Emerging targets in neuroinflammation-driven chronic pain

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.

Figures

Figure 1. Inflammation elicits pain via inflammatory mediators and peripheral sensitization

Tissue injury and infection cause inflammation via plasma extravasation and infiltration of immune cells such as macrophages, T cells, and neutrophils into the damaged tissue. The infiltrated immune cells and resident cells including mast cells, macrophages and keratinocytes release several inflammatory mediators, such as bradykinin, prostaglandins, H+, ATP, nerve growth factors (NGF), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and proinflammatory chemokines (CCL2, CXCL1, CXCL5). Nociceptor neurons express the receptors for all these inflammatory mediators, which act on their respective receptors on peripheral nociceptor nerve fibers. These receptors include GPCRs, ionotropic receptors, and tyrosine kinase receptors, and their activation results in the generation of second messengers such as Ca2+ and cAMP, which in turn activates several kinases, such as the PKA, PKC, CaMK, PI3K, and MAPKs (ERK, p38, and JNK). Activation of these kinases causes hypersensitivity and hyperexcitability of nociceptor neurons (known as peripheral sensitization), through modulation of key transduction molecules such as transient receptor potential ion channel A1 and V1 (TRPA1 and TRPV1) and Piezo (a stretch-activated ion channel) as well as key conduction molecules such as the sodium channels NaV1.7, NaV1.8 and NaV1.9. Nociceptor neurons also express TLRs (that is, TLR3, TLR4, and TLR7), which can be activated by exogenous ligands (known as pathogen-activated molecular patterns, which include viral and bacterial components) and endogenous ligands (known as danger-activated molecular patterns, such as RNAs). Certain miRNAs (e.g., let-7b) serve as novel pain mediators to activate nociceptors via TLR7 which is coupled with TRPA1 (the coupling is further enhanced when TLR7 is activated by let-7b). Bacterial infection (with Staphylococcus aureus) also directly activates nociceptors and induces neuronal hyperexcitability via releasing bacterial N-formylated peptides (FPs) and the formation of pore-forming toxin α-haemolysin (α-HL). Activation of nociceptors also releases substance P and CGRP which are involved in the generation of neurogenic inflammation. CGRP also negatively regulates lymphadenopathy after inflammation.

Figure 2. Neuroinflammation in the spinal cord drives chronic pain via neuron–glial interactions and central sensitization

Chronic pain, such as nerve injury and spinal cord injury-induced neuropathic pain, arthritis-induced inflammatory pain, cancer pain, and drug treatment-induced pain is a result of neuroinflammation in the spinal cord. This neuroinflammation is triggered by activity-dependent release of glial activators (that is, neurotransmitters, chemokines and proteases, and wnt ligands) from the central terminals of primary afferent neurons and/or by disruption of BBB. Neuroinflammation is characterized by the activation of microglia and astrocytes, the infiltration of immune cells to the PNS (e.g., DRG) and CNS (e.g., spinal cord), and the production of inflammatory and glial mediators such as proinflammatory cytokines and chemokines, growth factors and gliotransmitters (glutamate and ATP). These glial mediators can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Glial mediators can further act on glial and immune cells to facilitate neuroinflammation via autocrine and paracrine routes. Furthermore, neuroinflammation also generates anti-inflammatory cytokines and pro-resolution lipid mediators (PRLMs) to normalize neuroinflammation, synaptic plasticity and abnormal chronic pain.

Figure 3. Biosynthetic pathways of PRLMs resolvins and protectin and mechanisms of actions of protectin D1

(a) Omega-3 polyunsaturated fatty acids (DHA and EPA) are derived from dietary essentially fat which is enriched in fish oil. Resolvins (RvD1, RvD2) and protectin D1 (PD1, also known as neuroprotectin D1) are derived from DHA, whereas RvE1 is derived from EPA. Distinct synthetic enzymes, including COX-2, cytochrome P450, and 5- and 15-lipoxygenase (5-LOX and 12-LOX) are responsible for the biosynthesis of the PRLMs. (b) Structure and mechanisms of actions of PD1. Note that PD1 acts on immune and glial cells to control neuroinflammation as well as on neurons and synapses to normalize synaptic and neuronal plasticity.

Figure 4. Protectin D1 protects neuropathic pain and prevents nerve injury-induced spinal LTP and neuroinflammation in mice

(a) Local peri-surgical pretreatment with NPD1 (300 ng per mouse, via peri-sciatic administration) prevents mechanical allodynia induced by chronic constriction injury (CCI). *P<0.05, compared to sham control, #P<0.05, compared to corresponding vehicle (that is, phosphate buffered saline solution, PBS) control. (b) Intrathecal injection of NPD1 (100 ng per mouse) 2 weeks after nerve injury reduces CCI-induced mechanical allodynia. *P<0.05, compared to corresponding vehicle (that is, PBS) control. (c) Dose-dependent inhibition of CCI-induced mechanical allodynia by NPD1 (20–500 ng per mouse administered intrthecially, which approximately equals 0.06–1.4 nmol) and gabapentin (i.t., 10–100 μg ≈ 58.4–584.1 nmol). Mechanical allodynia was tested 3 h after the drug injection. Note that the effective doses of gabapentin are much higher than that of NPD1. (d) NPD1 (300 ng) reduces LTP in the spinal cord that is induced by nerve injury; *P<0.05 versus PBS. (e) Iba1 (microglial marker) immunostaining in the dorsal horns of sham control and CCI mice (1 week) with pretreatment of PBS or NPD1. Nerve injury causes upregulation of Iba1 in the dorsal horn of mice; this can be reduced by pretreatment with NPD1 but not PBS. Scale, 50 μm. (f, g) Peri-surgical treatment with NPD1 prevents nerve injury-induced spinal cord neuroinflammation (as measured by the expression of GFAP, IL-1β, and CCL2 mRNAs and phosphorylation of p38/ERK (p-p38/pERK, g) in the dorsal horn. *P<0.05, #P<0.05. Data are mean ± SEM. Modified from the paper of Xu et al. (2013, Annals of Neurology) with permission from the press.