Summary

This study investigates the impact of chronic rotator cuff tears and fatty infiltration on neuropathic pain in a mouse model, finding that gabapentin significantly improves pain-related metrics and functional outcomes, suggesting its potential as an effective treatment for rotator cuff tear associated pain.

Abstract

Disclosure: All authors have no disclosures

Introduction

Chronic rotator cuff tear (RCT) presents a significant pain burden leading to substantial functional impairment. Despite advances in treatment, pain management remains an area lacking in significant improvement. Up to 20% of patients are on opioids for RCT-related pain and continue use even after surgery. Additionally, fatty infiltration (FI) is believed to contribute to RCT-related pain. Thus, understanding underlying pain pathways associated with chronic RCTs is essential for developing effective therapeutic strategies. We hypothesize that RCTs and FI cause neuropathic pain that can be alleviated by gabapentin.

Methods

Dorsal root ganglion (DRG) were harvested four weeks post-injury from adult mice (n=6/group) and stained for ATF3, an injury marker for sensory neurons, across three conditions: naive, complete tendon transection (TT) of right rotator cuff, and TT with transected suprascapular nerve (TT+DN). To assess the effects of different medications on RCT pain, separate adult mice underwent TT+DN procedure (n=7). After 12 weeks, they were treated with intraperitoneal injection of gabapentin (30mg/kg), buprenorphine (3.25mg/kg), or ketorolac (10mg/kg). To test the impact of FI on pain, mice (n=6) received glycerol injection into the right supraspinatus and were treated with gabapentin. Function and pain metrics were recorded via BlackBox, a novel AI-based gait imaging system, and analyzed with DeepLabCut, using next-generation machine-learning algorithms.

Results

Mouse DRGs analysis revealed increased ATF3 expression in the TT and TT+DN groups. In the follow-up experiment with 7 mice that underwent TT+DN, we observed a significant decline in right forepaw weightbearing (p =0.002) and stride length (p =0.021) at week 12 compared to baseline. Subsequent gabapentin treatment post TT+DN led to significant improvements in weightbearing (p =0.021) and stride length similar to baseline levels. In contrast, buprenorphine treatment led to significant increase only in right forepaw stride length (p =0.007), but did not affect weightbearing, while ketorolac did not lead to any improvement in pain. When assessing the impact of FI following glycerol injection, mice exhibited a decrease in right forepaw weightbearing (p = 0.027) and stride length (p = 0.003) after four weeks. Gabapentin treatment in mice with FI significantly improved weightbearing (p<0.001) and stride length (p<0.001), bring them back to levels comparable to baseline.

Discussion

Our study demonstrates the correlation between RCT and neuropathic pain, as strongly indicated by the upregulation of ATF3 in the DRG. Similar functional responses to gabapentin between glycerol-injected and rotator cuff injury mice show a clear relationship between FI and pain after RCT. While we did see improvement in stride length with the administration of buprenorphine, this is likely confounded by the opioid-induced euphoric effects. However, the improved weightbearing and stride length outcomes with gabapentin clearly indicates its effectiveness for pain relief in this model. Altogether, these findings suggest that RCTs and FI can induce a neuropathic-like response leading to neural sensitization and chronic pain. Gabapentin, given its positive effects on functional outcomes, can serve as a potential therapeutic option for managing RCT associated pain.