Age-Dependent Neuropathic Pain Response in Duchenne Muscular Dystrophy

Topic:

Translational Research

Poster Number: 262 T

Author(s):

Alex Youn, AB, University of California, San Francisco, Leila Hennessy, BA, University of California, San Francisco, Department of Orthopaedic Surgery, Ashley Fang, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Hiroyori Fusagawa, MD, University of California, San Francisco, Department of Orthopaedic Surgery, Taylor Walker, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Eddie Garcia, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Miguel Lizarraga, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Hanzhi Zhang, BS, University of California, Davis, Aboubacar Wague, AB, University of California, San Francisco, Department of Orthopaedic Surgery, Justin Lau, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Sankalp Sharma, BS, University of California, San Francisco, Department of Orthopaedic Surgery, Brian Feeley, MD, University of California, San Francisco, Department of Orthopaedic Surgery, Xuhui Liu, MD, University of California, San Francisco, Department of Orthopaedic Surgery

Background
Chronic pain is a common and debilitating feature of Duchenne muscular dystrophy (DMD), yet its classification and underlying mechanisms remain poorly defined. In this study, we used novel behavioral assays to characterize pain in a DMD mouse model and examined the emergence of neuropathic pain over disease progression through differential responses to various analgesics.
Methods
Adult (9-month-old; N=7) and aged (18-month-old; N=7) male D2-mdx mice were used, along with adult wildtype male DBA/2J controls (N=4). Isometric hindlimb torque was assessed via neuromuscular electrical stimulation. Saline (vehicle control), ketorolac (10 mg/kg), morphine (10 mg/kg), or gabapentin (30 mg/kg), a drug clinically used for treating neuropathic pain were administered to mice and pain-related behaviors were evaluated using Blackbox—for spontaneous pain evaluation—and a hindlimb grip strength assay—for evoked pain evaluation.
Results
As expected, hindlimb maximum isometric torque was significantly less in DMD adult and aged mice, compared to DBA2/J control, respectively: 11.50mN-m vs. 4.16mN-m vs. 3.45mN-m, p<.001. For pain assays, baseline measurements were established after vehicle control administration of saline. At baseline, Blackbox revealed a decreased weightbearing ratio (forelimbs/hindlimbs) in the DMD adult and aged groups, compared to DBA2/J control: 0.46 vs. 0.33, p=0.08; 0.46 vs. 0.29, p=0.02. In the adult DMD group, morphine and gabapentin both significantly improved weightbearing, compared to saline control: 0.33 vs. 0.51, p=0.002; 0.33 vs. 0.52, p=0.001. Morphine, ketorolac, and gabapentin all showed efficacy in the aged DMD group: 0.29 vs. 0.53, p=0.002; 0.29 vs. 0.43, p=0.02; 0.29 vs. 0.46, p=0.005. Evoked pain grip strength—normalized to body weight—revealed analgesic improvement only with morphine in the DMD adult group at baseline: 3.80 vs. 5.16, p=0.002; in contrast, morphine and gabapentin improved grip strength in the DMD aged group: 1.68 vs. 3.62, p<.001; 1.68 vs. 2.72, p=0.02. Notably, none of those drugs had any effects on DBA2/J control mice. Conclusion In this study, we employed novel behavioral assays to characterize age-related pain and the response to analgesic in DMD mice. Gabapentin produced a significant analgesic effect, supporting a role for neuropathic mechanisms in the development of chronic pain. These findings identify neuropathic pathways as a potential therapeutic target for the treatment of DMD-related pain.