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Effect of Memantine on the Levels of Neuropeptides and Microglial Cells in the Brain Regions of Rats with Neuropathic Pain

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Abstract

Neuropathic pain induced by sciatic nerve injury not only causes peripheral dysfunctions but also affects the cortical and subcortical regions of the brain. It is still unknown whether neuropathic pain could relate to behavioral and neurochemical alterations in the central nervous system. This paper deals with the effect of peripheral neuropathic pain on mechanical allodynia, neuropeptide levels, neuropeptide-degrading enzyme activities, and microglial cells in the brain regions of rats by applying chronic constriction injury, a partial sciatic nerve injury. We examined the possible protection effect on the allodynia and changes in levels of neuropeptides and microglial activation in chronic constriction injury of the rat brain by memantine. On 4 days after chronic constriction injury, the induction of mechanical allodynia was suppressed by memantine treatment. Reductions in the substance P in the hypothalamus and somatostatin in the periaqueductal gray of chronic constriction injury rat brain were reversed by memantine. This suggests the role of these neuropeptides in pain information processing in the brain. Immunohistochemical experiments revealed that the expression of CD11b, a marker protein of microglia, was increased in the hypothalamus and periaqueductal gray in the chronic constriction injury rat brain as compared with the controls, and memantine treatment could suppress the activation of microglia, suggesting the involvement of microglia in pain mechanism. The present behavioral, biochemical, and immunohistochemical studies demonstrated that peripheral neuropathic pain affects the neuropeptide levels and microglial activation in the brain regions, and these events described above may play an important role in neuropathic pain pathogenesis.

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Abbreviations

AMC:

7-Amino-4-methylcoumarin

anti-SOM:

Antisomatostatin

anti-SP:

Antisubstance P

BSA:

Bovine serum albumin

CCI:

Chronic constriction injury

CNS:

Central nervous system

DAB:

3,3′-Diaminobenzidine

EIA:

Enzyme immunoassay

GABA:

γ-Aminobutyric acid

HRP:

Horseradish peroxidase

NMDA:

N-Methyl-d-aspartate

PAG:

Periaqueductal gray

PBS:

Phosphate-buffered saline

PNS:

Peripheral nervous system

POP:

Prolyl oligopeptidase

SOM:

Somatostatin

SOM-LI:

SOM-like immunoreactivity

SP:

Substance P

SP-LI:

SP-like immunoreactivity

Suc-Gly-Pro-MCA:

Succinylglycyl-l-proline 4-methylcoumaryl-7-amide

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Acknowledgments

We are very grateful to Dr. Akira Tanaka for his valuable and helpful advice on the experiments and manuscript preparation.

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Authors and Affiliations

  1. Department of Research and Development, Abbott Diagnostic Division, Minato, Tokyo, 106-8535, Japan

    Katsumichi Takeda

  2. Laboratory of Molecular Recognition, Graduate School of Integrated Science, Yokohama City University, Yokohama, 236-0027, Japan

    Mai Muramatsu

  3. Department of Analytical Chemistry of Medicines, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo, 194-8543, Japan

    Toshiyuki Chikuma

  4. Department of Research and Development, Bioelectro Analytical Science, Inc., Sumida, Tokyo, 131-0045, Japan

    Takeshi Kato

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  1. Katsumichi Takeda
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  2. Mai Muramatsu
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  4. Takeshi Kato
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Correspondence to Toshiyuki Chikuma.

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Takeda, K., Muramatsu, M., Chikuma, T. et al. Effect of Memantine on the Levels of Neuropeptides and Microglial Cells in the Brain Regions of Rats with Neuropathic Pain. J Mol Neurosci 39, 380–390 (2009). https://doi.org/10.1007/s12031-009-9224-5

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