NTX/day. Response was seen in 23 patients (13 CD; 10 UC), with a median duration of 2 months (IQR 2–3 months). Serum was obtained from 7 patients before NTX and 3 months into treatment. Formalin-fixed paraffin-embedded (FFPE) biopsies were obtained from 12 patients before treatment and 5 patients 3 months into treatment. MOR expression in IECs (Caco2 and HCT116) was determined by rt-polymerase chain reaction (PCR), IEC cell viability was determined by MTT assay, and wound healing was determined by scratch wound assays. Cytokine levels in supernatants from IECs and patient sera were determined by ELISA. The effect of NTX on endoplasmic reticulum (ER) stress was determined in IECs by Western blot analysis of GRP78 expression and by immunohistochemistry on FFPE slides from low-dose NTX treated patients.

RESULTS: IEC express MOR mRNA, allowing for direct NTX interaction. IEC viability was not affected by NTX at concentrations up to 100 μg/ml. At 1 μg/ml, NTX significantly improved cell migration into scratch wounds compared with control (330 ± 27 vs 140 ± 19 pixels, p = 0.0021 for HCT116, 470 ± 16 vs 248 ± 19, p < 0.001 for Caco2). Although no TNFα production could be detected in IEC supernatants, neither basal nor E. Coli-induced IL8 secretion were affected by NTX. Likewise, no modulation of TNFα or IL8 levels upon NTX was observed in patient sera. Mucosal ER stress is known to play an important role in IBD, and could be induced in IECs upon treatment with either E. Coli (DH5α) or Tunicamycin (2μM). Interestingly, NTX significantly reduced this ER stress. High levels of ER stress were observed in the inflamed intestinal interstitium and crypts from IBD patients before low-dose NTX treatment, and decreased upon NTX treatment (1.14 ± 0.5 vs 0.8 ± 0.5 and 0.9 ± 0.4 vs 0.7 ± 0.6) although statistical significance was not reached because of low patient numbers. However, in 3 paired samples, NTX treatment reduced interstitial ER stress.

CONCLUSION: NTX may have a beneficial effect in the treatment of IBD by directly stimulating epithelial wound healing and reducing intestinal ER stress.

male enhancement: strengthen pc muscles erection enhancers over the counter strong erection exercises big weiners lowered libido what is ed in medical terms natural ed treatments are black cocks bigger how to force an erection erectile dysfunction ed penis enlargement devices fda approved male enhancement stimulate the penis glans pumping self pleasuring men zestra cream enzyte ingredients libido suppressant prime male for sale penis enlargments yellow hornet pills best male performance pills pill stores sec store near me cock pumping yellow pill 50 penis puberty wicked pills no sex drive after hysterectomy mail order prescriptions from canada big blue pill how to prevent an erection last tablets male penis anatomy how to combat ed what causes erectile dysfunction yohimbine testosterone genital implants suck on my dick cenforce reviews is a 6 inch penis big 5 in dick primal male xl buying pain meds silicone injected cock massage penis corona penis erectile dysfunction va rating boys with big penis penis becoming erect multi mineral supplement levitra 20mg how to use webmd blood pressure chart zyntix amazon real male enhancement reviews animal test supplements

vape: iphone case vape smok tf s6 how to charge a vape battery without a charger voopoo custom faceplate suorin edge cheap e cigarette lilac city vapor vapor barriers for crawl space vicks vaporub toenail fungus uwell crown retail free vapor kit rx200 battery check smoque vapors vaporizer for sale near me spencers ecig serenity vape juice is it safe to charge 18650 batteries in ecig is vitamin vaping safe ecig airline policy vapor apparel wholesale logic lqd ecig review how to make a vape at home can you mail vape juice can you put regular e juice in a smok nord e cigarette workplace policy vaping oil ingredients e cigarette 901 jam monster apple vaping ban washington state tank band vape best vaping temperature smok tfv8 vs tfv8 baby vaping effects on body box mods with rda is smoking worse than vaping ecig maple grove best voltage to vape lung disease linked to vaping mg of nicotine in 1 cigarette vape set e cigarettes free starter kit davinci iq vaporizer seller factory reset voopoo drag where to buy vape batteries near me hash oil vape tank juul kit near me volcano ecig pearlridge uwell nunchaku kit aspire k1 starter kit amazon smok o rings uwell crown 4 review smok tfv8 rba deck what is in vape juice without nicotine voopoo drag not charging fully space vape vsop

weight loss: percentage of weight loss calculator final trim weight loss pills review healthy weight loss tips is peanut good for weight loss best weight loss food for dogs loss weight for free shopping lists for weight loss peanut diet for weight loss trx weight loss why take water pills for weight loss cinnamon weight loss dr oz can cinnamon help with weight loss apple cider weight loss drink recipe tanisha weight loss weight loss diet for diabetics niacin for weight loss weight loss gym jennifer hudson before weight loss healthy sandwiches for weight loss weight loss tips for men weight loss wraps near me estrogen replacement weight loss weight loss surgery denver weight loss success stories 100 pounds basmati rice weight loss soy weight loss mango and weight loss mineral oil weight loss clean eating blogs weight loss lipozene weight loss pills side effects low cortisol weight loss chinese diet pills green weight loss enhancement pills 30 day diet plan for weight loss diet pills for dogs contrave weight loss results select diet pills cla walgreens all diet pills names weight loss routines 2 diet pills order weight loss pills quick weight loss carb blocker weight loss pills usa quick fast weight loss diets dr rand mcclain weight loss apple juice diet weight loss best wii workout games for weight loss diet challenge for weight loss weight loss albuquerque parsley diet weight loss water weight loss pills walgreens pure garcinia cambogia extract weight loss shake for diabetics burn fat diet hcg diet pills sold at walmart

cbd oil: cbd oil rochester ny best price for cbd oil best vape for cbd oil legal buds review cbd weed legal cbd and warfarin tru infusion cbd cbd oil and focus cbd laws in utah 2018 vermont cbd store designs for health cbd oil euphoria strain cbd how to take cbd sublingually cbd merchant account reviews high cbd autoflower seeds organic cannabis oil cbd rich cbd flower wisconsin does cbd make you laugh phytodabs cbd herb definition do you need a card for cbd oil cbd oil for sale in nj whats cbd stand for cbd for stomach issues lifted liquids cbd full spectrum cbd oil in colorado springs new cbd oil how is cbd oil produced wildflower cbd coupon code of mice and men characterization chart cbd suppository recipe formula 303 good life cbd oil bloody flux cbd oil tanks cbd oil and ibuprofen interaction dose for cbd cbd to treat anxiety costs to manufacture cbd medterra cbd oil coupon alpha vs gamma motor neurons taking cannabis oil primebody hemp oil kwan loong oil cannabidiol mechanism of action slow metabolism pills blood run line how are people made where to buy act dry mouth lozenges find the right dose of cbd hemp oil flying with cbd oil 2017 online shopping cbd oil 1000mg review delta botanicals nebraska cbd oil cbd balm for anxiety