sb-366791 and Spinal-Cord-Injuries

Spinal cord injury (SCI) is an extremely serious type of physical trauma observed in clinics. Especially, neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effectively therapeutic agents and treatment strategies. Proteinase-activated receptors (PARs) are a family member of G-protein-coupled receptors and are activated by a proteolytic mechanism. One of its subtypes PAR2 has been reported to be engaged in mechanical and thermal hyperalgesia. Thus, in this study we specifically examined the underlying mechanisms responsible for SCI evoked-neuropathic pain in a rat model. Overall, we demonstrated that SCI increases PAR2 and its downstream pathways TRPV1 and TRPA1 expression in the superficial dorsal horn of the spinal cord. Also, we showed that blocking spinal PAR2 by intrathecal injection of FSLLRY-NH2 significantly inhibits neuropathic pain responses induced by mechanical and thermal stimulation whereas FSLLRY-NH2 decreases the protein expression of TRPV1 and TRPA1 as well as the levels of substance P and calcitonin gene-related peptide. Results of this study have important implications, i.e. targeting one or more of these signaling molecules involved in activation of PAR2 and TRPV1/TRPA1 evoked by SCI may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI.

Topics: Acetanilides; Anilides; Animals; Cinnamates; Injections, Spinal; Male; Neuralgia; Oligopeptides; Purines; Rats; Rats, Wistar; Receptor, PAR-2; Spinal Cord Injuries

Calcitonin gene-related peptide (CGRP) released from sensory neurons increases the production of a neuroprotective substance insulin-like growth factor I (IGF-I), and sensory neuron stimulation contributes to a reduction of spinal cord injury (SCI) by inhibiting inflammatory responses in rats. Because receptors for prostaglandin E₂ (EP receptors) are present on sensory neurons, it is possible that prostaglandin E₁ analog limaprost reduces SCI by increasing IGF-I production through sensory neuron stimulation. We examined this possibility in rats subjected to compression-trauma-induced SCI. Limaprost increased the CGRP release from dorsal root ganglion (DRG) neurons isolated from rats, and this increase was reversed by pretreatment with the EP4 receptor antagonist ONO-AE3-208. Spinal cord tissue levels of CGRP and IGF-I were increased after the induction of SCI, peaking at 2 h postinduction. The intravenous administration of limaprost enhanced increases of spinal cord tissue levels of CGRP, IGF-I, and IGF-I mRNA at 2 h after the induction of SCI. Increases of spinal cord tissue levels of tumor necrosis factor, caspase-3, myeloperoxidase, and the number of apoptotic nerve cells were inhibited by the administration of limaprost. Motor disturbances of hind legs in animals subjected to the compression-trauma-induced SCI were reduced by the administration of limaprost. These effects of limaprost were reversed completely by pretreatment with a specific transient receptor potential vanilloid 1 inhibitor SB366791 and by sensory denervation. These observations strongly suggest that limaprost may increase the IGF-I production by stimulating sensory neurons in the spinal cord, thereby ameliorating compression-trauma-induced SCI through attenuation of inflammatory responses.

Topics: Alprostadil; Anilides; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Caspase 3; Cells, Cultured; Cinnamates; Denervation; Disease Models, Animal; Drug Therapy, Combination; Ganglia, Spinal; Gene Expression; Insulin-Like Growth Factor I; Male; Movement; Neurons; Rats; Rats, Wistar; RNA, Messenger; Sensory System Agents; Specific Pathogen-Free Organisms; Spinal Cord; Spinal Cord Injuries; Vasodilator Agents

We previously demonstrated that activation of sensory neurons increases endothelial prostaglandin I(2) (PGI(2)) production by releasing calcitonin gene-related peptide (CGRP). Since PGI(2) 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(1alpha) levels. SB366791, CGRP (8-37) and indomethacin (IM) enhanced increases in spinal cord tissue TNF levels at 2h 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(1alpha). These observations strongly suggest that activation of sensory neurons might ameliorate compression trauma-induced SCI, inhibiting TNF production through enhancement of endothelial PGI(2) 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.

Topics: 6-Ketoprostaglandin F1 alpha; Anilides; Animals; Calcitonin Gene-Related Peptide; Cinnamates; Cyclooxygenase Inhibitors; Epoprostenol; Gene Expression Regulation; Indomethacin; Male; Motor Activity; Neurons, Afferent; Peptide Fragments; Rats; Rats, Wistar; Spinal Cord Injuries; Tumor Necrosis Factors