Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice

Abstract

Lysophosphatidic acid (LPA) signaling is known to play key roles in the initiation and maintenance of various chronic pain models. Here we examined whether LPA signaling is also involved in diabetes-induced abnormal pain behaviors. The high-fat diet (HFD) showing elevation of blood glucose levels and body weight caused thermal, mechanical hyperalgesia, hypersensitivity to 2000 or 250 Hz electrical-stimulation and hyposensitivity to 5 Hz stimulation to the paw in wild-type (WT) mice. These HFD-induced abnormal pain behaviors and body weight increase, but not elevated glucose levels were abolished in LPA1−/− and LPA3−/− mice. Repeated daily intrathecal (i.t.) treatments with LPA1/3 antagonist AM966 reversed these abnormal pain behaviors. Similar abnormal pain behaviors and their blockade by daily AM966 (i.t.) or twice daily Ki16425, another LPA1/3 antagonist was also observed in db/db mice which show high glucose levels and body weight. Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA1−/− and LPA3−/− mice. These results suggest that LPA1 and LPA3 play key roles in the development of both type I and type II diabetic neuropathic pain.

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak‐Gamcho Decoction: A Network Pharmacology Study

“…e activation of epidermal growth factor receptor (EGFR; encoded by EGFR) and AKT (encoded by AKT1) is associated with the development and enhancement of diverse types of pain, and their therapeutic modulation might be associated with analgesic properties [139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156]. Lysophosphatidic acid receptor 1 (encoded by LPAR1) activity is involved in pain behavior arising from bone cancer, inflammation, diabetes, and neuropathy, and its pharmacological or genetic ablation might reduce the pain response [157][158][159][160][161][162][163][164][165]. Lysophosphatidic acid receptor 3 (encoded by LPAR3) plays crucial roles in the development and maintenance of neuropathic pain, and its blockade exerts analgesic effects [163,166,167].…”

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

“…Hence, targeting LPA receptors or autotaxin, the enzyme that produces LPA, may lead to treatments for neuropathic pain . In fact, LPA1 and LPA3 receptors have been reported to mediate the development of diabetic neuropathic hyperalgesia and hypoalgesia in mice . Examples of LPA receptor antagonists that have been identified include Ki-16425 ( 46 ) (nonselective) and ONO-9780307 ( 47 ) (LPA1 receptor selective). , Compound 46 completely blocked allodynic behaviors in the LPA-induced and partial sciatic nerve ligation neuropathic pain models .…”

Lysophosphatidic acid receptor type‐1 mediates brain activation in micro‐positron emission tomography analysis in a fibromyalgia‐like mouse model

“…However, this was not evident in Phase I, which is responsible for spinal reflexes by chemical stimulation. In a series of our studies, we have reported that hyperalgesia and/or allodynia were completely lost in LPAR1‐KO mice or central administration of LPAR1/3 antagonist in many neuropathic pain models (Inoue et al, 2004; Uchida et al, 2014; Ueda, 2021; Ueda et al, 2019, 2020b) and various FM‐like pain models (Ueda & Neyama, 2017). In these studies, the basal threshold in mechanical, thermal and electrical stimulation‐induced rapid pain responses was not affected in LPAR1‐KO mice.…”

“…In a series of our studies, we have reported that hyperalgesia and/or allodynia were completely lost in LPAR1-KO mice or central A t-value of 2.98 is used as the threshold corresponding to the P < 0.005 (uncorrected) threshold. LPAR1-KO, lysophosphatidic acid receptor type-1 knockout; WT, wild-type; ICS, intermittent cold stress; ACC, anterior cingulate cortex; dmStr, dorsomedial striatum; LS, lateral septal nucleus; dHP, dorsal hippocampus; MD, mediodorsal thalamus; PVT, paraventricular thalamus; pIC, posterior insular cortex; PCC, posterior cingulate cortex; AMY, amygdala; Ent, entorhinal cortex; vHP, ventral hippocampus; DR, dorsal raphe nucleus; PAG, periaqueductal gray; aIC, anterior insular cortex administration of LPAR1/3 antagonist in many neuropathic pain models (Inoue et al, 2004;Uchida et al, 2014;Ueda, 2021;Ueda et al, 2019Ueda et al, , 2020b and various FM-like pain models (Ueda & Neyama, 2017). In these studies, the basal threshold in mechanical, thermal and electrical stimulation-induced rapid pain responses was not affected in LPAR1-KO mice.…”

“…A recent study demonstrated that abnormal pain behaviors in these FM‐like models were abolished in lysophosphatidic acid receptor type‐1 (LPAR1) knockout (LPAR1‐KO) mice or reversed by repeated intracerebroventricular (i.c.v.) treatment with an LPAR1 antagonist (Ueda & Neyama, 2017), as reported in many cases of neuropathic pain models (Ahn et al, 2009; Inoue et al, 2004; McDougall et al, 2017; Ueda, 2021; Ueda et al, 2018, 2019, 2020b). These findings indicate that LPAR1 plays a key role in the development and maintenance of a wide variety of chronic pain models (Ueda, 2017, 2021).…”