59: The Alteration of Proprioception & Its Roles of Modulation in Painful Diabetic Neuropathy

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Electrophysiology, Assessment and Measurement of Pain/Nociception, Behavioral studies

Background and Aims: Effective treatments for neuropathic pain remain an unmet medical need in diabetic neuropathy. However, the mechanisms in peripheral sensitization of painful diabetic neuropathy are largely unclear. According to previous research, the characteristics of rate-dependent depression of the Hoffmann reflex involved in proprioceptive function are good biomarkers for painful diabetic neuropathy in both animal and human studies[1-2]. Deletion of proprioceptive (parvalbumin-positive) neurons in DRG leads to enhanced nociceptor activity and increases acute thermal and mechanical pain behaviors[3].
Aims: to identify what are the roles of proprioceptors in PDN and to assess proprioceptor morphological change or degeneration after diabetic induction

Methods: A mouse model of streptozotocin (STZ)-induced diabetic neuropathy at the age of 14-20 weeks was examined for pain hypersensitivity. The von Frey test, muscle withdrawal threshold, neurometer current perception threshold, balance beam, and grid walking test were performed. The soleus muscles were collected for immunofluorescence staining of sensory nerve terminals in muscle spindles. The severity of degeneration in muscle spindles was evaluated in four categories[4]. We evaluated the number of muscle spindles, the density of sensory nerve terminals[5] in muscle spindles, and the modified variation index (difference between maximal and minimal inter-rotational distance [IRD] and axonal width [AW][6-7]) as indicators.

Results: Mechanical hyperalgesia (both von Frey and muscle withdrawal threshold) was observed 4 weeks after STZ injection in diabetic mice. The thresholds for 2000 Hz stimulation increased significantly 7 weeks after STZ induction. Thresholds for 5 Hz stimulation were transiently reduced only in the 7th week, whereas thresholds for 250 Hz stimulation remained unchanged. There is no difference in the total number of muscle spindles, density of sensory nerve terminals in each muscle spindle, IRD, and AW. However, more severe degeneration of muscle spindle structure and a higher modified variation index in IRD were observed in diabetic mice.

Conclusions: muscle spindle degeneration and reduced Aß fiber sensitivity in painful diabetic mice suggest that proprioceptor and large-fiber neuropathy may play important roles in diabetes-induced pain chronicity.

References: 1. Marshall, A.G., et al., Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy. Diabetes, 2017. 66(5): p. 1380-1390.
2. Worthington, A., et al., Spinal Inhibitory Dysfunction in Patients With Painful or Painless Diabetic Neuropathy. Diabetes Care, 2021. 44(8): p. 1835-1841.
3. Fuller, A.M., et al., Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons. Brain, 2023. 146(10): p. 4033-4039.
4. Watkins, B., et al., Degeneration of muscle spindles in a murine model of Pompe disease. Sci Rep, 2023. 13(1): p. 6555.
5. Gerwin, L., et al., Impaired muscle spindle function in murine models of muscular dystrophy. The Journal of Physiology, 2020. 598(8): p. 1591-1609.
6. Muller, K.A., et al., Abnormal muscle spindle innervation and large-fiber neuropathy in diabetic mice. Diabetes, 2008. 57(6): p. 1693-701.
7. Cao, R., et al., Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals. Nat Commun, 2023. 14(1): p. 744.

Presenting Author: Yi-Chen Lin
Submitting Author: Yi-Chen Lin

Senior Author: Chih-Cheng Chen

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Cheng-Han Lee: Ph.D. - Institute of Biomedical Sciences, Academia Sinica and Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan
• Yi-Fan Chen: Ph.D. - The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, and Academia Sinica
• Chih-Cheng Chen: Ph.D. - Institute of Biomedical Sciences, Academia Sinica and Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan