Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain

Dysfunctional glial glutamate transporters and over production of pro-inflammatory cytokines (including interleukin-1 beta, IL-1 beta) are two prominent mechanisms by which glial cells enhance neuronal activities in the spinal dorsal horn in neuropathic pain conditions. Endogenous molecules regulating production of IL-1 beta and glial glutamate functions remain poorly understood. In this study, we revealed a dynamic alteration of GSK3 beta activities and its role in regulating glial glutamate transporter 1 (GLT-1) protein expression in the spinal dorsal horn and nociceptive behaviors following the nerve injury. Specifically, GSK3 beta was expressed in both neurons and astrocytes in the spinal dorsal horn. GSK3 beta activities were suppressed on day 3 but increased on day 10 following the nerve injury. In parallel, protein expression of GLT-1 in the spinal dorsal horn was enhanced on day 3 but reduced on day 10. In contrast to these time-dependent changes, the activation of astrocytes and over-production of IL-1 beta were found on both day 3 and day 10. Meanwhile, thermal hyperalgesia was observed from day 2 through day 10 and mechanical allodynia from day 4 through day 10. Pre-emptive pharmacological inhibition of GSK3 beta activities significantly ameliorated thermal hyperalgesia and mechanical allodynia at the late stage but did not have effects at the early stage. These were accompanied with the suppression of GSK3 beta activities, prevention of decreased GLT-1 protein expression, inhibition of astrocytic activation, and reduction of IL-beta in the spinal dorsal horn on day 10. These data indicate that the increased GSK3 beta activity in the spinal dorsal horn is attributable to the downregulation of GLT-1 protein expression in neuropathic rats at the late stage. Further, we also demonstrated that the nerve-injury-induced thermal hyperalgesia on day 10 was transiently suppressed by pharmacological inhibition of GSK3 beta. Our study suggests that GSK3 beta may be a potential target for the development of analgesics for chronic neuropathic pain. Published by Elsevier Inc.