Antiallodynic effects of propentofylline Elicited by interrupting spinal glial function in a rat model of bone cancer pain

Yao, Ming; Chang, Xiangyang; Chu, Yu‐Xia; Yang, Jianping; Wang, Lina; Cao, He‐He; Liu, Mingjuan; Xu, Qi-nian

doi:10.1002/jnr.22711

Cited by 33 publications

(19 citation statements)

References 34 publications

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“…The rapid onset of pain behaviors seen with intrathecal injection is consistent with both the documented existence of pre-existing pools of proinflammatory cytokine protein in spinal cord as measured by ELISA (for example, (Yao et al, 2011, Christianson et al, 2012, Jin et al, 2012, Sun et al, 2012)) and with previous studies of intrathecally administered LPS and other TLR4 agonists. LPS has been shown to induce allodynia from 20 min-3 hours following intrathecal injection in rats (Saito et al, 2010, Loram et al, 2011), and 1–6 hours following intrathecal injection in male mice (Sorge et al, 2011).…”

Section: Discussionsupporting

confidence: 85%

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Lewis¹,

Hutchinson²,

Zhang³

et al. 2013

Brain, Behavior, and Immunity

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We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.

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Section: Discussionsupporting

confidence: 85%

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Lewis¹,

Hutchinson²,

Zhang³

et al. 2013

Brain, Behavior, and Immunity

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“…While the central and peripheral mechanisms responsible for these various types of cancer associated pain are still under investigation, it is clear the spinal cord glial cells play a major role (Yao et al, 2011), but apparently not in all types of cancer pain (Ducourneau et al, 2014, Hironaka et al, 2014). In this regard Ducourneau et al (Ducourneau et al, 2014) showed no increase in GFAP in the spinal cord in a rat cancer pain model in which MRMT-1 mammary gland carcinoma cells were injected into the tibia, while Wang et al, (Wang et al, 2012) showed an increase in GFAP in the spinal cord in a rat model in which Walker 256 mammary gland carcinoma cells were injected into the tibia.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, astrocyte activation in the spinal cord appears to be an important contributor to the chronic pain associated with inflammation (Ikeda et al, 2012), HIV (Shi et al, 2012), chemotherapy-induced neuropathy (Zhang et al, 2012, Ruiz-Medina et al, 2013) and tumor-induced pain (Geis et al, 2010, Yao et al, 2011, Ren et al, 2012). Activation may result in altered cell morphology, changes in receptor expression, or release of factors by glial cells, which ultimately enhance nociceptive transmission (Ren and Dubner, 2008).…”

Section: Introductionmentioning

confidence: 99%

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

et al. 2015

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While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in GFAP and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. Secondly, this increase in mechanical hyperalgesia and cold allodynia is mirrored by significant increases in both spinal astrocyte activity and aromatase expression in the dorsal horn of fibrosarcoma-bearing mice. Importantly, we show that aromatase is only found within a subset of astrocytes and not in neurons in the lumbar spinal cord. Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.

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“…It has been well accepted that after nerve injury, levels of proinflammatory cytokines increased in the spinal cord and became the primary activators of the JNK pathway [4,28,29]. Several studies have found the up-regulation of TNF-α, IL-1β and IL-6 in the spinal cord in the CIBP model [30,31]. Thus, after intra-tibial inoculation with carcinoma cells, it is probable that the increased release of proinflammatory cytokines induced JNK activation in the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats

Wang

Mao-Ying

et al. 2012

Mol Brain

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BackgroundThe most frequent pain in patients with metastatic breast and prostate cancer is bone pain, which can be severe and difficult to treat. The mechanisms underlying this pain remain unclear. Here we investigated the role of c-jun N-terminal kinase (JNK) pathway in the spinal cord in cancer-induced bone pain (CIBP).ResultsIn this study, we used an established rat CIBP model to investigate the possible role of JNK activation in the spinal cord. After intra-tibial inoculation with Walker 256 rat mammary gland carcinoma cells, the rats displayed mechanical allodynia on day 5, which lasted to day 16. The activation of JNK in neurons and astrocytes in the spinal cord was found on day 12 and day 16 after intra-tibial inoculation with carcinoma cells. A single intrathecal injection with JNK inhibitor SP600125 by lumbar puncture attenuated mechanical allodynia on day 12, and repeated intrathecal injection of SP600126 from day 10 to day 14 had a cumulative analgesic effect on CIBP.ConclusionsTaken together, our results demonstrated for the first time that JNK activation in the spinal cord is required in the maintenance of CIBP. Inhibition of the spinal JNK pathway may provide a new therapy for CIBP management.

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Antiallodynic effects of propentofylline Elicited by interrupting spinal glial function in a rat model of bone cancer pain

Cited by 33 publications

References 34 publications

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats

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