Glutamate transporter activators as anti-nociceptive agents

The effective management of chronic pain remains enigmatic. There is a paucity of effective mechanistically-based approaches employed. Chronic visceral pain is a particularly difficult subcategory to manage. Glutamate is the most predominant excitatory neurotransmitter and mediates many aspects of sensory function including acute and chronic pain. There is a growing literature describing the efficacy of physiologically dominant glutamate transporter GLT-1 up-regulation in attenuating chronic visceral and somatic nociception. Since glutamate is the major excitatory neurotransmitter released in the first central synapse of the pain-transmitting afferent neurons, augmentation of GLT-1 activity, which reduces extracellular levels of glutamate, may be an important target for pain management strategies. This review summarizes studies in our laboratory and others which highlight findings that GLT-1 up-regulation by transgenic, pharmacologic and viral transfection approaches attenuate a host of nociceptive responses emanating from visceral or somatic sources in animal models. The study also outlines the future work that will be required to ascertain the translational potential of this approach.