Alternative Splicing of Nrcam Gene in Dorsal Root Ganglion Contributes to Neuropathic Pain

NrCAM, a neuronal cell adhesion molecule in the L1 family of the immunoglobulin superfamily, is subjected to extensively alternative splicing and involved in neural development and some disorders. The aim of this study was to explore the role of Nrcam mRNA alternative splicing in neuropathic pain. A next generation RNA sequencing analysis of dorsal root ganglions (DRGs) showed the differential expression of two splicing variants of Nrcam, Nrcam⁺¹⁰ and Nrcam⁻¹⁰, in the injured DRG after the fourth lumbar spinal nerve ligation (SNL) in mice. SNL increased the exon 10 insertion, resulting in an increase in the amount of Nrcam⁺¹⁰ and a corresponding decrease in the level of Nrcam⁻¹⁰ in the injured DRG. An antisense oligonucleotide (ASO) that specifically targeted exon 10 of Nrcam gene (Nrcam ASO) repressed RNA expression of Nrcam⁺¹⁰ and increased RNA expression of Nrcam⁻¹⁰ in in vitro DRG cell culture. Either DRG microinjection or intrathecal injection of Nrcam ASO attenuated SNL-induced the development of mechanical allodynia, thermal hyperalgesia, or cold allodynia. Nrcam ASO also relieved SNL- or chronic compression of DRG (CCD)-induced the maintenance of pain hypersensitivities in male and female mice. Perspective: We conclude that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis. Targeting Nrcam alternative splicing via the antisense oligonucleotides may be a new potential avenue in neuropathic pain management.