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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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Working hypothesis of neuropathic hyperalgesia and allodynia. This model depicts possible mechanisms of neuropathic pain following partial sciatic nerve injury in mice. Detailed interpretation is described in the text.
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Figure 6: Working hypothesis of neuropathic hyperalgesia and allodynia. This model depicts possible mechanisms of neuropathic pain following partial sciatic nerve injury in mice. Detailed interpretation is described in the text.

Mentions: In patients and experimental animals with neuropathic pain, mild tactile stimulation causes burning pain. This phenomenon, termed allodynia, has been the focus in our study of neuropathic pain mechanisms. The possibility that tactile Aβ and nociceptive Aδ or C fibers cross at the level of sensory fibers, or at the level of pain transmission in the spinal dorsal horn, would seem to be a reasonable explanation [3]. Collateral sproutings from primary afferent fibers, which induces ephaptic or physical crosstalk between different types of fibers, have long been speculated to be involved in the plasticity or reorganization mechanisms of spinal neuronal circuits for pain transmission [90]. Evidence of LPA-induced demyelination accompanying loss of insulation could account for the physical crosstalk (presumed structural basis of ephaptic crosstalk) between non-nociceptive (Aβ) and nociceptive (C and Aδ) fibers, which is observed in mice with nerve injury (Fig. 5). On the other hand, subsequent to peripheral nerve injury, the regenerating axon terminals are known to sprout to the skin area that is typically denervated [51]. Local NGF release from skin cells is expected to drive this sprouting, because anti-NGF treatment prevents sprouting [91]. Further studies focused on growth factor-induced sprouting after LPA activation are needed. Altogether, we propose a hypothesis for mechanisms of neuropathic hyperalgesia and allodynia after partial sciatic nerve injury (Fig. 6) as follows: 1) intense stimulation of sensory neurons after sciatic nerve injury activates target neurons in the dorsal horn to induce de novo biosynthesis of LPC, which is in turn converted to LPA by ATX/LPLD; 2) LPA is then produced at the dorsal root fibers proximal to the spinal cord. LPC may be also produced at the dorsal root, where it is converted to LPA; 3) LPA binds to LPA1 receptors, resulting in retraction of peptidergic unmyelinated C-fibers. The C-fibers are deprived of spinal pain transmission, due to down-regulation of various pain-related molecules (B2-type BK receptor on fibers, SP level in the dorsal horn), as well as the possible retraction of central nerve endings; 4) myelinated Aδ-fibers exhibit hypersensitivity due to up-regulation of TRPV1, B1-type BK receptor, and Cavα2δ-1. However, it remains to be shown that the LPA1 receptor is involved in expression changes of key molecules. It also remains to be determined whether LPA1 receptor signaling directly causes the down-regulation of these molecules; 5) LPA, which is released at the dorsal root, demyelinates the Aδ- and Aβ-fibers on the dorsal root through the LPA1 receptor, followed by physical (or ephaptic) crosstalk between the C-fiber and Aδ-fiber, and between the Aδ-fiber and Aβ-fiber. Sprouting also causes novel pain transmission in the spinal dorsal horn. These two events following demyelination may regulate the mechanisms of neuropathic allodynia.


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

Ueda H - Mol Pain (2008)

Working hypothesis of neuropathic hyperalgesia and allodynia. This model depicts possible mechanisms of neuropathic pain following partial sciatic nerve injury in mice. Detailed interpretation is described in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Working hypothesis of neuropathic hyperalgesia and allodynia. This model depicts possible mechanisms of neuropathic pain following partial sciatic nerve injury in mice. Detailed interpretation is described in the text.
Mentions: In patients and experimental animals with neuropathic pain, mild tactile stimulation causes burning pain. This phenomenon, termed allodynia, has been the focus in our study of neuropathic pain mechanisms. The possibility that tactile Aβ and nociceptive Aδ or C fibers cross at the level of sensory fibers, or at the level of pain transmission in the spinal dorsal horn, would seem to be a reasonable explanation [3]. Collateral sproutings from primary afferent fibers, which induces ephaptic or physical crosstalk between different types of fibers, have long been speculated to be involved in the plasticity or reorganization mechanisms of spinal neuronal circuits for pain transmission [90]. Evidence of LPA-induced demyelination accompanying loss of insulation could account for the physical crosstalk (presumed structural basis of ephaptic crosstalk) between non-nociceptive (Aβ) and nociceptive (C and Aδ) fibers, which is observed in mice with nerve injury (Fig. 5). On the other hand, subsequent to peripheral nerve injury, the regenerating axon terminals are known to sprout to the skin area that is typically denervated [51]. Local NGF release from skin cells is expected to drive this sprouting, because anti-NGF treatment prevents sprouting [91]. Further studies focused on growth factor-induced sprouting after LPA activation are needed. Altogether, we propose a hypothesis for mechanisms of neuropathic hyperalgesia and allodynia after partial sciatic nerve injury (Fig. 6) as follows: 1) intense stimulation of sensory neurons after sciatic nerve injury activates target neurons in the dorsal horn to induce de novo biosynthesis of LPC, which is in turn converted to LPA by ATX/LPLD; 2) LPA is then produced at the dorsal root fibers proximal to the spinal cord. LPC may be also produced at the dorsal root, where it is converted to LPA; 3) LPA binds to LPA1 receptors, resulting in retraction of peptidergic unmyelinated C-fibers. The C-fibers are deprived of spinal pain transmission, due to down-regulation of various pain-related molecules (B2-type BK receptor on fibers, SP level in the dorsal horn), as well as the possible retraction of central nerve endings; 4) myelinated Aδ-fibers exhibit hypersensitivity due to up-regulation of TRPV1, B1-type BK receptor, and Cavα2δ-1. However, it remains to be shown that the LPA1 receptor is involved in expression changes of key molecules. It also remains to be determined whether LPA1 receptor signaling directly causes the down-regulation of these molecules; 5) LPA, which is released at the dorsal root, demyelinates the Aδ- and Aβ-fibers on the dorsal root through the LPA1 receptor, followed by physical (or ephaptic) crosstalk between the C-fiber and Aδ-fiber, and between the Aδ-fiber and Aβ-fiber. Sprouting also causes novel pain transmission in the spinal dorsal horn. These two events following demyelination may regulate the mechanisms of neuropathic allodynia.

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