Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.

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

“…LPA-mediated signalling via Gα 12/13 and activation of the signalling pathways involving RhoA, Rhokinase, ROCK and Ras appear to be involved in NP (Inoue et al, 2004;Radeff-Huang et al, 2004;Ueda, 2006). Inhibition of Rho signalling pathways by Clostridium botulinum C3 exoenzyme (BoTXC3) or the antagonist Y-27632 (see Table 1), prior to peripheral nerve injury, blocks hyperalgesia and nociceptive responses in mice (Ahn et al, 2009;Inoue et al, 2004;Inoue et al, 2006).…”

“…Inhibition of Rho signalling pathways by Clostridium botulinum C3 exoenzyme (BoTXC3) or the antagonist Y-27632 (see Table 1), prior to peripheral nerve injury, blocks hyperalgesia and nociceptive responses in mice (Ahn et al, 2009;Inoue et al, 2004;Inoue et al, 2006). Confirmation that the RhoA pathway is activated through LPAR 1 subtype was demonstrated utilising Lpar1 -/-knock-out mice, which do not exhibit nociceptive responses or sensitivity after LPA injections (Inoue et al, 2006).…”

“…Confirmation that the RhoA pathway is activated through LPAR 1 subtype was demonstrated utilising Lpar1 -/-knock-out mice, which do not exhibit nociceptive responses or sensitivity after LPA injections (Inoue et al, 2006). Furthermore, several studies showed that intrathecal administration of LPA mimics partial sciatic nerve injury in mice (Inoue et al, 2004;Inoue et al, 2006;Ueda, 2006) whereas a related lipid, sphingosine 1-phosphate (S1P), does not produce such allodynia (Ishii et al, 2004), thus highlighting the specificity of LPA. The observation that neuropathic pain can be attenuated by prophylactic treatments which block Rho signalling or LPAR activation (see Table 1) when they are administered pre-but not post-injury (Inoue et al, 2004) suggests that LPAR activation may trigger demyelination and initiate NP.…”

A neuroscientist's guide to lipidomics

“…We do not know, but it is clear that most lipid signals in the brain operate, like 2-AG, by travelling short distances from their sites of production and engaging G-protein-coupled receptors on neighbouring neurons and glial cells. In addition to those already cited, other important examples include lysophosphatidic acid (a neurotrophic signal also involved in the initiation of neuropathic pain) 72,73 , platelet-activating factor (a retrograde messenger implicated in hippocampal long-term potentiation) 74 and anandamide (an endocannabinoid ligand) 33 (fIG. 5).…”

Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead

“…Based on their interesting properties, LPAs have been implicated in a wide range of complex physiological responses, including the contraction of smooth muscle, demyelization, wound healing, coagulation, and immunological competence. 4 Furthermore, these physiological functions can be related to a number of pathophysiological responses, such as cancer, 5 neuropathic pain, 6 and fibrosis. 7 The biological effects of LPAs are mediated through G protein-coupled receptors (GPCRs).…”