Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain

Shigeo Hasegawa, Yuta Kohro, Miho Shiratori, Satoshi Ishii, Takao Shimizu, Makoto Tsuda, Kazuhide Inoue

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA2 activation to produce tactile allodynia remain to be determined. Principal Findings: Here we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of nai{dotless}̈ve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFα and IL-1β, both of which were inhibited by pretreatment with a PAFR antagonist. Conclusions: Our results indicate that the PAF/PAFR system has an important role in production of TNFα and IL-1β in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

Original languageEnglish
Article numbere10467
JournalPloS one
Volume5
Issue number5
DOIs
Publication statusPublished - Sep 14 2010

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platelet-activating factor
Hyperalgesia
Spinal Ganglia
Neuralgia
pain
Rodentia
rodents
Cytokines
receptors
tumor necrosis factors
Platelet Activating Factor
interleukin-1
Interleukin-1
Cytosolic Phospholipases A2
nerve tissue
phospholipase A2
Tumor Necrosis Factor-alpha
peripheral nerves
Peripheral Nerve Injuries
Neurons

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain. / Hasegawa, Shigeo; Kohro, Yuta; Shiratori, Miho; Ishii, Satoshi; Shimizu, Takao; Tsuda, Makoto; Inoue, Kazuhide.

In: PloS one, Vol. 5, No. 5, e10467, 14.09.2010.

Research output: Contribution to journalArticle

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AB - Background: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA2 activation to produce tactile allodynia remain to be determined. Principal Findings: Here we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of nai{dotless}̈ve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFα and IL-1β, both of which were inhibited by pretreatment with a PAFR antagonist. Conclusions: Our results indicate that the PAF/PAFR system has an important role in production of TNFα and IL-1β in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

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