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  • Review Article
  • Published:

Emerging targets in neuroinflammation-driven chronic pain

Nature Reviews Drug Discovery volume 13, pages 533–548 (2014)Cite this article

Subjects

Key Points

  • Chronic pain cannot be effectively treated using current drugs such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs).

  • Inflammation is intimately linked to the development of acute pain. Neuroinflammation within the peripheral nervous system and central nervous system is responsible for generating and sustaining the sensitization of nociceptive neurons that leads to chronic pain.

  • Therefore, targeting the processes and molecules that are involved in neuroinflammation could lead to better treatments for chronic pain.

  • Emerging targets include chemokines that mediate interactions between neurons and glial cells, lipid mediators that act on neurons and glia to resolve inflammation, as well as other molecules that modulate neuroinflammation, such as proteases and WNT signalling molecules.

  • Here, we highlight the key role of these targets in the development of chronic pain and discuss the key advantages, potential disadvantages and challenges associated with therapeutically targeting them.

Abstract

Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This Review focuses on emerging targets — such as chemokines, proteases and the WNT pathway — that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders.

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Figure 1: Inflammation elicits pain via inflammatory mediators and peripheral sensitization.
Figure 2: Neuroinflammation in the spinal cord drives chronic pain via neuron–glia interactions and central sensitization.
Figure 3: Biosynthetic pathways of PRLMs: resolvins and protectin, and the mechanisms of action of protectin D1.
Figure 4: Protectin D1 protects against neuropathic pain and prevents nerve injury-induced spinal LTP and neuroinflammation in mice.

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Acknowledgements

The work of the authors is supported by US National Institutes of Health (NIH) grants R01DE17794 (The National Institute of Dental and Craniofacial Research; NIDCR) and R01DE22743 (NIDCR) to R.-R.J., R21NS082985 (The National Institute of Neurological Disorders and Stroke; NINDS) to Z.-Z.X., Transformative R01NS67686 (NINDS) to R.-R.J and Charles N. Serhan, and the National Natural Science Foundation of China grant (NSFC 31171062, 31371121) to Y.J.G.

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Authors and Affiliations

  1. Departments of Anesthesiology and Neurobiology, Duke University Medical Center, 595 LaSalle Street, Durham, 27710, North Carolina, USA

    Ru-Rong Ji & Zhen-Zhong Xu

  2. Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, 226001, Jiangsu, China

    Yong-Jing Gao

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Glossary

Mechanical allodynia

A painful response to a normally innocuous mechanical stimulation. It is also regarded as a cardinal feature of chronic pain.

Trigeminal ganglia

The location of cell bodies of primary sensory neurons, including nociceptive and touch neurons that innervate the orofacial area.

Trigeminal nucleus

A collection of cell bodies located in the brainstem that receive sensory inputs from the orofacial area.

Inflammation

A biological response of vascular tissue to harmful stimuli, such as tissue injury, infection or irritants. The classical signs of acute inflammation — which is protective and promotes healing — are pain, heat, redness, swelling and loss of function.

Primary afferent neurons

Sensory neurons that carry sensory information from the periphery to the central nervous system.

Chemokines

A family of about 50 small, secreted cytokines that act on G protein-coupled receptors. They can be classified into four subfamilies: the C family, the CC family, the CXC family and the CX3C family.

Primary sensory neurons

Neurons with cell bodies located in the dorsal root and trigeminal ganglia. Their peripheral terminals innervate skin and muscle and their central axons terminate in the spinal cord and trigeminal nucleus.

Mitogen-activated protein kinases

(MAPKs). The MAPK family consists of extracellular signal-regulated kinase 1 (ERK1), ERK2, p38 MAPK, JUN N-terminal kinase (JNK) and ERK5, and is activated by phosphorylation. MAPKs have important roles in intracellular signalling in neurons and glia and in the genesis of pain hypersensitivity.

Neuroinflammation

Local inflammation in the peripheral and central nervous system, which is more efficient at driving chronic pain than systemic inflammation.

Glial mediators

Molecules that are produced and secreted by glial cells, including small molecules (for example, glutamate, ATP and nitric oxide) and large molecules (for example, pro-inflammatory cytokines and chemokines, as well as growth factors). They can modulate nociceptor excitability and nociceptive synaptic transmission.

Glial activation

The process of transcriptional and/or translational changes (gene expression), post-translational changes (phosphorylation), morphological changes and the proliferation of glial cells in the peripheral nervous system (PNS) and central nervous system (CNS), which is implicated in the development and maintenance of chronic pain. Glial cells have different activation states.

Neurogenic inflammation

Inflammation that is triggered by the activation of primary afferent neurons and the subsequent local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide. Neurogenic inflammation is responsible for the pathogenesis of migraine.

Dorsal root ganglion

(DRG). A sensory ganglion of the dorsal root that lies alongside the spinal cord. It is the location of cell bodies of primary sensory neurons, including nociceptive and touch neurons that innervate differ parts of the body.

C-fibres

Small-diameter unmyelinated afferent nerve fibres that have low conduction velocity and carry sensory pain information from the periphery to the central nervous system. They can be activated by capsaicin, an ingredient that gives rise to the hot sensation caused by eating chilli peppers.

Anion reversal potential

The membrane potential at which there is no net flow of a particular anion ion (Cl−) from one side of the membrane to the other. After nerve injury, a decrease in the Cl− anion reversal potential (a shift to less negative potentials) reduces glycine and/or GABAA (γ-aminobutyric acid type A) receptor-mediated hyperpolarization, leading to the genesis of neuropathic pain.

Gate control mechanism

A mechanism proposed by Ronald Melzack and Patrick Wall during the early 1960s, which suggests that the spinal cord dorsal horn contains a neural circuit that undergoes excitatory and inhibitory modulation that serves as a gate that either allows or blocks the transmission of pain signals to the brain.

Spinal nerve ligation

A form of nerve injury that is used to induce long-lasting neuropathic pain in rodents.

Satellite cells

Glial cells that surround neurons in the dorsal root and trigeminal ganglia. Like astrocytes, these cells express glial fibrillary acidic protein (GFAP) and contribute to the pathogenesis of pain.

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Ji, RR., Xu, ZZ. & Gao, YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13, 533–548 (2014). https://doi.org/10.1038/nrd4334

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