Inflammation in the pathophysiology of neuropathic pain

Abstract

Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model

“…65,66 Patients with painful neuropathies also presented increased depression scores. Increased expression of the proinflammatory cytokines IL-2 and tumor necrosis factor alpha (TNF-α) were shown to be associated with painful neuropathies, while increased expression of the anti-inflammatory IL-10 was observed in patients with painless neuropathies.…”

“…Increased expression of the proinflammatory cytokines IL-2 and tumor necrosis factor alpha (TNF-α) were shown to be associated with painful neuropathies, while increased expression of the anti-inflammatory IL-10 was observed in patients with painless neuropathies. 65,66 Patients with painful neuropathies also presented increased depression scores. It is nevertheless difficult to establish a causal relation between these observations.…”

Ginsenoside Rf relieves mechanical hypersensitivity, depression‐like behavior, and inflammatory reactions in chronic constriction injury rats

“…The neuroprotective and antinociceptive effects of anti‐inflammatory agents have been well documented to reverse the established behavioral and biochemical deficits in neuropathic pain (Ellis & Bennett, ; Ji, Chamessian, & Zhang, ; Liu et al, ; Sommer et al, ). Ginsenosides have unique biological activity, such as anti‐inflammation, antioxidation, and antiapoptosis, which prompted us to hypothesize that the anti‐inflammatory activity of ginsenoside Rf might significantly contribute to its antinociceptive efficacy.…”

“…Neuropathic pain, one of the leading and disabling clinical problems, is commonly caused by peripheral nerve injuries and diseases, and its pain symptoms are not adequately controlled by currently available medical therapies (Finnerup et al, ). Accumulating evidence reveals a close link between inflammation and neuropathic pain (Sommer, Leinders, & Uceyler, ). Increased levels of proinflammatory cytokines in the nerves, the dorsal root ganglion (DRG), and the spinal cord have been found to stimulate and sensitize nociceptors and their central synaptic targets, ultimately leading to the neuropathic pain states (Ellis & Bennett, ; Sommer et al, ).…”

“…Accumulating evidence reveals a close link between inflammation and neuropathic pain (Sommer, Leinders, & Uceyler, ). Increased levels of proinflammatory cytokines in the nerves, the dorsal root ganglion (DRG), and the spinal cord have been found to stimulate and sensitize nociceptors and their central synaptic targets, ultimately leading to the neuropathic pain states (Ellis & Bennett, ; Sommer et al, ). Blocking proinflammatory factors peripherally and centrally exhibits a reduction in nociceptive hypersensitivity in neuropathic pain animal models (Burke, Kerr, Moriarty, Finn, & Roche, ; Crain, Nikodemova, & Watters, ; Kigerl et al, ).…”