High-affinity glutamate transporters in chronic pain: an emerging therapeutic target.

Abstract

Neurons responsible for sensing noxious stimuli and conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. Members of the SLC1A family of high-affinity glutamate transporters (GluTs) are differentially expressed in sensory neurons and surrounding glial cells. These plasma membrane proteins along with glutamate/cystine exchanger, light chain of cystine/glutamate exchanger, are responsible for fine tuning of extracellular glutamate concentrations and, thus, for modulation of excitatory signalling in the spinal cord. Emerging data point at key roles of GluTs in molecular mechanisms of chronic pain and analgesia, incl. development of opioid tolerance. Pharmacological inhibition or antisense down-regulation of spinal GluTs can induce/aggravate pain behaviours, whereas increasing of expression of GluTs by viral gene transfer or positive pharmacological modulators can mitigate chronic pain. Furthermore, some drugs, originally introduced for targeting different pathological conditions, but in parallel exhibiting analgesic properties (e.g. anti-convulsants valproate and riluzole, β-lactam- and tetracycline antibiotics, tricyclic anti-depressants), can enhance glutamate transport in the spinal cord. Thus, molecular modulation of GluTs may turn into prospective therapeutic approach for the management of chronic pain. However, precise pharmacological targeting of this transport system requires in-depth elucidation of molecular factors and signalling pathways underlying expression and activity of individual GluT subtypes, including their splice variants. Neurons conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. High-affinity glutamate transporters (GluTs) regulate extracellular glutamate concentrations and, thus, modulate excitatory signalling in pain circuits. The present review critically analyses accumulated data on the roles of GluTs in molecular mechanisms of chronic pain, as well as perspectives for targeting this transport system in pain therapies.