Document Type : Original Research Articles
Authors
1
Department of Surgery, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
2
Department of Anatomical Science, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
3
Department of Pharmacology and Toxicology, Sapienza university, Rome, Italy.
4
Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
5
Department of Pathology, School of Medicine, Lorestan University of Medical Science, Khorramabad, Iran.
6
Department of Biostatistics and Epidemiology, School of Health and Nutrition, Lorestan University of Medical Sciences, Khorramabad, Iran.
7
Department of Anesthesiology, Lorestan University of Medical Sciences, Khorramabad, Iran.
Abstract
Background: Duloxetine is widely prescribed for the management of neuropathic pain; however, the contribution of spinal serotonergic signaling to its neuroprotective effects following peripheral nerve injury remains incompletely understood. This study investigated the role of spinal serotonin in duloxetine-mediated functional and biochemical recovery using a chronic constriction injury (CCI) model in rats.
Methods: Forty adult male Wistar rats were randomly assigned to five groups (n = 8 each): sham-operated, CCI, CCI + duloxetine (10 mg/kg, i.p.), CCI + p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), and CCI + duloxetine + PCPA. Electrophysiological function (MNCV and SNCV), spinal serotonin (5-HT), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and sciatic nerve histopathology were evaluated.
Results: CCI significantly impaired motor and sensory nerve conduction, reduced spinal serotonin levels, and increased spinal BDNF and NfL concentrations, accompanied by marked perineural inflammatory cell infiltration. Duloxetine significantly restored MNCV and SNCV, increased spinal serotonin levels, reduced BDNF and NfL concentrations, and attenuated histopathological inflammation. Pharmacological depletion of serotonin with PCPA substantially diminished the beneficial effects of duloxetine on electrophysiological, biochemical, and histopathological outcomes, although partial protection was retained.
Conclusion: These findings demonstrate that spinal serotonergic signaling plays a pivotal role in the neuroprotective effects of duloxetine following peripheral nerve injury. The concurrent modulation of BDNF and NfL further suggests their potential utility as complementary biomarkers of neuronal plasticity and axonal injury during neuropathic pain progression and recovery. Targeting spinal serotonergic pathways may represent a promising therapeutic strategy for enhancing functional recovery after peripheral nerve injury.
Mechanistic and Translational Relevance: Our findings identify spinal serotonergic signaling as a principal mechanism underlying duloxetine-mediated neuroprotection after peripheral nerve injury and suggest that BDNF and neurofilament light chain may serve as complementary biomarkers for evaluating treatment response and disease progression in neuropathic pain.
Graphical Abstract
Keywords
Subjects
