Pain‐releasing action of <scp>P</scp>latelet‐activating factor (<scp>PAF</scp>) antagonists in neuropathic pain animal models and the mechanisms of action

Motoyama, Naoyo; Morita, Kenichi; Kitayama, Tomoya; Shiraishi, Seiji; Uezono, Yasuhito; Nishimura, Fusanori; Kanematsu, Takashi; Dohi, Toshihiro

doi:10.1002/j.1532-2149.2013.00289.x

Cited by 17 publications

(15 citation statements)

References 25 publications

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“…The pain relieving effects of PAF receptor antagonists are long lasting. We have previously suggested that the anti-allodynia effect of PAF antagonists in sciatic nerve injured mice is at least in part mediated by spinal relief of PAF-induced dysfunction of GlyRα3 [8]. In agreement with this concept, the present results showed that the intrathecal introduction of siRNA of PAF receptor mRNA effectively improved bone cancer pain behaviors in FBC mice.…”

Section: Discussionsupporting

confidence: 90%

“…Therefore, PAF signaling in the microenvironment of the spinal pain transduction system may be increased by bone cancer due to peripheral nerve injury. We have further revealed a unique mode of action of TCV-309; TCV-309 is a specific competitive inhibitor of PAF receptors [21], but the potency of TCV-309 intensified as a function of time after administration, and the mode of action changed from a competitive manner within several hours after the injection of TCV-309 to a non-competitive manner later [8]. The intensification of the anti-allodynia potency of TCV-309 and change in its mode of action to a non-competitive manner as a function of time led us to speculate about a different mechanism of action; such as down-regulation of PAF receptors by binding TCV-309 to PAF receptors in the later stage of after nerve injury.…”

Section: Discussionmentioning

confidence: 99%

“…Intrathecal injection of the PAF receptor antagonist, WEB 2086, a benzodiazepine derivative for 9 days post-surgery in rats suppressed the development of mechanical allodynia in a rat spared nerve injury model [7]. PAF receptor antagonists, TCV-309 (PAF related), BN 50739 (natural product related compound), and WEB 2086, produced profound and long lasting anti-allodynia effects in several different neuropathic pain models in mice, including a partial sciatic nerve ligation injury model, a partial infraorbital nerve ligation model, a chronic constriction of the infraorbital nerve injury model (CCI model) and a streptozotocin (STZ)-induced diabetes model [8]. The evidence suggests that PAF contributes to neural tissue damage and pain behavior after nerve injury.…”

Section: Introductionmentioning

confidence: 99%

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Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors

Morita

Shiraishi²,

Motoyama

et al. 2014

PLoS ONE

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Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors

Morita

Shiraishi²,

Motoyama

et al. 2014

PLoS ONE

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“…The future use of PAFR‐KO mice (in addition to the use of pharmacological agents) will assist in understanding this loop. Moreover, given that intrathecal injection of a PAFR antagonist attenuates neuropathic pain (21) and PAF‐induced allodynia (34), the spinal cord is an important candidate area for functional study of the PAF–pain loop. Finally, LPCAT2 and PAFR were expressed in microglia of the spinal cord dorsal horn (7), but the roles of other cells in the production and action of PAF should be investigated in the context of the PAF–pain loop.…”

Section: Discussionmentioning

confidence: 99%

“…PSL was performed as previously reported (21). In brief, 8-wk-old male WT, LPCAT2-KO, or LPCAT1-KO (22) mice were anesthetized with isoflurane and partial ligation of the sciatic nerve was performed by tying off the distal one-third to one-half of the sciatic nerve connected to the spinal cord (at vertebrae L3-L5) according to the procedure described in rats by Seltzer et al (23) and adapted for mice by Malmberg and Basbaum (24).…”

Section: Psl Modelmentioning

confidence: 99%

Relief from neuropathic pain by blocking of the platelet‐activating factor‐pain loop

et al. 2017

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Neuropathic pain resulting from peripheral neuronal damage is largely resistant to treatment with currently available analgesic drugs. Recently, ATP, lysophosphatidic acid, and platelet-activating factor (PAF) have been reported to play important inductive roles in neuropathic pain. In the present study, we found that pain-like behaviors resulting from partial sciatic nerve ligation (PSL) were largely attenuated by deficiency of lysophosphatidylcholine acyltransferase (LPCAT)2, which is one of the PAF biosynthetic enzymes. By contrast, deficiency of the other PAF biosynthetic enzyme, LPCAT1, did not ameliorate neuropathic pain. With regard to the mechanism of the observed effects, LPCAT2 was detected in wild-type spinal cord microglia, and the absence of LPCAT2 expression precluded spinal PAF expression in LPCAT2-knockout mice. Furthermore, ATP-stimulated PAF biosynthesis in macrophages was decreased by pretreatment with the PAF receptor antagonist ABT-491, indicating the existence of a positive feedback loop of PAF biosynthesis, which we designated the PAF–pain loop. In conclusion, LPCAT2 is a novel therapeutic target for newly categorized analgesic drugs; in addition, our data call for the re-evaluation of the clinical utility of PAF receptor antagonists.—Shindou, H., Shiraishi, S., Tokuoka, S. M., Takahashi Y., Harayama, T., Abe, T., Bando, K., Miyano, K., Kita, Y., Uezono, Y., Shimizu, T. Relief from neuropathic pain by blocking of the platelet-activating factor–pain loop.

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PAF‐induced inflammatory and immuno‐allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: Cell and nuclear effects

Sharif

2022

BioFactors

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Ocular allergies are becoming more prevalent as more airborne pollutants, irritants and microbes pervade our environment. Inflammatory and allergic mediators released by dendritic and mast cells within the conjunctiva cause allergic conjunctivitis (AC), a prevalent ocular surface disorder that affects >40% of the world's human population on a seasonal or perennial basis. Even though histamine is a major culprit, platelet‐activating factor (PAF) also contributes to AC, acting either directly or synergistically with histamine and other mediators. PAF receptor‐meditated inflammatory reactions, via cell‐membrane‐bound and nuclear‐membrane‐bound and nuclear PAF receptors, are also implicated in the etiology of other eye diseases such as uveitis, diabetic retinopathy, corneal and choroidal neovascularization, and age‐related macular degeneration which cause serious visual impairment and can lead to blindness. This review highlights the various deleterious elements implicated in the pathological aspects of ocular allergic reactions and inflammation and provides concepts and treatment options to mitigate these eye disorders with a special focus on PAF and PAF receptor antagonists.

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Pain‐releasing action of Platelet‐activating factor (PAF) antagonists in neuropathic pain animal models and the mechanisms of action

Cited by 17 publications

References 25 publications

Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors

Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors

Relief from neuropathic pain by blocking of the platelet‐activating factor‐pain loop

PAF‐induced inflammatory and immuno‐allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: Cell and nuclear effects

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