Transcriptional, Clinical and Somatosensory Profile of Patients with C1-2 Atlanto-Axial Pain

Background & Aims

There is no knowledge of the molecular mechanisms driving human neck pain. Atlanto-axial (C1-2) fusion surgery provides the opportunity to examine the transcriptomics profile of the dorsal root ganglion (DRG) that is resected as part of the surgical procedure in patients with acute and chronic C1-2 pain. In this study, we compared the transcriptome of patients with acute and chronic C1-2 pain and examined the clinical and somatosensory phenotypes. The aims were to identify transcriptional changes that could be associated with persistence of pain and identify phenotyping measures with high potential to be associated with transcriptional changes in future analyses with a larger patient cohort.

Methods

Twenty patients with acute (<3 months) and 21 with chronic (?3 months) neck pain undergoing C1-2 fusion were enrolled and completed prior to surgery quantitative sensory testing (QST) and self-report measures of pain-related outcomes, opioid use, and psychosocial characteristics (results not reported). DRGs could be recovered for bulk RNA sequencing from 13 patients, in 4 of them bilaterally, for a total of 17 DRGs: 10 from patients with acute pain and 7 from patients with chronic pain. Clinical and somatosensory characteristics were analyzed by descriptive statistics (median, interquartile range, percentage). Those measures displaying elevated values and high variability were deemed to be appropriate for future correlation analyses with RNA sequencing.

Results

Duration of pain in the patients with acute and chronic pain was 2.0 (1.0-5.5) and 365.0 days (213.0-730.0), respectively. Pain intensity (0-10 numerical rating scale) was 7.0 (4.0-9.0) and 4.5 (4.0-6.0). Twenty and 23.8% reported using opioids in the past 6 months. Neck Disability Index scores (short form, 0-24 scale) were 17.5 (13.0-20.0) and 12.0 (6.0-19.0). QST revealed pain with brush in 1 patient, with light pressure in 4, with cold in 5, and prolonged pain after a series of 10 pinprick stimulations (reflecting pain facilitation) in 7. Using DESeq2, 66 genes were found to be significantly different in DRGs from patients with chronic pain, compared to patients with acute pain; 33 genes were significantly increased in patients with chronic pain. GFRA3 and ADGRB3 were among the genes found to be significantly more highly expressed. These genes were previously found to be associated with osteoarthritis pain and cell-to-cell communication.

Conclusions

Significant differences were found between the patients with chronic versus acute neck pain in the transcriptomes, indicating potential changes to neurons or other cell types in the C2 DRG of patients with chronic neck pain. We plan future adequately powered studies to examine associations between DRG transcriptomic changes and levels of pain and disability. Neuropathic pain features as detected by QST were present in a subset of patients who may have C2 neuropathy in addition to musculoskeletal pain. In future studies, we will examine this subset for gene expressions that could distinguish them from patients with predominantly musculoskeletal pain features.