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

Abstract

Neuropathic pain can arise from lesions to peripheral or central nerve fibres leading to spontaneous action potential generation and a lowering of the nociceptive threshold. Clinically, neuropathic pain can manifest in many chronic disease states such as cancer, diabetes or multiple sclerosis (MS). The bioactive lipid, lysophosphatidic acid (LPA), via activation of its receptors (LPARs), is thought to play a central role in both triggering and maintaining neuropathic pain. In particular, following an acute nerve injury, the excitatory neurotransmitters glutamate and substance P are released from primary afferent neurons leading to upregulated synthesis of lysophosphatidylcholine (LPC), the precursor for LPA production. LPC is converted to LPA by autotaxin (ATX), which can then activate macrophages/microglia and modulate neuronal functioning. A ubiquitous feature of animal models of neuropathic pain is demyelination of damaged nerves. It is thought that LPA contributes to demyelination through several different mechanisms. Firstly, high levels of LPA are produced following macrophage/microglial activation that triggers a self-sustaining feed-forward loop of de novo LPA synthesis. Secondly, macrophage/microglial activation contributes to inflammation-mediated demyelination of axons, thus initiating neuropathic pain. Therefore, targeting LPA production and/or the family of LPA-activated G protein-coupled receptors (GPCRs) may prove to be fruitful clinical approaches to treating demyelination and the accompanying neuropathic pain. This review discusses our current understanding of the role of LPA/LPAR signalling in the initiation of neuropathic pain and suggests potential targeted strategies for its treatment. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'.

Keywords: AM095 (PubChem CID: 53303875); Demyelination; G protein-coupled receptor; KI-16425 (PubChem CID: 10367662); Lysophosphatidic acid; Neuroinflammation; Neuropathic pain; PF-8380 (PubChem CID: 25265312); VPC-12249 (PubChem CID: 10282223).