Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury

Abstract

Localized increases in synaptic strength constitute a synaptic basis for learning and memory in the CNS and may also contribute to the maintenance of neuropathic pain after spinal cord injury (SCI) through the de novo formation or elaboration of postsynaptic dendritic structures. To determine whether SCI-induced dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain, we analyzed spine morphometry, localization, and functional influence in dorsal horn (DH) neurons in adult rats 1 month after sham surgery, contusion SCI, and SCI treated with a selective inhibitor of Rac1 activation, NSC23766. After SCI, DH neurons located in lamina IV-V exhibited increased spine density, redistributed spines, and mature spines compared with control neurons, which was associated with enhancement of EPSCs in computer simulations and hyperexcitable responsiveness to innocuous and noxious peripheral stimuli in unit recordings in vivo. SCI animals also exhibited symptoms of tactile allodynia and thermal hyperalgesia. Inhibition of the small GTP-binding protein Rac1 ameliorated post-SCI changes in spine morphology, attenuated injury-induced hyperexcitability of wide-dynamic range neurons, and progressively increased pain thresholds over a 3 d period. This suggests that Rac1 is an important intracellular signaling molecule involved in a spinal dendritic spine pathology associated with chronic neuropathic pain after SCI. Our report provides robust evidence for a novel conceptual bridge between learning and memory on the one hand, and neuropathic pain on the other.

Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain

“…A small slit was made in the atlanto-occipital membrane, between the base of the skull and spinal vertebra C1 and a 32 gauge catheter was threaded caudally to the lumbar enlargement and secured by suturing. To prevent CSF leakage and infection, the rostral opening was heat sealed by pinching the exposed tip with a sufficiently heated forcep (Tan et al, 2008). The catheter tip location was confirmed within the intrathecal space after the animals were killed.…”

“…Only a few studies have investigated the possibility of morphological alterations of postsynaptic structures within second-order sensory neurons in diabetes as an underlying mechanism for diabetic neuropathic pain (Yamano et al, 1986;Malone et al, 2008). Our previous work has shown that structural alterations of synaptic spines within dorsal horn neurons can have adverse functional implications (Tan et al, 2009a), which may contribute neuropathic pain in spinal cord injury (SCI) and peripheral nerve injury (Tan et al, 2008.…”

Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

“…Similarly, not all moderately contused rats developed allodynia, although the reported incidence varies from 20% (Nesic, et al, 2005), to 50% (Drew et al, 2004), to 100% (Tan et al, 2008). To determine the number of SCI rats that developed allodynia after SCI, we first established a cutoff criterion for discriminating the mechanical sensitivity of SCI rats that displayed painful behavior from spontaneous fluctuations in mechanical sensitivity among uninjured rats.…”

Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury

“…Various studies in experimental animals uncovered a mosaic of injury-induced molecular and cellular changes in segments caudal to a SCI (Krenz and Weaver, 1998;Ballermann and Fouad, 2006;Kitzman, 2006Kitzman, , 2007Soares et al, 2007;Hou et al, 2008;Tan et al, 2008;Hou et al, 2009;Boulenguez et al, 2010;Murray et al, 2010;Ichiyama et al, 2011;Singh et al, 2011;Kapitza et al, 2012;Tan et al, 2012). Depending upon the SCI model and specific functional assessments, these alterations in the properties of neuronal circuits have alternatively been classified as beneficial or detrimental.…”