Abstract
Abnormal serotonin 2C receptor (5HTR2C) alternative splicing and RNA editing are involved in the etiology of pain disorders. Functional 5HTR2C can only be generated when alternative exon Vb is included within the mRNA; the small nucleolar RNA RBII-52 is complementary to exon Vb and promotes its inclusion. The expression of HBII-52 (the human equivalent of RBII-52) is reduced in Prader-Willi syndrome, patients of which have a high pain threshold. Here, we measured the pain threshold in a rat model of orofacial neuropathic pain and related it to the expression levels of wild-type and variant 5HTR2C and RBII-52. We generated an infraorbital nerve loose ligation model of neuropathic pain in rats and measured the pain threshold of the animals using mechanical stimulation with von Frey filaments. We then sacrificed the animals and examined the RNA levels of 5HTR2C and RBII-52 in the cervical spinal cord by real-time PCR. On post-injury day 28, pain threshold values in injured rats were significantly lower than in sham-operated or na?ve animals. The levels of total and exon Vb-skipped 5HTR2C mRNA were significantly lower in injured rats than in that sham-operated or na?ve rats, and the ratio of exon Vb-skipped 5HTR2C to total 5HTR2C was significantly higher. There were no significant differences in RBII-52 expression among the groups. Our data suggest that neuropathic pain induces serotonergic dysfunction mediated by 5HTR2C alternative splicing. 5HTR2C might be subject to complicated and fine regulation both by RNA editing and by alternative splicing.
Highlights
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused in the majority of cases by deletion of the paternally derived chromosome 15 or maternal uniparental disomy of chromosome 15 [1,2]
Pain thresholds in the territory affected by infraorbital nerve loose ligation (ION-LL) were significantly lower for injured rats than for sham-operated or naïve animals (Figure 2(a))
Using a model of orofacial neuropathic pain, we investigated the relationship between pain sensitivity and alternative splicing of 5HTR2C pre-mRNA or expression of the snoRNA RBII-52
Summary
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused in the majority of cases by deletion of the paternally derived chromosome 15 (del15q11-13) or maternal uniparental disomy of chromosome 15 [1,2]. Five adenosines (present at editing sites A-E Figure 1(a)), located within a sequence encoding the putative second intracellular domain of 5HTR2C, can be converted to inosines This editing can alter the coding potential of three triplet codons and permits the generation of 24 different receptor isoforms ranging from the unedited Ile156Asn158Ile160 (INI) to the fully edited Val156Gly158Val160 (VGV). Receptors resulting from fully edited transcripts, and from partially edited transcripts that include editing of at least the E site or of both the E and C sites, differ from non-edited receptors by their lower affinity for serotonin and, their reduced ability to activate G-protein [9,10,11] Such differences in G-protein coupling efficiency associated with RNA editing can be accounted for by differences in the conformational properties of the second intracellular loop in 5HTR2C [12].
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