Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain

Abstract

Inflammation is the body's response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia.

Keywords: Inflammation; Neurogenic inflammation; Neuroinflammation; Pain.

Figure 1.

Schematic illustration of peripheral sensitization induced by peripheral glial activation and neuroinflammation in dorsal root ganglia (DRG) following surgeries and opioid exposure. Activation of peripheral glia (i.e. SGCs: satellite glial cells) by surgery and/or opioid treatment results in secretion of glial mediators such as TNF and IL-1β, leading to peripheral sensitization, postsurgical pain, and opioid-induced hyperalgesia and tolerance.

Figure 2.

Schematic illustration of central sensitization induced by glial activation and neuroinflammation in the spinal cord following surgery and/or opioid exposure. Activation of central glia (microglia and astrocytes) in the spinal cord by surgery and/or opioids treatment results in secretion of glial mediators including TNF, IL-1β, CCL2, CXCL1, and BDNF. These factors can act as neuromodulators to induce central sensitization via the modulation of excitatory and inhibitory synaptic transmission. Central sensitization is a driving force of postsurgical pain as well as opioid-induced hyperalgesia and tolerance.