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Inhibitory effect of intrathecally administered AM404, an endocannabinoid reuptake inhibitor, on neuropathic pain in a rat chronic constriction injury model

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Abstract

Background

The endocannabinoid system modulates a wide variety of pain conditions. Systemically administered AM404, an endocannabinoid reuptake inhibitor, exerts antinociceptive effects via activation of the endocannabinoid system. However, the mechanism and site of AM404 action are not fully understood. Here, we explored the effect of AM404 on neuropathic pain at the site of the spinal cord.

Methods

Male Sprague–Dawley rats were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of intrathecal administration of AM404 on mechanical and cold hyperalgesia were examined using the electronic von Frey test and cold plate test, respectively. Motor coordination was assessed using the rotarod test. To understand the mechanisms underlying the action of AM404, we tested the effects of pretreatment with the cannabinoid type 1 (CB1) receptor antagonist AM251, CB2 receptor antagonist AM630, and transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine.

Results

AM404 attenuated mechanical and cold hyperalgesia with minimal effects on motor coordination. AM251 significantly inhibited the antihyperalgesic action of AM404, whereas capsazepine showed a potentiating effect.

Conclusions

These results indicate that AM404 exerts antihyperalgesic effects primarily via CB1, but not CB2, receptor activation at the site of the spinal cord. TRPV1 receptors appear to play a pronociceptive role in CCI rats. The endocannabinoid reuptake inhibitor may be a promising candidate treatment for neuropathic pain.

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Funding

This work was supported by JSPS KAKENHI Grant Number JP18K08838 (KH).

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Authors and Affiliations

  1. Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan

    Yasunori Haranishi & Tadanori Terada

  2. Division of Anesthesia, Kawashima Orthopaedic Hospital, 17 Miyabu, Nakatsu, 871-0012, Japan

    Yasunori Haranishi

  3. Division of Operative Medicine, Hospital of the University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8556, Japan

    Koji Hara

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  1. Yasunori Haranishi
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Contributions

YH contributed to the conception of the study, the acquisition, analysis and interpretation of data for the study, and drafting the manuscript. KH contributed to the design of the study, the acquisition and interpretation of data for the study, and revising the manuscript critically for important intellectual content. TT contributed to the acquisition and interpretation of data for the study and approved final manuscript.

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Correspondence to Koji Hara.

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Haranishi, Y., Hara, K. & Terada, T. Inhibitory effect of intrathecally administered AM404, an endocannabinoid reuptake inhibitor, on neuropathic pain in a rat chronic constriction injury model. Pharmacol. Rep 73, 820–827 (2021). https://doi.org/10.1007/s43440-021-00250-2

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  • DOI: https://doi.org/10.1007/s43440-021-00250-2

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