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Glial dysfunction and persistent neuropathic postsurgical pain

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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 10 Issue 1

Abstract

Background

Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosen-sory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.

A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.

Aim

This topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.

Method

Relevant literature was searched for in PubMed.

Results

Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged.Astrocyte dysfunction can be experimentally restored using the combined actions of a μ–opioid receptor agonist, a μ–opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons.

Conclusion

Surgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.

Implications

Larger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.

Keywords: Pain; Persistent postsurgical pain; Neuropathic pain; Neuroinflammation; Glia

1 Introduction: the clinical problem of persistent pain after surgery

Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. The pain signals transmitted from the site of injury to the brain cause us to avoid harmful, noxious stimuli. However, severe pain that is sustained for a long time after the injury has healed serves no useful purpose and is a disabling condition. Persistent pain is devastating for individuals and causes substantial health impairment and significant social, financial, and work-related difficulties [1, 2,3]. From a social point of view, persistent pain is a large burden and results in the use of extensive resources for sick leave, disability retirement, and rehabilitation.

Persistent postsurgical pain, which is often defined as pain that remains for 3 months or more after surgery, is the second most common cause of chronic pain after degenerative disease [4]. Recent reports regarding persistent postsurgical pain confirm that it is a complex and highly significant clinical problem [5, 6, 7, 8]. A study that included 2043 patients [9] demonstrated that 12% of patients who underwent an elective, mixed type of surgery developed moderate persistent postsurgical pain and 7% developed severe persistent postsurgical pain. Persistent postsurgical pain after a number of surgical procedures has been described, the prevalence of persistent postsurgical pain varies with the type of surgery, ranging from 50% for limb amputation, 30% for breast surgery, and 10% for hernia repair [5,10,11].

1.1 Neuropathic pain conditions in persistent postsurgical pain (PPP)

Persistent postsurgical pain is strongly associated with neuropathic pain 12,13]. Depending on the type of surgery, neuropathic pain is experienced by 3% (laparoscopic surgery) to 68% (breast surgery) of patients with persistent postsurgical pain. Neuropathic pain is characterised by lesion to or disease of the somatosensory nervous system 14,15]. It is recognised by pain that is distributed and localised along the innervation territory of the affected nerve, and it is always accompanied by a sensory disturbance, such as hyperesthesia or hypoesthesia, in the affected area. When established, neuropathic pain is difficult to treat, and conventional pain therapy is often insufficient.

It seems that nerve damage is a prerequisite for the development of neuropathic pain. However, nerve damage does not always produce neuropathic pain 13,16].

Possible mechanisms for the transition from acute physiological pain to persistent pain that remains after an acute injury has healed include nerve injury followed by inflammation in the peripheral nervous system (PNS) and CNS 17,18].

1.2 Objectives of this review

This review will focus on neuroinflammation and subsequent glial dysfunction [19] as possible contributors to the development of persistent postsurgical neuropathic pain [20, 21, 22]. Other possible mechanisms for persistent pain include long-term potentiation, peripheral as well as central sensitisation, neuronal plasticity, neural ectopic activity and disinhibition [23, 24, 25]. These entities, which all concur with our theory, are not the main focus of this review and therefore, will not be further discussed here.

2 Methods

Concerning the literature search for this paper a convenient selection of publications from searching PubMed was used. Search words were pain, neuroinflammation, glia, astrocytes, microglia, persistent postsurgical pain, persistent postoperative pain, neuropathic pain, inflammation, morphine, endomorphin, naloxone, levetiracetam and also different combinations of these.

3 Peripheral injuries can cause low-grade neuroinflammation

When an injury occurs in peripheral tissue, pro-inflammatory mediators, such as nitric oxide, bradykinin, tissue factors, and prostaglandins, are released into the bloodstream, and white blood cells are attracted to the injury site. The endothelium that lines the blood vessels becomes permeable, and leucocytes migrate from the blood vessels to the injury site [26]. A peripheral inflammatory process can also induce low-grade inflammation in the CNS; this process is known as neuroinflammation 27,28].

3.1 Blood-brain barrier made permeable by cytokines

After a peripheral nerve injury, inflammatory activated leucocytes release pro-inflammatory cytokines [29]. These cytokines cause the blood-brain barrier (BBB) to become permeable, thereby allowing leucocytes to migrate through and transform into microglia in the CNS [3031, 32, 33]. The activated microglia produce more pro-inflammatory cytokines, such as IL-1 β and TNF-α. In turn, IL-1β activates astrocytes, which also release the pro-inflammatory cytokine IL-1 β. This combined response causes a change in the astrocyte network signalling, thus potentiating neuronal pain transmission [34, 35, 36, 37]. Furthermore, this reaction is associated with the development of new synapses and dysfunction of existing synapses [38, 39, 40, 41, 42, 43].

Neuroinflammation can also be initiated when a local peripheral injury produces inflammatory activation in the CNS [44], which is conveyed by neurogenic sites of action. Macrophages infiltrate the injured nerve [45] and cause an inflammatory reaction in the nerve cells.

3.2 Microglia and astrocytes’ function are altered by neuroinflammation

This reaction leads to microglia activation in the CNS and the release of pro-inflammatory cytokines that activate and alter astrocyte function 46,47].

Microglia and astrocytes are non-excitable neural cells that play an active role in the development of neuroinflammation [48, 49, 50, 51]. In the last few years, it has become clear that glial cells have important metabolic and immune functions [52] and may play an important role in the modulation of synaptic pain transmission 53,54]. Astrocytes and microglia are glial cells that surround, support, and interact with neurons in the CNS. They respond to inflammatory stimuli and may play an important role in modulating the inflammatory activity in the CNS, as observed after peripheral injuries [55]. Astrocytes are coupled in networks and communicate with each other and with neurons 56,57] thereby modulating neuronal activity [58]. Inflammation causes dysfunction in glial-neuron communication due to inflammatory-induced alterations in astrocyte function that disturb the two-way interaction between astrocytes and neurons. This disturbance results in increased excitability in neurons, and synaptic pain transmission is enhanced and prolonged 59,60].

4 Microglia and astrocytes’ important role in development of neuropathic pain

The CNS consists of neurons and glial cells; the latter account for 70% of the cells. Microglia and astrocytes are important for the development of persistent pain [61]. Additionally, dorsal root ganglion satellite cells, which are astrocyte-like cells in the PNS, may play a role in the development of neuropathic pain [53]. However, they will not be discussed further in this review.

4.1 Microglia initiates neuroinflammation

Microglia are resident macrophages in the CNS, and they rapidly respond to an injury by proliferating, changing shape and producing pro-inflammatory cytokines [25]. Within 2 days of a peripheral nerve injury, there is marked proliferation of microglia in the spinal cord [62]. Hence, microglia are most likely the cell type that initiates inflammation in the CNS, thereby leading to further activation and spread of inflammation by the astrocytes [46].

4.2 Astrocytes can modify neuronal activity

Astrocytes are the most abundant cells in the CNS. They are star-shaped cells with long, slender processes. Astrocytes are coupled by gap junctions in syncytial networks and occupy a strategic position between the vasculature and the neurons, where they monitor and modify neuronal activity and transmitter release [59]. Astrocytes can release a rich variety of neuroactive substances, and they also express receptors for these substances. They surround neural synapses with their end-feet and monitor and modulate synaptic activity. One astrocyte can contact approximately 100,000 synapses 63,64], which makes their impact on synaptic transmission significant.

4.2.1 Astrocytic calcium (Ca2+) signalling

Astrocytes display a form of excitability that manifests as an increased intracellular Ca2+ concentration. Stimuli, such as transmitters released from neurons and glial cells, can evoke Ca2+ elevation in single astrocytes, which passes to adjacent astrocytes and leads to a Ca2+ wave that can propagate over long distances [65, 66,67].

4.2.2 Gap junction coupling

For this machinery to function, intercellular channels that are referred to as gap junctions appear to be necessary [68]. These channels enable direct exchange of ions, metabolites, and small molecules (less than 1.5 kDa in size) between contiguous cells [69]. Connexin43 (Cx43) is the primary gap junction protein [70]. Astrocytes in most parts of the CNS use two types of Ca2+ communication: intercellular communication through gap junctions and extracellular communication through diffusion of adenosine triphosphate (ATP), which then binds to purinoceptors on adjacent cells [70].

4.2.3 Glutamate-glutamine cycle

One of the roles of astrocytes is to clear the synaptic cleft of glutamate released from the neurons, thereby preventing neuro-toxicity due to excessive amounts of glutamate 71,72]. Neuronal activity releases glutamate into the neural synapse. The glutamate is taken up by astrocytes and converted to glutamine by the enzyme glutamine synthetase. Glutamine is released back into the synaptic cleft, taken up by neurons, and metabolised to glutamate, which is again released into the synaptic cleft; this process is referred to as the glutamate-glutamine cycle 73,74].

The inflammatory activated astrocytes cannot sufficiently clear the synaptic cleft of glutamate. Glutamate is an excitatory neuro-transmitter, and the increased glutamate level in the synaptic cleft makes the neurons more excitable [75].

5 Astrocytic cellular dysfunction in inflammatory conditions

Cellular changes that occur during neuroinflammation render the astrocyte networks unable to interact appropriately with neurons, thereby altering synaptic transmission (Figs. 1 and 2). During inflammation, the expression and affinities of several receptors are changed.

Fig. 1 In the normal state, (1) TLR4 is downregulated; (2) Ca2+ waves are controlled; (3) Na+/K+-ATPase works optimally; (4) the actin filaments are well-organised; and (5) the IL-1β release is minimal and gap junctions are open [90].
Fig. 1

In the normal state, (1) TLR4 is downregulated; (2) Ca2+ waves are controlled; (3) Na+/K+-ATPase works optimally; (4) the actin filaments are well-organised; and (5) the IL-1β release is minimal and gap junctions are open [90].

Fig. 2 In an inflammatory state, (1) TLR4 is upregulated; (2) Ca2+ waves oscillate; (3) Na+/K+-ATPase is downregulated; (4) actin filaments are disrupted; and (5) IL-1 β release is increased, and gap junctions close. Furthermore, there is an increased extracellular release of ATP, which causes Ca2+ release in adjacent astrocytes via the P2X7 receptor [90].
Fig. 2

In an inflammatory state, (1) TLR4 is upregulated; (2) Ca2+ waves oscillate; (3) Na+/K+-ATPase is downregulated; (4) actin filaments are disrupted; and (5) IL-1 β release is increased, and gap junctions close. Furthermore, there is an increased extracellular release of ATP, which causes Ca2+ release in adjacent astrocytes via the P2X7 receptor [90].

5.1 Toll like receptor-4 is a pro-inflammatory receptor

In astrocytes, Toll-like receptor 4 (TLR4) is an inflammatory receptor that responds to lipopolysaccharide (LPS) by increasing its expression and activity 76,77]. Activation of TLR4 leads to an increase in the release of the pro-inflammatory cytokines TNF-a and IL-1 β [78]. Activation of TLR4 can be inhibited by ultralow doses ofnaloxone [79] and interestingly, it can be increased by prolonged morphine administration [80].

5.2 Astrocytes communicate with Ca2+ waves

Astrocytes communicate and modulate synaptic activity through Ca2+ waves. Release of Ca2+ can be stimulated by substances released from both neurons and glial cells 81,82]. Receptors on the surface of astrocytes are coupled to G proteins and release Ca2+ from the endoplasmic reticulum via phospholi-pase C and inositol-triphosphate (IP3) [83]. These Ca2+ waves can propagate from one cell to another via gap junctions. An increase in cytosolic Ca2+ leads to release of gliotransmitters, i.e., substances that can influence and modulate synaptic transmission [68]. Prolonged neuroinflammation causes dysfunction of this signalling system 84,85].

5.3 Na+/K+ ATPase modulates Ca2+ signalling

Influx of Ca2+ across the plasma membrane is driven by the Na+ electrochemical gradient across the plasma membrane and the Na+ pump, Na+/K+-ATPase, which indirectly modulates Ca2+ signalling [86]. Inflammatory stimuli disturb the Ca2+ homeosta-sis in astrocyte networks, possibly by interfering with the activity of Na+/K+-ATPase [86].

5.4 An intact cytoskeleton is needed for Ca2+ signalling

Na+/K+-ATPase, the actin filaments that constitute the cytoskeleton, and the endoplasmic reticulum are associated through the adaptor protein ankyrin B [87]. Na+/K+-ATPase is connected to the actin filaments by the protein ankyrin B, and the actin filaments are connected to the endoplasmic reticulum by the same protein. If the actin filaments are disrupted, the Ca2+ release is disturbed. An intact cytoskeleton is required for propagation of Ca2+ waves in astrocytes, and disruption of the cytoskeleton abolishes Ca2+ waves by changing the balance among the Ca2+-regulating processes [88]. In inflammatory states, the cytoskeleton is disrupted.

5.5 Pro-inflammatory cytokine IL-1 β closes gap junctions

In the CNS, IL-1 β is mainly produced by microglia that are active in initiating the inflammatory process, whereas astrocytes, which also produce significant amounts of IL-1 β, are dominant in maintaining neuroinflammation [89]. The increase in IL-1 β closes the gap junctions, thereby inhibiting the normal propagation of Ca2+ waves through the astrocytic networks [90].

5.6 Inflammation disrupts astrocytes’ communication

In inflammatory states, the increase in pro-inflammatory cytokines leads to increased production of ATP. These changes disturb the normal Ca2+ signalling [91], which can result in Ca2+ oscillations. Gap junctions close because of high levels of IL-1 β, and the intercellular Ca2+ waves and propagation from cell to cell are attenuated [92]. The increased extracellular release of ATP acts on purinergic receptors on adjacent astrocytes, consequently stimulating the release of intracellular Ca2+ in adjacent cells [93]. This stimulation leads to poorly controlled extracellular propagation of the Ca2+ waves, and the increased intracellular Ca2+ release exhibits oscillatory behaviour [70] (Fig. 2).

6 Reversing glial dysfunction (Fig. 3 )

The cellular changes that occur during experimental neuroinflammation render the astrocyte network unable to interact appropriately with neurons and synaptic transmission [94]. To restore the cellular changes caused by the experimental neuroinflammation described above, we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine.

Fig. 3 Treatment with a combination of endomorphin-1, naloxone and levetiracetam restores (1) TLR4 expression, (2) Ca2+ release, (3) Na+/K+-ATPase expression, (4) actin filament organisation, and (5) release of IL-1β. Furthermore, the combination unblocks gap junctions and promotes propagation of the intercellular Ca2+ waves through the gap junctions [90].
Fig. 3

Treatment with a combination of endomorphin-1, naloxone and levetiracetam restores (1) TLR4 expression, (2) Ca2+ release, (3) Na+/K+-ATPase expression, (4) actin filament organisation, and (5) release of IL-1β. Furthermore, the combination unblocks gap junctions and promotes propagation of the intercellular Ca2+ waves through the gap junctions [90].

6.1 Endomorphin-1 stimulates the μ-opioid receptor and Na+/K+ATPase

Endomorphin-1 (EM-1) is a peptide and an endogenous μ-opioid receptor agonist [95, 96, 97]. EM-1 is released from nerve endings into the general circulation [98]. It has also been found in inflammatory tissue, implying that it may interact with immune cells. Astrocytes possess μ-opioid receptors, and endomorphins may play a role in the control of neuroinflammatory activity 99,100]. Morphine activates the μ-opioid receptor, which in turn activates the second messenger protein Gi/o. The complex of μ-opioid receptor and Gi/o works by multiple mechanisms to inhibit neural pain impulses, thereby decreasing pain sensations in the brain 101,102]. EM-1 and morphine have been shown to stimulate Na+/K+-ATPase activity in vitro [103].

6.2 Naloxone inhibits the excitatory second messenger protein Gs and restores actin filaments

Naloxone is an effective μ-opioid receptor antagonist when used at higher doses (mg), and it is widely used in clinical practice to reverse opioid overdoses [104].

At ultralow doses (pg) the mechanism of naloxone is different. In states of low-grade neuroinflammation, such as chronic pain states 31,105], and even after long-term morphine treatment 106,107] the μ-opioid receptor shifts its coupling from the inhibitory Gi/o protein to the excitatory Gs protein 108,109]. This switch causes diminished pain relief and increased morphine tolerance. Naloxone at ultralow concentrations has the ability to block μ-opioid receptor-coupling to the excitatory Gs protein and causes the μ-opioid receptor to couple to the inhibitory Gi/o protein 110,111]. Naloxone can also restore to some extent, inflammatory disrupted actin filaments [77].

6.3 Levetiracetam opens blocked gap junctions

Levetiracetam is an effective anti-epileptic drug. Levetiracetam inhibits the neural release of transmitters into the synaptic cleft by binding to a protein that regulates exocytosis 112,113]. In our experimental work, levetiracetam was used for its anti-inflammatory properties. Levetiracetam has been shown, in inflammation-reactive astrocyte models, to restore functional gap junction coupling [114] by increasing the expression of connexin 43, the predominant gap junction protein, and decreasing the enhanced IL-1 β level [115].

6.4 Experimental studies of the combination endomorphin-1, naloxone and levetiracetam

The combination of the endogenous μ-opioid agonist endomorphin-1, the μ-opioid antagonist naloxone at ultralow concentrations and the anti-epileptic drug levetiracetam yielded promising results as regards restoration of cellular changes caused by experimentally induced inflammation [94].

During inflammation, the μ-opioid receptor switches its normal activation target from the Gi/o protein to the Gs protein [110,111,116]. At ultralow doses, naloxone blocks Gs and forces Gi/o activation, which promotes normal endomorphin-1-induced Ca2+ release [117]. Second, the addition of levetiracetam in combination with endomorphin-1 and ultralow doses of naloxone restored the actin filaments, attenuated the release of IL-1β and unblocked the gap junctions, thus enabling restoration of Ca2+ signalling (Fig. 3). Experimentally, a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam can attenuate inflammatory-induced astrocytic changes and restore intercellular Ca2+ signalling. It is possible that this type of action influences the intercellular communication between astrocytes and exerts effects on synaptic pain transmission in neurons. Nevertheless, there is a large difference between results produced in a laboratory using cellular cultures and outcomes in a clinical setting. Thus, these results need to be assessed in a clinical setting.

7 Clinical applications

Our group performed a pilot study consisting of eleven patients with persistent pain following multiple surgeries, who were being treated with continuous intrathecal morphine administration; in the study, ultralow-dose naloxone was administered via the same route [118]. The reason for not using the above discussed triple combination is that we wanted the option to investigate the effect of each agent individually in vivo.

Two dosages of naloxone were used: 40 ng/24 h and 400 ng/24 h. Neither of these interventions was associated with statistically significant changes in pain status, as assessed with the Numeric Rating Scale (NRS) (Fig. 4). Nevertheless, three study patients who did not improve with placebo experienced marked pain relief with one of the doses of adjuvant intrathecal naloxone.

Fig. 4 Effects of interventions on pain (percentage of subjects) expressed as “Improved” (dark blue), “Unchanged” (medium blue), or “Worse” (light blue). NAL, naloxone. N = 11 [90].
Fig. 4

Effects of interventions on pain (percentage of subjects) expressed as “Improved” (dark blue), “Unchanged” (medium blue), or “Worse” (light blue). NAL, naloxone. N = 11 [90].

An unexpected finding was that adjuvant naloxone 40 ng/24 h significantly improved the perceived quality of sleep compared with the placebo (Fig. 5) [118].

Fig. 5 Effects of interventions on perceived quality of sleep (percentage of subjects), expressed as “Improved” (dark blue), “Unchanged” (medium blue), or “Worse” (light blue). NAL, naloxone. p indicates a comparison between placebo and NAL 40 ng/24 h. N = 11 [90].
Fig. 5

Effects of interventions on perceived quality of sleep (percentage of subjects), expressed as “Improved” (dark blue), “Unchanged” (medium blue), or “Worse” (light blue). NAL, naloxone. p indicates a comparison between placebo and NAL 40 ng/24 h. N = 11 [90].

The underlying mechanisms of the clinical findings are complex. In healthy states, morphine stimulates the μ-opioid receptor, which in turn stimulates the inhibitory Gi/o protein; however, in states of low-grade inflammation, this coupling decreases, and the coupling of the μ-opioid receptor to the excitatory Gs protein increases [119, 120, 121]. As described above, using cellular cultures, it has been demonstrated that ultralow doses of naloxone can inhibit the Gs protein, and the μ-opioid receptor coupling to the Gi/o protein subsequently increases [122].

8 Conclusions

Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflamma-tion can cause an imbalance in the glial-neuron interaction and communication.

Experimentally induced inflammation causes changes in astro-cyte function. The expression of the inflammatory receptor TLR4 is increased, the Ca2+ wave signalling is changed, the expression of Na+/K+-ATPase is decreased, the actin filaments are disorganised, and the release of IL-1β is increased. These changes cause an imbalance in the astrocyte-neuron interaction that renders the neurons overly excitable, which produces enhanced and prolonged pain signalling.

The disturbed signalling can be restored in vitro by treating astrocytes with a combination of endomorphin-1, and ultralow doses of naloxone and levetiracetam. Ultralow doses of naloxone block the excitatory Gs protein. Subsequently, the action of endomorphin-1 on the inhibitory Gi/o protein is enhanced. Levetiracetam attenuates the inflammatory-induced release of glial IL-1 β. The combination of endomorphin-1, naloxone, and levetiracetam successfully counteracts the inflammatory-induced cellular changes caused by LPS. This restoration is essential for intercellular astrocyte Ca2+ communication and the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.

9 Implications

Surgery or trauma causes inflammation at the site of injury. Nerve injury causes low-grade inflammation in the CNS and PNS. Neuroinflammation that persists after the acute injury has healed may be an important component of establishing persistent postsurgical neuropathic pain. Restoring inflammatory-activated astrocytes, thereby inhibiting enhanced pain transmission in neurons, is a potentially interesting method. Larger studies in clinical settings are needed before the abovementioned findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.

Highlights

  • Peripheral nerve injury can cause low-grade neuroinflammation.

  • Low-grade neuroinflammation causes imbalance in the neuron-glia interaction.

  • The disturbed neuron-glia interaction produces prolonged and exaggerated pain transmission.

  • By targeting glial dysfunction instead of neurons, a new arena for the development of pharmacological agents is opened.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.10.001

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  1. Conflicts of interest: The author has no conflicts of interest to report.

Acknowledgements

The author wishes to express her sincere gratitude to Professor Elisabeth Hansson for excellent scientific advice and proofreading.

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Received: 2015-06-09
Revised: 2015-10-10
Accepted: 2015-10-13
Published Online: 2016-01-01
Published in Print: 2016-01-01

© 2015 Scandinavian Association for the Study of Pain

Articles in the same Issue

  1. Editorial comment
  2. Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
  3. Original experimental
  4. Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  5. Editorial comment
  6. Genetic variability of pain – A patient focused end-point
  7. Observational study
  8. COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
  9. Editorial comment
  10. Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
  11. Clinical pain research
  12. Complex regional pain syndrome following viper-bite
  13. Editorial comment
  14. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
  15. Original experimental
  16. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
  17. Editorial comment
  18. Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
  19. Observational study
  20. Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
  21. Editorial comment
  22. Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
  23. Clinical pain research
  24. Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
  25. Editorial comment
  26. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  27. Original experimental
  28. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  29. Editorial comment
  30. Targeting glial dysfunction to treat post-surgical neuropathic pain
  31. Topical review
  32. Glial dysfunction and persistent neuropathic postsurgical pain
  33. Editorial comment
  34. Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
  35. Original experimental
  36. Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
  37. Editorial comment
  38. Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option
  39. Original experimental
  40. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
  41. Editorial comment
  42. The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
  43. Observational study
  44. Obesity has an impact on outcome in lumbar disc surgery
  45. Editorial comment
  46. Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
  47. Clinical pain research
  48. Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
  49. Editorial comment
  50. Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
  51. Clinical pain research
  52. A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients
https://doi.org/10.1016/j.sjpain.2015.10.002
Keywords for this article
Pain; Persistent postsurgical pain; Neuropathic pain; Neuroinflammation; Glia

Articles in the same Issue

  1. Editorial comment
  2. Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
  3. Original experimental
  4. Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  5. Editorial comment
  6. Genetic variability of pain – A patient focused end-point
  7. Observational study
  8. COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
  9. Editorial comment
  10. Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
  11. Clinical pain research
  12. Complex regional pain syndrome following viper-bite
  13. Editorial comment
  14. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
  15. Original experimental
  16. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
  17. Editorial comment
  18. Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
  19. Observational study
  20. Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
  21. Editorial comment
  22. Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
  23. Clinical pain research
  24. Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
  25. Editorial comment
  26. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  27. Original experimental
  28. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  29. Editorial comment
  30. Targeting glial dysfunction to treat post-surgical neuropathic pain
  31. Topical review
  32. Glial dysfunction and persistent neuropathic postsurgical pain
  33. Editorial comment
  34. Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
  35. Original experimental
  36. Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
  37. Editorial comment
  38. Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option
  39. Original experimental
  40. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
  41. Editorial comment
  42. The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
  43. Observational study
  44. Obesity has an impact on outcome in lumbar disc surgery
  45. Editorial comment
  46. Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
  47. Clinical pain research
  48. Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
  49. Editorial comment
  50. Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
  51. Clinical pain research
  52. A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients
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