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.


Anesthesiology. 2018;129(2):343-366. 

In This Article

Alternative Treatments That can Modulate Neuroinflammation

Although direct targeting of neuroinflammation via inhibitors of cytokines, chemokines, and mitogen-activated protein kinases could be effective, these drugs may also produce side effects such as infection after long-term treatment and impair the resolution of inflammation.[39] In this review, we highlight the alternative approaches that can control excessive neuroinflammation, including specialized proresolution mediators, cell therapies, and neuromodulation (Figure 6).

Specialized proresolution mediators, including lipoxins, resolvins, protectins, and maresins, are biosynthesized from polyunsaturated fatty acids, including the omega-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, two major components of fish oil. Specialized proresolution mediators have multiple beneficial actions for treating inflammation-associated disease conditions.[257,258] Lipoxin A4, resolvin D1, resolvin E1, resolvin D2, neuroprotectin D1, and maresin 1, at very low doses (10 to 500, ng range), reduced inflammatory pain, postoperative pain, and neuropathic pain in animal models.[187,202,258–263] In the hippocampus, treatment with resolvin D1 prevented long-term potentiation impairment by reducing proinflammatory cytokines after surgery.[264] The benefits of these specialized proresolution mediators include high potency, favorable safety profile, and multiple mechanisms of action including but not limited to control of inflammation in peripheral tissues, control of neuroinflammation in the peripheral nervous system and CNS, resolution of synaptic plasticity, modulation of transient receptor potential ion channel A1 and V1 activities, and protection against nerve injury.[39,226,258,264] Spinal administration of neuroprotectin D1, even 2 h after long-term potentiation induction, is also effective in reversing long-term potentiation in the intact spinal cord.[202,261] Specialized proresolution mediators are especially effective in preventing neuroinflammation, postoperative pain, and neuropathic pain after nerve injury and surgery, although posttreatment of specialized proresolution mediators also exhibit transient analgesic effects. Notably, thoracotomies produce a high incidence of chronic postoperative pain by nerve compression.[265] Wang and Strichartz[263] found that intrathecal and perioperative treatment with resolvin D1 and resolvin D2 effectively prevents postoperative pain in a rat model of chronic postthoracotomy.

Cell therapies are emerging treatments for chronic pain and neurodegenerative conditions. Implantation of bone marrow stem cells produces long-term pain relief.[266,267] Bone marrow stromal cells or bone marrow stem cells promote tissue regeneration and tissue repair by secreting growth factors and control inflammation and neuroinflammation by secreting antiinflammatory mediators such as transforming growth factor β1.[266] A single intrathecal injection of bone marrow stem cells not only inhibits nerve injury-induced neuropathic pain for many weeks via secretion of transforming growth factor β1 but also blocks nerve injury-induced neuroinflammation (glial activation and cytokine/chemokine upregulation) in dorsal root ganglia and spinal cord tissues.[266] This paracrine modulation of neuroinflammation by bone marrow stem cells is very different from typical cell replacement strategies, such as implantation of forebrain GABAergic precursor cells into the spinal cord to generate functional GABAergic neurons for chronic pain control.[268] Furthermore, subcutaneous treatment with human umbilical cord blood–derived multipotent stem cells reduced peripheral neuropathic pain in rats and inhibited spinal matrix metalloprotease 9 and 2 expression after nerve injury.[269] Macrophages and T cells also play a role in the resolution of pain. Proresolution macrophages (M2-like) may inhibit neuroinflammation and chronic pain by secreting specialized proresolution mediators and antiinflammatory cytokines such as interleukin-10.[26,270] Adoptive transfer of regulatory T cells (Treg) reduced neuropathic pain, whereas CD8+ cytotoxic T cells increased neuropathic pain after chemotherapy after intrathecal injection.[30] However, adoptive transfer of CD8+ T cells via systemic route was also shown to resolve chemotherapy-induced neuropathic pain by increasing interleukin-10 receptor expression in dorsal root ganglia neurons.[271] Autologous conditioned serum is prepared from whole blood that is incubated with glass beads to initiate monocyte activation. Autologous conditioned serum contains increased levels of interleukin-1 receptor antagonist interleukin-1ra as well as the antiinflammatory cytokines interleukin-4 and interleukin-10 and demonstrates efficacy in relieving pain in patients with knee osteoarthritis.[272,273] Platelet-rich plasma was also shown to reduce clinical pain in knee osteoarthritis via possible modulation of inflammatory responses.[274]

Neuromodulation via electrical and magnetic stimulation, such as spinal cord stimulation, deep brain stimulation, transcranial magnetic stimulation, transcutaneous electrical nerve stimulation, vagus nerve stimulation, auricular stimulation, and dorsal root ganglia stimulation, as well as acupuncture including electroacupuncture, has been used to provide pain relief in patients and animals[275,276]via activation of specific neural pathways,[277,278] suppression of nociceptive neuron activities (e.g., wide dynamic neurons and projection neurons in the spinal cord[279,280]), and release of pain suppressing neurotransmitters and neuromodulators.[281] However, transient modulation of neuronal activity in the pain circuits during stimulation cannot explain the long-term benefits of neuromodulation. Increasing evidence suggests that neuromodulation such as vagus nerve stimulation can powerfully regulate inflammation.[282,283] Although acupuncture elicits transient analgesia via releasing opioid peptides and adenosine,[281,284] acupuncture and sciatic nerve activation also regulates inflammation and sepsis through vagus nerve activation and dopamine release.[285] In 1984, Maixner and Randich[286] demonstrated an antinociceptive role of vagal stimulation. Notably, acupuncture also causes neuronal activation in the nucleus of solitary tract to mediate vagal responses.[287,288] In a rodent model of inflammatory muscle pain, acupuncture elicits antiinflammatory effects via interleukin-10 release.[289] The identification of the "inflammatory reflex" reveals a neural circuit capable of providing information in real time to the brain about the body's inflammatory status, allowing rapid neural regulatory responses via the vagus nerve.[290] This has clear implications in developing novel bioelectronic technologies to treat pain and improve postoperative outcomes in vulnerable patients.[283]