L1 cell adhesion molecule is essential for the maintenance of hyperalgesia after spinal cord injury

Abstract

Spinal cord injury (SCI) results in a loss of normal motor and sensory function, leading to severe disability and reduced quality of life. A large proportion of individuals with SCI also suffer from neuropathic pain symptoms. The causes of abnormal pain sensations are not well understood, but can include aberrant sprouting and reorganization of injured or spared sensory afferent fibers. L1 is a cell adhesion molecule that contributes to axonal outgrowth, guidance and fasciculation in development as well as synapse formation and plasticity throughout life. In the present study, we used L1 knockout (KO) mice to determine whether this adhesion molecule contributes to sensory dysfunction after SCI. Both wild-type (WT) and KO mice developed heat hyperalgesia following contusion injury, but the KO mice recovered normal response latencies beginning at 4 weeks post-injury. Histological analyses confirmed increased sprouting of sensory fibers containing calcitonin gene related peptide (CGRP) in the deep dorsal horn of the lumbar spinal cord and increased numbers of interneurons expressing protein kinase C gamma (PKCγ) in WT mice 6 weeks after injury. In contrast, L1 KO mice had less CGRP+ fiber sprouting, but even greater numbers of PKCγ+ interneurons at the six week time point. These data demonstrate that L1 plays a role in maintenance of thermal hyperalgesia after SCI in mice, and implicate CGRP+ fiber sprouting and the upregulation of PKCγ expression as potential contributors to this response.

Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

“…Given that several studies have shown a stimulatory effect of VEGF on axonal growth (Zachary, 2005), and that aberrant axonal growth/sprouting underlies the development of neuropathic pain post-SCI (Hoschouer et al, 2009;Kalous et al, 2007;Macias et al, 2006), we hypothesized that VEGF 165 stimulates excessive axonal growth, and thus increases mechanical hypersensitivity in SCI rats (Fig. 2).…”

“…2). In previous studies (Hoschouer et al, 2009;Kalous et al, 2007;Macias et al, 2006), researchers also reported that SCI pain was associated with excessive sprouting of pain-processing unmyelinated axons expressing calcitonin gene-related peptide (CGRP). Therefore we analyzed the effect of VEGF 165 on CGRP labeling in the dorsal horns in two regions: (1) laminae I and II (which normally contain most of the CGRP-positive axons), and (2) laminae III-V (which normally contain only a small number of CGRP-expressing axons).…”

“…Although collateral axonal sprouting may be of great importance in recovery after SCI (Helgren and Goldberger, 1993;Murray and Goldberger, 1974), the results of several studies have suggested that excessive sprouting of primary afferents, primarily nonmyelinated axons, is one cause of the neuropathic pain seen after SCI (Christensen and Hulsebosch, 1997;Hofstetter et al, 2005;Hoschouer et al, 2009;Krenz and Weaver, 1998;Ondarza et al, 2003;Romero et al, 2000). Excessive sprouting of nonmyelinated sensory axons within dorsal horns was not only found in animal models of SCI (Cameron et al, 2006;Tang et al, 2007), but was also seen in human SCI patients (Ackery et al, 2007).…”

“…It has been shown that this functional reorganization within the dorsal horns results from excessive and nonspecific sprouting of primary afferent sensory fibers, and loss of supraspinal innervations/neurons after injury (Hoschouer et al, 2009;Kalous et al, 2007). It was also shown that contusion SCI induces increased abundance and extensive spreading of primary afferents, and that a reduction in the abundance of sensory axons is associated with decreased pain after SCI (Nesic et al, 2008).…”

Sensory Stimulation Prior to Spinal Cord Injury Induces Post-Injury Dysesthesia in Mice

“…and antibiotics (5 mg=kg gentocin, s.q.) for 5 days following surgery, and bladder expression twice a day for the duration of the study (Hoschouer et al, 2008).…”