Spinal cord compression injury in adult rats initiates changes in dorsal horn remodeling that may correlate with development of neuropathic pain

Abstract

Spinal cord injury commonly causes chronic, neuropathic pain. The mechanisms are poorly understood but may include structural plasticity within spinal and supraspinal circuits. Our aim was to determine whether structural remodeling within the dorsal horn rostral to an incomplete injury differs from a complete spinal cord transection. Four immunohistochemical populations of primary afferent C-fibers, and descending catecholamine and serotonergic projections, were examined in segments T9-T12 at 2 and 12 weeks after a T13 clip-compression injury in adult male rats. Dorsal root ganglia were also examined. Two weeks after injury, fibers immunoreactive for calcitonin gene-related peptide (CGRP) or GDNF-family receptors (GFRalpha1, GFRalpha2, GFRalpha3) showed distinct injury responses within the superficial dorsal horn. CGRP fibers decreased, but GFRalpha1, GFRalpha2 and GFRalpha3 fibers did not change. In contrast, all groups were decreased by 12 weeks after injury. Catecholamine fibers showed a decrease at 2 weeks followed by an increase in density at 12 weeks, whereas serotonergic fibers showed a decrease (restricted to deep dorsal horn) at 12 weeks. These results show that the dorsal horn of the spinal cord undergoes substantial structural plasticity rostral to a compression injury, with the most profound effect being a prolonged and possibly permanent loss of primary afferent fibers. This loss was more extensive and more prolonged than the loss that follows spinal cord transection. Our results provide further evidence that anatomical reorganization of sensory and nociceptive dorsal horn circuits rostral to an injury could factor in the development or maintenance of spinal cord injury pain.

Characterization of bladder sensory neurons in the context of myelination, receptors for pain modulators, and acute responses to bladder inflammation

“…Each of the primary antibodies has been characterized extensively in previous studies (Forrest and Keast, 2008; Kalous et al, 2009; Kiasalari et al, 2010) and showed general patterns of staining comparable to these earlier reports. To identify neurons that could potentially be influenced by GFLs, we used antibodies raised against the preferred receptors for GDNF (GFRα1), neurturin (GFRα2), and artemin (GFRα3).…”

“…TRPV1 is a marker of polymodal nociceptor neurons that is expressed by the majority of bladder afferent neurons (Bennett et al, 2003). Previous studies of DRGs at other spinal levels have shown that the majority of CGRP-IR neurons express TRPV1 (Kiasalari et al, 2010) and that GFRα3-IR is expressed in a sub-population of CGRP-IR neurons (Orozco et al, 2001; Kalous et al, 2009). From these previous studies we also predicted that GFRα1- and GFRα2-IR would be found in the non-peptidergic population (Bennett et al, 1998; Kalous et al, 2007, 2009).…”

Spinal Cord Injury Triggers an Intrinsic Growth-Promoting State in Nociceptors

“…For example, in some of these reports the density of CGRPpositive fibers decreased in some dorsal horn laminae while increasing in others. Furthermore, other studies have described only decreases of CGRP-positive fiber density across most of the dorsal horn after complete spinal transection (Kalous et al, 2007) and spinal compression injury (Kalous et al, 2009). Differences also appear to exist between the growth-promoting effects of central and peripheral injury; a conditioning lesion of the sciatic nerve enhances the intrinsic growth state of some DRG neurons but, in contrast to our findings after SCI, not those expressing CGRP (Kalous and Keast, 2010).…”

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

“…To increase assay sensitivity, we separately assessed neurite outgrowth in peptidergic C-fiber neurons that are CGRP-immunoreactive (Orozco et al, 2001; Forrest and Keast, 2008; Kalous et al, 2009; Keast et al, 2010; Forrest et al, 2013). These CGRP-positive C-fibers in DRGs express the ARTN receptor, GFRα3, while the CGRP-negative neurons express receptors of other GFLs (Bennett et al, 1998; Senba et al, 2007).…”