Lysophosphatidic Acid as the Initiator of Neuropathic Pain

Abstract

The injury-induced intense stimulation of spinal cord neurons causes lysophosphatidic acid (LPA) biosynthesis. LPA 1 receptor activation causes demyelination and sprouting of dorsal root fibers, leading to an induction of synaptic reorganization underlying allodynia, in which innocuous (tactile) stimuli cause intense pain. The LPA 1 signal also initiates the up-regulation of Ca v a a2d d1 in dorsal root ganglion and PKCg g in the dorsal horn, underlying mechanisms for characteristic neuropathic hyperalgesia in myelinated sensory (A-type) fibers. On the other hand, the LPA 3 receptor mediates microglia activation at the early stage after nerve injury and LPAinduced LPA biosynthesis. Thus, both the LPA 1 and LPA 3 receptors play key roles in the initiation step using a feed-forward system for neuropathic pain.

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…The induction of neuropathic pain by LPA not only relies on its actions on neurons, Schwann cells and oligodendrocytes, but also through its effects on other cell types such as astrocytes, macrophages/microglia and immune cells (Goldshmit et al, 2012;Ma et al, 2010;Smith et al, 1999;Ueda, 2011). LPA has been shown to increase inflammation and glial cell proliferation in zebrafish and inhibit neural regeneration after traumatic injury (Goldshmit et al, 2012).…”

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

“…Even though the expression level of LPARs is known to decrease with age Choi et al 2008;Chun 2005;Noguchi et al 2009), LPA-mediated signaling seems to play important roles in aged animals, as well. Previously, LPAR1-deficient mice have been shown to exhibit impaired performance in a number of behavioral tasks, including the prepulse inhibition test (Harrison et al 2003) and hippocampus-mediated spatial memory test (Dash et al 2004), and in pain sensation (Lin et al 2012;Ueda 2011). In addition, abnormal neurogenesis within the embryonic cerebral cortex as well as in the adult hippocampus have been reported in LPAR1-deficient mice .…”

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

“…2,3) Both abnormal production and degradation of LPA are assumed to be relevant to pathophysiological conditions of human such as cancer metastasis, 4) atherosclerosis, 5) organ fibrosis 6) and pain. 7) Although LPA-producing enzymatic activity in human plasma and bovine fetal serum was demonstrated to be largely due to autotaxin (ATX), 8,9) physiological regulation of the circulating LPA level is not yet well understood. 3,10) In this study, we focused our inquiry on whether the stress of nutritional restriction affected the in vivo plasma level and molecular species composition of LPA using quantifying lysophosphatidylcholine (LPC) and LPA by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its mechanism by comparing LPA-producing and -degrading enzymatic activities during 12 and 24 h fasting.…”