Pathological pain and the neuroimmune interface

Key Points

  • Local and recruited immunocompetent cells (such as microglia, astrocytes, endothelial cells, perivascular macrophages and T cells) in the central nervous system (CNS) detect neurotransmitters, chemokines and endogenous danger signals that are released by lesioned or diseased sensory neurons.

  • Immunocompetent cells in the central nervous system subsequently release cytokines, chemokines, prostaglandins, neurotrophic factors and reactive oxygen species that dysregulate synaptic transmission leading to amplification of nociceptive signalling.

  • Other facets of the immune response to neuronal lesion and disease are gaining recognition, including the necessity of pro-inflammatory mediators for repair, and regulation of pro-inflammatory responses by anti-inflammatory mediators.

  • Hence, the most successful treatment approaches targeting the immune system will probably integrate basic science understanding of nuanced immune responses.

  • Despite there being only indirect evidence for a CNS immune component to chronic pain in humans, immune-targeted therapies are showing early signs of success in treating such pain.

Abstract

Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs — which focus on suppressing aberrant neuronal activity — new strategies to manipulate neuroimmune pain transmission hold considerable promise.

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Figure 1: Physiological pain processing.
Figure 2: Initiation of central immune signalling.
Figure 3: Neuroimmune enhancement of nociception.

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Acknowledgements

Funding sources: P.M.G. is a CJ Martin Fellow of the Australian Government National Health and Medical Research Council and an American Australian Association Sir Keith Murdoch Fellow. M.R.H. is an Australian Research Council Fellow.

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Correspondence to Peter M. Grace.

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Glossary

Celsus

Aulus Cornelius Celsus was a first century Roman encyclopaedist who gathered extensive writings from the Greek empire and translated them into Latin. In his great work De Medicina, he characterized the four cardinal signs of inflammation: heat, pain, swelling and redness.

Sickness response

A defence mechanism triggered by the recognition of anything foreign to the host. An organized constellation of responses initiated by the immune system but co-ordinated and partially created by the brain, including physiological responses (for example, fever, increased sleep, hyperalgesia and allodynia), behavioural responses (for example, decreased social interaction, sexual activity, and food and water intake), and hormonal responses (increased release of classic hypothalamo–pituitary–adrenal and sympathetic hormones).

Hyperalgesia

Increased pain from a stimulus that normally provokes pain. A form of nociceptive hypersensitivity.

Peripheral sensitization

Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields, such as that developing upon inflammation.

Glia

Resident non-neuronal cells in the nervous system first described by Rudolf Virchow in 1856, that maintain the structural integrity of the nervous system, provide trophic support to neurons, insulate one neuron from another, and destroy pathogens and clear debris. Astrocytes and microglia are among the most thoroughly characterized glial cells and are immunocompetent.

Allodynia

Pain in response to a stimulus that does not normally provoke pain. A form of nociceptive hypersensitivity.

Gliosis

The transition from a role in physiological maintenance or surveillance to a reactive phenotype that is characterized by changes in cell number, morphology, phenotype, motility, protein expression and by the release of immunoregulatory products.

Neuroimmune interface

Proposed to describe the bidirectional, modulatory signalling between immune cells and neurons. We argue that such interfaces are formed in the central nervous system and can explain the sensory adaptations underlying pathological pain.

Central immune signalling

The process and consequences of immune mediator release by reactive immunocompetent cells in the central nervous system.

Nociceptive pain

Physiological pain produced by intense noxious stimuli that activate high-threshold nociceptor neurons.

Inflammatory pain

Occurs in response to tissue injury and the subsequent inflammatory response.

First-order primary afferent neurons

Sensory neurons the cell bodies of which lie in the trigeminal or spinal dorsal root ganglia, with projections that transmit nociceptive signals from the periphery (the peripheral terminal) to the spinal cord (the central terminal).

Central synapses

The synapses between first-order neurons, which form the presynaptic terminal, and nociceptive projection neurons, which form the postsynaptic terminal.

Second-order nociceptive projection neurons

Neurons projecting from the medullary dorsal horn or the superficial laminae of the spinal dorsal horn to the brainstem or thalamic nuclei.

Spinal dorsal horn

Two longitudinal subdivisions of grey matter in the posterior part of the spinal cord that receive terminals from afferent fibres originating from each side of the body that encode several types of sensory information, including nociception.

Hindbrain

Also known as the rhombencephalon. An area rostral to the spinal cord that gives rise to the cerebellum, pons and medulla.

Nociception

The neural process of encoding noxious mechanical, thermal and/or chemical stimuli that occurs in afferent fibres, which send signals to the central nervous system. Pain is expressed as the complex emotional and behavioural response to the central integration of nociceptive signals.

Third-order neurons

Sensory neuronal projections originating from thalamic nuclei.

Central sensitization

A period of facilitated transmission in nociceptive projection neurons that is characterized by a decreased activation threshold and an increased responsiveness to nociceptive stimuli.

Windup

Cumulative increases in membrane depolarization elicited by repeated C-fibre stimulation.

Masseter

A facial muscle that has a major role in chewing.

Blood–CNS barrier

A barrier formed by astrocyte end-feet and the tight junctions between endothelial cells lining blood vessels that excludes constituents of the systemic circulation from entry into the central nervous system (CNS). It forms an important boundary between the sensitive microenvironment of the CNS and the relatively volatile environment of the systemic circulation.

Trigeminal sensory neurons

Neurons found in the trigeminal nerve that mediate facial sensation and motor functions, including biting and chewing.

Dorsal root ganglia

(DRG). The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. Each cell body is encapsulated by satellite glia, with the entire ganglia being surrounded by a capsule of connective tissue and a perineurium.

Brain-derived neurotrophic factor

(BDNF). A neurotrophin expressed at high levels in the central nervous system that is vital for the growth and survival of neurons, and has been implicated in many forms of synaptic plasticity.

C-fibres

Small diameter, unmyelinated primary afferent sensory fibres, with small cell bodies in the dorsal root ganglion. Some C-fibres are mechanically insensitive, but most are polymodal, responding to noxious, thermal, mechanical and chemical stimuli.

Lamina I neurons

The most superficial aspect of the spinal dorsal horn from which second-order nociceptive projection neurons originate.

Reversal potential

The membrane potential at which chemical and electrical drive are equal and opposite, such that there is no net flow of ions across the membrane. The direction of flow reverses above and below this potential.

Anti-allodynic and anti-hyperalgesic

Compounds that oppose allodynia and hyperalgesia to restore basal sensory thresholds.

Radiculopathy

A condition arising from a compressed spinal nerve root that is associated with pain, numbness, tingling or weakness along the course of the nerve.

Carpal tunnel syndrome

A syndrome arising from compression of the median nerve — which runs from the forearm into the palm of the hand — that is associated with itching numbness, burning and/or tingling.

Complex regional pain syndrome

An idiopathic chronic pain condition that usually affects an arm or leg and typically develops after an injury, surgery, stroke or heart attack, but the pain is out of proportion to the severity of the initial injury, if any.

Capsaicin

The active component of chilli peppers. It selectively binds to transient receptor potential cation channel subfamily V member 1 (TRPV1) on nociceptive and heat-sensing neurons.

Postherpetic neuralgia

Neuropathic pain that occurs in some patients following infection with the varicella zoster virus, predominantly affecting the face.

Peripheral benzodiazepine binding site

GABAA receptors in the central nervous system (CNS) represent the primary site of action for benzodiazepines, such as diazepam. The peripheral benzodiazepine binding site was originally discovered in the periphery a secondary binding site, but has since been identified in the CNS.

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Grace, P., Hutchinson, M., Maier, S. et al. Pathological pain and the neuroimmune interface. Nat Rev Immunol 14, 217–231 (2014). https://doi.org/10.1038/nri3621

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