Abstract and Introduction
Abstract
Chronic pain is maintained in part by central sensitization, a phenomenon of synaptic plasticity, and increased neuronal responsiveness in central pain pathways after painful insults. Accumulating evidence suggests that central sensitization is also driven by neuroinflammation in the peripheral and central nervous system. A characteristic feature of neuroinflammation is the activation of glial cells, such as microglia and astrocytes, in the spinal cord and brain, leading to the release of proinflammatory cytokines and chemokines. Recent studies suggest that central cytokines and chemokines are powerful neuromodulators and play a sufficient role in inducing hyperalgesia and allodynia after central nervous system administration. Sustained increase of cytokines and chemokines in the central nervous system also promotes chronic widespread pain that affects multiple body sites. Thus, neuroinflammation drives widespread chronic pain via central sensitization. We also discuss sex-dependent glial/immune signaling in chronic pain and new therapeutic approaches that control neuroinflammation for the resolution of chronic pain.
Introduction
Chronic pain is a major health concern that affects one in three Americans and costs the U.S. economy $635 billion dollars each year.[1,2] Acute pain is often elicited by acute inflammation and has biologic significance to protect the wounded tissue. Chronic pain is maladaptive, has no beneficial biologic significance, and is characterized by spontaneous pain (e.g., burning) as well as evoked pain in response to noxious (hyperalgesia) or nonnoxious (allodynia) stimuli. It is generally believed that neuronal plasticity in pain-coding pathways and circuits results in chronic pain. Neuronal plasticity consists of peripheral sensitization in primary sensory neurons of dorsal root ganglia and trigeminal ganglia[3–5] and central sensitization of pain-processing neurons in the spinal cord and brain.[6–9]
The perception of pain is typically associated with inflammation, a complex biologic response of the somatosensory, immune, neuronal, autonomic, and vascular/circulatory system to tissue damage, pathogens, or irritants. Acute inflammation, which generally results in perception of pain, serves an important protective or survival role by removing harmful stimuli, initiating the healing process, and restoring tissue integrity (Table 1). Primary afferents that respond to tissue injury (i.e., nociceptors) include unmyelinated C-fibers and myelinated Aδ-fibers that terminate in skin, muscle, joints, and visceral organs, with their cell bodies located in dorsal root ganglia and trigeminal ganglia. Nociceptors are activated or sensitized by inflammatory mediators such as bradykinin, prostaglandins, nerve growth factor, and proinflammatory cytokines such as tumor necrosis factor-α, interleukin 1β, and proinflammatory chemokines (e.g., [CC motif] ligand 2, CXC motif chemokine 5)[3,10,11] that directly bind and stimulate G-protein–coupled receptors, ionotropic receptors, and tyrosine kinase receptors. It is noteworthy that all of these receptors are expressed on the terminals and/or cell bodies of nociceptors.[3,5] Cytokine profiles observed in human skin are also associated with inflammation and pain and thus may serve as biomarkers for chronic pain.[12,13] Activation of a mosaic of peripheral receptors results in hypersensitivity and hyperexcitability of nociceptor neurons (peripheral sensitization) through modulation of various ion channels, such as transient receptor potential ion channels (e.g., transient receptor potential ion channels A1, V1, and V4), sodium channels (e.g., subtypes Nav1.7/1.8/1.9),[3,4,14] and mechanosensitive Piezo ion channels.[15,16] MicroRNA may serve as a novel inflammatory and pain-evoking mediator. For example, miR-let-7b induces spontaneous pain via activation of Toll-like receptor 7 and transient receptor potential ion channel A1.[17] Furthermore, the activation of protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase C in primary sensory neurons critically contributes to the induction and maintenance of peripheral sensitization. For instance, activation of p38 mitogen-activated protein kinase in dorsal root ganglia neurons initiates peripheral sensitization by increasing transient receptor potential ion channel V1 activity in response to tumor necrosis factor[18] and also by increasing NaV1.8 activity in response to interleukin-1β, and furthermore, this activation maintains peripheral sensitization and chronic pain by increasing transient receptor potential ion channel V1 expression.[20,21] In parallel, peripheral tumor necrosis factor and interleukin-1β have been strongly implicated in the pathogenesis of inflammatory and neuropathic pain.[22–26]
Of note, nociceptors and immune cells have bidirectional interactions.[27] Nociceptors not only listen to immune cells by responding to inflammatory mediators but also talk to immune cells and modulate the immune response to inflammation.[28,29] Like immune cells, nociceptors express cytokines, chemokines, and Toll-like receptors that are essential for immune modulation.[19,30–32] Release of cytokines and chemokines from nociceptors can rapidly regulate resident immune cells and attract circulating cells to the area of local inflammation that engage primary afferents and cell bodies in the nerve and dorsal root ganglia. For example, nociceptor-produced chemokine (CC motif) ligand 2 regulates local macrophage activation in dorsal root ganglia after chemotherapy via Toll-like receptor signaling, resulting in neuropathic pain.[19,33] Activation of nociceptors, especially C-fibers, also produces neurogenic inflammation via releasing neuropeptides such as substance P and calcitonin gene–related peptide or prostanoids[28] (Table 1). Neurogenic inflammation occurs immediately after intradermal administration of capsaicin and mustard oil via respective activation of transient receptor potential ion channels A1 and V1. Neurogenic inflammation results in rapid plasma extravasation and edema, even before the infiltration of immune cells. Neurogenic inflammation plays an important role in inflammatory diseases such as asthma and psoriasis but also contributes to pain conditions such as migraine and complex regional pain syndrome after bone fracture.[34] Nociceptors may differentially regulate inflammation in a context-dependent manner. For example, ablation of nociceptors decreases neurogenic inflammation but also enhances inflammation after bacterial infection by releasing calcitonin gene–related peptide.[35]
Peripheral inflammation with resulting persistent nociceptive input also leads to the increased release of neurotransmitters (glutamate, substance P, calcitonin gene–related peptide, and brain-derived growth factor) from the primary afferent central terminals in the spinal cord and trigeminal nucleus. Through signal transduction, these neurotransmitters produce a state of neuronal hyperactivity and hyperexcitability in the spinal cord and brain known as central sensitization.[36,37] Activation of postsynaptic glutamate N-methyl-D-aspartate (NMDA) receptors and plasma cell membrane surface insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are essential steps for the induction and maintenance of central sensitization.[6,38]
Anesthesiology. 2018;129(2):343-366. © 2018 American Society of Anesthesiologists | Lippincott Williams & Wilkins
