Elsevier

Brain Research Reviews

Volume 51, Issue 2, August 2006, Pages 240-264
Brain Research Reviews

Review
Immune and inflammatory mechanisms in neuropathic pain

https://doi.org/10.1016/j.brainresrev.2005.11.004Get rights and content

Abstract

Tissue damage, inflammation or injury of the nervous system may result in chronic neuropathic pain characterised by increased sensitivity to painful stimuli (hyperalgesia), the perception of innocuous stimuli as painful (allodynia) and spontaneous pain. Neuropathic pain has been described in about 1% of the US population, is often severely debilitating and largely resistant to treatment. Animal models of peripheral neuropathic pain are now available in which the mechanisms underlying hyperalgesia and allodynia due to nerve injury or nerve inflammation can be analysed. Recently, it has become clear that inflammatory and immune mechanisms both in the periphery and the central nervous system play an important role in neuropathic pain. Infiltration of inflammatory cells, as well as activation of resident immune cells in response to nervous system damage, leads to subsequent production and secretion of various inflammatory mediators. These mediators promote neuroimmune activation and can sensitise primary afferent neurones and contribute to pain hypersensitivity. Inflammatory cells such as mast cells, neutrophils, macrophages and T lymphocytes have all been implicated, as have immune-like glial cells such as microglia and astrocytes. In addition, the immune response plays an important role in demyelinating neuropathies such as multiple sclerosis (MS), in which pain is a common symptom, and an animal model of MS-related pain has recently been demonstrated. Here, we will briefly review some of the milestones in research that have led to an increased awareness of the contribution of immune and inflammatory systems to neuropathic pain and then review in more detail the role of immune cells and inflammatory mediators.

Introduction

Neuropathic pain is caused by lesion or inflammation of the nervous system and is relatively common, with an incidence estimated at 0.6% to 1.5% in the US population (Warfield and Fausett, 2002). It is often severely debilitating and largely resistant to treatment (Harden and Cohen, 2003) mainly because the underlying mechanisms are still poorly understood. Symptoms of neuropathic pain may include allodynia (pain resulting from a stimulus that is normally non-painful), hyperalgesia (an excessive response to painful stimuli) and spontaneous pain. The study of neuropathic pain can be traced back to Weir Mitchell and his classic work on nerve injuries from the American Civil War (Mitchell, 1872). Since that time, a great deal has been written on neuropathic pain and its possible causes, but it was only with the development of animals models of pain due to nerve injury that some real progress was made in understanding some of the mechanisms involved. For recent reviews of these mechanisms, see Julius and Basbaum (2001) and Scholz and Woolf (2002). The first widely used animal model of neuropathic pain was chronic constriction injury of the rat sciatic nerve (Bennett and Xie, 1988), in which the sciatic nerve is encircled by four ligatures of chromic gut. This leads to the cardinal symptoms of neuropathic pain—hyperalgesia, allodynia and apparent spontaneous pain. Other widely used animal models include partial ligation of the sciatic nerve (Seltzer et al., 1990) and section of one or more of the spinal nerves which contribute to the sciatic (Kim and Chung, 1992). Research on these animal models of peripheral neuropathic pain (the pain syndrome resulting from lesions of the peripheral nervous system) has made it clear that a number of mechanisms are involved, including ectopic excitability of sensory neurones, altered gene expression of sensory neurones and sensitisation of neurones in the dorsal horn of the spinal cord (Scholz and Woolf, 2002, Woolf, 2004). However, there is increasing evidence that inflammatory and immune mechanisms also play a role, and we will begin by looking at a brief history of how this evidence has accumulated. We will then look in more detail at the evidence for involvement of immune cells and inflammatory mediators in neuropathic pain. However, the review does not provide exhaustive coverage of all immune and inflammatory mechanisms that contribute to pain following nerve injury. For readers who would like to know more about these and other aspects of neuropathic pain, several recent reviews are available, dealing with immune and glial mechanisms (Watkins and Maier, 2002, Watkins and Maier, 2005, DeLeo et al., 2004, McMahon et al., 2005, Tsuda et al., 2005), inflammatory aspects (Woolf and Costigan, 1999, DeLeo and Yezierski, 2001, DeLeo et al., 2004, Sommer and Kress, 2004) and cytokines (Sommer and Kress, 2004).

At the time that the first animal models of pain due to nerve injury were developed, it was widely believed that injury or loss of myelinated and unmyelinated sensory axons in the sciatic nerve was the key factor in producing symptoms of neuropathic pain. However, some studies in the early 1990s suggested that other factors might also be involved. For example, Maves showed that chromic gut alone placed next to the sciatic nerve induced thermal hyperalgesia without any loss of myelinated axons (Maves et al., 1993). Of course, it had long been known that C-polymodal nociceptors are sensitised or activated by chemical stimuli, including inflammatory mediators (Wood and Docherty, 1997), but these effects were thought of as being responsible for inflammatory pain, and little attention was given to the idea that immune or inflammatory cells or their mediators might play a role in neuropathic pain until the advent of useful animal models. It was also known that nerve injury resulted in activation of mast cells (Olsson, 1967) and recruitment of neutrophils and macrophages (Perry et al., 1987). However, it was not until 1993 that ‘acute changes in the endoneurial microenvironment’ were explicitly linked with the initial development of hyperalgesia (Frisen et al., 1993, Sommer et al., 1993). Further work confirmed suggestions that the factors responsible for neuropathic hyperalgesia included Wallerian degeneration and macrophage activation (Sommer et al., 1995). At around the same time, Clatworthy followed up the observations of Maves et al. and showed that suppression of the inflammatory response in the injured sciatic nerve blocked the development of hyperalgesia, while enhancing the inflammatory response augmented the hyperalgesia (Clatworthy et al., 1995). Evidence on the involvement of immune cells and inflammatory mediators in hyperalgesia was reviewed at this time, and it was suggested that these mediators (and cytokines in particular) were a probable link between the activation or recruitment of immune cells to the injured nerve and the development of hyperalgesia and neuropathic pain (Tracey and Walker, 1995, Watkins et al., 1995). Glial cells supporting neurones in the spinal cord (Meller et al., 1994) and Schwann cells supporting axons in the peripheral nerve (Constable et al., 1994, Wagner and Myers, 1996a) were added to the list of cell types which might contribute to neuropathic pain. In fact, glial cells and Schwann cells may also play an active role in the immune process by releasing mediators, including cytokines, and acting as antigen-presenting cells following nerve injury (Argall et al., 1992, Bergsteinsdottir et al., 1992, Constable et al., 1994). These ideas were not widely accepted at the time, but, gradually, evidence accumulated to give them further support. For example, tumour necrosis factor (TNF) and interleukins 1 and 6 (IL-1, IL-6) had already been shown to induce acute or short-term hyperalgesia (Ferreira et al., 1988, Cunha et al., 1992) but were now implicated directly in neuropathic pain, involving chronic hyperalgesia and allodynia (Wagner and Myers, 1996b, DeLeo et al., 1997, Arruda et al., 1998).

Another example is the contribution of nerve growth factor (NGF), which shares many attributes with typical cytokines (Bonini et al., 2003). NGF is best known for its role in protecting some neuronal types from cell death during development, but Levine and his colleagues showed that the N-terminal octapeptide of NGF elicited hyperalgesia in the rat when applied to injured tissue (Taiwo et al., 1991). These experiments were provoked by apparent similarities between the NGF fragment and bradykinin—an inflammatory mediator known to activate or sensitise nociceptors and to elicit hyperalgesia (Dray and Perkins, 1993, Dray, 1997). By this stage, it was known that the level of NGF rises substantially in inflamed tissue and in injured nerve (Heumann et al., 1987, Weskamp and Otten, 1987), and a causal relationship between tissue levels of NGF and inflammatory hyperalgesia was confirmed by showing that anti-NGF antibodies reduced inflammatory hyperalgesia (Lewin et al., 1994, Woolf et al., 1994). NGF was later shown to contribute to neuropathic hyperalgesia as well (Herzberg et al., 1997, Theodosiou et al., 1999). The underlying mechanism is not clear, but it is agreed that NGF has a cytokine-like action on inflammatory cells (Otten, 1991) including mast cells, basophils, neutrophils and lymphocytes. Furthermore, NGF is produced and released by leukocytes such as macrophages and T lymphocytes (Vega et al., 2003). NGF is a potent degranulator of mast cells (Pearce and Thompson, 1986), which appear to play an important role in inflammatory (Woolf et al., 1996) as well as neuropathic hyperalgesia (Zuo et al., 2003). It seems likely that mediators released by activated mast cells contribute to hyperalgesia following nerve injury — histamine has been strongly implicated (Zuo et al., 2003), but several other mediators may also be involved.

It is now apparent that early animal models of neuropathic pain suffer from the disadvantage that symptoms such as hyperalgesia are most likely the combined result of nerve injury itself (e.g. ectopic firing of injured sensory axons) and the release of algesic mediators by immune cells activated near the site of injury. In fact, neuropathic pain may develop without any injury of sensory axons. This was shown in rats by induction of neuropathic hyperalgesia by placing segments of chromic gut next to the sciatic nerve (Maves et al., 1993) or by lesion of the ventral roots of spinal nerves (Li et al., 2002, Sheth et al., 2002). In both cases, typical signs of neuropathic pain were elicited without damage to sensory axons, implying that sensitisation or activation of sensory fibres by inflammatory mediators is sufficient to cause neuropathic pain. As a result of observations like these, inflammatory models of neuropathic pain have been developed in which carrageenan or complete Freund's adjuvant (Eliav et al., 1999) or zymosan (Chacur et al., 2001) is applied around the intact sciatic nerve of the rat. These models should help us to understand the role of inflammatory and immune mechanisms in neuropathic pain.

Autoimmune diseases of the nervous system including multiple sclerosis (MS) and Guillain–Barré syndrome (GBS) are among the most common disabling neurologic diseases, which cause not only demyelination with impaired motor function, but also abnormal sensory phenomena including chronic neuropathic pain. MS is an autoimmune demyelinating disease of the central nervous system that causes relapsing and chronic neurological impairment. Pain is experienced by approximately 65% of patients with MS at some time during the course of their disease (Kerns et al., 2002). GBS is an acute inflammatory demyelinating neuropathy caused by an autoimmune attack on the peripheral nervous system and characterised by motor disorders such as weakness or paralysis and variable sensory disturbances (Hughes et al., 1999). Pain is a common symptom of GBS occurring in 70–90% of cases (Pentland and Donald, 1994, Moulin et al., 1997). Immune cells including macrophages and T cells are believed to play a critical role in the pathogenesis of both MS and GBS and may contribute to the related pain. Studying neuropathic pain in these autoimmune syndromes has been hampered by the lack of proper animal models for autoimmunity-related pain. However, recent study in mice has shown that transient demyelination of peripheral afferents without axonal loss results in neuropathic pain behaviour (Wallace et al., 2003), and a suitable animal model of MS-related pain has recently been developed using both active and passive induction of experimental autoimmune encephalomyelitis (Aicher et al., 2004).

While there is good evidence that inflammatory mediators contribute to neuropathic pain, it is not clear just how or where these mediators act. Do they act directly on receptors located on the cell membrane of the neurone or do they activate non-neuronal cells (such as mast cells or Schwann cells), which then release a secondary mediator that exerts a direct action on neuronal receptors? Are the neuronal receptors for chemical mediators located on the nerve terminals or cell bodies of sensory neurones, even though these may be many centimetres from the lesion site? The answer to the first question is that both direct and indirect mechanisms are likely to operate. Some mediators (such as prostaglandin E2) probably sensitise nociceptors directly by acting on receptors on the neuronal cell membrane (Pitchford and Levine, 1991). While IL-1 may also have a direct action on nociceptors (Sommer and Kress, 2004), it has additional indirect actions by eliciting the production of prostaglandins (Cunha et al., 1992) or even more indirectly via neural pathways from vagal afferents to the brainstem and then to the spinal cord (Watkins et al., 1995). The answer to the second question is that receptors for inflammatory mediators may be located not only on the neuronal cell body and peripheral nerve terminals, but also on the axon itself.

Recent work by Grafe and his colleagues makes it clear that some of the neuronal receptors are located on the axon itself (Irnich et al., 2002, Lang et al., 2003, Moalem et al., 2005). This makes it easier to understand how mediators released by immune cells clustered around the nerve lesion can influence the excitability of sensory neurones — since these mediators would be released close to axonal receptors and would not need to diffuse distally to nerve terminals or proximally to cell bodies. For example, it was shown that ATP increased the excitability of unmyelinated C-fibres in an in vitro preparation of an isolated segment of the sural nerve, in which no cell bodies or nerve terminals were present. Tissue levels of ATP are raised in inflamed tissue, and ATP activates nociceptors causing pain and hyperalgesia (Sawynok and Liu, 2003); it also plays a role in neuropathic pain (Barclay et al., 2002, Jarvis et al., 2002). It may well be that ATP contributes to neuropathic pain by its action on axonal receptors.

Section snippets

Immune cells

Several inflammatory and immune-like glial cells have been implicated in the pathogenesis of neuropathic pain. They include mast cells, neutrophils, macrophages and T cells in the peripheral nervous system (Fig. 1) and microglia (Fig. 2) and astrocytes in the central nervous system. Table 1 summarises immune cells and the mediators they release with their most significant actions.

Mediators

The mediators released by inflammatory and immune cells may act directly to sensitise or activate neurones (usually nociceptors in the periphery or dorsal horn neurones in the spinal cord). Alternatively, they may act on a non-neuronal cell, which on activation releases another mediator that does act directly on the neurone. These mediators form a long and increasing list that includes bradykinin, ATP and adenosine, serotonin, eicosanoids, cytokines, neurotrophins and reactive oxygen species (

Conclusions

Our understanding of the involvement of immune cells and inflammatory mediators in neuropathic pain has greatly increased in the last decade. Work on animal models of nerve injury has implicated complex neuronal changes in response to the trauma. However, recent studies have emphasised the important contribution of inflammatory cells and immune-like glial cells, as well as their mediators, to neuropathic pain. This review summarises current views on immune and inflammatory modulation of the

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