MSC reverses opioid tolerance and opioid-induced hyperalgesia in rodents

Opioids are commonly prescribed to millions of patients for chronic pain. While they bring pain relief, they are associated with opioid tolerance (OT) – the body grows used to opioid medication and requires higher doses to manage pain adequately. Another condition associated with opioid use is opioid-induced hyperalgesia (OIH), where the patient grows even more sensitive to pain. Neuroinflammation has been shown to play a central role in OT and OIH, so the anti-inflammatory, neuroregenerative and neuroprotective properties of MSC position them as an interesting treatment option.

Hua and colleagues have recently shown that OT and OIH were significantly reversed after bone marrow MSC transplantation in rats and mice receiving opioids. The results, a joint collaboration from centers in Ohio, Illinois and China, were published in Nature Scientific Reports. Following MSC administration, the development of OT was significantly attenuated and reversed in the rodents, with a peak at 12 days after start of treatment. Additionally, morphine sensitivity was significantly and consistently lowered, and pain thresholds were reduced to the baseline. OIH development was also significantly prevented. Microglia activation and BDNF release (key in the development of tolerance) were attenuated, and IBA-1 positive cells in microglia were restored to their resting state. These results are encouraging news for OT and OIH treatment research with MSC.


Sci Rep. 2016 Aug 24;6:32096.

Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

Hua Z, Liu L, Shen J, Cheng K, Liu A, Yang J, Wang L, Qu T, Yang H, Li Y, Wu H, Narouze J, Yin Y, Cheng J.


More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy.

PMID: 27554341 PMCID: PMC4995471

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