Resident glial cell activation in response to perispinal inflammation leads to acute changes in nociceptive sensitivity: Implications for the generation of neuropathic pain

Abstract

Injury or disease affecting the spinal cord is often accompanied by abnormal, chronic pain. Recent estimates suggest that approximately 60% of patients with multiple sclerosis are affected by significant changes in pain sensitivity or experience ongoing neuropathic pain of unknown etiology. Chronic pain is also a significant concern after direct spinal cord trauma. Inflammatory events and the changes in astrocyte and microglia reactivity at the spinal level in response to injury or disease are now recognized as important processes that can initiate pain hypersensitivity. Changes in the structural integrity or permeability of the blood-brain barrier/blood-spinal cord barrier (BBB/BSCB) can facilitate the inflammatory events that result in these abnormal pain states. It remains unclear, however, whether chronic pain in these disorders is dependent on the influx of peripheral leukocytes or whether changes in the reactivity of resident glial cells within the central nervous system alone are sufficient. To address this question, we generated a model of perispinal inflammation that resulted in significant changes in the reactivity of resident astrocytes and microglia within the spinal cord but maintained the integrity of the BSCB. A number of similar changes at the behavioural and cellular level occur in this model that mimic the responses seen in animal models of multiple sclerosis or spinal cord injury (SCI). However, these changes are short lived and resolve over the course of a 2-week observation period. Our findings suggest that the chronicity of pain after injury or disease in the nervous system is dependent on the integrity of the BBB/BSCB.

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

“…In the event of peripheral injury, the enhanced or abnormal nerve input is likely the most convenient and efficient way to alert simultaneously central neurons and glia, although infiltration of peripheral immune cells and immune mediators through a compromised blood-brain barrier/blood-spinal cord barrier may also play a role [50]. Injury-triggered signaling cascade engage reciprocal activation between presynaptic terminals, postsynaptic neurons, microglia and astrocytes, leading to long-lasting persistent pain.…”

“…However, this phenomenon is not universal. In chemotherapy-induced peripheral neuropathic pain, glial activation is only seen for astrocytes, but not microglia [49, also see 50]. In a female bone cancer pain model, reactive astrocytosis occurred earlier than microglial activation and microglia did not appear to be involved in the initiation, but was critical in the maintenance, of persistent pain hypersensitivity [28*].…”

Psychological Stress as a Modulator of Functional Recovery Following Spinal Cord Injury

“…Indeed, chronic inflammation resulting from the injury leads to a wide range of clinical conditions such as decreased pulmonary function (100), neuropathic pain (101–103), compromised physical recovery (104, 105), and exacerbated depressive symptoms (106). Moreover, SCI-induced chronic inflammation can result in infections and cardiovascular diseases, two leading causes of death after SCI (107).…”

Toll-Like Receptors 2, -3 and -4 Prime Microglia but not Astrocytes Across Central Nervous System Regions for ATP-Dependent Interleukin-1β Release

“…However, prolonged, inflammation overrides the bounds of physiological control and eventually becomes destructive1. Inflammation is increasingly seen as a key feature in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and perhaps even neuropsychiatric illness2345. Further, chronic stress may induce transient spinal neuroinflammation, triggering long-lasting anxiety-induced hyperalgesia6.…”