Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Abstract

Nuclear factor-kappa B (NF-κB) is a ubiquitously expressed protein complex regulating the transcription of genes involved in inflammation and pain. Increased NF-κB activity in immune and nervous system cells is linked to several chronic pain conditions in humans as well as inflammation- and nerve injury-evoked pain in animals. A recent in vitro study further demonstrates that increased NF-κB activity in astrocytes decreases transcription of catechol-o-methyltransferase (COMT), an enzyme that inactivates catecholamines that cause pain. The purpose of the present study was to examine the relationship between systemic and astrocytic NF-κB activity, pain, and COMT expression in an animal model of inflammation. Results demonstrated that administration of the inflammatory stimulant complete Freund’s adjuvant (CFA) led to increased pain and decreased COMT protein expression in an NF-κB-dependent manner. Specifically, we found that rats and mice receiving intraplantar CFA exhibited increased behavioral responses to mechanical and thermal heat stimuli. CFA-evoked pain was blocked in rats receiving a pre-emptive systemic dose of the NF-κB inhibitor MG132 and exacerbated in IKKca mice with constitutive NF-κB activity in astrocytes. Furthermore, we observed NF-κB-linked reductions in COMT expression in midbrain at 6h and 1d following CFA in rats and at 1h and 1d in forebrain and midbrain following CFA in IKKca mice. Collectively, these results demonstrate that systemic and astrocytic NF-κB activity drive inflammatory pain and regulate the expression of COMT in forebrain and midbrain structures.

Metabolomics Signature for Non‐Responders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients: The Newfoundland Osteoarthritis Study

“…High concentrations of plasma BCAAs have been shown to increase oxidative stress and inflammation through the nuclear factor‐κB (NF‐κB) signaling pathway, which controls a number of pro‐inflammatory genes. Many of the pro‐inflammatory genes regulated by NF‐κB, such as tumor necrosis factor α, interleukin‐1β, and cyclooxygenase‐2 (COX‐2), play important roles in pain regulation . COX‐2 is an integral enzyme in the production of eicosanoids, which are themselves downstream products of PC metabolism due to the release of arachidonic acid, the precursor of eicosanoids, during the conversion of PC to lysoPC by phospholipase A 2 .…”

“…Many of the pro-inflammatory genes regulated by NF-κB, such as tumor necrosis factor α, interleukin-1β, and cyclooxygenase-2 (COX-2), play important roles in pain regulation. 40 COX-2 is an integral enzyme in the production of eicosanoids, 33 which are themselves downstream products of PC metabolism due to the release of arachidonic acid, the precursor of eicosanoids, during the conversion of PC to lysoPC by phospholipase A 2 . 41 Both NF-κB and COX-2 have been reported to be involved in OA; NF-κB signaling induces hypertrophy in chondrocytes, promotes synovitis and cartilage degradation, and alters resorption of bone, leading to abnormal bone formation.…”

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF3N,N-diethyl-N′-phenylpiperazine

“…We explored the effects of p-CF 3 diEPP in the CFA test, composed of inactivated and dried Mycobacterium tuberculosis and adjuvant, a widely used model of persistent inflammatory pain. The CFA model is based on hypersensitivity, paw swelling, and nuclear factor-kB-mediated transcription of tumor necrosis factora involved in the formation of the principal mediators of inflammation (Hartung et al, 2015). Mice were injected intraplantarly with 20 ml of CFA (50%, diluted in mineral oil).…”

Nuclear Factor Kappa B Increases CX3CR1 Expression in BV-2 Microglial Cells and Aggravates Neuropathic Pain

“…Its target genes are still incompletely understood in the nervous system. Already known regulated genes in neuronal tissue make up inducible NO-synthase (iNOS), μ-opiod receptors, brainderived neurotrophic factor, calmodulin-dependent protein kinase II, and catechol-omethyltransferase (COMT) [46,47]. Previous studies show that increased NF-κB activity enhances transcription of genes that cause pain (e.g., iNOS) and decreases ones that ease pain (e.g., COMT).…”