Effects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain

doi:10.1016/j.ejphar.2005.09.045

European Journal of Pharmacology

Volume 524, Issues 1–3, 7 November 2005, Pages 80-83

https://doi.org/10.1016/j.ejphar.2005.09.045 Get rights and content

Abstract

Injury to the spinal nerves of mice induces mechanical allodynia and thermal hyperalgesia. In the injured spinal cord, the expression of glucocorticoid receptor mRNA was increased, whereas it was decreased in N-type Ca²⁺-channel-deficient mice, in which neuropathic pain is eliminated. Intrathecal and intraperitoneal injection of the glucocorticoid receptor antagonist RU486 produced antinociceptive effects, whereas intracerebroventricular injection was without effect. The more selective antagonist dexamethasone 21-mesylate suppressed both mechanical allodynia and thermal hyperalgesia. These results suggest that spinal glucocorticoid receptors play an important role in neuropathic pain, and that controlling the activity of glucocorticoid receptors may be of great importance in the treatment of neuropathic pain.

Introduction

Injury to peripheral nerves induces neuropathic pain-like responses in rodents. We have previously demonstrated that mice lacking N-type voltage-dependent Ca²⁺ channels (VDCC) show markedly reduced symptoms of neuropathic pain-related behavior induced by spinal nerve injury (Saegusa et al., 2001), suggesting a critical role of N-type VDCC in the development of neuropathic pain. Although several studies have demonstrated that blockade of this channel is effective against neuropathic pain in rodents (Bowersox et al., 1996, Scott et al., 2002), it has been reported that clinical application of an N-type VDCC blocker is limited by its serious side effects (Penn and Paice, 2000). Therefore, it is desirable to develop a new drug that alleviates neuropathic pain without having severe side effects.

To search for new molecules involved in the signaling cascade from N-type VDCC to neuropathic pain, we investigated the genes that are differentially expressed in the spinal cord following nerve injury using microarray techniques and compared the gene expression profiles with those of N-type VDCC-deficient mice. Our present study of cDNA microarray analysis identifies the glucocorticoid receptor as a candidate target for the management of neuropathic pain. Therefore, we examined the effects of glucocorticoid receptor antagonists on neuropathic pain-like responses in mice.

Section snippets

Animals

Male C57BL/6J mice (Clea Japan, Inc., Tokyo, Japan) and N-type VDCC-deficient mice (Saegusa et al., 2001) weighing 22–26 g were used. They were housed three per cage under controlled temperature (22 ± 1 °C) and humidity (55 ± 10%) with a 12-h light/dark cycle with food and water freely available. All behavioral experiments were performed in a sound-proof room during the light cycle (7:00 AM–7: 00 PM). Experiments were conducted with the approval of the Animal Care Committee of Tokyo Medical and

cDNA microarray analysis

Using cDNA microarray techniques, we found that the level of expression of 934 genes out of 10,000 genes in the spinal cord was increased more than 1.2-fold by spinal nerve injury as compared with the level in sham-operated mice. Most of these 934 genes were also up-regulated in the spinal cord from nerve-injured N-type VDCC-deficient mice, but the expression of 70 genes was reduced more than 1.2-fold compared with that in sham-operated N-type VDCC-deficient mice. The glucocorticoid receptor

Discussion

We previously demonstrated that the neuropathic pain-like behavior induced by spinal nerve injury is eliminated in mice lacking N-type VDCC (Saegusa et al., 2001). Using cDNA microarray techniques, we found that the level of expression of several genes in the spinal cord is increased by nerve injury. The glucocorticoid receptor gene is one of the genes whose expression level was modestly increased in the wild-type spinal cord. It is of particular interest that the glucocorticoid receptor is

Acknowledgments

We would like to thank R. Yabe, W. Han, J. Wang, T. Adachi, T. Sasaki, D. Kondo and T. Ogawa for technical assistance. This work was supported by the Grant-in-Aid for Scientific Research, JSPS (15300121) and by the Preventure Program, JST.

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Short communicationEffects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain

Abstract

Introduction

Section snippets

Animals

cDNA microarray analysis

Discussion

Acknowledgments

Brain Res.

Eur. J. Pharmacol.

Pain

Eur. J. Pharmacol.

Pain

Anti-inflammatory actions of glucocorticoids: molecular mechanisms

Clin. Sci. (Lond)

Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain

J. Pharmacol. Exp. Ther.

Short communication
Effects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain