Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

Abstract

Significant decreases in the protein levels of potassium-chloride co-transporter 2 (KCC2) were detected in the ipsilateral spinal dorsal horn 4h following loose ligation of the sciatic nerve. These decreases were associated with a change in hindlimb weight distribution suggestive of pain behavior. In contrast, no changes in GABA-A receptor subunit alpha-1 levels were detected. The decreases in KCC2 coincided with a significant ipsilateral increase in BDNF protein levels. Both the decreases in KCC2 levels and the early pain behavior were prevented by intrathecal pre-treatment with the BDNF-sequestering TrkB/Fc chimera protein or the tyrosine kinase blocker K252a. The ligationassociated decreases in KCC2 levels were transient. In the ipsilateral spinal dorsal horn of ligated animals exhibiting weight-bearing pain behavior 7 days after the ligation the KCC2 levels were identical to those in control or sham-operated animals. These data suggested that TrkB-dependent reduction in KCC2 protein levels in the spinal dorsal horn was an early consequence of peripheral nerve injury. This decrease in KCC2 may have elicited an early increase in overall dorsal horn neuronal excitability perhaps through a loss of GABA inhibition which is critically dependent on KCC2 activity. The increased neuronal excitability may in turn have caused enhanced and exaggerated communication between primary afferents and dorsal horn neurons to contribute to the early behavioral signs of pain.

Effects of Sciatic Nerve Axotomy on Excitatory Synaptic Transmission in Rat Substantia Gelatinosa

“…This is thought to involve downregulation of the Cl Ϫ transporter KCC2 and collapse of the Cl Ϫ concentration gradient such that GABA and glycine may produce smaller hyperpolarizing responses or even depolarizing responses (Coull et al 2005;Keller et al 2007;Miletic and Miletic 2008;Prescott et al 2006). It should be noted, however, that these changes have been studied primarily in lamina I.…”

<b>Plantar injection of formalin in rats reduces the expression of a potassium chroride cotransporter KCC2 in the spinal cord and a kinase inhibitor suppresses this r</b><b>eduction </b>

“…If the BDNF released by C fibers contributes to the decrease in the expression of KCC2, it is likely that the downregulation of KCC2 is mostly observed at the termini of C fibers. In neuropathic pain, the expression level of KCC2 decreases as a result of the action of the TrkB receptor, and this change leads to the reversal of GABA activity (3,11). Because the TrkB receptor has a high affinity for BDNF (7), the latter may be responsible for the TrkB receptor-mediated downregulation of KCC2.…”

“…The TrkB receptor participates in the downregulation of KCC2 expression during neuropathic pain (11). In this study, we determined whether the TrkB receptor is also involved in the acute pain caused by the plantar injection of formalin.…”

“…In addition, the excitatory effect of GABA has been confirmed in several experimental pain conditions, such as neuropathic pain (3). Previous reports have shown that in neuropathic pain, brain-derived neurotrophic factor (BDNF), which is released from activated microglia, switches the effect of GABA on spinal cord layer II neurons to the excitatory mode (2) and that via the TrkB receptor, BDNF reduces KCC2 expression in the dorsal horn of the spinal cord (11). These data suggest that in neuropathic pain, the reduced expression of KCC2 may switch the effect of GABA from the inhibitory mode to the excitatory mode and cause the aggravation of pain and that microglia are a major regulator of the expression levels of KCC2.…”

BDNF mediated TrkB activation is a survival signal for transitional cell carcinoma cells

“…TrkB-Fc sequesters BDNF and consequently functions as a specific TrkB inhibitor (37)(38)(39). Blockade of BDNF/TrkB interaction by TrkB-Fc delayed the progression of the xenograft bladder tumor in SCID mice through inhibition of TrkB phosphorylation.…”