Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active ...crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.
Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, ...pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.
In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic ...effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.
Although cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in idiopathic pulmonary fibrosis ...(IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in nonresolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to proapoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. Unlike senescent normal lung fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand (FasL)-induced and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Senescent IPF fibroblasts exhibited decreased expression of FasL and TRAIL receptors and caveolin-1, as well as increased AKT activation, compared with senescent normal lung fibroblasts. Although quercetin alone was not proapoptotic, it abolished the resistance to FasL- or TRAIL-induced apoptosis in IPF fibroblasts. Mechanistically, quercetin upregulated FasL receptor and caveolin-1 expression and modulated AKT activation. In vivo quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype in aged mice. Collectively, these data indicate that quercetin reverses the resistance to death ligand-induced apoptosis by promoting FasL receptor and caveolin-1 expression and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.
During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase ...of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.
Purpose
Delayed-onset muscle soreness (DOMS) describes an entity characterized by ultrastructural muscle damage. Hesperidin methyl chalcone (HMC) is a synthetic flavonoid presenting analgesic, ...anti-inflammatory, and antioxidant properties. We evaluated the effects of HMC upon DOMS.
Method
In a preventive paradigm, 31 sedentary young men were submitted to a randomized, double-blinded parallel trial and received HMC 500 mg or one placebo capsule × 3 days before an intense dynamic exercise protocol (concentric/eccentric actions) applied for lower limbs for inducing muscle damage. Assessments were conducted at baseline, and 24 and 48 h after, comprising physical performance, and post-muscle soreness and damage, inflammation, recovery of muscle strength, and postural balance associated with DOMS. HMC safety was also evaluated. Thirty participants completed the study.
Results
HMC improved the performance of participants during exercise (40.3 vs 51.3 repetitions to failure,
p
= 0.0187) and inhibited CPK levels (90.5 vs 57.9 U/L,
p
= 0.0391) and muscle soreness during passive quadriceps palpation (2.6 vs 1.4 VAS cm,
p
= 0.0439), but not during active actions, nor did it inhibit IL-1β or IL-10 levels. HMC improved muscle strength recovery, and satisfactorily refined postural balance, without inducing injury to kidneys or liver.
Conclusions
Preemptive HMC supplementation may be beneficial for boosting physical performance and for the amelioration of clinical parameters related to DOMS, including pain on muscle palpation, increased blood CPK levels, and muscle strength and proprioceptive deficits, without causing adverse effects. These data advance the understanding of the benefits provided by HMC for DOMS treatment, which supports its usefulness for such purpose.
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The inflammatory response in the joint can induce an intense accumulation of leukocytes in the tissue that frequently results in severe local damage and loss of function. Neutrophils ...are essential cells to combat many pathogens, but their arsenal can contribute or aggravate articular inflammation. Here we summarized some aspects of neutrophil biology, their role in inflammation and indicated how the modulation of neutrophil functions could be useful for the treatment of different forms of arthritis.
Background and Purpose
Maresin 1 (MaR1) is a specialised pro‐resolving lipid mediator with anti‐inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and ...spinal cord cells by MaR1 in the context of inflammatory pain.
Experimental Approach
Mice were treated with MaR1 before intraplantar injection of carrageenan or complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed using the electronic von Frey and thermal hyperalgesia using a hot plate. Spinal cytokine production and NF‐κB activation were determined by ELISA and astrocytes and microglia activation by RT‐qPCR and immunofluorescence. CGRP release by dorsal root ganglia (DRG) neurons was determined by EIA. Neutrophil and macrophage recruitment were determined by immunofluorescence, flow cytometry, and colorimetric methods. Trpv1 and Nav1.8 expression and calcium imaging of DRG neurons were determined by RT‐qPCR and Fluo‐4AM respectively.
Key Results
MaR1 reduced carrageenan‐ and CFA‐induced mechanical and thermal hyperalgesia and neutrophil and macrophage recruitment proximal to CGRP+ fibres in the paw skin. Moreover, MaR1 reduced NF‐κB activation, IL‐1β and TNF‐α production, and spinal cord glial cells activation. In the DRG, MaR1 reduced CFA‐induced Nav1.8 and Trpv1 mRNA expression and calcium influx and capsaicin‐induced release of CGRP by DRG neurons.
Conclusions and Implications
MaR1 reduced DRG neurons activation and CGRP release explaining, at least in part, its analgesic and anti‐inflammatory effects. The enduring analgesic and anti‐inflammatory effects and also post‐treatment activity of MaR1 suggest that specialised pro‐resolving lipid mediators have potential as a new class of drugs for the treatment of inflammatory pain.
Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) ...challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1β, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
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•Specialized pro-resolving lipid mediators (SPMs) actively resolve inflammation.•SPMs are powerful non-opioid analgesic drugs.•SPMs block peripheral and central sensitization to ...reduce pain.•SPMs are not immunosuppressive drugs.•Some SPMs show long-lasting analgesic and anti-inflammatory effects.
We now appreciate that the mechanism of resolution depends on an active and time-dependent biosynthetic shift from pro-inflammatory to pro-resolution mediators, the so-called specialized pro-resolving lipid mediators (SPMs). These SPMs are biosynthesized from the omega-3 fatty acids arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), or docosahexaenoic acid (DHA). Despite effective for a fraction of patients with rheumatic diseases and neuropathic pain, current analgesic therapies such as biological agents, opioids, corticoids, and gabapentinoids cause unwanted side effects, such as immunosuppression, addiction, or induce analgesic tolerance. A growing body of evidence demonstrates that isolated SPMs show efficacy at very low doses and have been successively used as therapeutic drugs to treat pain and infection in experimental models showing no side effects. Moreover, SPMs work as immunoresolvents and some of them present long-lasting analgesic and anti-inflammatory effects (i.e. block pain without immunosuppressive effects). In this review, we focus on how SPMs block pain, infection and neuro-immune interactions and, therefore, emerge as a new class of non-immunosuppressive and non-opioid analgesic drugs.
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