Anti-allodynic and promotive effect on inhibitory synaptic transmission of riluzole in rat spinal dorsal horn

Ryo Taiji,Manabu Yamanaka,Wataru Taniguchi,Naoko Nishio,Shunji Tsutsui,Terumasa Nakatsuka,Hiroshi Yamada

doi:10.1016/j.bbrep.2021.101130

Ryo Taiji, Manabu Yamanaka + Show 5 more

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https://doi.org/10.1016/j.bbrep.2021.101130

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Abstract

Riluzole (2-amino-6-(trifluoromethoxy)benzothiazole) is a drug known for its inhibitory effect on glutamatergic transmission and its anti-nociceptive and anti-allodynic effects in neuropathic pain rat models. Riluzole also has an enhancing effect on GABAergic synaptic transmission. However, the effect on the spinal dorsal horn, which plays an important role in modulating nociceptive transmission, remains unknown. We investigated the ameliorating effect of riluzole on mechanical allodynia using the von Frey test in a rat model of neuropathic pain and analyzed the synaptic action of riluzole on inhibitory synaptic transmission in substantia gelatinosa (SG) neurons using whole-cell patch clamp recordings. We found that single-dose intraperitoneal riluzole (4 mg/kg) administration effectively attenuated mechanical allodynia in the short term in a rat model of neuropathic pain. Moreover, 300 μM riluzole induced an outward current in rat SG neurons. The outward current induced by riluzole was not suppressed in the presence of tetrodotoxin. Furthermore, we found that the outward current was suppressed by simultaneous bicuculline and strychnine application, but not by strychnine alone. Altogether, these results suggest that riluzole enhances inhibitory synaptic transmission monosynaptically by potentiating GABAergic synaptic transmission in the rat spinal dorsal horn.

Highlights

Persistent neuropathic pain conditions, including allodynia, hyper algesia, and spontaneous pain, which result from injury or inflammation of the peripheral nerves, significantly reduce the ability to perform ac tivities of daily living and quality of life [1,2]
We found that single-dose intraperitoneal rilu zole administration effectively attenuated mechanical allodynia in the short term in spared nerve injury (SNI) rats
The results of patch-clamp recording from substantia gelatinosa (SG) neurons revealed that riluzole induced outward current, which was suppressed by bicuculline and strychnine when applied simultaneously, but not by strychnine alone

Summary

Introduction

Persistent neuropathic pain conditions, including allodynia, hyper algesia, and spontaneous pain, which result from injury or inflammation of the peripheral nerves, significantly reduce the ability to perform ac tivities of daily living and quality of life [1,2]. Riluzole (2-amino-6-(trifluoromethoxy)benzothiazole), a U.S Food and Drug Administration-approved drug for the treatment of amyo trophic lateral sclerosis [3], has been demonstrated to attenuate neural excitotoxicity by inhibiting glutamatergic transmission This involves multiple mechanisms, including attenuation of presynaptic glutamate release via blockade of both sodium and calcium channels [4,5,6], enhancement of glutamate transporter activity [7,8,9] and weak antagonism of post-synaptic NMDA receptors [4,10]. The Abbreviations: CCI, chronic constriction injury; SG, substantia gelatinosa; SNI, spared nerve injury; TTX, tetrodotoxin; IPSC, inhibitory postsynaptic current. * Corresponding author

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