Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia

Hua, Zhen; Liu, Liping; Shen, Jun; Cheng, Kwai Wa; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, Hongna; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

doi:10.1038/srep32096

Cited by 37 publications

(24 citation statements)

References 67 publications

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“…In vivo OIMA. Opioid-induced mechanical allodynia studies were designed and conducted based on previous reports (Chen et al, 2010;Hua et al, 2016). Briefly, mice were given subcutaneous injections of vehicle or m-opioid agonists twice per day for 4 days.…”

Section: Methodsmentioning

confidence: 99%

TRV0109101, a G Protein-Biased Agonist of theµ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration

Koblish¹,

Carr²,

Siuda³

et al. 2017

J Pharmacol Exp Ther

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Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased -opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in-arrestin1 and -arrestin2 mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the -arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for-arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia.

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Section: Methodsmentioning

confidence: 99%

TRV0109101, a G Protein-Biased Agonist of theµ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration

Koblish¹,

Carr²,

Siuda³

et al. 2017

J Pharmacol Exp Ther

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“…However, long-term and repeated use of morphine no doubt leads to serious side effects, such as morphine-induced hyperalgesia (MIH) and tolerance. 1 MIH is characterized as a paradoxical increase of pain after long-term morphine use, 2 and tolerance is defined as a gradual loss of drug potency and reduced duration of action. 3 The two side effects usually emerged together.…”

Section: Introductionmentioning

confidence: 99%

Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

Liu¹,

Yao²,

Wan³

et al. 2018

JPR

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PurposePreventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) signaling in opioid-induced hyperalgesia and tolerance.MethodsShh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF antibody were used.ResultsRepeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh signaling. In naïve mice, exogenous activation of Shh signaling caused a rapid increase of BDNF expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly suppressed smoothened agonist-induced hyperalgesia.ConclusionThese findings suggest that Shh signaling may be a critical mediator for MIH and tolerance by regulating BDNF expression. Inhibiting Shh signaling, especially during the early phase, may effectively delay or suppress MIH and tolerance.

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“…While our results suggest that alteration of P2X 4 R expression is a major mechanism of action of i.t. BMSCs, P2X 4 R may not be the only target of BMSC derived factors, and it is conceivable that, in addition to its effect on microglia, BMSCs could suppress neuropathic pain by modulating multiple processes in a combinatorial fashion [58, 59]. As future BMSC-based therapeutics are developed for neuropathic pain, we believe that combination therapies directed at multiple targets in neuropathic pain might be worthwhile.…”

Section: Discussionmentioning

confidence: 99%

Intrathecal injection of bone marrow stromal cells attenuates neuropathic pain via inhibition of P2X4R in spinal cord microglia

Teng

Zhang

Yue

et al. 2019

J Neuroinflammation

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BackgroundNeuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive.MethodsWe evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X4 (P2X4R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons.ResultsI.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X4R expression in the spinal cord microglia. BMSC-lysate also reduced P2X4R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X4R confirmed that modulation of P2X4R might be a key mechanism for the analgesic effects of i.t. BMSC.ConclusionAltogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC’s analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X4R downregulation.

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Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia

Cited by 37 publications

References 67 publications

TRV0109101, a G Protein-Biased Agonist of theµ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration

TRV0109101, a G Protein-Biased Agonist of theµ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration

Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

Intrathecal injection of bone marrow stromal cells attenuates neuropathic pain via inhibition of P2X4R in spinal cord microglia

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