Sage Journals: Discover world-class research

Abstract

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

Keywords

Inflammation chronic pain glial cell pro-inflammatory mediator specialized pro-resolving mediator

Introduction

Inflammation is associated with both pain and multiple disease outcomes, which is characterized by five typical signs: redness, swelling, heat, pain, and loss of function. Inflammation can be divided into three types according to the progress of pathology underlying the injured tissue: (1) acute inflammation occurs shortly after injury and persists for a few days; (2) chronic inflammation occurs when acute inflammation fails to resolve, which may last for several months or even years; (3) subacute inflammation is a transformational period spanning acute to the chronic stage, which lasts from 2 to 6 weeks.¹ The early stage of inflammation aims to eliminate internal threats and initiate tissue repair. As one of the five cardinal signs of inflammation, pain includes acute pain and chronic pain. Acute pain (also known as nociceptive pain) is considered as a protective reaction involving immune cells, and inflammatory mediators.² Chronic pain is known as not only a bothersome symptom but also a disease, which is a major health issue worldwide causing a considerable social and economic burden.³ An estimated more than 30% of adult worldwide suffer from pain according to reports,^4–6 the prevalence of chronic pain from different studies are shown in Table 1. Chronic inflammation is maladaptive and often leads to a considerable amount of chronic pain.¹⁶ Of note, inflammation plays a dual role (protective or detrimental) during different stages (acute or chronic phase).¹⁷

Table 1.

Prevalence of chronic pain in different countries and regions.

Patients and area	Ages	Participants	Definition of chronic pain	Prevalence, %	Refs
Patients with chronic low back pain in Brazil (Pelotas)	≥20	2732	≥7 weeks in the last 3 months	9.6	7
Patients with chronic low back pain in Brazil (Sao Paulo)	≥60	1271	Continuous pain ≥6 months	25.4	8
Patients with chronic low back pain in Germany	65–85	3189	Continuous pain≥ 6 months	M 55.2	9
Patients with chronic low back pain in Germany	65–85	3189	Continuous pain≥ 6 months	F 41.1	9
Patients with chronic pain in United States	≥18	33,028	Continuous pain ≥6 months	20.4	4
Patients with chronic pain in United States	≥18	31,997	Continuous pain ≥3 months	20.5	10
Patients with breast cancer in United States	≥18	1280	Continuous pain ≥6 months	33.3	11
Patients with cancer pain in French	18–82	864	Continuous pain ≥3 months	32.3	12
Patients with cancer pain in United States	≥18	7565	Continuous pain ≥3 months	32.5	13
Patients with chronic pain in Israel	18–74	1647	Continuous pain ≥3 months	31.3	14
Patients with chronic pain in China (Hong Kong)	≥18	5001	Continuous pain ≥3 months	34.9	15

Pain research in the past decades has confirmed that neuronal plasticity is the critical mechanism for the initiation and maintenance of chronic pain.¹⁸ The neuronal plasticity derives not only from the adaptive transformation of neurons themselves, but also from the change of microenvironment composed of immune and glial cells underlying acute and chronic pain. Under inflammatory conditions, there are increased levels of inflammatory mediators in the tissue from immune and glial cells and even neurons, which modulate nociceptors in the PNS and the pathways responsible for pain transmission in the CNS.¹ Neuroinflammation, a special manifestation of tissue inflammation, can occur in the PNS and CNS, the main characteristics of which are the activation of glial cells and the release of neuroinflammatory mediators (Figure 1).^19,20

Figure 1.

The cross-talk between neurons and non-neuronal cells leads to deterioration or resolution of pain. Non-neuronal cells [e.g. Schwann cells (SCs), satellite glial cells (SGCs), microglial cells, astrocytes, oligodendrocytes, macrophages, and neutrophils], produce both pro-inflammatory mediators (RED) and anti-inflammatory mediators (BLUE), which can act on their corresponding receptors of the nociceptors causing peripheral and central sensitization marked by a state of hypersensitivity and hyperexcitability of the nociceptor. The central terminals of the nociceptors in the spinal cord form nociceptive synapses with postsynaptic neurons to process pain transmission in the CNS. In addition, descending pathways also exert an inhibitory effect on pain transmission in the spinal cord.

Clinical approaches to treat chronic pain are hampered by various possible causes, such as triggering factors, inflammatory locations, and symptomatic manifestations. In addition, current treatments for persistent or chronic pain are not effective. It usually counteracts the available analgesics, such as opioids and non-steroidal anti-inflammatory drugs, which have serious side effects.^21,22 It is therefore imperative to develop new analgesics with a new mechanism of action. Notably, the pro-resolution phase of inflammation is now widely known as an active process in organism, controlled by the specialized pro-resolving mediators (SPMs).^23,24 The active process and receptors of SPMs have been confirmed to reduce inflammation, clear microbes, and alleviate pain (Table 2). Thus, SPMs may become promising analgesics for pain relief.

Table 2.

Anti-inflammatory mechanisms of SPMs in chronic pain.

SPMs	Endogenous sources	Exogenous sources	Anti-inflammatory mechanisms	Refs
Resolvin D1 (RvD1)	Neutrophils, macrophages, and platelets	Docosahexaenoic (DHA)	♦ Promotes resolution of inflammation	25–29
			♦ Decreases inflammatory response and apoptosis
			♦ Protects the endothelial integrity and barrier function
			♦ Inhibits the activity of TRPA1, TRPV3, and TRPV4
Resolvin D2 (RvD2)	Macrophages, epithelial cells, and platelets		♦ Decreases inflammatory response	30–33
			♦ Inhibits the activity of TRPV1 and TRPA1
			♦ Increases the production of anti-inflammatory mediator TGF-β1
			♦ Transforms the macrophages from inflammatory to anti-inflammatory phenotype
Resolvin D3 (RvD3)	Macrophages and neutrophils		♦ Inhibits the activity of TRPV1 and CGRP release via a G-protein coupled receptor, such as ALX/FPR2	34,35
Resolvin D3 (RvD3)	Macrophages and neutrophils		♦ Decreases the inflammatory cytokines and chemokines, such as TNF-α, IL-6, IL-1β, CCL2, and CCL3	34,35
Resolvin D4 (RvD4)	Neutrophils, macrophages, and dendritic cells		♦ Decreases the inflammatory response	36
Resolvin D5 (RvD5)	Neutrophils, macrophages, and platelets		♦ Decreases the expression of IL-6 in male mice with chronic pain	37
Resolvin D6 (RvD6)	Neutrophils and macrophages		♦ Increases the expression of rictor and hepatocyte growth factor (hgf) and rictor genes	38
Resolvin E1 (RvE1)	Neutrophils, eosinophils, platelets, and epithelial cells	Eicosapentaenoic (EPA)	♦ Inhibits the migration of neutrophils to inflammatory site	39,40
Resolvin E1 (RvE1)	Neutrophils, eosinophils, platelets, and epithelial cells		♦ Decreases the release of TNF-α, IL-1β, and IL-6	39,40
Resolvin E2 (RvE2)	Macrophages and dendritic cells		♦ Inhibits neutrophil infiltration	40
Resolvin E2 (RvE2)	Macrophages and dendritic cells		♦ Decreases the expression of pro-inflammatory cytokines	40
Resolvin E3 (RvE3)	Neutrophils and endothelial cells		♦ Inhibits inflammatory activity	41
Maresin 1 (MaR-1)	Macrophages	DHA	♦ Blocks NLRP3 inflammasome	42,43
Maresin 1 (MaR-1)			♦ Shifts from M1 macrophages to M2 phenotype	42,43
Maresin 2 (MaR-2)			♦ Blocks neutrophil and monocyte migration	44
Maresin 2 (MaR-2)			♦ Inhibits the activity of TRPA1, and the release of CGRP	44
Protectins D1	Neutrophils	DHA	♦ Inhibits T cell infiltration	45–47
Protectins D1	Neutrophils		♦ Reduces neutrophil recruitment
Neuroprotection D1	Epithelial cells		♦ Decreases inflammatory response
Lipoxins	Leukocytes, platelets, endothelial cells, and fibroblasts	Arachidonic acid (AA)	♦ Inhibits pro-inflammatory mediator production	48,49
Lipoxins	Leukocytes, platelets, endothelial cells, and fibroblasts	Arachidonic acid (AA)	♦ Blocks neutrophils infiltration	48,49

Peripheral inflammation contributes to the pathogenesis of chronic pain

Over the past few decades, accumulating evidence has revealed inflammation in the physiological and pathophysiological processes of chronic pain. Key participants involved are neutrophils, macrophages, and glial cells. In addition, inflammatory mediators (pro-inflammatory cytokines, chemokines), and SPMs also play a significant role in initiation and resolution of chronic pain (Figure 2). The neuroinflammation generated by peripheral glial cells in chronic pain conditions is more persistent, thereby contributing to the maintenance of chronic pain.⁵⁰

Figure 2.

Inflammation and peripheral sensitization in chronic pain. Inflammation manifests the releasing of inflammatory mediators from various types of cells, these inflammatory mediators including proinflammatory cytokines, chemokines, HMGB1 and ATP, which can bind with their respective receptors on the nociceptive neurons in peripheral, modulate their sensitivity and excitability, and then lead to chronic pain. In addition, SCs and macrophages also produce anti-inflammatory cytokines and pro-resolving mediators SPMs, which promote pain resolution.

Pain modulation by various cells in PNS

An increase in peripheral sensitization is characterized by the hyperexcitability and hypersensitivity of nociceptors caused by tissue injury and inflammation. Increasing evidence suggests that peripheral sensitization is the cardinal contributor to chronic pain in the peripheral, but not an independent factor. There are a variety of non-neuronal cells, such as immune cells and glial cells, are activated along the pain circuitry by painful injuries, causing a localized inflammation in the PNS and CNS (neuroinflammation). The activation of these cells, in turn, causes bi-directional interactions with nociceptors, which are crucial in the development and maintenance of chronic pain.² In addition, inflammatory mediators, such as cytokines and chemokines, produced by these cells also contribute to the initiation and maintenance of pain.^51,52 Comparatively, SPMs have been proven to promote the resolution of inflammation, alleviate pain, and promote tissue regeneration via specific cellular and molecular mechanisms. Therefore, SPMs exhibit potent anti-inflammatory actions and act as promising analgesics during the resolution phase of inflammation.^53–55

Neurons

A variety of noxious/painful stimuli are detected by neurons, which represent a heterogeneous neuron population that can be further classified in accordance with their characteristics, such as size of the soma, degree of myelination, expression of genes, cell surface markers, electrophysiological characteristics.^56–58 Afferents that respond to tissue injury include myelinated C-fibers and unmyelinated C-fibers that terminate in skin, muscle, joints, and visceral organs, with their neuronal bodies located in the dorsal root ganglia (DRGs) and trigeminal ganglia (TGs).

These neurons send centrally-projecting fibers to the dorsal horn (for DRG neurons) and spinal trigeminal nuclei of the medulla (for TG neurons), where they convey information to secondary nociceptive neurons via various neurotransmitters and neuropeptides.^18,58

Nociceptors are sensitized by inflammatory mediators (e.g. pro-inflammatory cytokines, chemokines, nerve growth factor, bradykinin, prostaglandins)^18,59–61 via their corresponding receptors [e.g. G-protein coupled receptors (GPCRs), tyrosine kinase receptors, and ionotropic receptors] that expressed on the terminals and/or cell bodies of nociceptors.^18,62 Peripheral receptor activation under pathological conditions cause hyperexcitability and hypersensitivity of nociceptive neurons (peripheral sensitization), via modulation of various ion channels, including transient receptor potential ion channels (TRPs, e.g. TRPA1, TRPV1, and TRPV4),^63–65 sodium channels (e.g. Nav1.7/1.8/1.9),^66–68 and mechanosensitive piezo ion channels.^69,70 The activation of protein kinases [e.g. protein kinase C (PKC) and protein kinase A (PKA), MAP kinases] in primary sensory neurons also participates in peripheral sensitization. For instance, during the pathogenesis of chronic pain, the activation of p38 in sensory neurons initiates and maintains peripheral sensitization by increasing TRPV1 activity in response to tumor necrosis factor-α (TNF-α)^71,72 and also by increasing the activity of Nav1.8 as a consequence of interleukin (IL)-1β.^73,74 A recent study indicated that TLR8 in TG neurons facilitates trigeminal neuropathic pain (TNP) via increasing intracellular Ca²⁺, activating ERK and p38, and further increasing the pro-inflammatory cytokines (e.g. TNF-α, IL-6, and IL-1β) in the TG after infraorbital nerve injury.⁷⁵ The CXCR3 activation by C-X-C motif chemokine ligand (CXCL) 10 in DRG neurons enhances neuronal excitability via activating p38 and ERK, which contributes to the maintenance of neuropathic pain.⁵²

A great deal of evidence suggests that peripheral sensory neurons not only respond to painful stimuli, but also play a role in inflammation and immunity as well.⁷⁶ Recent research has shown that peripheral sensory neurons express the proton-selective ion channel Hv1 that was previously known to be selectively expressed in microglia. Neuronal Hv1 is upregulated by peripheral inflammation, which in turn enhances inflammation and nociception. Inhibition of neuronal Hv1 by gene knockout or a selective blocker YHV98-4 reduces intracellular ROS production and alkalization in chronic inflammatory pain, restores downstream SHP-1-pAKT signaling, diminishes the release of chemokines, and finally reduces the effects of morphine-induced hyperalgesia and tolerance.⁷⁶

Peripheral glial cells: Schwann cells and satellite glial cells

Glial cells in the PNS consist of Schwann cells (SCs) in the peripheral nerve trunk and satellite glial cells (SGCs) in the DRGs and TGs. As a result of noxious stimuli, glial cells release multiple inflammatory mediators, sensitizing nociceptors at axons and somata which in turn participate in pain processing.²

SCs are the main glial cells of the PNS, which form myelin sheaths to provide nutrients for nerve fibers and maintain the homeostasis of the neuronal microenvironment.⁷⁷ After peripheral nerve injury, the activated SCs release pro-inflammatory cytokines, such as TNF-α and IL-1β, which contribute to nerve degeneration and the development of neuropathic pain.^78,79 For instance, experimental studies of chronic constriction injury (CCI) rat models have shown that SCs are activated and release the IL-1β at the injury site.^80,81 An increase of IL-1β then promotes SCs de-differentiation in Wallerian degeneration via the c-Jun/AP-1 signal axis.⁸² Activated SCs can destruct the blood-nerve barrier through the secretion of MMP-9, which recruits immune cells from the blood vessels into the injured nerve tissue and then releases more pro-nociceptive mediators.⁸³ Consequently, the increased pro-inflammatory mediators and activated SCs are implicated in pathological pain via glial-neuronal and neuro-immune interactions.

SGCs surround the somata of DRG and TG neurons and are coupled with each other through gap junctions, which are activated and proliferated due to injured nerves and inflammation. The activity of SGCs play a key role by participating in chronic pain through the following ways: (1) upregulation of glial fibrillary acidic protein (GFAP),^84,85 (2) enhanced gap junction-mediated SGC-SGC and neuron-SGC coupling,^86–88 (3) increased the sensitivity of SGCs to ATP that activates P2X7 receptors leading to TNF-α release. By contrast, it enhanced the P2X3 receptor-mediated responses and increased DRG excitability,^89–91 (4) decreased the expression of the Kir4.1,^92–94 and increased the release of pro-inflammatory mediators, such as TNF-α, IL-1β, IL-6, and CX3CL1.^95–98 A recent study has shown that the upregulation of P2Y14 receptors in TG SGCs may partially trigger orofacial inflammatory pain via activating ERK and p38 signaling, producing cytokines (IL-1β, TNF-α, and CCL2).⁹⁹

Neutrophils and macrophages

Neutrophils are considered as the body’s first line of defense against infection and various inflammatory signals, also viewed as important players in tissue repair. In the early stage of inflammation, neutrophils can fight against infections via phagocytosis and/or neutrophil extracellular traps (NETs). Neutrophils may exert analgesic effects by releasing opioid peptides, such as β-endorphin, met-enkephalin, and dynorphin A.¹⁰⁰ However, when the inflammation persists, neutrophils also release NETs to exacerbate tissue inflammation.¹⁰¹ Parisien et al. reported that transient neutrophil-induced inflammatory responses are protective against the transition from acute to chronic pain in participants with resolved pain within 3 months. A lack of neutrophils delays the resolution of chronic pain, whereas a supplement of neutrophils prevents the development of prolonged pain.¹⁰² Thus, the inhibition of acute inflammation may delay the resolution of chronic pain. In addition, the enhanced phagocytosis of apoptotic neutrophils by macrophages (also termed efferocytosis) has been revealed to reduce inflammation in synovitis.¹⁰³

A neuroimmune crosstalk contributes to chronic pathological pain including inflammatory and neuropathic components.^104,105 Macrophages play an important role in pain induction and maintenance with different mechanisms in the periphery.² The main functions of these cells in the immune system include phagocytosis, antigen presentation, and cytokine production. It is well known that monocytes differentiate into macrophages in tissues where they fight infection and repair wounds under inflammatory conditions.¹⁰⁶ These cells secret multiple mediators [e.g. TNF-α, IL-6, IL-1β] to regulate the excitability of the primary afferents^104,107 via modulation of ion channels (e.g. TRPA1, TRPV1, and Nav1.7–1.9),^18,50,53 which then enhance pain transduction and conduction.

In addition to pro-inflammatory cytokines, macrophages also release chemokines which contribute to the occurrence and maintenance of chronic pain.¹⁰⁸ Macrophages can produce chemokines CCL2.¹⁷ In a rat model of lumbar disc herniation, CCL2 was increased in DRG neurons, and its receptor CCR2 was increased in DRG macrophages.^109,110 Thus, CCL2/CCR2 signaling may be involved in the interaction of neuron-macrophages and contribute to the maintenance of chronic pain.

In the inflammatory microenvironment of local tissue, the macrophages recruited and resident undergo phenotypic and functional changes responding to mediators released by neurons or immune cells.^111–113 Pro-inflammatory macrophages are classified as M1 and anti-inflammatory macrophages are classified as M2. Lipopolysaccharide (LPS), granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), and TNF-α polarize macrophage M1 to produce marked effects on inhibiting microbes and tumors, and promoting tissue damage via the production of pro-inflammatory mediators. Transforming growth factor-β (TGF-β), macrophage colony-stimulating factor (M-CSF), IL-4, IL-10, and IL-13 polarize macrophage M2 to phagocytose apoptotic cells and promote tissue repair by secreting anti-proinflammatory mediators IL-10 and TGF-β.¹⁰⁴ After the peripheral nerve and/or adjacent tissues are damaged, macrophages cluster at the injured site, and along primary afferents and its bodies, where M1 macrophages sensitize the nociceptive neurons, which might be subsequently suppressed by M2 macrophages.^50,114 M1 macrophages release abundant inflammatory mediators, such as TNF-α, IL-6, IL-1β, nerve growth factor (NGF), insulin-like growth factor 1 (IGF-1), prostaglandin E2 (PGE2), CCL2, and CXCL1, to result in sensitized neurons by activating their specific receptors located in the nociceptive neurons.¹⁰⁴ An increase of high mobility group box 1 (HMGB1) from the activated M1 macrophages stimulates its membrane receptors, such as Toll-like receptor 4 (TLR4), advanced glycation end-product (RAGE), and then accelerates the CXCL12/CXCR4 signal axis in the peripheral nerve, and finally contributes to the pathogenesis of chronic pain.^{104,115–119}

As described above, activated macrophages (mainly M1 macrophages) induce inflammation through releasing pro-inflammatory mediators resulting in neuronal sensitization and then causing pain. Thus, inflammation acts as a role of foe in such situations. On the other hand, M2 macrophages release anti-inflammatory cytokines to suppress inflammation in the resolution phase and resolve pain. As literature reported, the GPR37 in macrophages were activated by neuroprotectin D1 (NPD1) to enhance macrophage phagocytosis and IL-10 production, and then promote the resolution of inflammatory pain.¹²⁰ Thus, macrophage activation under these circumstances plays a friend role in pain resolution.

Specialized pro-resolving mediators

SPMs are produced during the resolution phase of inflammation, including various bioactive molecules, such as resolvins (RvD1, RvD2, RvD5, RvE1),¹²¹ maresin (MaR1 and MaR2),^55,122,123 protectin (PD1)^124,125 or neuroprotectin (NPD1),^17,126 and lipoxins,^127,128 which derive from polyunsaturated fatty acids (PUFA).^{44,53–55,129} The synthesis of SPMs plays a crucial role in promoting transformation from a pro-inflammatory to an anti-inflammatory state, boosting a pro-resolution state, and further alleviating inflammatory pain.¹²³ In addition, SPMs might suppress the excessive sensitization of nociceptors via inhibiting specific channels (e.g. TRPA1 and TRPV1) to achieve the resolution of pain.¹²⁶ For example, the peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 and RvD1 has shown a powerful effect on reducing inflammatory pain induced by formalin, carrageenan, or complete Freund’s adjuvant (CFA). Moreover, intrathecal injection of RvE1 inhibits spontaneous pain and heat and mechanical hypersensitivity induced by capsaicin and TNF-α. RvE1 also inhibits TNF-α and TRPV1-induced excitatory postsynaptic current increases via inhibition of ERK signaling pathway.¹²⁷ MaR1 and PD1 can suppress the activity of TRPV1 in DRG neurons and reduce neuroinflammatory pain by inhibiting PKA and ERK activity.^128,129 MaR2 is a DHA-derived SPM produced by macrophages, which also demonstrates the ability to reduce TRPV1 and TRPA1 activation in DRG neurons exhibited by a reduction in calcium influx and suppressed pain-like behavior in LPS-induced inflammatory pain models, as well as capsaicin and AITC-induced spontaneous pain models of mouse.⁴⁴ Moreover, PD1 also decreases hyperexcitability by negatively regulating LTP in the spinal cord evoked by TNF-α.¹³⁰ Due to the serious side effects of traditional analgesics, SPMs have become a promising substitute for pain relief, for its potent pro-resolving and anti-inflammatory effects.¹²³

Central inflammation contributes to the pathogenesis of chronic pain

In the CNS, it is believed that chronic pain is persisted by central sensitization caused by synaptic plasticity in central pain pathways and an increase in neuronal responsiveness as a result of painful insults. Increasing evidence shows that central sensitization is caused by neuroinflammation in the CNS. A classical feature of neuroinflammation is that the glial cells are activated in the CNS, and they release multiple pro-inflammatory mediators to induce hyperalgesia and allodynia (Figure 1).

Pain modulation by central glial cells

Neuroinflammation in the CNS is caused by the activation of glial cells (such as microglia and astrocytes), which play a critical role in the initiation and maintenance of chronic pain.^131–135 Tissue inflammation or nerve injury induces the activation of glial cells, which leads to the release of inflammatory mediators, such as cytokines (e.g. TNF-α, IL-6, and IL-1β), chemokines (e.g. CXCL1, CX3CL1, and CCL2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS), to enhance neuronal excitability or synaptic transmission.^136–138

Microglia are the resident immune cells in CNS. Microglia become activated (also termed “microgliosis”) in response to disease states or peripheral nerve injury, characterized by significant morphological changes (hypertrophy), functional changes, and proliferation, which is related to transcriptomic changes.¹³⁹ The spinal microglia activation is evoked by pro-inflammatory mediators [e.g. IL-1β, caspase-6, colony-stimulating factor 1 (CSF1), and extracellular proteases] derived from sensory neurons.^139–143 After nerve injury, activation of microglia in the ipsilateral spinal dorsal horn can be quickly observed, and inhibition of microglia activation is sufficient to mitigate pain development.¹⁴⁴ However, it should be noted that microgliosis induced by nerve injury is transient and self-limiting, which weakens within a few weeks and remains at a reduced level in the later stage, that means in the later stage of microgliosis, microglia inhibitor and inhibition of activated microglia-associated cytokines are no longer effective in pain relief.^145,146 Thus, microglia and their pain mediators (cytokines and chemokines) are most actively involved in pain initiation. Of note, SPMs in CNS have been shown to contribute to the resolution of pain. The NPD1 biosynthesized by microglia has a powerful protective effect in pain relief.¹⁴⁷ In addition, microglia express many SPM receptors, such as GPR18 (RvD2 receptor), GPR32 (RvD1 receptor), and ChemR23 (RvE1 and RvE2 receptor).^148,149 RvE1 binds to ChemR23 to trigger pro-resolving responses and reduce chronic pain through inhibiting microglial activation in the SC.^150,151 Consequently, activation of these microglial receptors down-regulates the production of pro-inflammatory mediators (e.g. TNF-α, IL-1β), and up-regulates the secretion of anti-inflammatory mediators (e.g. IL-10, TGF-β), thus promoting the regression of pathological pain.¹³⁹ Besides, ion channels on microglia are involved in regulation of inflammatory pain, such as Hv1, P2X4, P2X7, and TRPV4. Hv1 has been implicated in the pathogenesis of neuropathic pain by regulating ROS production and microglia-astrocyte communication.¹⁵² The microglial P2X4 channel participates in inflammatory pain through activating microglia, and then releasing pro-inflammatory mediators.¹⁵³ The ATP-gated ion channel P2X7 on microglia have been revealed to modulate inflammatory pain through regulating NLRP3/Caspase-1 pathway.¹⁵⁴ TRPV4 expression in spinal resident microglia is increased in the mouse model of SNI, which transforms peripheral nerve injury into central sensitization and neuropathic pain through releasing lipocalin-2.¹⁵⁵

Astrocytes are more abundant (approximately 2-4 times) compared to microglia, and play crucial effects on controlling the extracellular microenvironment, repairing the imbalance of potassium, glutamate, and water homeostasis under normal physiological conditions.^156,157 Astrocytes are activated in various pathological conditions and convert to reactive states (also termed “astrogliosis”) characterized by obvious morphological changes, a significant increase of GFAP, and a significant cellular proliferation, which is considered to be coupled with a loss of homeostatic functions of astrocytes.^58,158 Astrocytes are activated after nerve injury generally following microglial activation (e.g. 1 week), but remain longer time (at least 5 months or more) in a reactive state that contributes to the maintenance of chronic pain.¹⁵⁹ Numerous pieces of evidence show that decreasing activation of astrocyte can attenuate pain behaviors in chronic pain models.^160–162

Glia in the CNS are dominated by oligodendrocytes, which account for 46∼75%.⁵⁸ There is, however, relatively little research on the role of oligodendrocytes in chronic pain pathogenesis. Some studies suggest that there may be an interaction between oligodendrocyte damage and pain in patients with multiple sclerosis.¹⁶³ Moreover, oligodendrocytes play a role in maintaining pain in common conditions.¹⁶⁴ Previous experiments suggest that the role of oligodendrocytes in pain regulation may be connected with primary afferent nerve, microglia, and astrocytes.¹⁶⁵ Oligodendrocyte-derived IL-33 in the dorsal SC plays an important role in neuropathic pain. IL-33 is increased in neuropathic pain model, and its receptor IL-33R (ST2) deficiency has been exhibited analgesic effects. IL-33-induced pain has been significantly alleviated through inhibition of PI3K, MAPKs (p38, ERK, and JNK), and NF-κB.¹⁶⁵

Following peripheral nerve injury (e.g. SNI), microglia are generally thought to activate before astrocytes. Microglia activation in the early stage is necessary for the initial generation of acute pain. Activated microglia secret pro-inflammatory mediators to increase sensitivity of nearby nociceptive neurons and astrocytes, resulting in astrogliosis, which contributes to the maintenance of chronic pain.⁵⁸ Understanding the role of inflammation in different stages is helpful for intervention selections for pain relief.

Neurons in the spinal cord

Chemokines combined with their receptors in spinal neurons contribute to the establishment and maintenance of chronic pain. For instance, CXCL1 and CCL2, which are expressed in spinal astrocytes, act respectively on CXCR2 and CCR2 in spinal neurons after spinal nerve ligation (SNL) to enhance excitatory synaptic transmission (astrocyte-to-neuron signal axis). CXCL13 in spinal neurons is also highly up-regulated after SNL and induces spinal astrocyte activation through its receptor CXCR5 (neuron-to-astrocyte signal axis).¹⁶⁶

Descending pathways have been revealed to modulate pain transmission in spinal cord, such as the anterior cingulate cortex (ACC)-spinal cord pathway, noradrenergic descending pathways, and dopaminergic descending pathways.^167–169 Descending pathway of the ACC-spinal cord facilitates SNI-induced neuropathic pain through a rostral ventromedial medulla (RVM)-independent manner.¹⁶⁷ Descending noradrenergic pathways also exert an inhibitory effect on pain transmission in chronic pain models.^170–172 Peripheral inflammation activates the descending noradrenergic pathways from the locus coeruleus (LC) to the spinal cord, which prevents the hyperalgesia development.¹⁷³ As a result of unilateral hind paw inflammation, descending NE-containing neurons in the LC are stimulated, increasing the level of NE in the ipsilateral dorsal horn.¹⁷⁴ A recent study has reported that activation of LC-spinal cord noradrenergic neurons alleviated neuropathic pain in mice via down-regulating the expression of pro-inflammatory cytokines (TNF-α and IL-1β), up-regulating the expression of anti-inflammatory cytokines (IL-4 and IL-10), and inhibiting activation of microglia and astrocytes in SDH.¹⁷⁵

Conclusion and prospects

Given the important role of inflammation (including neuroinflammation) in the induction and maintenance of chronic pain, it may be effective to directly target inflammation through cytokines, chemokines, and MAP kinase inhibitors. There are also possible side effects of these drugs, such as infection after long-term use and an inability to resolve inflammation. Thus, some alternative approaches that can control an excess of inflammation are emerging, including SPMs and cell therapies.

A large number of research suggest that microglia play a vital role in pain generation. When microglia are activated, pro-inflammatory and anti-inflammatory factors are produced in an imbalance. Therefore, discovering original ways to stimulate endogenous anti-inflammatory factors and inhibit pro-inflammatory factors may still be the challenge for researchers. It is generally known that increased production of pro-inflammatory cytokines (e.g. TNFα, IL-6, and IL-1β) mediates allodynia and hyperalgesia.¹⁷⁶ Thus, inhibiting microglial activation by decreasing the production of pro-inflammatory cytokines may have an analgesic effect. TNF-α blocker etanercept has been reported to reduce neuropathic pain in a rodent model of spinal cord injury through intrathecal administration,¹⁷⁷ and administration of etanercept to patients with severe sciatica also showed effective.¹⁷⁸ Administration of anti-IL-1β antibodies also demonstrated a reduce of neuropathic pain.¹⁷⁹

The chemokines not only regulate inflammation in the immune system, but also causes neuroinflammation in PNS and CNS, and promotes the initiation and maintenance of various types of chronic pain. Thus, the chemokine system provides an ideal candidate for treatments of chronic pain. According to the preclinical studies, there are three candidate directions for the therapeutic drugs targeting chemokine and its receptor: (1) blocking or neutralizing antibodies; (2) small-molecule inhibitors; (3) therapeutic small interfering RNA (siRNA). The antibodies of CGRP and its receptors have been used to treat migraine by subcutaneous or intravenous injection.¹⁸⁰ The small molecule CCR5 antagonist maraviroc has been observed to alleviate neuropathic pain in clinical practice.^181,182

Many studies have proved that SPMs can control inflammation effectively and hold the potential to suppress pain while promoting pain relief. However, the instability and high production cost of SPMs limits their direct application to patients.¹⁸³ Omega-3 fatty acids (such as DHA and EPA) derived from food are precursors of SPMs and have been shown to reduce inflammatory pain in patients, which may be through its own GPCRs, such as GRP120.^184,185 A randomized trial has shown that dietary omega-3 fatty acids may alleviate headaches in patients.¹⁸⁶ However, the efficacy of these SPMs precursors for pain relief is much lower compared to their metabolites. Thus, it will be promising to study the synergistic effects of SPM precursors from diet and neuromodulation on chronic pain will be promising, since it targets inflammation and neuroinflammation.

Currently, there has been a rise in gene therapy that is practiced in various inherited diseases in clinics. The recombinant adeno-associated virus (rAAV) is often used as a vector to deliver genes in gene therapy because the rAAV lacks any detrimental viral gene, does not integrate into the genome of humans, and provides persistent gene expression. With respect to the benefits of rAAV, gene therapy will be a promising treatment to tackle the ticklish chronic pain by silencing and increasing the pro-inflammatory and anti-inflammatory mediators, respectively.

Footnotes

Author contributions

Xiao-Xia Fang wrote the manuscript. Meng-Nan Zhai designed the tables. Meixuan Zhu participated in writing and editing the manuscript. Cheng He, Heng Wang, and Juan Wang drew the figures. Zhi-Jun Zhang initiated and supervised the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (NSFC) (31970938, 81571070) and the Natural Science Research Program of Jiangsu Province (BK20191448).

ORCID iD

Zhi-Jun Zhang

Appendix

References

Pahwa

Goyal

Jialal

. Chronic inflammation. Treasure Island FL: StatPearls, 2022.

Chamessian

Zhang

. Pain regulation by non-neuronal cells and inflammation. Science 2016; 354: 572–577.

Treede

Rief

Barke

Aziz

Bennett

Benoliel

Cohen

Evers

Finnerup

First

Giamberardino

Kaasa

Korwisi

Kosek

Lavandʼhomme

Nicholas

Perrot

Scholz

Schug

Smith

Svensson

Vlaeyen

JWS

Wang

. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the international classification of diseases (ICD-11). Pain 2019; 160: 19–27.

Dahlhamer

Lucas

Zelaya

Nahin

Mackey

DeBar

Kerns

Von Korff

Porter

Helmick

. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. MMWR Morb Mortal Wkly Rep 2018; 67: 1001–1006.

Fayaz

Croft

Langford

Donaldson

Jones

. Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies. BMJ Open 2016; 6: e010364.

Cohen

Vase

Hooten

. Chronic pain: an update on burden, best practices, and new advances. Lancet 2021; 397: 2082–2097.

Meucci

Fassa

Paniz

Silva

Wegman

. Increase of chronic low back pain prevalence in a medium-sized city of southern Brazil. BMC Musculoskelet Disord 2013; 14: 155.

Dellaroza

Pimenta

Duarte

Lebrao

. [Chronic pain among elderly residents in Sao Paulo, Brazil: prevalence, characteristics, and association with functional capacity and mobility (SABE study)]. Cad Saude Publica 2013; 29: 325–334.

Scherer

Hansen

Gensichen

Mergenthal

Riedel-Heller

Weyerer

Maier

Fuchs

Bickel

Schon

Wiese

Konig

van den Bussche

Schafer

. Association between multimorbidity patterns and chronic pain in elderly primary care patients: a cross-sectional observational study. BMC Fam Pract 2016; 17: 68.

10.

Yong

Mullins

Bhattacharyya

. Prevalence of chronic pain among adults in the United States. Pain 2022; 163: e328–e332.

11.

Bao

Seidman

Seluzicki

Blinder

Meghani

Farrar

Mao

. Living with chronic pain: perceptions of breast cancer survivors. Breast Cancer Res Treat 2018; 169: 133–140.

12.

Janah

Bouhnik

Touzani

Bendiane

Peretti-Watel

. Underprescription of step III opioids in french cancer survivors with chronic pain: a call for integrated early palliative care in oncology. J Pain Symptom Manage 2020; 59: 836–847.

13.

Sanford

Sher

Butler

Ahn

Aizer

Mahal

. Prevalence of chronic pain among cancer survivors in the United States, 2010–2017. Cancer 2019; 125: 4310–4318.

14.

Sharon

Greener

Hochberg

Brill

. The prevalence of chronic pain in the adult population in israel: an internet-based survey. Pain Res Manag 2022; 2022: 3903720.

15.

Wong

Fielding

. Prevalence and characteristics of chronic pain in the general population of Hong Kong. J Pain 2011; 12: 236–245.

16.

Muley

Krustev

McDougall

. Preclinical assessment of inflammatory pain. CNS Neurosci Ther 2016; 22: 88–101.

17.

Chen

Donnelly

. Regulation of pain by neuro-immune interactions between macrophages and nociceptor sensory neurons. Curr Opin Neurobiol 2020; 62: 17–25.

18.

Basbaum

Bautista

Scherrer

Julius

. Cellular and molecular mechanisms of pain. Cell 2009; 139: 267–284.

19.

Fang

Wang

Song

Wang

Zhang

. Neuroinflammation involved in diabetes-related pain and itch. Front Pharmacol 2022; 13: 921612.

20.

Xanthos

Sandkuhler

. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 2014; 15: 43–53.

21.

Hylands-White

Duarte

Raphael

. An overview of treatment approaches for chronic pain management. Rheumatol Int 2017; 37: 29–42.

22.

Han

Wang

Cao

Wang

Xie

Wang

Zheng

Luo

Han

. Tweety-homolog 1 facilitates pain via enhancement of nociceptor excitability and spinal synaptic transmission. Neurosci Bull 2021; 37: 478–496.

23.

Panigrahy

Gilligan

Serhan

Kashfi

. Resolution of inflammation: an organizing principle in biology and medicine. Pharmacol Ther 2021; 227: 107879.

24.

Chiang

Serhan

. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem 2020; 64: 443–462.

25.

Arnardottir

Thul

Pawelzik

Karadimou

Artiach

Gallina

Mysdotter

Carracedo

Tarnawski

Caravaca

Baumgartner

Ketelhuth

Olofsson

Paulsson-Berne

Hansson

Back

. The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection. J Clin Invest 2021; 131: e142883.

26.

Guo

Shen

Fei

. ResolvinD1 protects the airway barrier against injury induced by influenza a virus through the Nrf2 pathway. Front Cell Infect Microbiol 2020; 10: 616475.

27.

Xie

Wang

Liu

Wang

Yao

. ResolvinD1 reduces apoptosis and inflammation in primary human alveolar epithelial type 2 cells. Lab Invest 2016; 96: 526–536.

28.

Chattopadhyay

Raghavan

Rao

. Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function. Redox Biol 2017; 12: 438–455.

29.

Bang

Yoo

Yang

Cho

Kim

Hwang

. Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br J Pharmacol 2010; 161: 707–720.

30.

Spite

Norling

Summers

Yang

Cooper

Petasis

Flower

Perretti

Serhan

. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 2009; 461: 1287–1291.

31.

Park

Liu

Serhan

. Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1. J Neurosci 2011; 31: 18433–18438.

32.

Zhang

Liu

Zhu

Wen

Yang

Sun

. Resolvin D2 relieving radicular pain is associated with regulation of inflammatory mediators, Akt/GSK-3β signal pathway and GPR18. Neurochem Res 2018; 43: 2384–2392.

33.

Dort

Orfi

Fabre

Molina

Conte

Greffard

Pellerito

Bilodeau

Dumont

. Resolvin-D2 targets myogenic cells and improves muscle regeneration in duchenne muscular dystrophy. Nat Commun 2021; 12: 6264.

34.

Lee

Tonello

Jeon

Park

Ford

Davidson

Kim

Park

Berta

. Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis. Theranostics 2020; 10: 12111–12126.

35.

Kim

Joshi

Sheen

Kim

Kyung

Choi

Kim

Kwon

Roh

Choi

Sohn

Kim

Park

Kumar

Han

. Resolvin D3 promotes inflammatory resolution, neuroprotection, and functional recovery after spinal cord injury. Mol Neurobiol 2021; 58: 424–438.

36.

Cherpokova

Jouvene

Libreros

DeRoo

Chu

de la Rosa

Norris

Wagner

Serhan

. Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood 2019; 134: 1458–1468.

37.

Baggio

da Luz

FMR

Lopes

Ferreira

LEN

Araya

Chichorro

. Sex dimorphism in resolvin D5-induced analgesia in rat models of trigeminal pain. J Pain 2022; 24(5): 717–729.

38.

Pham

Kakazu

Nshimiyimana

Petasis

Jun

Bazan

HEP

. Elucidating the structure and functions of Resolvin D6 isomers on nerve regeneration with a distinctive trigeminal transcriptome. FASEB J 2021; 35: e21775.

39.

Siddiquee

Patel

Rajalingam

Narke

Kurade

Ponnoth

. Effect of omega-3 fatty acid supplementation on resolvin (RvE1)-mediated suppression of inflammation in a mouse model of asthma. Immunopharmacol Immunotoxicol 2019; 41: 250–257.

40.

Chen

Xia

Cheng

Zhang

. Resolvin E1 accelerates pulp repair by regulating inflammation and stimulating dentin regeneration in dental pulp stem cells. Stem Cell Res Ther 2021; 12: 75.

41.

Fukuda

Ikeda

Muromoto

Hirashima

Ishimura

Fujiwara

Aoki-Saito

Hisada

Watanabe

Ishihara

Matsuda

Shuto

. Synthesis of resolvin E3, a proresolving lipid mediator, and its deoxy derivatives: identification of 18-deoxy-resolvin e3 as a potent anti-inflammatory agent. J Org Chem 2020; 85: 14190–14200.

42.

Tang

Gao

Long

Huang

Chen

Fan

Jiang

. Maresin 1 mitigates high glucose-induced mouse glomerular mesangial cell injury by inhibiting inflammation and fibrosis. Mediators Inflamm 2017; 2017: 2438247.

43.

Dalli

Zhu

Vlasenko

Deng

Haeggstrom

Petasis

Serhan

. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J 2013; 27: 2573–2583.

44.

Fattori

Zaninelli

Ferraz

Brasil-Silva

Borghi

Cunha

Chichorro

Casagrande

Verri

Jr . Maresin 2 is an analgesic specialized pro-resolution lipid mediator in mice by inhibiting neutrophil and monocyte recruitment, nociceptor neuron TRPV1 and TRPA1 activation, and CGRP release. Neuropharmacology 2022; 216: 109189.

45.

Kohli

Levy

. Resolvins and protectins: mediating solutions to inflammation. Br J Pharmacol 2009; 158: 960–971.

46.

Serhan

Fredman

Yang

Karamnov

Belayev

Bazan

Zhu

Winkler

Petasis

. Novel proresolving aspirin-triggered DHA pathway. Chem Biol 2011; 18: 976–987.

47.

Butovich

. On the structure and synthesis of neuroprotectin D1, a novel anti-inflammatory compound of the docosahexaenoic acid family. J Lipid Res 2005; 46: 2311–2314.

48.

Minciullo

Catalano

Mandraffino

Casciaro

Crucitti

Maltese

Morabito

Lasco

Gangemi

Basile

. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz) 2016; 64: 111–126.

49.

Headland

Norling

. The resolution of inflammation: Principles and challenges. Semin Immunol 2015; 27: 149–160.

50.

Gao

. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 2014; 13: 533–548.

51.

Sommer

Leinders

Uceyler

. Inflammation in the pathophysiology of neuropathic pain. Pain 2018; 159: 595–602.

52.

Kong

Sha

Zhao

Gao

. CXCL10/CXCR3 signaling in the DRG exacerbates neuropathic pain in mice. Neurosci Bull 2021; 37: 339–352.

53.

Matsuda

Huh

. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth 2019; 33: 131–139.

54.

Chavez-Castillo

Ortega

Cudris-Torres

Duran

Rojas

Manzano

Garrido

Salazar

Silva

Rojas-Gomez

De Sanctis

Bermudez

. Specialized pro-resolving lipid mediators: the future of chronic pain therapy? Int J Mol Sci 2021; 22: 10370.

55.

Fattori

Pinho-Ribeiro

Staurengo-Ferrari

Borghi

Rossaneis

Casagrande

Verri

Jr . The specialised pro-resolving lipid mediator maresin 1 reduces inflammatory pain with a long-lasting analgesic effect. Br J Pharmacol 2019; 176: 1728–1744.

56.

Lallemend

Ernfors

. Molecular interactions underlying the specification of sensory neurons. Trends Neurosci 2012; 35: 373–381.

57.

Julius

Basbaum

. Molecular mechanisms of nociception. Nature 2001; 413: 203–210.

58.

Donnelly

Andriessen

Chen

Wang

Jiang

Maixner

. Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics 2020; 17: 846–860.

59.

Tran

Gillard

Hurley

Hammond

Miller

. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 2001; 21: 5027–5035.

60.

Dawes

Calvo

Perkins

Paterson

Kiesewetter

Hobbs

Kaan

Orengo

Bennett

McMahon

. CXCL5 mediates UVB irradiation-induced pain. Sci Transl Med 2011; 3: 90ra60.

61.

Nackley

Huh

Terrando

Maixner

. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 2018; 129: 343–366.

62.

Gold

Gebhart

. Nociceptor sensitization in pain pathogenesis. Nat Med 2010; 16: 1248–1257.

63.

De Logu

Geppetti

. Ion channel pharmacology for pain modulation. Handb Exp Pharmacol 2019; 260: 161–186.

64.

Hargreaves

Ruparel

. Role of oxidized lipids and trp channels in orofacial pain and inflammation. J Dent Res 2016; 95: 1117–1123.

65.

Shibata

Tang

. Implications of transient receptor potential cation channels in migraine pathophysiology. Neurosci Bull 2021; 37: 103–116.

66.

Cao

Zhang

Jiang

Zhao

Qian

Gao

. CXCL13/CXCR5 enhances sodium channel Nav1.8 current density via p38 MAP kinase in primary sensory neurons following inflammatory pain. Sci Rep 2016; 6: 34836.

67.

Hucho

Levine

. Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 2007; 55: 365–376.

68.

Pan

Liu

Lin

Zhang

. Modulation of Nav1.8 by lysophosphatidic acid in the induction of bone cancer pain. Neurosci Bull 2016; 32: 445–454.

69.

Kim

Coste

Chadha

Cook

Patapoutian

. The role of drosophila piezo in mechanical nociception. Nature 2012; 483: 209–212.

70.

. Demystifying mechanosensitive piezo Ion channels. Neurosci Bull 2016; 32: 307–309.

71.

Obata

Katsura

Mizushima

Yamanaka

Kobayashi

Dai

Fukuoka

Tokunaga

Tominaga

Noguchi

. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 2005; 115: 2393–2401.

72.

Jin

Gereau

RWt

. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci 2006; 26: 246–255.

73.

Liu

Chen

Wang

Yin

. TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation. Sci Rep 2016; 6: 28188.

74.

Huang

Hsu

Rosner

Rupert

Song

. Topical application of compound Ibuprofen suppresses pain by inhibiting sensory neuron hyperexcitability and neuroinflammation in a rat model of intervertebral foramen inflammation. J Pain 2011; 12: 141–152.

75.

Zhao

Jiang

Bai

Cao

Zhang

Guo

Chen

Wang

Gao

Zhang

. TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain in mice. Neurosci Bull 2021; 37: 550–562.

76.

Zhang

Ren

Guo

Liao

Luo

Chen

Zhang

Yang

Liao

Shen

Huang

Guo

Mei

Zuo

Liu

Yang

Jiang

. Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects. Cell Res 2022; 32: 461–476.

77.

Clements

Byrne

Camarillo Guerrero

Cattin

Zakka

Ashraf

Burden

Khadayate

Lloyd

Marguerat

Parrinello

. The wound microenvironment reprograms Schwann cells to invasive mesenchymal-like cells to drive peripheral nerve regeneration. Neuron 2017; 96: 98–114.

78.

Shamash

Reichert

Rotshenker

. The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 2002; 22: 3052–3060.

79.

Liedtke

. STING-ing pain: how can pro-inflammatory signaling attenuate pain? Neurosci Bull 2021; 37: 1075–1078.

80.

Wang

Shen

Guo

Bolick

Wang

. Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition. Exp Mol Med 2018; 50: e445.

81.

Yin

Chen

Wang

Zhu

Fan

. Interleukin-1 receptor associated kinase 1 mediates the maintenance of neuropathic pain after chronic constriction injury in rats. Neurochem Res 2019; 44: 1214–1227.

82.

Chen

Luo

Wang

Zhu

Wang

. Interleukin-1β promotes schwann cells de-differentiation in Wallerian degeneration via the c-JUN/AP-1 pathway. Front Cell Neurosci 2019; 13: 304.

83.

Calvo

Dawes

Bennett

. The role of the immune system in the generation of neuropathic pain. Lancet Neurol 2012; 11: 629–642.

84.

Stephenson

Byers

. GFAP immunoreactivity in trigeminal ganglion satellite cells after tooth injury in rats. Exp Neurol 1995; 131: 11–22.

85.

Hanani

Spray

. Emerging importance of satellite glia in nervous system function and dysfunction. Nat Rev Neurosci 2020; 21: 485–498.

86.

Warwick

Hanani

. The contribution of satellite glial cells to chemotherapy-induced neuropathic pain. Eur J Pain 2013; 17: 571–580.

87.

Huang

Belzer

Hanani

. Gap junctions in dorsal root ganglia: possible contribution to visceral pain. Eur J Pain 2010; 14: 49.e1–49.e11.

88.

Blum

Procacci

Conte

Hanani

. Systemic inflammation alters satellite glial cell function and structure. A possible contribution to pain. Neuroscience 2014; 274: 209–217.

89.

Burnstock

. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 2007; 87: 659–797.

90.

Fields

Burnstock

. Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 2006; 7: 423–436.

91.

Zhang

Chen

Wang

Huang

. Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci USA 2007; 104: 9864–9869.

92.

Vit

Ohara

Bhargava

Kelley

Jasmin

. Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. J Neurosci 2008; 28: 4161–4171.

93.

Takeda

Takahashi

Nasu

Matsumoto

. Peripheral inflammation suppresses inward rectifying potassium currents of satellite glial cells in the trigeminal ganglia. Pain 2011; 152: 2147–2156.

94.

Tang

Schmidt

Perez-Leighton

Kofuji

. Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia. Neuroscience 2010; 166: 397–407.

95.

Huang

Chen

. Communication between neuronal somata and satellite glial cells in sensory ganglia. Glia 2013; 61: 1571–1581.

96.

Souza

Talbot

Lotufo

Cunha

Ferreira

. Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci USA 2013; 110: 11193–11198.

97.

Afroz

Arakaki

Iwasa

Oshima

Hosoki

Inoue

Baba

Okayama

Matsuka

. CGRP induces differential regulation of cytokines from satellite glial cells in trigeminal ganglia and orofacial nociception. Int J Mol Sci 2019; 20: 711.

98.

Mitterreiter

Ouwendijk

WJD

van Velzen

van Nierop

Osterhaus

Verjans

. Satellite glial cells in human trigeminal ganglia have a broad expression of functional toll-like receptors. Eur J Immunol 2017; 47: 1181–1187.

99.

Lin

Zhang

Liu

Fang

Liu

Huang

Wang

Liao

Zhou

Shen

. The P2Y(14) receptor in the trigeminal ganglion contributes to the maintenance of inflammatory pain. Neurochem Int 2019; 131: 104567.

100.

Rittner

Hackel

Voigt

Mousa

Stolz

Labuz

Schafer

Schaefer

Stein

Brack

. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog 2009; 5: e1000362.

101.

Castanheira

FVS

Kubes

. Neutrophils and NETs in modulating acute and chronic inflammation. Blood 2019; 133: 2178–2185.

102.

Parisien

Lima

Dagostino

El-Hachem

Drury

Grant

Huising

Verma

Meloto

Silva

Dutra

GGS

Markova

Dang

Tessier

Slade

Nackley

Ghasemlou

Mogil

Allegri

Diatchenko

. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med 2022; 14: eabj9954.

103.

Ouyang

Zhang

Kuang

Yang

Jin

Yang

Xie

Tan

Chen

Jiang

Liu

Luo

Chen

. Pulsed electromagnetic field inhibits synovitis via enhancing the efferocytosis of macrophages. Biomed Res Int 2020; 2020: 4307385.

104.

Domoto

Sekiguchi

Tsubota

Kawabata

. Macrophage as a Peripheral Pain Regulator. Cells 2021; 10: 1881.

105.

Tan

Lin

Zhou

. The macrophage IL-23/IL-17A pathway: a new neuro-immune mechanism in female mechanical pain. Neurosci Bull 2022; 38: 453–455.

106.

Hogg

Horne

Greaves

. Endometriosis-associated macrophages: origin, phenotype, and function. Front Endocrinol (Lausanne) 2020; 11: 7.

107.

Zelenka

Schafers

Sommer

. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 2005; 116: 257–263.

108.

Jiang

Liu

Gao

. Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Pharmacol Ther 2020; 212: 107581.

109.

Zhu

Cao

Zhu

Liu

Chen

Gao

. Contribution of chemokine CCL2/CCR2 signaling in the dorsal root ganglion and spinal cord to the maintenance of neuropathic pain in a rat model of lumbar disc herniation. J Pain 2014; 15: 516–526.

110.

Zhu

Gao

. CCL2/CCR2 contributes to the altered excitatory-inhibitory synaptic balance in the nucleus accumbens shell following peripheral nerve injury-induced neuropathic pain. Neurosci Bull 2021; 37: 921–933.

111.

Davies

Jenkins

Allen

Taylor

. Tissue-resident macrophages. Nat Immunol 2013; 14: 986–995.

112.

Wynn

Vannella

. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 2016; 44: 450–462.

113.

Shapouri-Moghaddam

Mohammadian

Vazini

Taghadosi

Esmaeili

Mardani

Seifi

Mohammadi

Afshari

Sahebkar

. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018; 233: 6425–6440.

114.

Baral

Udit

Chiu

. Pain and immunity: implications for host defence. Nat Rev Immunol 2019; 19: 433–447.

115.

Sekiguchi

Domoto

Nakashima

Yamasoba

Yamanishi

Tsubota

Wake

Nishibori

Kawabata

. Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice: evidence for a neuroimmune crosstalk. Neuropharmacology 2018; 141: 201–213.

116.

Nishida

Tsubota

Kawaishi

Yamanishi

Kamitani

Sekiguchi

Ishikura

Liu

Nishibori

Kawabata

. Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats. Toxicology 2016; 365: 48–58.

117.

Tsujita

Tsubota

Sekiguchi

Kawabata

. Role of high-mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain. Br J Pharmacol 2021; 178: 798–812.

118.

Yamasoba

Tsubota

Domoto

Sekiguchi

Nishikawa

Liu

Nishibori

Ishikura

Yamamoto

Taga

Kawabata

. Peripheral HMGB1-induced hyperalgesia in mice: redox state-dependent distinct roles of RAGE and TLR4. J Pharmacol Sci 2016; 130: 139–142.

119.

Irie

Tsubota

Ishikura

Sekiguchi

Terada

Tsujiuchi

Liu

Nishibori

Kawabata

. Macrophage-derived HMGB1 as a pain mediator in the early stage of acute pancreatitis in mice: targeting RAGE and CXCL12/CXCR4 axis. J Neuroimmune Pharmacol 2017; 12: 693–707.

120.

Bang

Xie

Zhang

Wang

. GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J Clin Invest 2018; 128: 3568–3582.

121.

. Specialized pro-resolving mediators as resolution pharmacology for the control of pain and itch. Annu Rev Pharmacol Toxicol 2023; 63: 273–293.

122.

Wang

Zhao

Wen

Wang

Sun

. A novel mechanism of specialized proresolving lipid mediators mitigating radicular pain: the negative interaction with NLRP3 inflammasome. Neurochem Res 2020; 45: 1860–1869.

123.

Zhang

Jia

Sun

. The roles of special proresolving mediators in pain relief. Rev Neurosci 2018; 29: 645–660.

124.

Serhan

Chiang

Dalli

. The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Semin Immunol 2015; 27: 200–215.

125.

Martini

Berta

Forner

Chen

Bento

Rae

. Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J Neuroinflammation 2016; 13: 75.

126.

Fattori

Zaninelli

Rasquel-Oliveira

Casagrande

Verri

Jr . Specialized pro-resolving lipid mediators: a new class of non-immunosuppressive and non-opioid analgesic drugs. Pharmacol Res 2020; 151: 104549.

127.

Zhang

Liu

Park

Berta

Yang

Serhan

. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat Med 2010; 16: 592–597. 1p following 597.

128.

Lim

Park

Hwang

. Biological roles of resolvins and related substances in the resolution of pain. Biomed Res Int 2015; 2015: 830930.

129.

Serhan

Dalli

Karamnov

Choi

Park

Zhu

Petasis

. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J 2012; 26: 1755–1765.

130.

Park

Liu

Serhan

. Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci 2011; 31: 15072–15085.

131.

Gao

. Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010; 7: 482–493.

132.

Xiang

Wang

Shao

Fang

Wang

Sun

Liu

Fang

. Electroacupuncture stimulation alleviates CFA-induced inflammatory pain via suppressing P2X3 expression. Int J Mol Sci 2019; 20: 3248.

133.

Berta

Nedergaard

. Glia and pain: is chronic pain a gliopathy? Pain 2013; 154(Suppl 1): S10–S28.

134.

Gosselin

Suter

Decosterd

. Glial cells and chronic pain. Neuroscientist 2010; 16: 519–531.

135.

Parusel

Hunt

. Chemogenetic and optogenetic manipulations of microglia in chronic pain. Neurosci Bull 2023; 39: 368–378.

136.

Wei

Piirainen

Chen

Kalso

Pertovaara

Tian

. Spinal versus brain microglial and macrophage activation traits determine the differential neuroinflammatory responses and analgesic effect of minocycline in chronic neuropathic pain. Brain Behav Immun 2016; 58: 107–117.

137.

Song

Xiong

Guan

Cao

Manyande

Zhou

Zheng

Tian

. Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes. Acta Pharmacol Sin 2016; 37: 753–762.

138.

Zhu

Zhao

Wang

Gao

Zhang

. Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain. Brain Res Bull 2014; 109: 54–60.

139.

Chen

Zhang

Qadri

Serhan

. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 2018; 100: 1292–1311.

140.

Guan

Kuhn

Wang

Colquitt

Solorzano

Vaman

Guan

Evans-Reinsch

Braz

Devor

Abboud-Werner

Lanier

Lomvardas

Basbaum

. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 2016; 19: 94–101.

141.

Abbadie

Bhangoo

De Koninck

Malcangio

Melik-Parsadaniantz

White

. Chemokines and pain mechanisms. Brain Res Rev 2009; 60: 125–134.

142.

Berta

Park

Xie

Liu

. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion. J Clin Invest 2014; 124: 1173–1186.

143.

Yang

Xie

Zhu

. Specialized microglia resolve neuropathic pain in the spinal cord. Neurosci Bull 2023; 39: 173–175.

144.

Grace

Strand

Galer

Urban

Wang

Baratta

Fabisiak

Anderson

Cheng

Greene

Berkelhammer

Zhang

Ellis

Yin

Campeau

Rice

Roth

Maier

Watkins

. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci USA 2016; 113: E3441–E3450.

145.

Raghavendra

Tanga

DeLeo

. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003; 306: 624–630.

146.

Kohno

Shirasaka

Yoshihara

Mikuriya

Tanaka

Takanami

Inoue

Sakamoto

Ohkawa

Masuda

Tsuda

. A spinal microglia population involved in remitting and relapsing neuropathic pain. Science 2022; 376: 86–90.

147.

Asatryan

Bazan

. Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. J Biol Chem 2017; 292: 12390–12397.

148.

Thion

Low

Silvin

Chen

Grisel

Schulte-Schrepping

Blecher

Ulas

Squarzoni

Hoeffel

Coulpier

Siopi

David

Scholz

Shihui

Lum

Amoyo

Larbi

Poidinger

Buttgereit

Lledo

Greter

Chan

JKY

Amit

Beyer

Schultze

Schlitzer

Pettersson

Ginhoux

Garel

. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 2018; 172: 500–516.

149.

Xie

Luo

Qiu

. Resolution of inflammatory pain by endogenous chemerin and g protein-coupled receptor ChemR23. Neurosci Bull 2021; 37: 1351–1356.

150.

Berta

. Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J Neuroimmune Pharmacol 2013; 8: 37–41.

151.

Arita

Bianchini

Aliberti

Sher

Chiang

Hong

Yang

Petasis

Serhan

. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 2005; 201: 713–722.

152.

Furutani

. Targeting Hv1 proton channel for pain control. Cell Res 2022; 32: 419–420.

153.

Zhang

Luo

Zhu

. The role of P2X4 receptors in chronic pain: a potential pharmacological target. Biomed Pharmacother 2020; 129: 110447.

154.

Sun

Jiang

Yan

. Ligand-gated ion channel P2X7 regulates NLRP3/caspase-1-mediated inflammatory pain caused by pulpitis in the trigeminal ganglion and medullary dorsal horn. Brain Res Bull 2023; 192: 1–10.

155.

Liu

Lan

Zang

Feng

Zhao

Yang

Xie

Wang

Ver Heul

Chen

Samineni

Wang

Lavine

Gereau

RWt

. A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain. J Clin Invest 2023; 133: e161507.

156.

Donnelly

Nedergaard

. Astrocytes in chronic pain and itch. Nat Rev Neurosci 2019; 20: 667–685.

157.

Zhang

. Targeting GATA1 and p2x7r locus binding in spinal astrocytes suppresses chronic visceral pain by promoting DNA demethylation. Neurosci Bull 2022; 38: 359–372.

158.

Eng

Ghirnikar

Lee

. Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 2000; 25: 1439–1451.

159.

Zhang

De Koninck

. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006; 97: 772–783.

160.

Watkins

Martin

Ulrich

Tracey

Maier

. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 1997; 71: 225–235.

161.

Okada-Ogawa

Suzuki

Sessle

Chiang

Salter

Dostrovsky

Tsuboi

Kondo

Kitagawa

Kobayashi

Noma

Imamura

Iwata

. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 2009; 29: 11161–11171.

162.

Gao

. Astrocytes in chronic pain: cellular and molecular mechanisms. Neurosci Bull 2023; 39: 425–439.

163.

Urits

Adamian

Fiocchi

Hoyt

Ernst

Kaye

Viswanath

. Advances in the understanding and management of chronic pain in multiple sclerosis: a comprehensive review. Curr Pain Headache Rep 2019; 23: 59.

164.

Gritsch

Thilemann

Wortge

Mobius

Bruttger

Karram

Ruhwedel

Blanfeld

Vardeh

Waisman

Nave

Kuner

. Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice. Nat Commun 2014; 5: 5472.

165.

Zarpelon

Rodrigues

Lopes

Souza

Carvalho

Pinto

Ferreira

Alves-Filho

McInnes

Ryffel

Quesniaux

Reverchon

Mortaud

Menuet

Liew

Cunha

Verri

Jr . Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain. FASEB J 2016; 30: 54–65.

166.

Zhang

Jiang

Gao

. Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci 2017; 74: 3275–3291.

167.

Chen

Taniguchi

Chen

Tozaki-Saitoh

Song

Liu

Koga

Matsuda

Kaito-Sugimura

Wang

Inoue

Tsuda

Nakatsuka

Zhuo

. Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. Nat Commun 2018; 9: 1886.

168.

Liu

Tao

. Role of descending dopaminergic pathways in pain modulation. Curr Neuropharmacol 2019; 17: 1176–1182.

169.

Llorca-Torralba

Borges

Neto

Mico

Berrocoso

. Noradrenergic locus coeruleus pathways in pain modulation. Neuroscience 2016; 338: 93–113.

170.

Caputi

Nicora

Simeone

Candeletti

Romualdi

. Tapentadol: an analgesic that differs from classic opioids due to its noradrenergic mechanism of action. Minerva Med 2019; 110: 62–78.

171.

Hayashida

Obata

. Strategies to treat chronic pain and strengthen impaired descending noradrenergic inhibitory system. Int J Mol Sci 2019; 20: 822.

172.

Pertovaara

. The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol 2013; 716: 2–7.

173.

Maeda

Tsuruoka

Hayashi

Nagasawa

Inoue

. Descending pathways from activated locus coeruleus/subcoeruleus following unilateral hindpaw inflammation in the rat. Brain Res Bull 2009; 78: 170–174.

174.

Tsuruoka

Hitoto

Hiruma

Matsui

. Neurochemical evidence for inflammation-induced activation of the coeruleospinal modulation system in the rat. Brain Res 1999; 821: 236–240.

175.

Wei

Zhou

Zou

Liu

Xiao

Liu

Tan

Cao

. Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. J Neuroinflammation 2022; 19: 123.

176.

Watkins

Milligan

Maier

. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol 2003; 521: 1–21.

177.

Marchand

Tsantoulas

Singh

Grist

Clark

Bradbury

McMahon

. Effects of etanercept and minocycline in a rat model of spinal cord injury. Eur J Pain 2009; 13: 673–681.

178.

Genevay

Stingelin

Gabay

. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Ann Rheum Dis 2004; 63: 1120–1123.

179.

Wang

Yuan

Fan

. Interleukin-1 beta of Red nucleus involved in the development of allodynia in spared nerve injury rats. Exp Brain Res 2008; 188: 379–384.

180.

Charles

Pozo-Rosich

. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 2019; 394: 1765–1774.

181.

Piotrowska

Kwiatkowski

Rojewska

Makuch

Mika

. Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - evidence from in vivo and in vitro studies. Neuropharmacology 2016; 108: 207–219.

182.

Matsushita

Tozaki-Saitoh

Kojima

Masuda

Tsuda

Inoue

Hoka

. Chemokine (C-C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain. Anesthesiology 2014; 120: 1491–1503.

183.

Tao

Lee

Donnelly

. Neuromodulation, specialized proresolving mediators, and resolution of pain. Neurotherapeutics 2020; 17: 886–899.

184.

Goldberg

Katz

. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 2007; 129: 210–223.

185.

Talukdar

Bae

Imamura

Morinaga

Fan

Watkins

Olefsky

. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010; 142: 687–698.

186.

Ramsden

Faurot

Zamora

Palsson

MacIntosh

Gaylord

Taha

Rapoport

Hibbeln

Davis

Mann

. Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain 2015; 156: 587–596.

Inflammation in pathogenesis of chronic pain: Foe and friend

Abstract

Keywords

Introduction

Peripheral inflammation contributes to the pathogenesis of chronic pain

Pain modulation by various cells in PNS

Neurons

Peripheral glial cells: Schwann cells and satellite glial cells

Neutrophils and macrophages

Specialized pro-resolving mediators

Central inflammation contributes to the pathogenesis of chronic pain

Pain modulation by central glial cells

Neurons in the spinal cord

Conclusion and prospects

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

Appendix

References