Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model.

Kenta Nakao,Atsushi Fujiwara,Sayuri Matsunami,Seiji Ito,Shinji Takai,Manabu Kitano,Denan Jin,Toshiaki Minami,Nobuyasu Komasawa

doi:10.1155/2019/2956920

Kenta Nakao, Atsushi Fujiwara + Show 7 more

Open Access

https://doi.org/10.1155/2019/2956920

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Abstract

Bone cancer pain control is difficult because it includes various characteristics of pain such as nociceptic and neuropathic pain. In this study, we investigated the effect of yokukansan (YKS), one of the traditional Japanese herbal medicines, on cancer pain in mouse bone metastasis model. Oral administration of YKS significantly alleviated pain behavior measured by quantitative body weight bearing. Furthermore, the pain behavior was also significantly alleviated by intrathecal and intraperitoneal administration of matrix metalloproteinase- (MMP-) 9 inhibitor, but not of MMP-2 inhibitor. MMP-9 expression was significantly elevated in the bone tissue on day 3 after carcinoma cell injection and in the ipsilateral spinal cord on day 7, which was suppressed by YKS administration. Taken together, these results suggest that YKS alleviates cancer pain via suppressing MMP-9 expression in bone metastasis model in mice.

Highlights

Common cancers such as those of the breast, lung, and prostate frequently metastasize to multiple sites in bones, where they can cause significant and intractable pain [1]
Cancer-induced bone pain is a mixed-mechanism pain state exhibiting elements of both neuropathic and inflammatory pain, but with distinctive modifications made to the tissue and nerves in the periphery as well as unique neurochemical changes at the spinal cord level [6]
On day 3-10 after the operation the mice developed abnormal gait, posture, and guarding behavior of the hind paw on the right-side ipsilateral to the 4T1 breast cancer cell injection into the tibia when placed on the dynamic weight bearing (DWB) device

Summary

Introduction

Common cancers such as those of the breast, lung, and prostate frequently metastasize to multiple sites in bones, where they can cause significant and intractable pain [1]. Once cancer cells have metastasized to bone, they generate pain by releasing algogenic substances including protons, bradykinin, endothelins, prostaglandins, proteases, and tyrosine kinase activators [3] The release of these factors by cancer cells can induce sensitization and activation of nerve fibers that innervate the bone. Tumor growth in bone can generate neuropathic pain by directly injuring nerve fibers as well as by inducing an active and highly pathological sprouting of both sensory and sympathetic nerve fibers that normally innervate the bone [5] This structural reorganization of sensory and sympathetic nerve fibers in the bone, combined with the cellular and neurochemical reorganization that occurs in the spinal cord and brain, appears to contribute to the peripheral and central sensitization that is common in advanced bone cancer pain. These mechanistic insights have shown that bone cancer pain is a complex mixture of nociceptic and neuropathic types of pain produced by various cytokines and hormones [6]

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