Pain regulation by non-neuronal cells and inflammation

Abstract

Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

Copyright © 2016, American Association for the Advancement of Science.

Figures

Fig. 1

Interactions between non-neuronal cells, neurons, and inflammation/neuroinflammation in different pain conditions after injury and insult. Note that non-neuronal cells can modulate pain in different directions by producing either pro- or anti-nociceptive mediators.

Fig. 2

Interactions between distinct parts of a nociceptor with different types of non-neurons cells including keratinocytes, Schwann cells, satellite glial cells, oligodendrocytes, and astrocytes, as well as immune cells (e.g., macrophages and T cells), microglia, cancer cells, and stem cells. These non-neuronal cells produce both pro-nociceptive (highlighted in red) and anti-nociceptive (highlighted in blue) mediators, which can bind their respective receptors on the nociceptor to modulate its sensitivity and excitability. The central terminal of the nociceptor forms a nociceptive synapse with a postsynaptic neuron in the spinal cord dorsal horn to mediate pain transmission in the CNS.

Fig. 3

Neuron-glial interactions in the spinal cord for the amplification of chronic pain. Painful injuries such as nerve injury, arthritis, cancer, and treatment (chemotherapy) cause hyperactivity of nociceptors and secretion of glial modulators from their central terminals, leading to the activation of microglia and astrocytes in the spinal cord dorsal horn. Upon activation, microglia and astrocytes secrete neuromodulators to drive chronic pain, by inducing synaptic and neuronal plasticity. Note that pre- and post-synaptic neurons can both “listen” and “talk” to microglia and astrocytes.

Fig. 4

Infections and tissue injury regulate pain via both neuronal and non-neuronal mechanisms through TLRs. Bacterial infections can modulate pain through direct interactions with specific receptors such as FPR and TLR on primary sensory neurons including nociceptors and mechanoceptors, leading to increased and decreased pain sensitivity. TLRs are expressed by neurons, glial cells, and immune cells and are activated by PAMP (infections), as well as DAMP, endogenous TLR ligands (e.g., HMGB1, miRNAs) released after tissue injury.