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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 electric stimulation-induced paw flexion (a, EPF) and paw withdrawal (b, EPW) test in mice. (c) Frequency-specific stimulation of different sensory fibers is closely related to differential expression of voltage-dependent Nav channels, which have distinct kinetics patterns during activation, inactivation, and recovery from inactivation or repriming. Because type I and II C-fibers are stimulated by LF-stimuli, nociceptive responses or p-ERK signals can be blocked by neonatal capsaicin pretreatment, or by NK1 and NMDA receptor anatgonists. Aδ- and Aβ-fibers, on the other hand, are stimulated by MF or HF stimuli, respectively. NMDA or non-NMDA receptor antagonists block spinal transmission caused by MF or HF-stimuli, respectively.
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Figure 1: Schematic model of electric stimulation-induced paw flexion (a, EPF) and paw withdrawal (b, EPW) test in mice. (c) Frequency-specific stimulation of different sensory fibers is closely related to differential expression of voltage-dependent Nav channels, which have distinct kinetics patterns during activation, inactivation, and recovery from inactivation or repriming. Because type I and II C-fibers are stimulated by LF-stimuli, nociceptive responses or p-ERK signals can be blocked by neonatal capsaicin pretreatment, or by NK1 and NMDA receptor anatgonists. Aδ- and Aβ-fibers, on the other hand, are stimulated by MF or HF stimuli, respectively. NMDA or non-NMDA receptor antagonists block spinal transmission caused by MF or HF-stimuli, respectively.

Mentions: In order to characterize Aβ fiber-mediated pain transmission, we have recently developed novel nociception tests, using the Neurometer®, called electrical stimulation-induced paw flexion (EPF) and paw withdrawal (EPW) tests [7,38]. The EPF test uses the same apparatus as the APF test; however, the EPF test utilizes electrodes placed on the plantar surface and instep, rather than a cannula filled with drug solution (Fig. 1a). In the EPW test, the mouse is hand-held and electrical stimulation is applied to the paw (Fig. 1b). Latency of paw withdrawal behavior is evaluated as the nociceptive threshold. In both the EPF and EPW tests, the threshold is consistently reproducible, even after repeated applications to the same mouse. According to the manufacturer's protocol for Neurometer®, low (LF, 5 Hz), medium (MF, 250 HZ), and high frequency (HF, 2000 Hz) electrical stimulation results in stimulation of C-, Aδ-, and Aβ-fibers, respectively [39,40]. Through the use of electrophysiology, Koga et al. [41] confirmed frequency-specific stimulation of sensory fibers characterization with the Neurometer®. This specificity could be attributed to different electrical characteristics of C-, Aδ-, and Aβ-fibers. C-fibers generate a slow sodium-dependent spike due to the presence of tetrodotoxin (TTX) – resistant sodium channels, Nav1.8 and Nav1.9, which exhibit slow kinetics patterns for activation, inactivation, and recovery from inactivation or repriming, while A-fibers predominantly express TTX-sensitive channels such as Nav1.1, Nav1.6, Nav1.7, which exhibit fast kinetics patterns to allow high frequency firing [42,43], as shown in Fig. 1c.


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

Ueda H - Mol Pain (2008)

Schematic model of electric stimulation-induced paw flexion (a, EPF) and paw withdrawal (b, EPW) test in mice. (c) Frequency-specific stimulation of different sensory fibers is closely related to differential expression of voltage-dependent Nav channels, which have distinct kinetics patterns during activation, inactivation, and recovery from inactivation or repriming. Because type I and II C-fibers are stimulated by LF-stimuli, nociceptive responses or p-ERK signals can be blocked by neonatal capsaicin pretreatment, or by NK1 and NMDA receptor anatgonists. Aδ- and Aβ-fibers, on the other hand, are stimulated by MF or HF stimuli, respectively. NMDA or non-NMDA receptor antagonists block spinal transmission caused by MF or HF-stimuli, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic model of electric stimulation-induced paw flexion (a, EPF) and paw withdrawal (b, EPW) test in mice. (c) Frequency-specific stimulation of different sensory fibers is closely related to differential expression of voltage-dependent Nav channels, which have distinct kinetics patterns during activation, inactivation, and recovery from inactivation or repriming. Because type I and II C-fibers are stimulated by LF-stimuli, nociceptive responses or p-ERK signals can be blocked by neonatal capsaicin pretreatment, or by NK1 and NMDA receptor anatgonists. Aδ- and Aβ-fibers, on the other hand, are stimulated by MF or HF stimuli, respectively. NMDA or non-NMDA receptor antagonists block spinal transmission caused by MF or HF-stimuli, respectively.
Mentions: In order to characterize Aβ fiber-mediated pain transmission, we have recently developed novel nociception tests, using the Neurometer®, called electrical stimulation-induced paw flexion (EPF) and paw withdrawal (EPW) tests [7,38]. The EPF test uses the same apparatus as the APF test; however, the EPF test utilizes electrodes placed on the plantar surface and instep, rather than a cannula filled with drug solution (Fig. 1a). In the EPW test, the mouse is hand-held and electrical stimulation is applied to the paw (Fig. 1b). Latency of paw withdrawal behavior is evaluated as the nociceptive threshold. In both the EPF and EPW tests, the threshold is consistently reproducible, even after repeated applications to the same mouse. According to the manufacturer's protocol for Neurometer®, low (LF, 5 Hz), medium (MF, 250 HZ), and high frequency (HF, 2000 Hz) electrical stimulation results in stimulation of C-, Aδ-, and Aβ-fibers, respectively [39,40]. Through the use of electrophysiology, Koga et al. [41] confirmed frequency-specific stimulation of sensory fibers characterization with the Neurometer®. This specificity could be attributed to different electrical characteristics of C-, Aδ-, and Aβ-fibers. C-fibers generate a slow sodium-dependent spike due to the presence of tetrodotoxin (TTX) – resistant sodium channels, Nav1.8 and Nav1.9, which exhibit slow kinetics patterns for activation, inactivation, and recovery from inactivation or repriming, while A-fibers predominantly express TTX-sensitive channels such as Nav1.1, Nav1.6, Nav1.7, which exhibit fast kinetics patterns to allow high frequency firing [42,43], as shown in Fig. 1c.

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