Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

Abstract

Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

Metabolomic analysis coupled with extreme phenotype sampling identified that lysophosphatidylcholines are associated with multisite musculoskeletal pain

“…We also observed younger age was associated with MSMP, which could be due to higher physical workload and mental stress before retirement in the MSMP group, 24 , 66 supporting what Neupane et al 44 suggested that MSMP in midlife often persisted to old age in a MSMP trajectory study over 28 years. Cytokines are believed to play a role in pain modulation 19 , 42 , 64 ; however, we did not observe any association between MSMP and plasma levels of MIF, IL-6, IL-1β, or TNF-α. Although further studies are needed to confirm this, our findings were consistent with others.…”

Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

“…There is increasing evidence that revealed the role of macrophages including activated M1 macrophages, and inducible nitric oxide synthase (iNOS) in pain conditions in fibromyalgia [21]. Significantly, macrophages can mediate microglial activation through the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [22]. In addition, levels of pro-inflammatory cytokines and chemokines are enhanced in serum and could contribute to inflammation at the systemic level.…”

Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle

“…Recombinant human cytokines and cytokine receptors have been used as therapeutic targets to modulate inflammatory activity, driven in part by the pain patients experience as a result of acute and chronic inflammatory diseases [ 182 , 183 ]. Three core pro-inflammatory cytokines have been of particular interest in this realm: TNF-α, IL-1β, and IL-6.…”