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Glial Amino Acid Transporters pp 225–253Cite as

Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology

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Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 16))

Abstract

The vast majority of peripheral neurons sensing noxious stimuli and conducting pain signals to the dorsal horn of the spinal cord utilize glutamate as a chemical transmitter of excitation. High-affinity glutamate transporter subtypes GLAST/EAAT1, GLT1/EAAT2, EAAC1/EAAT3, and EAAT4, differentially expressed on sensory neurons, postsynaptic spinal interneurons, and neighboring glia, ensure fine modulation of glutamate neurotransmission in the spinal cord. The glutamate transport system seems to play important roles in molecular mechanisms underlying chronic pain and analgesia. Downregulation of glutamate transporters (GluTs) often precedes or occurs simultaneously with development of hypersensitivity to thermal or tactile stimuli in various models of chronic pain. Moreover, antisense knockdown or pharmacological inhibition of these membrane proteins can induce or aggravate pain. In contrast, upregulation of GluTs by positive pharmacological modulators or by viral gene transfer to the spinal cord can reverse the development of such pathological hypersensitivity. Furthermore, some multi-target drugs displaying analgesic properties (e.g., tricyclic antidepressant amitriptyline, riluzole, anticonvulsant valproate, tetracycline antibiotic minocycline, β-lactam antibiotic ceftriaxone and its structural analog devoid of antibacterial activity, clavulanic acid) can significantly increase the spinal glutamate uptake. Thus, mounting evidence points at GluTs as prospective therapeutic target for chronic pain treatment. However, design and development of new analgesics based on the modulation of glutamate uptake will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of this transport system in the spinal cord.

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Abbreviations

AA:

Arachidonic acid

ALS:

Amyotrophic lateral sclerosis

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ASCT:

Alanine/serine/cysteine transporter

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

CCI:

Chronic constriction injury;

DHK:

Dihydrokainate

DL-THA:

DL-threo-beta-hydroxyaspartate

DRG:

Dorsal root ganglion

EAAC1:

Excitatory amino acid carrier 1

EAAT:

Excitatory amino acid transporter

EAE:

Experimental autoimmune encephalitis

FDA:

Food and Drug Administration

FGF:

Fibroblast growth factor

GLAST:

Glutamate/aspartate transporter

GLT1:

Glutamate transporter 1

GluT:

Glutamate transporter

HSD:

Hypoxic spreading depression

HSF-1:

Heat-shock factor 1

IL:

Interleukin

INFy:

Interferon γ

L-t2,4-PDC:

L-trans-Pyrrolidine-2,4-dicarboxylic acid

MAP kinase:

Mitogen-activated protein kinase

MG-132:

Z-Leu-Leu-Leu-CHO peptide

MND:

Motor neuron disease; MS, multiple sclerosis

MS-153:

(R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline

NF-κB:

Nuclear factor κB

NG108-15:

Neuroblastoma-glioma hybrid cell line clone 108–15

NGF:

Nerve growth factor

NMDA:

N-methyl-D-aspartic acid

Nrf2:

Nuclear factor erythroid 2-related factor 2

NSAID:

Nonsteroidal anti-inflammatory drug

OGD:

Oxygen-glucose deprivation

PGE:

Prostaglandin E

PI3 kinase:

Phosphoinisitide-3 kinase

PKC:

Protein kinase C

pSNL:

Partial sciatic nerve ligation

SIN:

Sciatic inflammatory neuropathy

SMA:

Spinal muscular atrophy

SNI:

Spared nerve injury

SNL:

Spinal nerve ligation

SRI6:

So-sparing peroxynitrite decomposition catalyst

STZ:

Streptozotocin

TBOA:

Threo-beta-benzyloxyaspartate

TG:

Trigeminal ganglion

TNF:

Tumor necrosis factor

TRPV-1:

Transient receptor potential cation channel subfamily V member 1

WB:

Western blotting

xCT:

Cystine/glutamate exchange transporter

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Acknowledgments

This work was supported by grants from the Lundbeck Foundation (R88-A9077-B1012), Augustinus Fonden (2014−2016), Oda and Hans Henningsen’s Foundation (2015), and Ilia State University. Personal assistance by Mr. Alexandre Gegelashvili is cordially acknowledged.

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The author declares no conflicts of interest.

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  1. Institute of Chemical Biology, Ilia State University, K. Cholokashvili Ave 3/5, 0162, Tbilisi, Georgia

    Georgi Gegelashvili

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark

    Georgi Gegelashvili & Ole Jannik Bjerrum

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Correspondence to Georgi Gegelashvili .

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    Arturo Ortega

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Gegelashvili, G., Bjerrum, O.J. (2017). Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology. In: Ortega, A., Schousboe, A. (eds) Glial Amino Acid Transporters. Advances in Neurobiology, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-55769-4_11

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