Lysophosphatidic acid LPA1 and LPA3 receptors play roles in the maintenance of late tissue plasminogen activator-induced central poststroke pain in mice

Hiroshi Ueda,Hiroyuki Neyama,Keita Sasaki,Chiho Miyama,Ryusei Iwamoto

doi:10.1016/j.ynpai.2018.07.001

Hiroshi Ueda, Hiroyuki Neyama + Show 3 more

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https://doi.org/10.1016/j.ynpai.2018.07.001

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Journal: Neurobiology of Pain	Publication Date: Jul 20, 2018
Citations: 30	License type: cc-by

Affiliation: Nagasaki University

Abstract

We developed a mouse model for central post-stroke pain (CPSP), a centrally-originated neuropathic pain (NeuP). In this mode, mice were first injected with Rose Bengal, followed by photo-irradiation of left middle cerebral artery (MCA) to generate thrombosis. Although the MCA thrombosis was soon dissolved, the reduced blood flow remained for more than 24 h due to subsequent occlusion of microvessels. This photochemically induced thrombosis (PIT) model showed a hypersensitivity to the electrical stimulation of both sides of paw, but did not show any abnormal pain in popular thermal or mechanical nociception tests. When tissue-type plasminogen activator (tPA) was injected 6 h after the PIT stress, tPA-dependent hypersensitivity to the electrical paw stimulation and stable thermal and mechanical hyperalgesia on both sides for more than 17 or 18 days after the PIT treatment. These hyperalgesic effects were abolished in lysophosphatidic acid receptor 1 (LPA1)- and lysophosphatidic acid receptor 3 (LPA3)-deficient mice. When Ki-16425, an LPA1 and LPA3 antagonist was treated twice daily for 6 days consecutively, the thermal and mechanical hyperalgesia at day 17 and 18 were significantly reversed. The liquid chromatography–mass spectrometry (LC–MS/MS) analysis revealed that there is a significant increase in several species of LPA molecules in somatosensory S-I and medial dorsal thalamus (MD), but not in striatum or ventroposterior thalamus. All these results suggest that LPA1 and LPA3 signaling play key roles in the development and maintenance of CPSP.

Highlights

Stroke is one of common medical emergencies leading to irreversible neurological damage with severe complications including the dysfunction of motor skills, cognition, sensory perception and even death (De Vloo et al, 2017; Jensen and Finnerup, 2013)
The lesion responsible for pain in Central post-stroke pain (CPSP) was initially claimed that it is located at the contralateral thalamus, and the syndrome was for years called ‘thalamic syndrome’ (Dejerine and Roussy, 1906)
photochemically induced thrombosis (PIT) to occlude the middle cerebral artery (MCA) caused a rapid decrease in the blood flow in a dose-dependent manner of Rose Bengal (RB)

Summary

Introduction

Stroke is one of common medical emergencies leading to irreversible neurological damage with severe complications including the dysfunction of motor skills, cognition, sensory perception and even death (De Vloo et al, 2017; Jensen and Finnerup, 2013). There are limited strategies to restore the blood flow to treat acute ischemia stroke. The short time frame for safe intervention has a limitation of clinical use, since it is still estimated that reperfusion strategies could treat less than 10% of all acute stroke patients. One of the reasons for such a short time window is that intervention beyond this time window increases risk and leads to worsened outcome (Lees et al, 2010). If these reperfusion therapies are applied too late, there is an increased risk of cerebral hemorrhage, which can sometimes prove fatal (The NINDS t-PA Stroke Study Group, 1997). Central post-stroke pain (CPSP) or stroke-induced headache is one of representative cerebral hemorrhage-related toxic events (Jensen and Finnerup, 2013; Kumral et al, 1995; Tversky et al, 2016)

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