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Peripheral mechanisms of neuropathic pain - involvement of lysophosphatidic acid receptor-mediated demyelination.

Ueda H - Mol Pain (2008)

Bottom Line: These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications - decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions.Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms.These results lead to further hypotheses of physical communication between innocuous Abeta- and noxious C- or Adelta-fibers to influence the molecular mechanisms of allodynia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp

ABSTRACT
Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications - decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that lysophosphatidic acid receptor activation initiates neuropathic pain, as well as possible peripheral mechanism of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Abeta- and noxious C- or Adelta-fibers to influence the molecular mechanisms of allodynia.

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De novobiosynthesis of LPA in spinalcord neurons. The convertion of phosphatidyl choline (PC) to LPC is mediated by cPLA2 and iPLA2, which are activated by receptor-mediated MAPK, PKC, and [Ca2+]i increases. Autotaxin/lysophopholipase D (ATX/LPLD) subsequently converts LPC to LPA. The intense stimulation of sensory fibers might initiate de novo biosynthesis of LPA.
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Figure 3: De novobiosynthesis of LPA in spinalcord neurons. The convertion of phosphatidyl choline (PC) to LPC is mediated by cPLA2 and iPLA2, which are activated by receptor-mediated MAPK, PKC, and [Ca2+]i increases. Autotaxin/lysophopholipase D (ATX/LPLD) subsequently converts LPC to LPA. The intense stimulation of sensory fibers might initiate de novo biosynthesis of LPA.

Mentions: It is important to understand whether endogenous LPA plays a role in the development of neuropathic pain; if so, it will be important to demonstrate the mechanisms involved. Thermal hyperalgesia and mechanical allodynia after partial sciatic nerve ligation were mostly reversed by pretreatment with AS-ODN for LPA1 or in LPA1- mice [73]. Because no significant nociceptive threshold change was observed in uninjured LPA1- mice, it is evident that de novo LPA, produced by injury, is involved in the generation of a neuropathic pain state. Similar roles of de novo-produced LPA have also been observed in demyelination, decreased protein and gene expression of related myelin molecules (MBP and PMP22), and upregulation of PKCγ and of Cavα2δ-1 in mice with partial sciatic nerve ligation [73]. Furthermore, LPA1 receptor-mediated demyelination was specific to the dorsal root after the sciatic nerve injury. Taken together, these findings suggest that LPA is biosynthesized de novo in the spinal cord upon intense pain signals, and is subsequently released at the dorsal root to cause demyelination. Autotaxin (or lysophospholipase D), which converts lysophosphatidyl choline (LPC) to LPA, is a key enzyme for LPA production [75]. Recent studies revealed that phosphatidyl choline is converted to LPC by cytosolic phospholipase A2 (cPLA2) or calcium-independent PLA2 (iPLA2), both of which are regulated by Ca2+-related mechanisms. cPLA2 is activated through membrane translocation, which is stimulated by Ca2+ or phosphorylation by mitogen-activated kinase (MAPK) or PKCs [76-78], while iPLA2 is activated through the removal of calmodulin by calcium influx factor (CIF) produced after Ca2+ depletion in the endoplasmic reticulum [79,80]. Therefore, intense pain-signals after nerve-injury may induce an excess release of pain transmitters, SP, and glutamate, which in turn activate both cPLA2 and iPLA2 through different pathways (Fig. 3). Neurotrophic factors (e.g., BDNF) and cytokines may also contribute to cPLA2 activation through MAPK-activating pathways. More recently, neuropathic pain was shown to be induced by LPC (i.t.) or nerve injury and was absent in LPA1- or autotaxin- mice [81,82]. Our recent findings showed that LPC did not cause demyelination in ex vivo experiments, although many reports have demonstrated LPC-induced demyelination in vivo [83-85]. Taken together, these findings might suggest that de novo-produced LPC in the spinal cord is transported to the dorsal root, where it is then converted to LPA.


Peripheral mechanisms of neuropathic pain - involvement of lysophosphatidic acid receptor-mediated demyelination.

Ueda H - Mol Pain (2008)

De novobiosynthesis of LPA in spinalcord neurons. The convertion of phosphatidyl choline (PC) to LPC is mediated by cPLA2 and iPLA2, which are activated by receptor-mediated MAPK, PKC, and [Ca2+]i increases. Autotaxin/lysophopholipase D (ATX/LPLD) subsequently converts LPC to LPA. The intense stimulation of sensory fibers might initiate de novo biosynthesis of LPA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2365930&req=5

Figure 3: De novobiosynthesis of LPA in spinalcord neurons. The convertion of phosphatidyl choline (PC) to LPC is mediated by cPLA2 and iPLA2, which are activated by receptor-mediated MAPK, PKC, and [Ca2+]i increases. Autotaxin/lysophopholipase D (ATX/LPLD) subsequently converts LPC to LPA. The intense stimulation of sensory fibers might initiate de novo biosynthesis of LPA.
Mentions: It is important to understand whether endogenous LPA plays a role in the development of neuropathic pain; if so, it will be important to demonstrate the mechanisms involved. Thermal hyperalgesia and mechanical allodynia after partial sciatic nerve ligation were mostly reversed by pretreatment with AS-ODN for LPA1 or in LPA1- mice [73]. Because no significant nociceptive threshold change was observed in uninjured LPA1- mice, it is evident that de novo LPA, produced by injury, is involved in the generation of a neuropathic pain state. Similar roles of de novo-produced LPA have also been observed in demyelination, decreased protein and gene expression of related myelin molecules (MBP and PMP22), and upregulation of PKCγ and of Cavα2δ-1 in mice with partial sciatic nerve ligation [73]. Furthermore, LPA1 receptor-mediated demyelination was specific to the dorsal root after the sciatic nerve injury. Taken together, these findings suggest that LPA is biosynthesized de novo in the spinal cord upon intense pain signals, and is subsequently released at the dorsal root to cause demyelination. Autotaxin (or lysophospholipase D), which converts lysophosphatidyl choline (LPC) to LPA, is a key enzyme for LPA production [75]. Recent studies revealed that phosphatidyl choline is converted to LPC by cytosolic phospholipase A2 (cPLA2) or calcium-independent PLA2 (iPLA2), both of which are regulated by Ca2+-related mechanisms. cPLA2 is activated through membrane translocation, which is stimulated by Ca2+ or phosphorylation by mitogen-activated kinase (MAPK) or PKCs [76-78], while iPLA2 is activated through the removal of calmodulin by calcium influx factor (CIF) produced after Ca2+ depletion in the endoplasmic reticulum [79,80]. Therefore, intense pain-signals after nerve-injury may induce an excess release of pain transmitters, SP, and glutamate, which in turn activate both cPLA2 and iPLA2 through different pathways (Fig. 3). Neurotrophic factors (e.g., BDNF) and cytokines may also contribute to cPLA2 activation through MAPK-activating pathways. More recently, neuropathic pain was shown to be induced by LPC (i.t.) or nerve injury and was absent in LPA1- or autotaxin- mice [81,82]. Our recent findings showed that LPC did not cause demyelination in ex vivo experiments, although many reports have demonstrated LPC-induced demyelination in vivo [83-85]. Taken together, these findings might suggest that de novo-produced LPC in the spinal cord is transported to the dorsal root, where it is then converted to LPA.

Bottom Line: These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications - decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions.Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms.These results lead to further hypotheses of physical communication between innocuous Abeta- and noxious C- or Adelta-fibers to influence the molecular mechanisms of allodynia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp

ABSTRACT
Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications - decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that lysophosphatidic acid receptor activation initiates neuropathic pain, as well as possible peripheral mechanism of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Abeta- and noxious C- or Adelta-fibers to influence the molecular mechanisms of allodynia.

Show MeSH
Related in: MedlinePlus