Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Ru-Rong Ji, Ph.D.; Andrea Nackley, Ph.D.; Yul Huh, B.S., M.S.; Niccolò Terrando, Ph.D.; William Maixner, D.D.S., Ph.D.

Disclosures

Anesthesiology. 2018;129(2):343-366. 

In This Article

Neuroinflammation is Associated With Various Insults That Evoke Painful Sensations

A PubMed Search on September 30, 2017, using the keywords "neuroinflammation and pain" reveals a substantial increase in the number of publications in the last 10 yr, jumping from 12 in 2008 to 150 in 2016. There is also a similar increase in the number of "microglia and pain" publications over the same period of time (Figure 1). Neuroinflammation is a localized form of inflammation that occurs in the peripheral nervous system (including peripheral nerves and ganglia) and central nervous system (CNS, including the spinal cord and brain). Characteristic features of neuroinflammation are (1) vasculature changes that result in increased vascular permeability, (2) infiltration of leukocytes, (3) activation of glial cells, and (4) production of inflammatory mediators including cytokines and chemokines (Table 1). Although the CNS is normally protected by the blood–brain barrier, increased permeability of the blood–brain barrier is an important feature of neuroinflammation, leading to increased leukocyte invasion to the CNS. It is becoming increasingly appreciated that neuroinflammation is a major cause of several neurologic and neuropsychiatric diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, depression, bipolar disorder, and autism, as well as postoperative complications like neurocognitive disorders (e.g., delirium).[39–41]

Figure 1.

A PubMed Search on September 30, 2017, shows the number of publications on "neuroinflammation and pain" and "microglia and pain" in the last 10 yr. The numbers at the bottom show the total number of publications in PubMed.

It is noteworthy that neuroinflammation is associated with various painful insults and pathologies (Figure 2),[39] including but not limited to trauma such as traumatic brain injury, stroke, spinal cord injury, major surgeries including both cardiac and noncardiac procedures (e.g., amputation, thoracotomy, and mastectomy), and autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Other painful conditions, such as osteoarthritis, peripheral cancers (e.g., bone cancers), and viral infections (e.g., shingles/herpes zoster by varicella-zoster virus) also induce neuroinflammation in the peripheral nervous system and CNS.[27,42] Furthermore, painful neuroinflammation (e.g., glial activation) can be induced by chemotherapy drugs such as paclitaxel, anti–human immunodeficiency virus (HIV) treatment, and chronic opioid treatment.[43–46] Immune therapies are increasingly appreciated for treating cancers by boosting the activities of immune cells such as T cells and other immune cells.[47,48] These therapies also change pain sensitivity by modulating inflammation and neuroinflammation. Deficiency of the negative immune regulator B7-H1, also called programmed death ligand 1, enhances inflammation and neuropathic pain after chronic constriction injury of mouse sciatic nerve.[49] Notably, PD-1, the receptor for programmed death ligand 1, is not only present in immune cells but also expressed in nociceptor neurons of mouse and human dorsal root ganglia. Furthermore, programmed death ligand 1 can potently suppress nociceptor activities via regulating sodium and potassium ion channels in mouse and human nociceptors.[50] Many of these painful insults involve brain and spinal trauma and nerve injury resulting from major surgeries, drug treatments, and diabetic neuropathy in neuropathic pain conditions. Neurogenic inflammation of the skin and joints is not only induced by activation of peripheral C-fibers but may also be triggered by the dorsal root reflex in the spinal cord after either orthograde or anterograde neuronal activation, which permits peripheral inflammatory responses to occur via local insults or by CNS "top-down" activation of primary afferents.[51,52] Furthermore, neuroinflammation in the spinal cord and brain can also be neurogenic after neuronal activation in the CNS.[53]

Figure 2.

Neuroinflammation is associated with various insults that evoke painful sensations. These insults include but are not limited to trauma, major surgeries, drug treatments, autoimmune disease conditions, and other painful insults and tissue damage. Some of these insults such as major surgeries (breast surgery, amputation, thoracotomy), chemotherapy, and antiviral treatment will cause nerve injury, as highlighted in red. Others will cause immune activation (highlighted in purple) and tissue injury (highlighted in light blue). Neuroinflammation results in several adverse effects, such as chronic pain and neurodegenerative diseases including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), and stroke. Neuroinflammation is also associated with chronic overlapping pain conditions. After priming of the nociceptive circuit by previous injury, stress, or existing genomic, environmental, and psychologic factors, acute insult may cause transition from acute pain to chronic pain. CNS = central nervous system.

Although it is widely believed that chronic pain persists after the observable signs and symptoms of inflammation have resolved,[54] our understanding of neuroinflammation is changing this perspective. We now recognize that neuroinflammation is associated with and perhaps mediates the persistence and chronification of human pain conditions. Given the close proximity to pain neurocircuits, mediators of neuroinflammation are highly effective in modulating pain sensitivity. In particular, inflammation and neuroinflammation are differentially correlated with chronic pain. For example, HIV-infected patients with neuropathic pain show permanent neuroinflammation in the spinal cord.[55] Patients with fibromyalgia, a chronic widespread musculoskeletal pain condition,[56] also exhibit small fiber neuropathy together with chronic neuroinflammation.[57] The degree to which acute and chronic pain perception is mediated by the same cast of neuroinflammatory mediators is an interesting and open question.

It is noteworthy that a recent study by Wei et al.[58] has shown distinct roles for inflammation and central neuroinflammation in the acute phase versus the chronic phase of pain behavior in a rat model of complex regional pain syndrome. Although peripheral interleukin-1β levels only increased at 4 weeks, spinal levels of interleukin-1β increased at both 4 weeks (acute phase) and 16 weeks (chronic phase). Importantly, systemic administration of anakinra, a peripherally restricted interleukin-1 receptor antagonist, only inhibited nociceptive behaviors at 4 weeks but not at 16 weeks, though intrathecal injection of anakinra reduced nociceptive behaviors at both 4 and 16 weeks.[58] This study supports a critical role of central neuroinflammation in maintaining chronic pain in a rodent model of complex regional pain syndrome.

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