Chronic pain is a major health problem worldwide. Despite prolonged and extensive study in this field, it is only recently that the immune system has been implicated in peripheral neuropathic pain. The immune system might also have a role in the pain that is associated with CNS damage.
The immune system does not seem to have an active role in acute responses to painful stimuli (nociception). However, it is an active player in persistent pain states.
Several types of immune cell and, more importantly, many factors that these cells can release, are involved in inflammatory pain conditions. The sequential response of immune cells and the factors that contribute to inflammatory pain are well known and have led to new therapeutics. For example, tumour necrosis factor-α antibodies and neutralizing reagents have been used successfully to treat the pain of rheumatoid arthritis.
After peripheral nerve injury, the immune system seems to have a crucial role in the establishment of pain. Indeed, sequential infiltration of various immune cells into peripheral nervous structures occurs after this type of lesion. These cells release cytokines and chemokines that contribute directly and/or indirectly to pain. A common peripheral mechanism of action of these factors might be the induction of cyclooxygenase enzymes. However, the lack of effect of cyclooxygenase inhibitors in patients with neuropathic pain indicates that this mechanism is of limited importance. Another mechanism could be the retrograde transport of these mediators to the CNS.
Peripheral nerve injury leads to central changes that include, remarkably, changes in immune cell function. Microglia (the resident CNS macrophages) are activated in different neuropathic pain models, and several studies have shown that this response is particularly important in the initiation, as opposed to the maintenance, of neuropathic pain. However, the factors that activate microglia are still poorly understood. Whatever the mechanism of this activation, microglia can release several factors that directly and/or indirectly modulate pain-processing neurons.
Despite some inconsistencies and uncertainties in the literature, microglia seem to have a crucial role in peripheral neuropathic pain. The role of the immune system in pain after central damage is still relatively unexplored. However, there is circumstantial evidence that it is involved in the pain of spinal cord injury and multiple sclerosis.
From the perspective of pain, the challenge is to exploit this new knowledge of immune system involvement in nociceptive processing to develop novel analgesic strategies without interfering with the potential beneficial effects of the immune response.
During the past two decades, an important focus of pain research has been the study of chronic pain mechanisms, particularly the processes that lead to the abnormal sensitivity — spontaneous pain and hyperalgesia — that is associated with these states. For some time it has been recognized that inflammatory mediators released from immune cells can contribute to these persistent pain states. However, it has only recently become clear that immune cell products might have a crucial role not just in inflammatory pain, but also in neuropathic pain caused by damage to peripheral nerves or to the CNS.
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We are grateful to the Wellcome Trust, the International Spinal Research Trust and the Arthritis Research Campaign UK for the financial support that has made this work possible.
The authors declare no competing financial interests.
Pain has been defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage, or described in terms of such damage.
- MAST CELL
A multigranular cell that functions as a store for several key inflammatory/pain mediators (including NGF, TNFα, chemokines and histamine).
Small, secreted proteins that mediate and regulate immunity, inflammation and haematopoiesis. They act as intercellular mediators by binding to specific membrane receptors, which then signal through second messengers — often tyrosine kinases — to alter the target cell's behaviour.
Small polypeptide cytokines that can attract leukocyte subsets.
- NEUROPATHIC PAIN
This has been defined by the International Association for the Study of Pain as pain that is initiated or caused by a primary lesion or dysfunction in the nervous system.
Dimeric membrane proteins that are involved in several aspects of cell–cell interaction.
A non-neuronal cell type present in the spinal cord and brain (the resident CNS macrophage) that is characterized by its ramified morphology.
- ANNEXIN 1
A member of a superfamily of proteins named after their ability to annex membranes by binding to acidic phospholipids in the presence of cations; an important endogenous counter-regulator of inflammation.
A member of the formyl peptide receptor family of G-protein-coupled receptors that mediates the anti-inflammatory/protective activities of lipoxins and annexin 1, as well as the activating effects of amyloid-β fragments.
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Marchand, F., Perretti, M. & McMahon, S. Role of the Immune system in chronic pain. Nat Rev Neurosci 6, 521–532 (2005). https://doi.org/10.1038/nrn1700
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