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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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Schematic model of LPA-induced demyelination. The stimulation of LPA1 receptor first induces myelin to down-regulate compact myelin proteins, such as MBP, MPZ, and PMP22, and to loosen myelin structure. In addition, MAG is down-regulated and NOGO/p75 receptor complex (NgR/p75)-mediated activation of Rho-ROCK system is terminated. The latter mechanism results in inhibition of actin depolymerization, or sprouting. Degenerated Schwann cells (SCs) release neurotrophins, which in turn accelerate sprouting.
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Figure 4: Schematic model of LPA-induced demyelination. The stimulation of LPA1 receptor first induces myelin to down-regulate compact myelin proteins, such as MBP, MPZ, and PMP22, and to loosen myelin structure. In addition, MAG is down-regulated and NOGO/p75 receptor complex (NgR/p75)-mediated activation of Rho-ROCK system is terminated. The latter mechanism results in inhibition of actin depolymerization, or sprouting. Degenerated Schwann cells (SCs) release neurotrophins, which in turn accelerate sprouting.

Mentions: LPA1 receptor-mediated demyelination is an important subject in the field of neuropathic pain. We obtained evidence that LPA1 receptor activation mediates down-regulation of myelin proteins, such as peripheral myelin protein PMP22, myelin basic protein MBP, and myelin protein zero MP0, in in vivo injury models and ex vivo culture models [73,74]. Nerve injury-induced down-regulation of myelin proteins and their genes was reversed with BoTN/C3 pretreatment; however, further downstream mechanisms remain to be determined. Because the time-course of down-regulated protein levels is similar to the gene expression [74], the former mechanism seems to be a result of rapid degradation, and not a secondary event subsequent to the down-regulation of gene expression. It should be noted that myelin-associated glycoprotein (MAG) was also down-regulated, while growth associated protein 43, a marker protein for sprouting axonal growth, was up-regulated (Fujita, Ueda et al., unpublished data). This is consistent with the fact that MAG inhibits axonal growth through activation of the NOGO/p75 receptor complex and leads to inhibition of actin polymerization mechanisms [87-89] (Fig. 4). Thus, it is interesting to speculate that these mechanisms are responsible for ephaptic or physical crosstalk between different modalities of fibers through sprouted A-fiber branches.


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

Ueda H - Mol Pain (2008)

Schematic model of LPA-induced demyelination. The stimulation of LPA1 receptor first induces myelin to down-regulate compact myelin proteins, such as MBP, MPZ, and PMP22, and to loosen myelin structure. In addition, MAG is down-regulated and NOGO/p75 receptor complex (NgR/p75)-mediated activation of Rho-ROCK system is terminated. The latter mechanism results in inhibition of actin depolymerization, or sprouting. Degenerated Schwann cells (SCs) release neurotrophins, which in turn accelerate sprouting.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Schematic model of LPA-induced demyelination. The stimulation of LPA1 receptor first induces myelin to down-regulate compact myelin proteins, such as MBP, MPZ, and PMP22, and to loosen myelin structure. In addition, MAG is down-regulated and NOGO/p75 receptor complex (NgR/p75)-mediated activation of Rho-ROCK system is terminated. The latter mechanism results in inhibition of actin depolymerization, or sprouting. Degenerated Schwann cells (SCs) release neurotrophins, which in turn accelerate sprouting.
Mentions: LPA1 receptor-mediated demyelination is an important subject in the field of neuropathic pain. We obtained evidence that LPA1 receptor activation mediates down-regulation of myelin proteins, such as peripheral myelin protein PMP22, myelin basic protein MBP, and myelin protein zero MP0, in in vivo injury models and ex vivo culture models [73,74]. Nerve injury-induced down-regulation of myelin proteins and their genes was reversed with BoTN/C3 pretreatment; however, further downstream mechanisms remain to be determined. Because the time-course of down-regulated protein levels is similar to the gene expression [74], the former mechanism seems to be a result of rapid degradation, and not a secondary event subsequent to the down-regulation of gene expression. It should be noted that myelin-associated glycoprotein (MAG) was also down-regulated, while growth associated protein 43, a marker protein for sprouting axonal growth, was up-regulated (Fujita, Ueda et al., unpublished data). This is consistent with the fact that MAG inhibits axonal growth through activation of the NOGO/p75 receptor complex and leads to inhibition of actin polymerization mechanisms [87-89] (Fig. 4). Thus, it is interesting to speculate that these mechanisms are responsible for ephaptic or physical crosstalk between different modalities of fibers through sprouted A-fiber branches.

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