TY - CHAP

T1 - Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain

T2 - Molecular Mechanisms and Pharmacology

AU - Gegelashvili, Georgi

AU - Bjerrum, Ole Jannik

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1007/978-3-319-55769-4_11

DO - 10.1007/978-3-319-55769-4_11

M3 - Book chapter

C2 - 28828613

VL - 16

T3 - Advances in Neurobiology

SP - 225

EP - 253

BT - Glial Amino Acid Transporters

PB - Springer

ER -