Serotonin 2C receptor alternative splicing in a spinal cord injury model

Spinal cord injury can have debilitating consequences, commonly resulting in motor dysfunction below the lesion site and the development of chronic pain syndromes. The serotonin pathway is important for inhibiting noxious stimuli and facilitating motor function after spinal cord injury. The serotonin 2C receptor (5HTR2C) has several characteristic features, and is regulated by the amount of serotonin 2C receptor as well as RNA editing and alternative splicing. In this study, we used a rat model of spinal contusion injury to investigate the relationship between the pain threshold and 5HTR2C alternative splicing. The pain threshold was assessed using mechanical stimulation with von Frey filaments. We then used real-time PCR to examine the RNA levels of 5HTR2C in three sections of the spinal cord: the rostral, injury-core, and caudal positions. On postoperative day 12, the pain threshold in injured rats was significantly reduced compared with sham-operated and naïve rats. The total 5HTR2C levels were significantly lower in injured rats than in naïve rats at all positions, and significantly lower in injured rats compared with sham-operated rats at injury-core and caudal positions. The ratio of exon Vb-skipped nonfunctional 5HTR2C mRNA to total 5HTR2C was significantly higher in injured rats compared with naïve rats at the injury-core and caudal positions, and significantly higher in injured rats compared with sham-operated rats at the caudal position. These results indicate that spinal contusion injury, which causes neuropathic pain, induces serotonergic dysfunction. This dysfunction appears to be mediated by decreased 5HTR2C mRNA expression, and alternative splicing. These results confirm the importance of considering splice variants when examining 5HTR2C.