Review
Toll-like receptors in chronic pain

https://doi.org/10.1016/j.expneurol.2011.09.038Get rights and content

Abstract

Proinflammatory central immune signaling contributes significantly to the initiation and maintenance of heightened pain states. Recent discoveries have implicated the innate immune system, pattern recognition Toll-like receptors in triggering these proinflammatory central immune signaling events. These exciting developments have been complemented by the discovery of neuronal expression of Toll-like receptors, suggesting pain pathways can be activated directly by the detection of pathogen associated molecular patterns or danger associated molecular patterns. This review will examine the evidence to date implicating Toll-like receptors and their associated signaling components in heightened pain states. In addition, insights into the impact Toll-like receptors have on priming central immune signaling systems for heightened pain states will be discussed. The influence possible sex differences in Toll-like receptor signaling have for female pain and the recognition of small molecule xenobiotics by Toll-like receptors will also be reviewed.

Highlights

► Proinflammatory central immune signaling contributes to chronic pain. ► Toll-like receptors are now recognized to contribute to the chronic pain process. ► Recent evidence shows neuronal Toll-like receptor expression and activation. ► This review examines Toll-like receptors in chronic pain and xenobiotic recognition.

Introduction

Chronic pain is an extremely complex disease process affecting approximately 1.5 billion people worldwide, placing large economic and health burdens on the global community (Jacobs, 2005). Until recently, only neuronal mechanisms were recognized to contribute to pathological pain. However, our understanding has since developed, and aberrant signaling and activity of non-neuronal immune cells such as glia and peripheral immune cell trafficking through the central nervous system (CNS), are now recognized to play a substantial role in initiating and maintaining the chronic pain process (Grace et al., 2011, Haydon, 2001, Milligan and Watkins, 2009).

Communication between neuronal and non neuronal immunocompetent cells is critical to the maintenance of homeostasis within both the peripheral and central nervous systems, but under certain conditions this bi-directional communication can contribute to numerous neuropathologies (Ren and Dubner, 2010). Within the CNS this interaction between neurons and immunocompetent cells can be referred to as “central immune signaling” (Hutchinson et al., 2011). Critical to the central immune signaling process are specialized immune receptors, called Toll-like receptors (TLRs) (Austin and Moalem-Taylor, 2010, Ren and Dubner, 2010). TLRs are pattern recognition receptors which play an important innate immune role in sensing the presence of damage or danger originating both endogenously and exogenously, and translating this into a central immune signal that can be interpreted, and responded to, by neurons and other immunocompetent cells within the CNS.

TLR-induced central immune signaling is now appreciated to contribute to a myriad of CNS pathologies (e.g., CNS consequences of sepsis (Hoshino et al., 1999), Alzheimer's disease (Akiyama et al., 2000, Minoretti et al., 2006, Tan et al., 2008) and ischemic stroke (Abate et al., 2010, Caso et al., 2007, Tasaki et al., 1997)), with chronic pain being of specific interest here. Chronic pain associated TLR activation contributes to the pain pathology via the dysregulation of several cellular functions that are critical to the maintenance of homeostasis as well as via the release of numerous proinflammatory mediators, that all sum to enhance the neuroexcitatory tone (Austin and Moalem-Taylor, 2010, Ren and Dubner, 2010). Currently in the literature, excellent reviews and original data articles on pain that have included discussions of TLR involvement in nociception have each provided their own specific focus and expertise (Austin and Moalem-Taylor, 2010, Bokhari et al., 2009, Buchanan et al., 2010, Carty and Bowie, 2011, Combrinck et al., 2002, DeLeo et al., 2004, Frank et al., 2007, Guo and Schluesener, 2007, Inoue and Tsuda, 2009, Kim et al., 2009, Kohli et al., 2010, Loram et al., 2010, Marriott and Wilkin, 1993, Milligan and Watkins, 2009, Perry, 2004, Qi et al., 2011, Tasaki et al., 1997, Thorlin et al., 1998). This review will provide a distinct perspective by specifically focusing on the evolving role of TLRs in the induction and maintenance of chronic pain through the initiation of central immune signaling, and the implications that TLR-induced central immune signaling may have for pain processing.

Recent evidence has also identified sex differences in TLR-induced proinflammation, adding an additional layer of complexity and insight into central immune signaling (Calippe et al., 2008, Calippe et al., 2010). This newly identified interaction between TLRs and sex steroids may provide a tantalizing contribution to sex differences seen in pain sensitivity. It has additionally become evident that TLRs are able to detect small molecule xenobiotics; that is, chemicals that are found in an organism but which are not normally produced or expected to be present in it. In this context, xenobiotics include compounds such as opioids and other tricyclic compounds. The impact of drugs such as these on TLR-induced central immune signaling results in a modification of drug response and constrains their efficacy, as in the case of opioids, and may perhaps even contribute to their therapeutic indication, as in the case of amitriptyline for example (Hutchinson et al., 2008c, Hutchinson et al., 2009b, Hutchinson et al., 2010b, Snyder, 2004, Watkins et al., 2005). Accordingly, a review of the preclinical research on the role of TLRs in sex- and xenobiotic-induced central immune signaling and their corresponding role in the production and maintenance of chronic pain is included.

It is important to recognize that this burgeoning area of TLR-pain research is just as fraught with experimental design and data interpretation flaws as any other field. Hence, comments on experimental issues commonly encountered in this field will also be included. An appreciation of the topics outlined here and discussed in detail below will provide for a more complete understanding and appreciation of chronic pain mechanisms, which may in turn hopefully translate to improved analgesics and pave the way to improve pain relief.

Section snippets

Who contributes to central immune signaling?

Glia are the main non-neuronal cells in the CNS, outnumbering neurons by ten to one and form greater than 70% of the total brain and spinal cord cells (Milligan and Watkins, 2009). Traditionally, glia have been seen as merely structural support for neuronal cells (Haydon, 2001). However, they have now been acknowledged as key mediators of the CNS innate immune response, playing major roles in immune surveillance and the clearance of cellular debris (Faulkner et al., 2004, Milligan and Watkins,

Toll-like receptors: origins and the basics

The original link between Toll-like receptors and pain was made by the illness response field, a research area which arose before substances such as gram-negative bacterial lipopolysaccharide (LPS) were even discovered to be TLR ligands. Here, systemic live infection or pseudo-infection using LPS resulted in heightened pain states of allodynia or hyperalgesia and was associated with the presentation of the illness/sickness response (reviewed by Watkins and Maier, 2000). However, in these cases

Central immune signaling and pain: the basics

Early in the 1990's pain researchers discovered that glial cells were important mediators in the pathological pain process. Utilization of peripheral neuropathy models demonstrated increased glial activation markers. For instance, glial fibrillary acidic protein (GFAP) expression, a marker for astrocytic activation, is increased in the gray matter of the spinal cord in the chronic constriction injury model of neuropathic pain (Garrison et al., 1991). Further investigation showed that this

Toll-like receptors and pain

It was not until recent studies from the DeLeo group (DeLeo et al., 2004, Raghavendra et al., 2003, Raghavendra et al., 2004, Tanga et al., 2004, Tanga et al., 2005) that up regulation of TLR detection systems and requirement of, in this case TLR4, was shown in preclinical models for the initiation of pathological pain. Raghavendra et al. (2003) first demonstrated, following L5 nerve transection, that TLR4 mRNA increased significantly in a minocycline sensitive fashion, regardless of whether

Indirect evidence of Toll-like receptors in pain

In addition to the growing literature of direct assessment of TLR-induced central immune signaling and pain, there is also a parallel literature of TLR changes associated with pain. For example, in the transcriptional examination of differences between wild type and cholecystokinin B2 receptor knockout mice, reductions in supraspinal TLR4 were also identified (Koks et al. 2008). Interestingly, these cholecystokinin B2 receptor knockout mice are protected against allodynia induced by chronic

Sensitization of TLR signaling

Normal nociceptive pain is necessary and important for survival. However, acute protective pain transitions, in some cases, to a pathological chronic pain state. The underlying mechanism for the transition from acute to chronic pain is now beginning to be explored. While microglia can exhibit many activation states, the sensitized or “primed” state is of particular interest and has been shown to contribute to other potentiated neuroinflammatory diseases. Much of what is known about microglial

The inflammasome: a crucial translator of CNS TLR activation

It is evident that TLRs play a substantial role in the engagement of central immune cells, which are now known to play a role in pathological pain. The production of proinflammatory mediators released via TLR signaling however cannot produce pathological pain without a molecular scaffold complex, termed the inflammasome (Hoffman and Wanderer, 2010). The innate immune system not only includes TLRs but also another class of pattern recognition receptors termed NOD-like receptors (NLRs). Like

A role for TLR4 in enhanced female nociception?

Current research indicates that chronic pain preferentially affects females, with enhanced female nociception in both clinically and experimentally-induced pain (Fillingim et al., 2009). Epidemiological and experimental evidence demonstrates that women are overrepresented in numerous chronic pain conditions and are at greater risk for developing several chronic pain conditions (Fillingim et al., 2009, Riley et al., 1998). Furthermore, both women and female rodents display heightened sensitivity

TLR4 and opioid-induced pain and analgesia

Opioid analgesics are considered one of the first line therapies for neuropathic pain sufferers and are used to treat both acute and chronic pain (Park and Moon, 2010). Despite their continued use, the precise mechanisms of opioid pharmacological action, such as their action on immune signaling within the CNS, have not yet been fully appreciated. Furthermore, there are many complications associated with opioid exposure including but not limited to tolerance and hyperalgesia (Chang et al., 2007,

Conclusion

The revelations made in the past decade implicating TLRs in initiating and maintaining heightened pain states begins to complete the circuit of how central immune signaling is initiated and maintained chronically to contribute long term to neuropathic pain processes. However, the discovery of neuronal TLRs and their detection of DAMPs and PAMPs, bypassing classical immunocompetent cells and central immune signaling response systems, and their potential direct link to modification of nociceptive

Author disclosure statement

No competing financial interests exist.

Acknowledgments

This work was supported by the National Institutes of Health National Institute [, ]; the Australian Research Council Australian Research Fellowship [, ]; Lauren Nicotra is the recipient of an Australian Postgraduate Award.

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