Activation of p38 mitogen‐activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury

Abstract

Neuropathic pain is an expression of pathological operation of the nervous system, which commonly results from nerve injury and is characterized by pain hypersensitivity to innocuous stimuli, a phenomenon known as tactile allodynia. The mechanisms by which nerve injury creates tactile allodynia have remained largely unknown. We report that the development of tactile allodynia following nerve injury requires activation of p38 mitogen-activated protein kinase (p38MAPK), a member of the MAPK family, in spinal microglia. We found that immunofluorescence and protein levels of the dually phosphorylated active form of p38MAPK (phospho-p38MAPK) were increased in the dorsal horn ipsilateral to spinal nerve injury. Interestingly, the phospho-p38MAPK immunofluorescence in the dorsal horn was found exclusively in microglia, but not in neurons or astrocytes. The level of phospho-p38MAPK immunofluorescence in individual microglial cells was much higher in the hyperactive phenotype in the ipsilateral dorsal horn than the resting one in the contralateral side. Intrathecal administration of the p38MAPK inhibitor, 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), suppresses development of the nerve injury-induced tactile allodynia. Taken together, our results demonstrate that nerve injury-induced pain hypersensitivity depends on activation of the p38MAPK signaling pathway in hyperactive microglia in the dorsal horn following peripheral nerve injury.

P2X4 purinoceptor signaling in chronic pain

“…In macrophages, the P2X4R-p38 MAPK pathway is a signaling hub that activates cytosolic PLA2 which liberates arachidonic acid (AA) resulting in a cyclooxygenase (COX) dependent synthesis and release of prostaglandin E2 (PGE2), a key substrate that sensitizes primary sensory neurons and leads to hyperexcitability of peripheral nociceptive pathways that is a hallmark of inflammatory pain (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-dependent vesicular release of pre-made BDNF and also increased transcription and translation of BDNF. By demonstrating that p38-MAPK is a cellular intermediary in the release and synthesis of BDNF evoked by stimulating microglial P2X4R, we provided a unifying mechanism for observations that ongoing expression of neuropathic pain behaviors requires both the activation of P2X4R [17,75,79] and p38-MAPK [40,74,88]. These findings place p38 MAPK in the core P2X4R-BDNF signaling cascade and implicate p38 MAPK activation and BDNF release as an essential step in microglia-neuron communication leading to nerve injury induced pain hypersensitivity.…”

Do glial cells control pain?

“…This activation is evident as early as 12 hours and peaks after 3 days (Jin et al, 2003). Another groups using the same model also shows p38 activation in spinal microglia with slightly delayed time course (Tsuda et al, 2004). Other groups also demonstrate p38 activation in spinal microglia in different pain conditions (Hains & Waxman, 2006;Hua et al, 2005;Kim et al, 2002;Svensson et al, 2003;Svensson et al, 2005b;Xu et al, 2007a;Xu et al, 2007b).…”

Toll-like Receptor 2 Mediates Peripheral Nerve Injury-induced NADPH Oxidase 2 Expression in Spinal Cord Microglia

“…Although there is constitutive Nox2 mRNA expression, it can be assumed that p38 activation alone, in the presence of NF-B inhibitor, is able to increase Nox2 protein by activating translation from the constitutively expressed Nox2 mRNA. It is well known that p38 MAP kinase is activated in spinal cord microglia after nerve injury (27). p38 activation is a key signaling event that leads to pain-mediating gene expression in spinal cord microglia such as the expression of proinflammatory cytokines, Cox2, and inducible nitric oxide synthase after peripheral nerve injury and the subsequent neuropathic pain induction (28).…”