Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord

Abstract

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain

“…A transient increase of spinal glutamate and aspartate release has been observed following formalin or carrageenin injection (Sluka and Westlund 1993;Malmberg and Yaksh 1995) and in intramuscular pain model (Skyba et al 2005). Another illustration of the importance of spinal glutamate level in nociceptive transmission is underlined by the fact that inhibiting spinal glutamate uptake by transporter inhibitors leads to spontaneous nociceptive behaviors and sensory hypersensitivity (Liaw et al 2005). Moreover, peripheral neuropathy induced by spinal nerve ligation comes with alterations of spinal glutamatergic neurotransmission which contribute to allodynia and hyperalgesia.…”

Spinal Astrocytes as Therapeutic Targets for Pathological Pain

“…Several lines of evidence suggest that glutamate transporters have important roles in physiological and pathological pain (32). Pharmaco-logical inhibition of glutamate transporters in the spinal cords of normal animals leads to spontaneous nociceptive behaviors and hyperalgesia to mechanical and thermal nociceptive stimuli through facilitation of spinal glutamatergic synaptic activity (33). These findings suggest that glutamate uptake through spinal EAATs plays an important role in maintaining normal pain transmission under physiological conditions.…”

Neuroinflammation and Comorbidity of Pain and Depression

“…NMDA receptor activation in the dorsal horn is connected to most types of pathological inflammation-induced pain (Ren and Dubner, 2007). Pharmacological blockade of glutamate transporters in the dorsal horn increases extracellular glutamate in the spine and results in mechanical and thermal hyperalgesia (Liaw et al, 2005). Similarly, glutamate transporter blockade increases the number and duration of NMDA receptors activated by stimuli to the primary nociceptive afferents (Nie and Weng, 2009), and ligation of spinal nerves L 5 -L 6 in rats results in 70-90% reductions in glutamate uptake in the ipsilateral deep dorsal and ventral horns .…”