Abstract
A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input–output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.
Highlights
High-intensity mechanical or thermal stimuli will selectively increase the activity of populations of primary afferents, referred to as nociceptors, with the frequency of discharge reflecting the intensity of the stimulus
We seek to provide an overview focused on a curated list of cytokines identified in the context of neuronal modulation and damage, to play a role in changes in pain processing after tissue and nerve injury, and discuss roles that cytokines play at the interface of the neuronal and immune system interfaces divided across four levels of neuronal organization: [1] peripheral termini; [2] dorsal root ganglia (DRG); [3] spinal cords; and [4] supraspinal areas
The primary emphasis of this review has been on reviewing the role of cytokines at the levels of the peripheral terminus, the DRG, the spinal dorsal horn, and supraspinal circuits (Figure 2)
Summary
Gilson Gonçalves dos Santos 1†, Lauriane Delay 1†, Tony L. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. Neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. Current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury
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