Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

Abstract

The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors in rats. CCI induced an initial GT upregulation up to at least postoperative day 5 primarily within the ipsilateral spinal cord dorsal horn, which was followed by a GT downregulation when examined on postoperative days 7 and 14 by Western blot and immunohistochemistry. Intrathecal administration of the tyrosine kinase receptor inhibitor K252a and the mitogen-activated protein kinase inhibitor PD98059 for postoperative days 1-4 reduced and nearly abolished the initial GT upregulation in CCI rats, respectively. Prevention of the CCI-induced GT upregulation by PD98059 resulted in exacerbated thermal hyperalgesia and mechanical allodynia reversible by the noncompetitive NMDA receptor antagonist MK-801, indicating that the initial GT upregulation hampered the development of neuropathic pain behaviors. Moreover, CCI significantly reduced glutamate uptake activity of spinal GTs when examined on postoperative day 5, which was prevented by riluzole (a positive GT activity regulator) given intrathecally twice a day for postoperative days 1-4. Consistently, riluzole attenuated and gradually reversed neuropathic pain behaviors when the 4 d riluzole treatment was given for postoperative days 1-4 and 5-8, respectively. These results indicate that changes in the expression and glutamate uptake activity of spinal GTs may play a critical role in both the induction and maintenance of neuropathic pain after nerve injury via the regulation of regional glutamate homeostasis, a new mechanism relevant to the pathogenesis of neuropathic pain.

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

“…These three factors can be altered by glial cells under pathological pain conditions. For example, down-regulation of glial glutamate transporter pro- tein expression in spinal dorsal horn astrocytes is associated with allodynia and hyperalgesia induced by chronic nerve injury (58,59), chemotherapy (e.g. paclitaxel) (60), or opioids (61).…”

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…Downregulation might result in a decrease in glutamate uptake and a subsequent increase in excitatory synaptic transmission. Thus, neuropathic pain is attenuated by riluzole, a glutamate-transporter activator given intrathecally (Sung et al 2003). However, GLT-1 appears to have an opposite role in acute pain conditions.…”

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

“…The significance of glial activation in the turnover of glial glutamate transporters is not known. However, the development of both neuropathy and morphine tolerance, which share similar molecular and cellular mechanisms, involves glial activation and decreased glial glutamate transporters at the lumbar spinal cord (Song and Zhao, 2001;Mao et al, 2002;Raghavendra et al, 2002;Sung et al, 2003). Also, like propentofylline, neuropathy-induced chronic pain and development of morphine tolerance are attenuated by glial activation inhibitors and glutamate transporter activators (Nakagawa et al, 2001;Song and Zhao, 2001;Mao et al, 2002;Sung et al, 2003;Raghavendra et al, 2003a, b).…”