Activation of sensory neurons contributes to reduce spinal cord injury in rats
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.
Section snippets
Reagents
SB366791 (an antagonist of capsaicin) and indomethacin (IM) were purchased from Sigma Chemical Co (St. Louis, MO). Rat α-calcitonin gene-related peptide (CGRP) and human CGRP(8-37) were purchased from Peptide Institute (Osaka, Japan). All other reagents were of analytical grade.
Administration of various agents
SB366791 was dissolved in dimethyl-sulfoxide and further diluted with normal saline. A total of 500 μg/kg of SB366791 was injected intraperitoneally (ip) 30 min prior to SCI as described previously (Varga et al., 2005).
Changes in spinal cord tissue levels of CGRP and 6-keto-PGF1α in rats subjected to 20-min compression trauma-induced SCI
Spinal cord tissue levels of CGRP in experimental subjects were significantly increased after induction of SCI, peaking at 2 h after trauma, compared with levels observed in sham-operated animals (Fig. 1A). These levels were decreased at 3 h after trauma, but remained significantly higher than the levels in sham-operated animals for up to 12 h after trauma (Fig. 1A). Spinal cord tissue levels of 6-keto-PGF1α increased after trauma, peaking after 2 h, and remained significantly higher than those in
Discussion
In the present study, we demonstrated that spinal cord tissue levels of CGRP, a neuropeptide released from capsaicin-sensitive sensory neurons, in the injured spinal cord segment were significantly increased after 20-min compression trauma of the spinal cord, peaking at 2 h after trauma. These increases in CGRP levels were significantly inhibited by SB366791, a specific vanilloid receptor-1 antagonist, suggesting that capsaicin-sensitive sensory neurons might be activated in the pathologic
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