Delayed Activation of Spinal Microglia Contributes to the Maintenance of Bone Cancer Pain in Female Wistar Rats via P2X7 Receptor and IL-18

Yang, Yan; Li, Hui; Li, Tingting; Luo, Hao; Gu, Xiechong; Lü, Nonghua; Ji, Ru-Rong; Zhang, Yu‐Qiu

doi:10.1523/jneurosci.5250-14.2015

Cited by 169 publications

(170 citation statements)

References 64 publications

Supporting

Mentioning

161

Contrasting

Order By: Relevance

“…Furthermore, caspase-6, a microglial activator produced by primary afferents in the spinal cord, regulates persistent pain in male mice (Berta et al, 2016). However, microglial inhibitor minocycline was also shown to reduce neuropathic pain in female rats in the late phase of spinal cord injury (Chen et al, 2012) and attenuate bone cancer pain in female animals inoculated with breast cancer cells (Yang et al, 2015), suggesting that microglia in female animals may also have an active role in some pain conditions.…”

Section: Discussionmentioning

confidence: 99%

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Luo

Fitzsimmons

Mohan

et al. 2018

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

p38 mitogen-activated protein kinase (MAPK) consists of two major isoforms: p38α and p38β; however, it remains unclear which isoform is more important for chronic pain development. Recently, we developed potent, long-lasting, and p38 MAPK subtype-specific antisense oligonucleotides (ASOs). We examined the therapeutic effects of isoform-specific ASOs in several chronic pain models following single intrathecal injection (300 µg/10 µl) in CD1 mice. In the chronic constriction injury (CCI) model, p38α MAPK ASO, given on post-operative day 5, reduced CCI-induced mechanical allodynia in male but not female mice. In contrast, mechanical allodynia after CCI in both sexes was not affected by p38β MAPK ASO. Intrathecal injection of p38α or p38β ASO resulted in a partial reduction (≈50%) of spinal p38α or p38β mRNA level, respectively, in both sexes at two weeks. In contrast, intrathecal injection of the ASOs did not affect p38α and p38β MAPK mRNA levels in dorsal root ganglia. Intrathecal p38α ASO also reduced postoperative pain (mechanical and cold allodynia) in male mice after tibia fracture. However, intrathecal p38α ASO had no effect on mechanical allodynia in male mice after paclitaxel treatment. Intrathecal p38α MAPK ASO pre-treatment also prevented TLR4-mediated mechanical allodynia and downregulated levels of p38α MAPK and phosphorylated p38 MAPK following intrathecal treatment of lipopolysaccharide. In summary, our findings suggest that p38α MAPK is the major p38 MAPK isoform in the spinal cord and regulates chronic pain in a sex and model-dependent manner. Intrathecal p38α MAPK ASO may offer a new treatment for some chronic pain conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Luo

Fitzsimmons

Mohan

et al. 2018

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

show abstract

“…It is also possible that microglia may play different roles in different chronic pain conditions as well as in different phases of chronic pain development. For example, in a breast cancer pain condition, spinal microglia were shown to play an important role in the maintenance of bone cancer pain in female rats (Yang et al 2015). Of interest, naltrexone, an opioid receptor antagonist, may inhibit the activity of microglia at low doses.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

et al. 2016

View full text Add to dashboard Cite

Microglia are the resident immune cells in the spinal cord and brain. Mounting evidence suggests that activation of microglia plays an important role in the pathogenesis of chronic pain, including chronic orofacial pain. In particular, microglia contribute to the transition from acute pain to chronic pain, as inhibition of microglial signaling reduces pathologic pain after inflammation, nerve injury, and cancer but not baseline pain. As compared with inflammation, nerve injury induces much more robust morphologic activation of microglia, termed microgliosis, as shown by increased expression of microglial markers, such as CD11b and IBA1. However, microglial signaling inhibitors effectively reduce inflammatory pain and neuropathic pain, arguing against the importance of morphologic activation of microglia in chronic pain sensitization. Importantly, microglia enhance pain states via secretion of proinflammatory and pronociceptive mediators, such as tumor necrosis factor α, interleukins 1β and 18, and brain-derived growth factor. Mechanistically, these mediators have been shown to enhance excitatory synaptic transmission and suppress inhibitory synaptic transmission in the pain circuits. While early studies suggested a predominant role of microglia in the induction of chronic pain, further studies have supported a role of microglia in the maintenance of chronic pain. Intriguingly, recent studies show male-dominant microglial signaling in some neuropathic pain and inflammatory pain states, although both sexes show identical morphologic activation of microglia after nerve injury. In this critical review, we provide evidence to show that caspase 6—a secreted protease that is expressed in primary afferent axonal terminals surrounding microglia—is a robust activator of microglia and induces profound release of tumor necrosis factor α from microglia via activation of p38 MAP kinase. The authors also show that microglial caspase 6/p38 signaling is male dominant in some inflammatory and neuropathic pain conditions. Finally, the authors discuss the relevance of microglial signaling in chronic trigeminal and orofacial pain.

show abstract

“…What chemical signals do microglia pick up as a sign of injury? Among a handful of candidates, purines, as neurotransmitters, appear on the top of the list [15, 24-28*], although ATP could also be derived from other sources such as astrocytes [29]. Microglia-neuronal contact alters with changes in neuronal input.…”

Section: Introductionmentioning

confidence: 99%

“…In chemotherapy-induced peripheral neuropathic pain, glial activation is only seen for astrocytes, but not microglia [49, also see 50]. In a female bone cancer pain model, reactive astrocytosis occurred earlier than microglial activation and microglia did not appear to be involved in the initiation, but was critical in the maintenance, of persistent pain hypersensitivity [28*]. …”

Section: Introductionmentioning

confidence: 99%

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

Ren

Dubner

2016

Current Opinion in Pharmacology

View full text Add to dashboard Cite

Recent studies continue to support the proposition that non-neuronal components of the nervous system, mainly glial cells and associated chemical mediators, contribute to the development of neuronal hyperexcitability that underlies persistent pain conditions. In the event of peripheral injury, enhanced or abnormal nerve input is likely the most efficient way to activate simultaneously central neurons and glia. Injury induces phenotypic changes in glia and triggers signaling cascades that engage reciprocal interactions between presynaptic terminals, postsynaptic neurons, microglia and astrocytes. While some responses to peripheral injury may help the nervous system to adapt positively to counter the disastrous effect of injury, the net effect often leads to long-lasting sensitization of pain transmission pathways and chronic pain.

show abstract

Delayed Activation of Spinal Microglia Contributes to the Maintenance of Bone Cancer Pain in Female Wistar Rats via P2X7 Receptor and IL-18

Cited by 169 publications

References 64 publications

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

Contact Info

Product

Resources

About