Systems Pathology of Neuropathic Pain and Fibromyalgia

Abstract

Currently, only a few medicines have been approved for use in the clinical treatment of chronic pain, but they are not fully satisfying due to their side effects. From the view that radical treatment, rather than simply treating symptoms, is more important in addressing lifelong chronic pain, we have been investigating translational research for a mechanism-based medicine to treat pain. Through the characterization of various types of peripheral and central neuropathic pain in mice, we discovered that lysophosphatidic acid (LPA) plays roles in definitive mechanisms of the development and maintenance of neuropathic pain. We found LPA 1 receptor-and LPA 3 receptor-mediated amplification of LPA production could be a key mechanism underlying the initiation and maintenance of this pain. We have developed stress-induced fibromyalgia models, and have revealed that LPA 1 receptor-signaling also plays key roles in the mechanism. Throughout these studies, we found that LPA plays a key role in pain memory, and that LPA 1 receptor-and LPA 3 receptorantagonists could reverse the established pain, and thereby cure the disease source of pain.

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

“…Interestingly, Uchida et al found that LPA production significantly increased within 24 h after the first paclitaxel treatment [ 14 ]. The paclitaxel-induced mechanical allodynia disappeared in LPAR1- and LPAR3- knockout mice [ 14 ], as well as mice pretreated with LPAR1/3 antagonist Ki16425 [ 110 ]. Moreover, significant attenuation of nerve demyelination was also observed in LPAR1-/LPAR3- knockout mice [ 110 ].…”

“…The paclitaxel-induced mechanical allodynia disappeared in LPAR1- and LPAR3- knockout mice [ 14 ], as well as mice pretreated with LPAR1/3 antagonist Ki16425 [ 110 ]. Moreover, significant attenuation of nerve demyelination was also observed in LPAR1-/LPAR3- knockout mice [ 110 ]. In addition, the LPAR5 signaling was shown to enhance microglial migration/cytotoxicity and induced a distinct pro-inflammatory signature via the protein kinase D (PKD) pathway [ 111 ].…”

“…Furthermore, Ki16425 is one of the most investigated agents targeting both LPAR1 and LPAR3, and its anti-tumor effects were validated in several cancer cells [ 31 , 114 , 115 ]. As discussed above, Ki16425 may benefit the reduction of chemotherapy-induced NP [ 110 ]. A more potent dual LPAR1/3 antagonist, Debio-0719, was found to reduce pulmonary and bone metastases of murine 4T1 breast cancer cells without affecting primary tumor size [ 116 ].…”

Pain and Neuropathic Pain in Rheumatic Diseases

“…It was found that LPA 1 receptor-and LPA 3 receptormediated amplification of LPA production could be a key mechanism underlying the initiation and maintenance of this pain. Throughout these studies, we found that LPA plays a key role in pain memory, and that LPA 1 receptor-and LPA 3 receptor-antagonists could reverse the established pain, and thereby cure the disease source of pain [28]. Chronicity of neuropathic pain is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated [29].…”

“…Peripheral Fibers Increase of peripheral sensitivity Expression of endogenous ligands and receptors on injured nerve target Increase of NF-kB pathway activity Promote the production of leukotriene ▶fig. 1 Pathophysiology of neuropathic pain [21][22][23][24][25][26][27][28][29]. lysophosphatidic acid (LPA), gamma-aminobutyric acid (GABAergic) interneurons, nuclear factor 'kappa-light-chain-enhancer' (NF-κB).…”