Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Scandinavian Journal of Pain

Official Journal of the Scandinavian Association for the Study of Pain

Editor-in-Chief: Breivik, Harald


CiteScore 2018: 0.85

SCImago Journal Rank (SJR) 2018: 0.494
Source Normalized Impact per Paper (SNIP) 2018: 0.427

Online
ISSN
1877-8879
See all formats and pricing
More options …
Volume 19, Issue 4

Issues

Low-grade inflammation causes gap junction-coupled cell dysfunction throughout the body, which can lead to the spread of systemic inflammation

Elisabeth Hansson
  • Corresponding author
  • Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Blå Stråket 7, 3rd Floor, SE 413 45 Gothenburg, Sweden, Phone: +46-31-786 3363
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Eva Skiöldebrand
  • Section of Pathology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
  • Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-06-28 | DOI: https://doi.org/10.1515/sjpain-2019-0061

Abstract

Background and aims

Gap junction-coupled cells form networks in different organs in the body. These networks can be affected by inflammatory stimuli and become dysregulated. Cell signaling is also changed through connexin-linked gap junctions. This alteration affects the surrounding cells and extracellular matrix in organs. These changes can cause the spread of inflammatory substances, thus affecting other network-linked cells in other organs in the body, which can give rise to systemic inflammation, which in turn can lead to pain that can turn into chronic.

Methods

This is a review based on literature search and our own research data of inflammatory stimuli that can affect different organs and particularly gap-junction-coupled cells throughout the body.

Conclusions

A remaining question is which cell type or tissue is first affected by inflammatory stimuli. Can endotoxin exposure through the air, water and body start the process and are mast cells the first target cells that have the capacity to alter the physiological status of gap junction-coupled cells, thereby causing breakdown of different barrier systems?

Implications

Is it possible to address the right cellular and biochemical parameters and restore inflammatory systems to a normal physiological level by therapeutic strategies?

Keywords: low-grade inflammation; systemic inflammation; gap junction-coupled cell networks; Ca2+ signaling; endotoxins; Toll-like receptors

1 Introduction

The oral cavity and gut are complex units with a wide range of microorganisms, such as bacteria, viruses, fungi, protozoa and archaea; these microorganisms can influence these entities and by extension, influence systemic health [1], [2]. Low-grade inflammation can become chronic. Chronic inflammation can in turn lead to systemic inflammation and systemic diseases outside these units, such as cardiovascular diseases, arthritic diseases, neurodegenerative diseases, and diabetes [1], [3]. A low-grade systemic inflammation can lead to pain if the inflammation does not heal. The pain can persist and develop into chronic pain. This review focuses on endotoxin exposure in the human body, the importance of gap junction-coupled cells and how these cells are involved in inflammatory processes. Gap junction-coupled cells are found in virtually all organs in the body and react similarly in inflammatory situations in vitro. The question is how these cells are affected in the event of a foreign substance attack. Are other cells targeted first and alter the physiological status of gap junction-coupled cells? Moreover, can the disruption of gap junction-coupled cell networks lead to low-grade inflammation that can become chronic and systemic?

2 Methods

The review is based on literature search (PubMed) as well as our own research data of inflammatory stimuli that can affect different organs and particularly gap-junction-coupled cells throughout the body. Some clinical implications are discussed where low-grade inflammatory stimuli can develop into pain.

3 Causes of inflammation and low-grade inflammation

Invading bacteria, viruses, and parasitic infections can cause inflammation, and the acute phase is defined as the initial pathogen invasion of any organ, which can take hours to weeks depending on the pathogen and route of infection. Mucosal immunity in the gut and oral cavity is of interest. The innate immune system is activated, and a cascade of physiological events can rapidly affect the central nervous system (CNS).

For decades, determining the initial beginning and location of an inflammatory process has been a concern in science. The oral cavity [2] and various key elements of intestinal function, such as digestion, absorption, and barrier functions, are potential initiators of inflammation [4]. However, what is the starting signal for an inflammatory process to develop into low-grade inflammation, which in the longer term can lead to chronic pain will be discussed (Fig. 1).

Inflammation is a physiological response to injury that is designed to remove dangerous stimuli. Low-grade inflammation can be initiated in vivo after traumatic injury or in chronic diseases such as neurodegenerative, metabolic and autoimmune diseases. Gap junction-coupled network cells can be targeted, leading to the spread of inflammation and changes in biochemical cellular parameters. Astrocytes in the CNS are the most well-studied network-coupled cells that play a pivotal role in chronic neuroinflammation. This process in turn affects the surrounding cells in organs. These issues can cause the spread of inflammatory substances, thus affecting other network-linked cells in other organs in the body, which can cause systemic inflammation. Inducers of inflammation trigger the production of inflammatory mediators, which alter the functionality of tissues and organs and lead to harmful changes in different barrier systems.
Fig. 1:

Inflammation is a physiological response to injury that is designed to remove dangerous stimuli. Low-grade inflammation can be initiated in vivo after traumatic injury or in chronic diseases such as neurodegenerative, metabolic and autoimmune diseases. Gap junction-coupled network cells can be targeted, leading to the spread of inflammation and changes in biochemical cellular parameters. Astrocytes in the CNS are the most well-studied network-coupled cells that play a pivotal role in chronic neuroinflammation. This process in turn affects the surrounding cells in organs. These issues can cause the spread of inflammatory substances, thus affecting other network-linked cells in other organs in the body, which can cause systemic inflammation. Inducers of inflammation trigger the production of inflammatory mediators, which alter the functionality of tissues and organs and lead to harmful changes in different barrier systems.

3.1 The oral cavity

An interrelationship between oral bacteria and several diseases that can lead to systemic diseases has been discussed for a long time, and the teeth are the focus of infection [5]. The oral mucosa is exposed to a high diversity of microorganisms. However, the mucosa must be penetrated or damaged before antigens can modulate oral microbiome homeostasis. Nonetheless, the oral mucosa can be clinically asymptomatic but contain pathogenic bacteria. Both aerobic and anaerobic bacterial colonization exist and can act as a reservoir of inflammatory mediators such as tumor necrosis factor α (TNF-α) and interleukins, which can be released into the circulation from the diseased periodontium and be transported to distant sites of the body and cause different types of inflammatory diseases in susceptible individuals [6]. Examples of these diseases include pulmonary diseases, circulatory diseases, arthritic diseases, diabetes, and neurodegenerative diseases [3]. Moreover, proinflammatory cells and cytokines from the oral cavity can spread to the systemic circulation and increase the risk of inflammation at distant anatomical sites, such as joints and salivary glands [7]. When normal immune function becomes dysregulated during inflammation, autoantibodies can be produced [8]. For example, in rheumatoid arthritis (RA), an autoimmune response to citrullinated proteins can result in inflammation of the articular synovium and progressive destruction of cartilage and bone, which can be very painful [9], [10]. Smoking affects the oral microbiome and creates a pathogen-rich ecosystem [11]. In addition to the presence of citrullinated autoantibodies in RA, periodontitis and citrullination are strongly correlated in smokers [12], [13].

3.2 The gut

The gut microbiota is complex, and the amount of bacteria increases from the stomach through the intestines and reaches its optimum level in the colon. Genetics as well as the diet can influence the bacterial composition, thereby affecting immune cells and the immune system in the gut, which might cause low-grade inflammation [14], [15]. Helicobacter pylori in the stomach have been related to diseases outside the gut, and some of these diseases have been related to low-grade inflammation. Examples include cardiovascular diseases, hematological diseases, neurodegenerative diseases, respiratory diseases, ophthalmological diseases, otorhinolaryngologic diseases, and pancreatic diseases (for further information, see [1]). Helicobacter pylori can induce problems affecting the brain-gut axis, which integrates the central, peripheral, enteric, and autonomic nervous systems, as well as the endocrine and immunological systems. Moreover, disturbances in the upper and lower digestive system tract can cause irritable bowel syndrome [16]. Helicobacter pylori have neurotoxic effects that can cause neurogenic low-grade inflammation. In these inflammatory processes, two cell types are potentially important: mast cells and microfold cells (M-cells) [17]. Tropheryma whipplei associated with human leukocyte antigen (HLA) in the intestine has been shown to disrupt the gut-joint axis and cause recurrent inflammatory processes in the joints in patients [18].

Alterations in the gut microbiota might trigger the onset of osteoarthritis (OA) through low-grade inflammation, which becomes chronic. The activity of a new metabolic OA phenotype has been suggested [15]. Overall, OA is a low-grade chronic inflammatory disease of the articular cartilage that results in pain and joint disability [19].

4 Endotoxins

Chronic exposure to low concentrations of endotoxins may give rise to symptoms originating from different organs. Low-grade inflammation can be established by subclinical doses of circulating bacterial endotoxins [20] (Fig. 2).

The role of immunological factors in the pathogenesis of chronic diseases has not been fully clarified; however, they share a systemic inflammatory response. Low-grade chronic inflammation with elevations of serum pro-inflammatory markers has been shown in patients with OA, coronary heart disease, hypertension and Alzheimer’s disease. Several organs in the body comprise cells coupled into networks that communicate with each other through gap junctions. Examples of such cellular networks are astrocytes in the brain, keratinocytes in the skin and buccal membranes, chondrocytes and tenocytes in the articular cartilage and ligaments, connective tissue cells such as epithelial cells in several organs, and cardiac myofibroblasts in the heart. The body is exposed to endotoxins via inhalation, drinking water, food, and the oral cavity and microbiota in the intestine can also serve as a reservoir. Systematic inflammation affects network-coupled cells, which become inflamed and disrupted with a risk for further spread of inflammation throughout the body. The illustration was made by Pontus Andersson, ArtProduction, Gothenburg, Sweden.
Fig. 2:

The role of immunological factors in the pathogenesis of chronic diseases has not been fully clarified; however, they share a systemic inflammatory response. Low-grade chronic inflammation with elevations of serum pro-inflammatory markers has been shown in patients with OA, coronary heart disease, hypertension and Alzheimer’s disease. Several organs in the body comprise cells coupled into networks that communicate with each other through gap junctions. Examples of such cellular networks are astrocytes in the brain, keratinocytes in the skin and buccal membranes, chondrocytes and tenocytes in the articular cartilage and ligaments, connective tissue cells such as epithelial cells in several organs, and cardiac myofibroblasts in the heart. The body is exposed to endotoxins via inhalation, drinking water, food, and the oral cavity and microbiota in the intestine can also serve as a reservoir. Systematic inflammation affects network-coupled cells, which become inflamed and disrupted with a risk for further spread of inflammation throughout the body. The illustration was made by Pontus Andersson, ArtProduction, Gothenburg, Sweden.

There is a certain risk of inhaling endotoxins, including airborne particles and aerosols. The indoor environments of water-damaged buildings contain a complex mixture of mycotoxins and different types of bacteria, such as endotoxins. Acute exposures can give rise to influenza-like reactions, such as toxic pneumonia. Chronic exposure might cause a multisystem illness referred to as “sick building syndrome”, triggering a pro-inflammatory cytokine response in the occupants. This syndrome can result in elevated leptins and decreased levels of alpha melanocyte-stimulating hormone (MSH), indicating involvement of the hypothalamus as well as deficits in neurologic function [21].

Endotoxins have been detected in 800 Swedish tap water samples, which gave rise to symptoms such as pneumonitis [22]. Endotoxin activity has also been observed in drinking water at healthcare facilities in Japan [23].

Impaired gut barrier function has been associated with increased serum concentrations of lipopolysaccharide (LPS). This issue has been observed in healthy men who showed large variations in gut permeability. Increased gut permeability was associated with elevated serum HDL-cholesterol, which was associated with serum endotoxemia and low-grade systemic inflammation [24]. Enhanced gut permeability seems to be implicated in increasing circulating levels of LPS and a further link to increased platelet activation in patients with pneumonia complicated by cardiovascular events [25].

5 Toll-like receptors

Toll-like receptor (TLR) proteins play key roles in innate immune responses against infection. Recognition molecules bind to molecular structures in large groups of pathogens and are called pathogen-associated molecular patterns derived from invading bacteria or viruses. The TLRs belong to one of the most important pattern recognition receptor families. Currently, at least 13 different TLRs have been identified [26]. The first TLR identified was TLR4, which induces the activation and expression of NF-κB and the generation of inflammatory cytokines [27] that are important for the inflammatory system. TLRs trigger inflammation and stimulate glial cells that induce proinflammatory mediators and cytokines [28]. TLR4 is present on astrocytes and increases its expression after LPS induction [29]. TLR4 is most likely present on all cells involved in immune function [26], including gap junction-coupled cells. Examples of these cells include chondrocytes [30], cardiac fibroblasts [31], keratinocytes [32], and tenocytes [33]. TLRs are involved in the pathogenesis of autoimmune disease, chronic inflammatory and infectious diseases, leading to overproduction of autoantibodies [34]. In OA, due to inflammation, cartilage matrix degradation leads to protein fragmentation. These fragments can act as danger-associated molecular patterns and as well as activate TLRs. Thus, persistent inflammation results in chronic activation of the innate immune response [35].

6 Gap junction-coupled cells

Gap junction-coupled cells are found in various organs throughout the body [36] (Fig. 2). These cells are typically connected through connexin-based gap junction channels. Several connexins have been discovered, but the major constituent of gap junction channels seems to be connexin 43 (Cx43), and astrocytes in the CNS are the best studied gap junction-coupled cells [37]. Gap junction channels are pore-forming and composed of two hemichannels or connexons that face each other to enable cell-to-cell communication. These channels form a ring of six protein subunits called connexins. Molecules less than 1.5 kDA can pass through these channels. The occurrence of electrical coupling has also been demonstrated [38]. Additionally, communication between astrocytes via Ca2+ waves was identified [39] with a velocity of approximately 15–20 μm/s [40]. These findings led to a proposal of syncytium-like organization. Intracellular Ca2+ release is controlled by different signaling pathways that can be stimulated by different neurotransmitters, such as ATP, glutamate and 5-HT [40], [41], [42].

Hemichannels are located at the cell surface and allow the exchange of ions and signaling molecules between the cytoplasm and extracellular medium. These channels support the uptake and release of metabolites and autocrine and paracrine communication called “gliotransmission” [43], [44], [45]. Hemichannel opening is triggered by inflammatory mediators such as the endotoxin LPS, but it does not appear to alter gap junction communication. As a consequence of hemichannel opening, enhanced glutamate release through hemichannels is observed [46]. Furthermore, the ATP concentration increases, which results in increased ATP release through hemichannels and paracrine and autocrine stimulation of purinergic receptors, resulting in increased intracellular evoked Ca2+ release and extracellular Ca2+ signaling [47].

The cells forming gap junction-coupled syncytium networks can be targets leading to the spread of inflammation and changes in biochemical cellular parameters [36]. These cells control extracellular and intracellular homeostasis at all levels of the CNS and may also contribute to the homeostasis of the other nervous systems in the body [48], [49]. The strategic organization of astrocytes from the cellular level to whole organ level plays a pivotal role in chronic neuroinflammation [50], [51].

During inflammation, the expression and affinities of several receptors, particularly inflammatory receptors such as TLR4, the substance P receptor NK-1 and the tryptase receptor PAR-2, are changed [52]. The cytoskeleton is disrupted, and Ca2+ signaling is elevated, resulting in increased ATP production, thereby changing the balance of Ca2+-regulating processes [29], [53], [54], [55]. Increased release of ATP through Cx43 hemichannels causes Ca2+ propagation mediated by extracellular paracrine signaling [53]. This change in Ca2+ signaling causes reduced communication between cells via gap junctions [56]. Furthermore, Na+ transporters are downregulated at the cellular level [57], increased release of proinflammatory cytokines is observed [29], and the metabolic pump Na+/K+-ATPase is downregulated [58], [59].

Astrocytes are gap junction-coupled cells in the nervous system, and these cellular networks have long been proposed to lead to the spread of inflammation and changes in many cellular biochemical parameters [36], [50], [56], [60], [61], [62] (Fig. 2).

Gap junctions and Cx43 are also present in musculoskeletal tissues such as bone, cartilage, tendon and ligaments [63]. The bone cells, osteoblasts, osteocytes and osteoclasts, express Cx43, and gap junction communication seems to be important between osteoblasts for bone differentiation. Gap junction coupling has also been observed between osteoblasts and osteocytes, which might contribute to mechano-transduction [64] (Fig. 2).

The mucosa lines the epithelium and serves as a barrier that separates the lumen from the organ in most organs in the body, including the alimentary canal, respiratory tract, genitourinary tract, and oral cavity. Epithelial cells are connected through tight junctions, adherens junctions and gap junctions, and continuous endocytosis and recycling of junctional proteins occur over the cell membrane. During inflammation, connexin degradation can cause nutrient starvation [65]. Epithelial cells in different organs express Cx43 and have gap junction communication [66], and similar properties have been demonstrated between tenocytes in Achilles tendons [67] (Fig. 2).

Chondrocytes are the main cells in cartilage, and they express Cx43 in hyaline cartilage, which form articular cartilage and the growth plate [64]. Communication between chondrocytes via Ca2+ waves was identified in cultured cells. Intracellular Ca2+ release was evoked by different signaling pathways stimulated by ATP and 5-HT. These cells also express Cx43 and TLR4 [30].

Cardiac fibroblasts in heart tissue communicate by Ca2+ signaling through gap junction channel Cx43 protein [31] (Fig. 2).

Keratinocytes in skin show intercellular channels, allowing intercellular exchange of small metabolites through gap junction-coupled Cx43 channels [68]. These cells as well as keratinocytes from the buccal mucosa [69] express TLR4 [32] (Fig. 2).

7 Spread of inflammation can cause systemic inflammation

Gap junction communication has been identified between different cell types in several organs. The Ca2+ waves in syncytium networks are dynamic signaling elements that regulate cell homeostasis in normal physiological situations. During inflammation, Ca2+ excitability changes.

Astrocytes are integrators and modulators in all nervous systems and control neuronal activity and synaptic transmission. A single astrocyte can make contacts with multiple neurons and capillaries and enwrap many pre- and postsynaptic terminals [70]. Therefore, astrocytes play a metabolic role in the nervous system and modulate neighboring neurons. These cells have the capacity to clear elevated K+ from the extracellular space, take up neurotransmitters, and release gliotransmitters. Gliotransmission, a bidirectional signaling pathway, exists between astrocytes and neurons. Moreover, neural activity can trigger structural changes in astrocytes, and astrocytes can respond with long-term changes in certain properties.

Autoantibodies related to RA can develop several years before the onset of detectable joint inflammation. These autoantibodies develop outside the joints and may originate from oral, lung or gastrointestinal mucosal surfaces [71].

Metabolic disturbances can induce low-grade inflammation in all metabolically active organs, such as the liver, adipose tissue and heart, which might result in metabolic cardiomyopathy. A pro-inflammatory status and insulin resistance can account for some of these disturbances. In these conditions, glucose uptake and glucose utilization are reduced by increased fatty acid oxidization [72].

A correlation between obesity and chronic pain is a suggested link to systemic inflammation, which can develop in musculoskeletal pain, such as OA, low back pain, headaches, chronic widespread pain and fibromyalgia [73]. Adipokines such as leptin are secreted from adipose tissue and are important for the homeostasis of neuroendocrine and immune systems. Increased leptin is correlated with increased production of matrix metalloproteinases and matrix molecules, suggesting a role for leptin in the progression of OA [74], [75], [76].

Communication exists between chondrocytes and synovial cells in joints. The role and function of connexins in gap junctions in bone, muscle and joint tissue and whether communication between these different cell types occurs have been taken into consideration [64].

A remaining question is whether inflammatory reactive systemic networks in different organs possess a signaling system that can spread or propagate signals from gap junction-coupled cells in one organ to those in other organs on either the contralateral or ipsilateral side. An additional question is whether this process is an underlying mechanism of the establishment of systemic inflammation. An ongoing low-grade inflammation might give symptoms such as tiredness, widespread pain and cognitive dysfunctions [77]. Blood samples and cerebrospinal fluid give the opportunity to measure inflammation-related proteins and cytokines from patients with osteoarthritis, severe chronic pain, low-back pain and fibromyalgia [77], [78], [79], [80], [81], [82].

8 Damaged barriers in the body

Inducers of inflammation trigger the production of inflammatory mediators, which alter the functionality of tissues and organs and lead to harmful changes in different barrier systems, such as the blood-brain barrier (BBB), blood-retinal barrier, blood-nerve barrier, and blood-lymph barrier [83], [84] (Fig. 1). Inflammation causes changes in neurotransmitter systems and increased synthesis and release of pro-inflammatory mediators such as TNF-α and interleukin 1β (IL-1β). The affinities of several TLR receptors, especially TLR2 and TLR4, are signal sensors that recognize foreign substances. Nitric oxide synthase (iNOS) promotes increased nitric oxide (NO) production [85]. Vascular endothelial growth factor (VEGF) is considered a regulator of vascular permeability that induces leakage of the BBB by decreasing the expression of claudin-5, a tight junction protein [86].

9 Other cell types of importance

Mast cells develop in the bone marrow and circulate in the blood in low numbers as immature precursors. These cells migrate to target areas such as mucosal and connective tissues in the proximity of blood, lymphatic vessels and nerves and differentiate into mature cells in response to a currently unknown signal, such as an inflammatory signal, bacteria, virus or another agent.

Mast cells are heterogeneous with characteristic granule content [87]. These cells are the proposed first responders at the start of inflammation; mast cells respond to changes in the environment and communicate with other cells involved in the immune response, giving rise to signaling between different cell types. Mast cells have an enormous repertoire of cell surface receptors and can synthesize and release large amounts of different mediators, such as tryptases, chymases, histamine, 5-HT, nitric oxide, substance P, cytokines, chemokines, and many growth factors [87].

Mast cell progenitors can pass the BBB and establish themselves in the CNS. Once in the CNS, mast cells can interact with astrocytes, microglia and blood vessels [88]. Mast cell-released proteases activate PAR-2 receptors as well as ATP purinergic receptors expressed on both microglia and astrocytes, which can result in the release of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 [52], [88]. Long-term activation of pathogenic components on gap junction-coupled astrocytes can develop into dysregulated activation that can contribute to the pathology of autoimmune diseases as well as neurodegeneration and the development of degenerative diseases [89].

Microglia in the nervous system and macrophages in other parts of the body play a pivotal role as they stimulate different substances, such as bacterial endotoxins and viruses, as well as produce and release proinflammatory cytokines, such as TNF-α, IL-1β, IL-6 and many different growth factors. See recently published review articles [90], [91] for more details.

M-cells are located in the intestinal epithelium and localized to the luminal surface of Peyer’s patches and colon lymphoid follicles [17]. These cells have contact with immune cells and seem to play an important role in the mucosal immune response by transporting external antigens from the gut lumen to the lymphoid follicle.

10 Is it possible to return the inflammatory system to a physiological level?

The role of astrocytes as dynamic modulators of synaptic functions in the neuronal environment has made astrocytes attractive targets for novel therapeutic strategies.

In our experimental systems, we have evaluated different combinations of drugs that have powerful anti-inflammatory properties. Preliminary clinical tests have shown promising results in patients [79].

One drug combination has been evaluated in our experimental system in vitro. This combination consists of three compounds: a μ-opioid receptor antagonist, naloxone, at ultralow concentrations; a μ-opioid receptor agonist, endomorphin-1/morphine/(-)-linalool; and the anti-epileptic agent levetiracetam. The opioid antagonist naloxone at ultralow concentrations inhibits the Gs protein of the μ-opioid receptor and activates Na+/K+-ATPase activity. Opioid agonists activate the Gi/o protein of the opioid receptor [58], [59], [92], and levetiracetam decreases IL-1β release [93]. This combination returns the cellular parameters induced by LPS to physiological homeostatic levels and can resolve and restore disordered cellular inflammatory pathways, particularly the glutamate system.

Two of the above pharmaceutical compounds have been tested in postsurgical neuropathic pain patients with promising results [79]. We used an ultralow dose of naloxone as an adjuvant to long-term, uninterrupted intrathecal (IT) morphine infusion in patients with severe long-term inflammation and pain in whom conventional pain therapies had been insufficient. We added IT naloxone at dose levels within the nanogram level range, which were estimated to be far less than the dose needed to antagonize the effects of morphine. We found that compared to placebo, the addition of an ultralow dose of IT naloxone significantly improved the quality of sleep in these patients. Additionally, three of these 11 patients experienced pain relief [79].

As mentioned above, the increased release of ATP through Cx43 hemichannels causes Ca2+ propagation mediated by extracellular paracrine signaling [94] and reduces the communication between cells with gap junctions [56]. Therefore, a search for a suitable substance that affects the ATP system in some way was desirable. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil (Viagra®) was one alternative. Sildenafil induces cyclic GMP accumulation, which may inhibit inflammation [95]. Increased inflow of Ca2+ occurs through the N-methyl-D-aspartate (NMDA) receptor [96]. The Ca2+/calmodulin complex activates iNOS, which converts L-arginine to NO, resulting in the accumulation of cyclic GMP and the activation of protein kinase G (PKG) [97]. Cyclic GMP is rapidly hydrolyzed by PDEs among which PDE-5 plays a central role [98]. PDE inhibitors exert a direct anti-inflammatory effect by raising cyclic GMP. There are indications that the NO/cyclic GMP/PKG pathway is the central signaling mechanism and can therefore be a potential tool in diseases where inflammation, including neuroinflammatory disorders, play a central role [95], [98], [99]. Sildenafil can normalize endothelial function and has been proposed for pain therapy in humans and animals [100] due to its anti-inflammatory properties. Furthermore, our group has shown that at extremely low concentrations, sildenafil works as an anti-inflammatory substance in LPS-induced inflammatory reactive astrocytes, and the number of microglia was reduced [101].

In addition, we included 1α,25-dihydroxyvitamin D3 (vitamin D3). Vitamin D3 acts as an immune regulator to protect against BBB disruption [102], downregulates TLR4 and decreases TNF-α and IL-6 release [103], [104]. The combination of sildenafil and vitamin D3 has positive effects on the ATP system as well as some effects on the glutamate and 5-HT systems [52].

In the future, we will refine and optimize the concentrations of the different drug combinations. For several of these drugs, only extremely low concentrations have anti-inflammatory effects. Concentrations that are too high can result in negative effects or other issues.

11 Conclusions

This review highlights gap junction-coupled cells in different organs in the body and how different sources of inflammatory stimuli can affect them. These cells form systemic networks, which might be important in low-grade inflammation that in turn can lead to systemic inflammation where pain can be a prominent symptom. These networks can be affected by inflammatory stimuli, including endotoxins such as LPS, and become dysregulated. Cell signaling decreases through connexin-coupled gap junctions but increases through hemichannels. These changes result in decreased intercellular signaling but increased extracellular signaling that in turn affects the surrounding cells in organs. The question is which cell type or tissue is first affected by an inflammatory stimulus. Are other cells targeted first that in turn alter the physiological status of gap junction-coupled cells? One hypothesis is that mast cells mature in the organ that is first attacked by an inflammatory stimulus. Mast cells produce and release inflammatory substances, which in turn affect gap junction cell networks. The signaling through these systemic networks is disturbed, leading to dysfunctional homeostasis, which affects the cellular network’s control and modulation of other target cells in the organ. The breakdown of barrier systems occurs and can cause the spread of inflammatory substances, thus affecting other network-coupled cells in other organs that can cause systemic inflammation. This, in turn, can lead to pain that can turn into chronic pain. Our own results with different combinations of pharmaceuticals together with the literature, will lead to clinical implications. Our purpose is now to continue with pre-clinical and clinical trials in vivo.

Acknowledgements

Thanks to Springer Nature Author Services for gold language editing.

References

  • [1]

    Franceschi F, Zuccalà G, Roccarina D, Gasbarrini A. Clinical effects of Helicobacter pylori outside the stomach. Nat Rev Gastroenterol Hepatol 2014;11:234–42. PubMedCrossrefGoogle Scholar

  • [2]

    Zhang Y, Wang X, Li H, Ni C, Du Z, Yan F. Human oral microbiota and its modulation for oral health. Biomed Pharmacother 2018;99:883–93. CrossrefPubMedGoogle Scholar

  • [3]

    Kumar PS. From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease. J Physiol 2017;595:465–76. PubMedCrossrefGoogle Scholar

  • [4]

    Tappenden KA. Inflammation and intestinal function: where does it start and what does it mean? JPEN J Parenter Enteral Nutr 2008;32:648–50. PubMedCrossrefGoogle Scholar

  • [5]

    Kumar PS. Oral microbiota and systemic disease. Anaerobe 2013;24:90–3. CrossrefPubMedGoogle Scholar

  • [6]

    Demmer RT, Breskin A, Rosenbaum M, Zuk A, LeDuc C, Leibel R, Paster B, Desvarieux M, Jacobs DR Jr, Papapanou PN. The subgingival microbiome, systemic inflammation and insulin resistance: The Oral Infections, Glucose Intolerance and Insulin Resistance Study. J Clin Periodontol 2017;44:255–65. PubMedCrossrefGoogle Scholar

  • [7]

    Van der Meulen TA, Harmsen HJM, Bootsma H, Spijkervet FKL, Kroese FGM, Vissink A. The micribiome-systemic diseases connection. Oral Dis 2016;22:719–34. CrossrefPubMedGoogle Scholar

  • [8]

    Makrygiannakis D, af Klint E, Lundberg IE, Löfberg R, Ulfgren AK, Klareskog L, Catrina AI. Citrullination is an inflammation-dependent process. Ann Rheum Dis 2006;65:1219–22. PubMedCrossrefGoogle Scholar

  • [9]

    Yoshida M, Tsuji M, Kurosaka D, Kurosaka D, Yasuda J, Ito Y, Nishizawa T, Yamada A. Autoimmunity to citrullinated type II collagen in rheumatoid arthritis. Mod Rheumatol 2006;16: 276–81. PubMedCrossrefGoogle Scholar

  • [10]

    Ge C, Tong D, Liang B, Lönnblom E, Schneider N, Hagert C, Viljanen J, Ayoglu B, Stawikowska R, Nilsson P, Fields GB, Skogh T, Kastbom A, Kihlberg J, Burkhardt H, Dobritzsch D, Holmdahl R. Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage. JCI Insight 2017;2:pii: 93688. CrossrefGoogle Scholar

  • [11]

    Ganesan SM, Joshi V, Fellows M, Dabdoub SM, Nagaraja HN, O’Donnell B, Deshpande NR, Kumar PS. A tale of two risks: smoking, diabetes and the subgingival microbiome. ISME J 2017;11:2075–89. CrossrefPubMedGoogle Scholar

  • [12]

    Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38–46. CrossrefPubMedGoogle Scholar

  • [13]

    Wegner N, Lundberg K, Kinloch A, Fisher B, Malmström V, Feldmann M, Venables PJ. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev 2010;233:34–54. CrossrefPubMedGoogle Scholar

  • [14]

    Wen L, Duffy A. Factors influencing the gut microbiota, inflammation, and type 2 diabetes. J Nutr 2017;147:1468S–75S. PubMedCrossrefGoogle Scholar

  • [15]

    Szychlinska MA, Di Rosa M, Castorina A, Mobasheri A, Musumeci G. A correlation between intestinal microbiota dysbiosis and osteoarthritis. Heliyon 2019;5:e01134. CrossrefPubMedGoogle Scholar

  • [16]

    Budzyński J, Kłopocka M. Brain-gut axis in the pathogenesis of Helicobacter pylori infection. World J Gastroenterol 2014;20:5212–21. CrossrefPubMedGoogle Scholar

  • [17]

    Ramakrishnan SK, Zhang H, Ma X, Jung I, Schwartz AJ, Triner D, Devenport SN, Das NK, Xue X, Zeng MY, Hu Y, Mortensen RM, Greenson JK, Cascalho M, Wobus CE, Colacino JA, Nunez G, Rui L, Shah YM. Intestinal non-canonical NFκB signaling shapes the local and systemic immune response. Nat Commun 2019;10:660. CrossrefPubMedGoogle Scholar

  • [18]

    Moos V, Schneider T. Changing paradigms in Whipple’s disease and infection with Tropheryma whipplei. Eur J Clin Microbiol Infect Dis 2011;30:1151–8. CrossrefPubMedGoogle Scholar

  • [19]

    Blaney Davidson EN, van Caam AP, van der Kraan PM. Osteoarthritis year in review 2016: biology. Osteoarthritis Cartilage 2017;25:175–80. PubMedCrossrefGoogle Scholar

  • [20]

    Guo H, Diao N, Yuan R, Chen K, Geng S, Li M, Li L. Subclinical-dose endotoxin sustains low-grade inflammation and exacerbates steatohepatitis in high-fat diet-fed mice. J Immunol 2016;196:2300–8. PubMedCrossrefGoogle Scholar

  • [21]

    Shoemaker RC, House DE. Sick building syndrome (SBS) and exposure to water-damaged buildings: time series study, clinical trial and mechanisms. Neurotoxicol Teratol 2006;28:573–88. PubMedCrossrefGoogle Scholar

  • [22]

    Forssblad J, Annadotter H. Endotoxinsin Swedish tap water. www.svensktvatten.se 2009, project number 25–113. 

  • [23]

    Simazaki D, Hirose M, Hashimoto H, Yamanaka S, Takamura M, Watanabe J, Akiba M. Occurrence and fate of endotoxin activity at drinking water purification plants and healthcare facilities in Japan. Water Res 2018;145:1–11. CrossrefPubMedGoogle Scholar

  • [24]

    Robertson MD, Pedersen C, Hinton PJ, Mendis ASJR, Cani PD, Griffin BA. Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men. Nutr Metab Cardiovasc Dis 2018;28:1296–303. CrossrefPubMedGoogle Scholar

  • [25]

    Cangemi R, Della Valle P, Calvieri C, Taliani G, Ferroni P, Falcone M, Carnevale R, Bartimoccia S, D’Angelo A, Violi F. Low-grade endotoxemia and clotting activation in the early phase of pneumonia. Respirology 2016;21:1465–71. CrossrefPubMedGoogle Scholar

  • [26]

    Vu A, Calzadilla A, Gidfar S, Calderon-Candelario R, Mirsaeidi M. Toll-like receptors in mycobacterial infection. Eur J Pharmacol 2017;808:1–7. PubMedCrossrefGoogle Scholar

  • [27]

    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001;1:135–45. CrossrefPubMedGoogle Scholar

  • [28]

    Thakur KK, Saini J, Mahajan K, Singh D, Jayswal DP, Mishra S, Bishayee A, Sethi G, Kunnumakkara AB. Therapeutic implications of toll-like receptors in peripheral neuropathic pain. Pharmacol Res 2017;115:224–32. PubMedCrossrefGoogle Scholar

  • [29]

    Forshammar J, Block L, Lundborg C, Biber B, Hansson E. Naloxone and ouabain in ultra-low concentrations restore Na+/K+-ATPase and cytoskeleton in lipopolysaccharide-treated astrocytes. J Biol Chem 2011;286:31586–97. CrossrefGoogle Scholar

  • [30]

    Skiöldebrand E, Thorfve A, Björklund U, Johansson P, Wickelgren R, Lindahl A, Hansson E. Biochemical alterations in inflammatory reactive chondrocytes: evidence for intercellular network communication. Heliyon 2018;4:e00525. CrossrefPubMedGoogle Scholar

  • [31]

    Skiöldebrand E, Lundqvist A, Björklund U, Sandstedt M, Lindahl A, Hansson E, Mattsson Hulté L. Inflammatory activation of human cardiac fibroblasts leads to altered calcium signaling, decreased connexin 43 expression and increased glutamate secretion. Heliyon 2017;3:e00406. CrossrefPubMedGoogle Scholar

  • [32]

    Iotzova-Weiss G, Freiberger SN, Johansen P, Kamarachev J, Guenova E, Dziunycz PJ, Roux GA, Neu J, Hofbauer GFL. TLR4 as a negative regulator of keratinocyte proliferation. PLoS One 2017;12:e0185668. PubMedCrossrefGoogle Scholar

  • [33]

    Akbar M, Gilchrist DS, Kitson SM, Nelis B, Crowe LAN, Garcia-Melchor E, Reilly JH, Kerr SC, Murrell GAC, McInnes IB, Millar NL. Targeting danger molecules in teninopathy:the HMGB1/TLR4 axis. RMD Open 2017;3:e000456. PubMedCrossrefGoogle Scholar

  • [34]

    Liu Y, Yin H, Zhao M, Lu Q. TLR2 and TLR4 in autoimuune diseases: a comprehensive review. Clin Rev Allergy Immunol 2014;47:136–47. CrossrefGoogle Scholar

  • [35]

    Herrero-Beaumont G, Pérez-Baos S, Sánchez-Pernaute O, Roman-Blas JA, Lamuedra A, Largo R. Targeting chronic innate inflammatory pathways, the main road to prevention of osteoarthritis progression. Biochem Pharmacol 2019;165:24–32. PubMedCrossrefGoogle Scholar

  • [36]

    Hansson E, Skiöldebrand E. Coupled cell networks are target cells of inflammation, which can spread between different body organs and develop into systemic chronic inflammation. J Inflamm 2015;12:44. CrossrefGoogle Scholar

  • [37]

    Giaume C, McCarthy KD. Control of gap-junctional communication in astrocytic networks. Trends Neurosci 1996;8:319–25. Google Scholar

  • [38]

    Kettenmann H, Ransom BR. Electrical coupling between astrocytes and between oligodendrocytes studied in mammalian cell cultures. Glia 1988;1:64–73. PubMedCrossrefGoogle Scholar

  • [39]

    Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate induces calcium waves in cultured astrocytes: long-range glial signalling. Science 1990;247:470–3. CrossrefGoogle Scholar

  • [40]

    Blomstrand F, Khatibi S, Muyderman H, Hansson E, Olsson T, Rönnbäck L. 5-Hydroxytryptamine and glutamate modulate velocity and extent of intercellular calcium signalling in hippocampal astroglial cells in primary cultures. Neuroscience 1999;88:1241–53. CrossrefPubMedGoogle Scholar

  • [41]

    Muyderman H, Ängehagen M, Sandberg M, Björklund U, OlssonT, Hansson E, Nilsson M. α1-Adrenergic modulation of metabotropic glutamate receptor-induced calcium oscillations and glutamate release in astrocytes. J Biol Chem 2001;276:46504–14. CrossrefGoogle Scholar

  • [42]

    Hansson E, Rönnbäck L. Glial neuronal signaling in the central nervous system. FASEB J 2003;17:341–8. PubMedCrossrefGoogle Scholar

  • [43]

    Araque A, Sanzgiri RP, Parpura V, Haydon PG. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci 1998;18:6822–9. CrossrefPubMedGoogle Scholar

  • [44]

    Zorec R, Araque A, Carmignoto G, Haydon PG, Verkhratsky A, Parpura V. Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signaling route. ASN Neuro 2012;4:e00080. PubMedGoogle Scholar

  • [45]

    Giaume C, Leybaert L, Naus CC, Sáez JC. Connexin and pannexin hemichannels in brain glial cells: properties, pharmacology, and roles. Front Pharmacol 2013;4:1. Google Scholar

  • [46]

    Abudara V, Roux L, Dallérac G, Matias I, Dulong J, Mothet JP, Rouach N, Giaume C. Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes. Glia 2015;63:795–811. CrossrefPubMedGoogle Scholar

  • [47]

    Blum E, Procacci P, Conte V, Hanani M. Systemic inflammation alters satellite glial cell function and structure. A possible contribution to pain. Neuroscience 2014;274:209–17. CrossrefPubMedGoogle Scholar

  • [48]

    Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41–53. PubMedCrossrefGoogle Scholar

  • [49]

    Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev 2018;98:239–389. CrossrefPubMedGoogle Scholar

  • [50]

    Hansson E. Long-term pain, neuroinflammation and glial activation. Scand J Pain 2010;1:67–72. CrossrefPubMedGoogle Scholar

  • [51]

    Ikeda H, Kiritoshi T, Murase K. Contribution of microglia and astrocytes to the central sensitization, inflammatory and neuropathic pain in the juvenile rat. Mol Pain 2012;8:43. PubMedGoogle Scholar

  • [52]

    Hansson E, Björklund U, Skiöldebrand E, Rönnbäck L. Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytes – promising treatment of neuroinflammation. J Neuroinflammation 2018;15:321. CrossrefPubMedGoogle Scholar

  • [53]

    Cotrina ML, Lin JH-C, López-García JC, Naus CCG, Nedergaard M. ATP-mediated glia signaling. J Neurosci 2000;20:2835–44. CrossrefPubMedGoogle Scholar

  • [54]

    Beamer E, Kovács G, Sperlágh B. ATP released from astrocytes modulates action potential threshold and spontaneous excitatory postsynaptic currents in the neonatal rat prefrontal cortex. Brain Res Bull 2017;135:129–42. CrossrefPubMedGoogle Scholar

  • [55]

    Lacagnina MJ, Watkins LR, Grace PM. Toll-like receptors and their role in persistent pain. Pharmacol Ther 2018;184:145–58. Google Scholar

  • [56]

    Giaume C, Liu X. From a glial syncytium to a more restricted and specific glial networking. J Physiol 2012;106:34–9. Google Scholar

  • [57]

    Chatton J-Y, Magistretti PJ, Barros LF. Sodium signaling and astrocyte energy metabolism. Glia 2016;64:1667–76. CrossrefPubMedGoogle Scholar

  • [58]

    Block L, Björklund U, Westerlund A, Jörneberg P, Biber B, Hansson E. A new concept affecting restoration of inflammation-reactive astrocytes. Neuroscience 2013;250:536–45. CrossrefPubMedGoogle Scholar

  • [59]

    Hansson E, Werner T, Björklund U, Skiöldebrand E. Therapeutic innovation: Inflammatory-reactive astrocytes as targets of inflammation. IBRO Rep 2016;1:1–9. PubMedCrossrefGoogle Scholar

  • [60]

    Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003;2:973–85. CrossrefGoogle Scholar

  • [61]

    Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Int Med 2005;257:139–55. CrossrefGoogle Scholar

  • [62]

    Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol 2006;187:321–7. CrossrefGoogle Scholar

  • [63]

    Plotkin LI, Stains JP. Connexins and pannexins in the skeleton: gap junction, hemichannels and more. Cell Mol Life Sci 2015;72:2853–67. CrossrefPubMedGoogle Scholar

  • [64]

    Donahue HJ, Qu RW, Genetos DC. Joint diseases: from connexins to gap junctions. Nature 2018;14:42–51. Google Scholar

  • [65]

    Nighot P, Ma T. Role of autophagy in the regulation of epithelial cell junctions. Tissue Barriers 2016;4:e1171284. CrossrefPubMedGoogle Scholar

  • [66]

    Márquez-Rosado L, Solan JL, Dunn CA, Norris RP, Lampe PD. Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues. Biochem Biophys Acta 2012;1818:1985–92. CrossrefGoogle Scholar

  • [67]

    Maeda E, Pian H, Ohashi T. Temporal regulation of gap junctional communication between tenocytes subjected to static strain with physiological and non-physiological amplitueds. Biochem Biophys Res Commun 2017;482:1170–5. CrossrefPubMedGoogle Scholar

  • [68]

    Zhang X-F, Cui X. Connexin 43: key roles in the skin. Biomed Rep 2017;6:605–11. CrossrefPubMedGoogle Scholar

  • [69]

    Robledo-Sierra J, Sundberg J, Baza M, Öhman J, Hasséus B, Hansson E. Influence of inflammation on actin cytoskeleton on oral keratinocytes. In preparation. Google Scholar

  • [70]

    Araque A, Carmignoto G, Haydon P. Dynamic signaling between astrocytes and neurons. Annu Rev Physiol 2001;63:795–813. CrossrefPubMedGoogle Scholar

  • [71]

    Demoruelle MK, Deane KD, Holers VM. When and where does inflammation begin in rheumatoid arthritis? Curr Opin Rheumatol 2014;26:64–71. PubMedCrossrefGoogle Scholar

  • [72]

    Nishida K, Otsu K. Inflammation and metabolic cardiomyopathy. Cardiovasc Res 2017;113:389–98. CrossrefPubMedGoogle Scholar

  • [73]

    Paley CA, Johnson MI. Physical activity to reduce systemic inflammation associated with chronic pain and obesity. Clin J Pain 2016;32:365–70. PubMedCrossrefGoogle Scholar

  • [74]

    Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T, Moilanen E. Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol 2011;29:57–64. PubMedGoogle Scholar

  • [75]

    Koskinen A, Juslin S, Nieminen R, Moilanen T, Vuolteenaho K, Moilanen E. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways. Arthritis Res Ther 2011;13:R184. CrossrefPubMedGoogle Scholar

  • [76]

    Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gómez-Reino JJ, Mera A, Lago F, Gómez R, Gualillo O. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017;13:100–9. PubMedCrossrefGoogle Scholar

  • [77]

    Hysing E-B, Smith L, Thulin M, Karlsten R, Bothelius K, Gordh T. Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program. Scand J Pain 2019;19:235–44. CrossrefPubMedGoogle Scholar

  • [78]

    Lundborg C, Hahn-Zoric M, Biber B, Hansson E. Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain. J Neuroimmunol 2010;220:108–13. CrossrefPubMedGoogle Scholar

  • [79]

    Block L, Lundborg C, Bjersing J, Dahm P, Hansson E, Biber B. Ultralow dose of naloxone as an adjuvant to intrathecal morphine infusion improves perceived quality of sleep but fails to alter persistent pain. A randomized, double-blind, controlled study. Clin J Pain 2015;31:968–75. CrossrefGoogle Scholar

  • [80]

    Pedersen LM, Schistad E, Jacobsen LM, Røe C, Gjerstad J. Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: a 12-month prospective study. Brain Behav Immun 2015;46:132–6. CrossrefPubMedGoogle Scholar

  • [81]

    Karshikoff B, Jensen KB, Kosek E, Kalpouzos G, Soop A, Ingvar M, Höglund CO, Lekander M, Axelsson J. Why sickness hurts: A central mechanism for pain induced by peripheral inflammation. Brain Behav Immun 2016;57:38–46. CrossrefPubMedGoogle Scholar

  • [82]

    Bäckryd E, Lind A-L, Thulin M, Larsson A, Gerdle B, Gordh T. High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain 2017;158:2487–95. PubMedCrossrefGoogle Scholar

  • [83]

    Rönnbäck C, Hansson E. Gap junction coupled cells, barriers and systemic inflammation. Int J Open Access Ophthalmol 2017;2:7. Google Scholar

  • [84]

    Rönnbäck C, Hansson E. The importance and control of systemic inflammation due to damage of cellular barrier systems. Front Neurol 2019; https://doi.org/10.3389/fneur.2019.00533PubMed

  • [85]

    Bellaver B, dos Santos JP, Leffa DT, Bobermin LD, Roppa PHA, da Silva Torres IL, Gonçalves C-A, Souza DO, Quincozes-Santos A. Systemic inflammation as a driver of brain injury: the astrocyte as an emerging player. Mol Neurobiol 2018;55:2685–95. CrossrefPubMedGoogle Scholar

  • [86]

    Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, Asp L, Loo H, Laitman BM, Mariani JN, Straus Faber R, Zaslavsky E, Nudelman G, Raine CS, John GR. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain 2015;138:1548–67. CrossrefPubMedGoogle Scholar

  • [87]

    Traina G. Mast cells in the brain – old cells, new target. J Integr Neurosci 2017;16:S69–83. PubMedCrossrefGoogle Scholar

  • [88]

    Dong H, Zhang X, Qian Y. Mast cells and neuroinflammation. Med Sci Monit Basic Res 2014;20:200–6. PubMedCrossrefGoogle Scholar

  • [89]

    Hendriksen E, van Bergeijk D, Oosting RS, Redegeld FA. Mast cells in neuroiflammation and brain disorders. Neurosci Biobehav Rev 2017;79:119–33. CrossrefGoogle Scholar

  • [90]

    Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol 2017;79:619–43. CrossrefPubMedGoogle Scholar

  • [91]

    Hamidzadeh K, Christensen SM, Dalby E, Chandrasekaran P, Mosser DM. Macrophages and the recovery from acute and chronic inflammation. Annu Rev Physiol 2017;79:567–92. PubMedCrossrefGoogle Scholar

  • [92]

    Block L, Forshammar J, Westerlund A, Björklund U, LundborgC, Biber B, Hansson E. Naloxone in ultralow concentration restores endomorphin-1-evoked Ca2+ signaling in lipopolysaccharide pretreated astrocytes. Neuroscience 2012;205:1–9. CrossrefGoogle Scholar

  • [93]

    Haghikia A, Ladage K, Hinkerohe D, Vollmar P, Heupel K, Dermietzel R, Faustmann PM. Implications of anti-inflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. J Neurosci Res 2008;86:1781–8. PubMedCrossrefGoogle Scholar

  • [94]

    Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 1998;95:15735–40. CrossrefGoogle Scholar

  • [95]

    Peixoto CA, Nunes AKS, Garcia-Osta A. Phosphodiesterase-5 inhibitors: Action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition. Med Inflammation 2015;2015:1–17. Google Scholar

  • [96]

    Gérard F, Hansson E. Inflammatory activation enhances NMDA-triggered Ca2+ signaling and IL-1β secretion in primary cultures of rat astrocytes. Brain Res 2012;1473:1–8. PubMedCrossrefGoogle Scholar

  • [97]

    Shim S, Shuman M, Duncan E. An emerging role of cGMP in the treatment of schizophrenia: a review. Schozphrenia Res 2016;170:226–31. CrossrefGoogle Scholar

  • [98]

    Peixoto CA, Gomes FOS. The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review. J Inflamm 2015;12:54. CrossrefGoogle Scholar

  • [99]

    Rapôso C, Luna RLA, Nunes AKS, Thomé R, Peixoto CA. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull 2014;104:60–73. PubMedCrossrefGoogle Scholar

  • [100]

    Puzzo D, Sapienza S, Arancio O, Palmeri A. Role of phosphodiesterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis Treat 2008;4:371–87. PubMedGoogle Scholar

  • [101]

    Nunes AKS, Rapôso C, Björklund U, Cruz-Höfling MA, Peixoto CA, Hansson E. Sildenafil (Viagra) prevents and restores LPS-induced inflammation in astrocytes. Neurosci Lett 2016;630:59–65. CrossrefPubMedGoogle Scholar

  • [102]

    Enkhjargal B, McBridem DW, Manaenkom A, Reism C, Sakaim Y, Tang J, Zhang J. Intranasal administration of vitamin D attenuates blood-brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44/P-gp glycosylation signaling after subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab 2017;37:2555–66. CrossrefPubMedGoogle Scholar

  • [103]

    Jo WK, Zhang Y, Emrich HM, Dietrich DE. Glia in the cytokine-mediated onset of depression: fine tuning the immune response. Front Cell Neurosci 2015;9:1–13. Google Scholar

  • [104]

    Adamczak DM. The role of toll-like receptors and vitamin D in cardiovascular diseases a review. Int J Mol Sci 2017;18:2252. CrossrefGoogle Scholar

About the article

Received: 2019-04-11

Revised: 2019-05-14

Accepted: 2019-05-21

Published Online: 2019-06-28

Published in Print: 2019-10-25


Authors’ statements

Research funding: The authors thank Edit Jacobsson’s Foundation, Gothenburg, Sweden, and AFA Insurance, Stockholm, Sweden, for financial support.

Conflict of interest: Authors state no conflicts of interest.

Informed consent: Not applicable.

Ethical approval: Not applicable.


Citation Information: Scandinavian Journal of Pain, Volume 19, Issue 4, Pages 639–649, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1515/sjpain-2019-0061.

Export Citation

©2019 Elisabeth Hansson et al., Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.. This work is licensed under the Creative Commons Attribution 4.0 Public License. BY 4.0

Comments (0)

Please log in or register to comment.
Log in