Background & Aims

Traumatic nerve injury resulting from traumatic limb loss or amputation, in some cases, leads to the formation of painful neuromas. Symptomatic neuromas cause intractable spontaneous and evoked pain which may result in a significant reduction in the quality of life. Currently available therapies, including pharmacological agents, and surgical interventions such as targeted muscle reinnervation (TMR), and regenerative peripheral nerve interfaces (RPNI), have shown a degree of success, but are not effective in all patients. Novel therapies to treat symptomatic neuromas are therefore an unmet medical need (1). Our aim is to analyze human symptomatic neuromas to identify potential pain-specific signaling pathways which can serve as starting points to identify targets for novel therapies.

Methods

We collected human symptomatic neuromas with varying numeric rating scale (NRS, 0-10) pain scores from patients undergoing TMR or RPNI. These specimens were analyzed by 18-plex TMT mass spectrometry and compared to normal nerves from patients, or postmortem nerve samples. From a total of 31 neuromas and their proximal segment, from 15 patients, and 7 control nerves, we identified proteins that were selectively up- or downregulated in high pain neuromas when compared to low pain neuromas. These proteins were then assembled into signaling pathways, specifically enriched in high pain neuromas.

Results

We compared protein expression in neuromas with NRS values between 9-10 to those in neuromas with values 2-3 and identified 433 proteins that were differentially expressed in high pain neuromas. These proteins represent key regulatory pathways including, calcium signaling, SNARE, PKA, RHOA, Rho family GTPase, and CXCR4 signaling. Several myosin heavy and light chain proteins, and actin cytoskeleton related proteins also showed altered expression. Specific sets of ion channels were expressed in a pain score-dependent manner. Similar patterns were also observed in other functional protein families, including kinases and transcription factors.

Conclusions

We have identified several proteins and signaling pathways that are up- or downregulated in high pain neuromas when compared to those with low pain.

References

1. Biology and pathophysiology of symptomatic neuromas. CD Hwang, YAJ Hoftiezer, FV Raasveld, B Gomez-Eslava, EPA van der Heijden, S Jayakar, BJ Black, BR Johnston, BJ Wainger, W Renthal, CJ Woolf and KR Eberlin. Pain 2023 Oct 17. doi: 10.1097/j.pain.0000000000003055 (PMID: 37851396).

Presenting Author

Selwyn S. Jayakar

Poster Authors

Selwyn Jayakar

PhD

Boston Children's Hospital

Lead Author

E-mail

Aakanksha Jain

Boston Children’s Hospital

Lead Author

E-mail

Barbara Gomez-Eslava (MD

MS)

Boston Children’s Hospital and Department of Orthopedics surgery, Massachusetts General Hospital

Lead Author

E-mail

Floris V. Raasveld (MD)

Department of Orthopedics surgery, Massachusetts General Hospital

Lead Author

E-mail

William R. Renthal (MD PhD)

Department of Neurology , Brigham and Women's Hospital and Harvard Medical School

Lead Author

E-mail

Kyle R. Eberlin (MD)

Department of General Surgery, Massachusetts General Hospital, Harvard University

Lead Author

E-mail

Clifford Woolf

MB

Boston Childrens Hospital

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral