Secondary damage and neuroinflammation in the spinal dorsal horn mediate post-thalamic hemorrhagic stroke pain hypersensitivity: SDF1-CXCR4 signaling mediation

Abstract

Central post-stroke pain (CPSP) is an intractable neuropathic pain, which can be caused by primary lesion of central somatosensory system. It is also a common sequelae of the thalamic hemorrhagic stroke (THS). So far, the underlying mechanisms of CPSP remain largely unknown. Our previous studies have demonstrated that SDF1-CXCR4 signaling in the hemorrhagic region contributes to the maintenance of the THS pain hypersensitivity via mediation of the thalamic neuroinflammation. But whether the spinal dorsal horn, an initial point of spinothalamic tract (STT), suffers from retrograde axonal degeneration from the THS region is still unknown. In this study, neuronal degeneration and loss in the spinal dorsal horn were detected 7 days after the THS caused by intra-thalamic collagenase (ITC) injection by immunohistochemistry, TUNEL staining, electron microscopy, and extracellular multi-electrode array (MEA) recordings, suggesting the occurrence of secondary apoptosis and death of the STT projecting neuronal cell bodies following primary THS via retrograde axonal degeneration. This retrograde degeneration was accompanied by secondary neuroinflammation characterized by an activation of microglial and astrocytic cells and upregulation of SDF1-CXCR4 signaling in the spinal dorsal horn. As a consequence, central sensitization was detected by extracellular MEA recordings of the spinal dorsal horn neurons, characterized by hyperexcitability of both wide dynamic range and nociceptive specific neurons to suprathreshold mechanical stimuli. Finally, it was shown that suppression of spinal neuroinflammation by intrathecal administration of inhibitors of microglia (minocycline) and astrocytes (fluorocitrate) and antagonist of CXCR4 (AMD3100) could block the increase in expression levels of Iba-1, GFAP, SDF1, and CXCR4 proteins in the dorsal spinal cord and ameliorate the THS-induced bilateral mechanical pain hypersensitivity, implicating that, besides the primary damage at the thalamus, spinal secondary damage and neuroinflammation also play the important roles in maintaining the central post-THS pain hypersensitivity. In conclusion, secondary neuronal death and neuroinflammation in the spinal dorsal horn can be induced by primary thalamic neural damage via retrograde axonal degeneration process. SDF1-CXCR4 signaling is involved in the mediation of secondary spinal neuroinflammation and THS pain hypersensitivity. This finding would provide a new therapeutic target for treatment of CPSP at the spinal level.

Role of Sensory Pathway Injury in Central Post-Stroke Pain: A Narrative Review of Its Pathogenetic Mechanism

“…Although there is no direct clinical evidence suggesting secondary injury to the spinal cord in patients with CPSP, animal studies using rats and monkeys have demonstrated that stroke can cause secondary nonischemic injury not only at the infarction site but also in the distal spinal cord. 15 , 16 Secondary spinal cord injury was mainly characterized by detectable neuronal degeneration and loss in the dorsal horn of the spinal cord and associated neuroinflammatory changes. 16 The inflammatory response in the spinal cord was mainly associated with stromal cell-derived factor 1 (SDF-1), high-mobility group box-1 (HMGB1), and NOS signaling.…”

“… 15 , 16 Secondary spinal cord injury was mainly characterized by detectable neuronal degeneration and loss in the dorsal horn of the spinal cord and associated neuroinflammatory changes. 16 The inflammatory response in the spinal cord was mainly associated with stromal cell-derived factor 1 (SDF-1), high-mobility group box-1 (HMGB1), and NOS signaling. After a stroke, the glial cells in the spinal cord are activated.…”

Xenon ameliorates chronic post-surgical pain by regulating mitophagy in microglia and rats mediated by PINK1/Parkin pathway

“…Notably, an increasing number of investigators have devoted to microglia and pain research in the past 10 years ( Han et al, 2021 ; Yang et al, 2017 ; Zhang et al, 2018 ; Liao et al, 2020 ). Liang et al (2022) demonstrated that microglia in spinal dorsal horn tissue were significantly activated after CPSP, and inhibiting the activation of microglia was one of the effective methods for the treatment of CPSP. Our results were consistent with that, and Xe inhalation treatment effectively inhibited microglial activation, but the specific mechanism of microglia function regulation during CPSP was still unclear.…”

Gabapentin improves neuropathic pain in Minamata disease model rats

“…Neuropathic pain from nerve injuries other than diabetes and herpes is likely due to either peripheral nervespinal cord injury or blockage of the descending inhibitory pathways by thalamic injury, etc. [9][10][11][12]; both types of nerve injury are thought to cause neuropathic pain by stimulating the somatosensory cortex through neuronal activation in the dorsal horn of the spinal cord [13][14][15]. In my previous studies, a model of neuropathic pain with MeHg exposure has been established using rats [16,17].…”