Activation of sensory neurons contributes to reduce spinal cord injury in rats

Abstract

We previously demonstrated that activation of sensory neurons increases endothelial prostaglandin I₂ (PGI₂) production by releasing calcitonin gene-related peptide (CGRP). Since PGI₂ reduces post-traumatic spinal cord injury (SCI) by inhibiting tumor necrosis factor (TNF) production, activation of sensory neurons in the spinal cord tissue may ameliorate spinal cord injury. This study examines these possibilities using rat models of compression trauma-induced SCI. Both SB366791, a specific vanilloid receptor antagonist, and CGRP (8-37), a CGRP receptor antagonist, significantly inhibited trauma-induced increases in spinal cord tissue 6-keto-PGF_1α levels. SB366791, CGRP (8-37) and indomethacin (IM) enhanced increases in spinal cord tissue TNF levels at 2 h after trauma and exacerbated motor disturbances. Administration of CGRP significantly reduced motor disturbances and inhibited increases in spinal cord tissue TNF levels through enhancement of increases in tissue levels of 6-keto-PGF_1α.

These observations strongly suggest that activation of sensory neurons might ameliorate compression trauma-induced SCI, inhibiting TNF production through enhancement of endothelial PGI₂ production. Thus, although the spinal cord sensory neurons function as nociceptive neurons, they could also be critically involved in the cytoprotective system that attenuates SCI development and, thus, pharmacological stimulation of spinal cord sensory neurons might contribute to reduce spinal cord injury.

Introduction

Capsaicin-sensitive sensory neurons are nociceptive neurons that are activated by a wide variety of noxious physical and chemical stimuli (Dray, 1995). Since inhibition of sensory neuron activation results in a marked increase in the severity of inflammation (Okajima and Harada, 2006), sensory neurons might be involved in the maintenance of tissue integrity by regulating local inflammatory responses. Calcitonin gene-related peptide (CGRP) is a neuropeptide found in nerves within the central and peripheral nervous systems (Franco-Cereceda et al., 1987). We previously reported that CGRP, released from the sensory neurons, increases the endothelial production of PGI₂ in rats subjected to hepatic ischemia/reperfusion (Harada et al., 2002). PGI₂ is a well-known cytoprotective agent that increases tissue blood flow and inhibits leukocyte activation (Harada et al., 1999). Since various noxious stimuli that activate the sensory neurons to release CGRP are capable of inducing tissue damage (Fields, 1987), CGRP-induced increase in the endothelial production of PGI₂ might contribute to attenuation of local inflammatory responses, thereby reducing tissue injury.

Tumor necrosis factor (TNF) plays an important role in the development of compression trauma-induced spinal cord injury (SCI) in rats by activating neutrophils (Taoka et al., 1998a). We previously reported that iloprost, a stable derivative of PGI₂, reduces compression trauma-induced SCI by inhibiting neutrophil activation (Taoka et al., 1997a).

Since bradykinin (Pan et al., 2001) and lipoxygenase products have been shown to play an important role in the development of spinal cord injury (Genovese et al., 2005) and these substances have been shown to activate vanilloid receptor-1 on sensory neurons (Nagy et al., 2004), it is possible that sensory neurons are activated in the pathologic process leading to SCI.

Taken together, these observations raise the possibility that sensory neurons might be activated in the pathologic process leading to compression trauma-induced SCI, contributing to the reduction of the severity of SCI by increasing the endothelial production of PGI₂. In this study, we examined these possibilities using a rat model of compression trauma-induced SCI.