Autotaxin and Lysophosphatidic Acid₁ receptor-Mediated Demyelination of Dorsal Root Fibers by Sciatic Nerve Injury and Intrathecal Lysophosphatidylcholine

Abstract

BackgroundAlthough neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barré syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that lysophosphatidic acid receptor (LPA1) signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination.ResultsIn the present study, we have demonstrated that sciatic nerve injury induces marked demyelination accompanied by myelin-associated glycoprotein (MAG) down-regulation and damage of Schwann cell partitioning of C-fiber-containing Remak bundles in the sciatic nerve and dorsal root, but not in the spinal nerve. Demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPA1 receptor-deficient (Lpar1-/-) mice, but these alterations were not observed in sciatic nerve. However, LPA-induced demyelination in ex vivo experiments was observed in the sciatic nerve, spinal nerve and dorsal root, all which express LPA1 transcript and protein. Nerve injury-induced dorsal root demyelination was markedly attenuated in mice heterozygous for autotaxin (atx+/-), which converts lysophosphatidylcholine (LPC) to LPA. Although the addition of LPC to ex vivo cultures of dorsal root fibers in the presence of recombinant ATX caused potent demyelination, it had no significant effect in the absence of ATX. On the other hand, intrathecal injection of LPC caused potent dorsal root demyelination, which was markedly attenuated or abolished in atx+/- or Lpar1-/- mice.ConclusionsThese results suggest that LPA, which is converted from LPC by ATX, activates LPA1 receptors and induces dorsal root demyelination following nerve injury, which causes neuropathic pain.

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…Two weeks after SNI, the proximal segments of injured nerves displayed severe fiber dystrophy and a decrease of axon density (number of axons per square millimeter) in all animals ( Fig. 6 B), consistent with previous reports (Inoue et al, 2004;Nagai et al, 2010). To estimate the myelination status, we measured the axon (inner myelin sheath circle) and myelin diameters in the day 14 SNI sciatic nerve using NIH ImageJ software and calculated the g ratio, i.e., the numerical ratio between axon and fiber diameter.…”

“…In response to peripheral nerve injury, myelinating Schwann cells are activated and their myelin properties are modified, resulting in altered conduction properties of nociceptive fibers (Devor, 2006b;Thacker et al, 2007;Nagai et al, 2010). In particular, the myelin degradation of A␤ afferents promotes susceptibility of their axonal plasma membrane to pronociceptive stimuli, leading to ectopic depolarization and mechanical allodynia (Kobayashi et al, 2008).…”

“…We speculated that a disruption of myelin sheath integrity of peripheral nerves might be involved, because previous work demonstrated that (1) the myelin sheath is highly susceptible to degeneration caused by H 2 O 2 (Konat and Wiggins, 1985;Richter-Landsberg and Vollgraf, 1998;Laszkiewicz et al, 1999;Mronga et al, 2004;Perfeito et al, 2007), (2) the myelin sheath is disrupted and the proximal nerve stump seals off after peripheral nerve injury (Inoue et al, 2004;Devor, 2006a;Nagai et al, 2010), and (3) the dysmyelination of peripheral nerves induced by nerve injury or by delivery of bioactive lipids, such as lysophosphatidic acid, is accompanied by spontaneous action potentials in primary afferent nerves and sensitization of sensory processing, thereby contributing to neuropathic pain hypersensitivity (Devor et al, 1989;Wallace et al, 2003;Devor, 2006b;Ueda, 2008;Zhu et al, 2012). To monitor the time course of injury-induced dysmyelination of peripheral nerves in the SNI model, we first analyzed the protein levels of MPZ, the main peripheral myelin protein, in C57BL/6 mice during 21 d after SNI.…”

Lysophosphatidic Acid as the Initiator of Neuropathic Pain

“…Nerve injuryand intrathecal LPA-induced demyelination of dorsal root fibers through LPA1 receptor activation are evidenced by the down-regulation of myelin proteins, such as myelin basic protein (MBP), myelin protein zero (P0) and myelin-associated glycoprotein (MAG). 31,35,37) The ex vivo studies using dorsal root fibers also demonstrated that the addition of LPA causes demyelination within 24 h in scanning and transmission electron microscopy (SEM and TEM) analyses. 31) As well as typical demyelination of A-fibers, there was direct contact between neighboring C-fibers.…”

“…10,12,30) As the intrathecal LPA-induced abnormal pain shows quite similar characteristics to those in nerve injury-induced neuropathic pain, 30) LPA could be considered as a good tool for the studies of in vitro and in vivo mechanisms underlying neuropathic pain. [31][32][33][34][35][36][37] 2. LPA 1 -MEDIATED INITIATION OF NEUROPATHIC PAIN Among multiple mechanisms involved in the manifestation of nerve injury-induced neuropathic pain, the enhanced expression of Ca v a2d1 expression in DRG, PKCg expression and microglial activation in dorsal horn seem to be representative mechanisms for hyperalgesia, while the demyelination and following physical cross-talk among sensory fibers may underlie the mechanisms for allodynia.…”