Joint Nociception Research Articles

Visual exposure to green light therapy reduces knee joint pain and alters the lipidome in osteoarthritic rats.

Visual exposure to dim, green, light has been found to reduce pain levels in patients living with migraine, low back pain, and fibromyalgia. Preclinical studies discovered that the analgesic effect of green light was due to the central release of endogenous opioids and a reduction in inflammatory cytokines in the cerebrospinal fluid. The present study assessed the effect of green light therapy (GLT) on joint pain in a rat model of osteoarthritis (OA) and investigated the role of endolipids. Male and female Wistar rats (207-318 g) received an intra-articular injection of sodium monoiodoacetate (3 mg in 50 μL saline) into the knee to induce OA. On day 9, animals were placed in a room illuminated by either white (neutral-white 4000K; 20 lux) or green (wavelength: 525 nm; luminance: 20 lux) light for 5 days (8 hours per day). Joint nociception was assessed by von Frey hair algesiometry, dynamic weight bearing, and in vivo single unit extracellular recordings from knee joint mechanonociceptors. Compared to white light, GLT significantly reduced secondary mechanical hypersensitivity in both sexes and improved hindlimb weight bearing in females only. There was no effect of GLT on joint nociceptor activity in either sex. Serum lipidomics indicated an increase in circulating analgesic endolipids in response to GLT, particularly the N-acyl-glycines. Partial blockade of the endocannabinoid system with the G protein receptor-18/cannabinoid-1 receptor antagonist AM281 (500 μg/kg i.p.) attenuated GLT-induced analgesia. These data show for the first time that GLT acts to reduce OA pain by upregulating circulating analgesic endolipids, which then engage the endocannabinoid system.

Osteoarthritis induced by monosodium iodoacetate model

Objectives: this study aimed to highlight the evolution of the osteoarthritis (OA) model induced by monosodium iodoacetate (MIA) and its collaboration with the knowledge of the pathophysiology of inflammation, hypernociception and cartilage degeneration. Methods: PubMed and Science Direct were used with the descriptors: knee osteoarthritis or osteoarthritis of ankle) and (rat or osteoarthritis induced by monoiodoacetate) and (animal model of osteoarthritis or joint nociception). Studies containing rats, mice, and monoiodoacetate-induced osteoathritis were included. Exclusion criteria were: Animal models of osteoarthritis induced by destabilization; meniscectomy-induced osteoarthritis; non-invasive animal models of osteoarthritis induced by fracture, compression and tibial overload; animal models of osteoarthritis with large animals and models of osteoarthritis by papain or bacterial collagenase. We summarized studies that used MIA to induce knee or ankle OA in rats or mice and the evolution of the inflammatory markers. Results: a total of 38 original manuscripts met the inclusion criteria and were considered in the study. The model of OA induced by MIA is well-established and explored with several methodologies and has been widely used in different species. MIA induces cell death, progressive loss of chondrocytes and histological changes that mimics human OA. Studies with this model demonstrated inflammation, neurogenic hyperalgesia, release of cytokines and matrix metalloproteinases. More recently, molecular biology data confirm the activation of nuclear transcription factors, which modulates the expression of citokines in apoptotic chondrocytes. Conclusion: the MIA-induced OA has been useful in predicting several characteristics for the elucidation of osteoarthritis pathophysiology.

Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis

Non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking and climbing stairs. Piezo2 has been implicated in the development of mechanical pain, but the mechanisms by which this occurs remain poorly understood, including the role of nociceptors. Here we show that nociceptor-specific Piezo2 conditional knock-out mice were protected from mechanical sensitization associated with inflammatory joint pain in female mice, joint pain associated with osteoarthritis in male mice, as well as both knee swelling and joint pain associated with repeated intra-articular injection of nerve growth factor in male mice. Single cell RNA sequencing of mouse lumbar dorsal root ganglia and in situ hybridization of mouse and human lumbar dorsal root ganglia revealed that a subset of nociceptors co-express Piezo2 and Ntrk1 (the gene that encodes the nerve growth factor receptor TrkA). These results suggest that nerve growth factor-mediated sensitization of joint nociceptors, which is critical for osteoarthritic pain, is also dependent on Piezo2, and targeting Piezo2 may represent a therapeutic option for osteoarthritis pain control.

Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice.

Persistent arthritis pain after resolution of joint inflammation represents a huge health burden in patients with rheumatoid arthritis (RA). However, the underling mechanisms are poorly understood. We and other groups recently revealed that FcγRI, a key immune receptor, is functionally expressed in joint nociceptors. Thus, we investigated a potential role of sensory neuron expressed FcγRI in postinflammatory arthritis pain in a mouse model of collagen antibody-induced arthritis (CAIA). Here, we show that global deletion of Fcgr1 significantly attenuated mechanical hyperalgesia in the ankle and hind paw of female mice in both inflammatory and postinflammatory phases of CAIA. No obvious differences in cartilage destruction were observed after resolution of joint inflammation between genotypes. In situ hybridization (ISH) revealed that a larger proportion of dorsal root ganglion (DRG) neurons expressed Fcgr1 mRNA signal in the late phase of CAIA. Conditional deletion of Fcgr1 in primary sensory neurons produced similar analgesic effects without affecting joint swelling. Knockdown of Fcgr1 expression within DRG in the postinflammatory phase of CAIA alleviated persistent pain. Inflammation within DRG after resolution of joint inflammation in the CAIA model was evidenced by T cell and neutrophil infiltration and upregulated mRNA expression of numerous inflammatory mediators. Yet, such changes were not altered by genetic deletion of Fcgr1. We suggest that neuroinflammation within the DRG after resolution of joint inflammation might upregulate FcγRI signaling in DRG neurons. Sensory neuron expressed FcγRI thus merits exploration as a potential target for the treatment of arthritis pain that persists in RA patients in remission.

Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity.

Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits via both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.

Proteinase activated receptor-4 signals pain in early but not late-stage post-traumatic osteoarthritis in rats

Purpose: Serine proteinases such as thrombin and cathepsin-G are known to cleave and subsequently activate proteinase activated receptor-4 (PAR-4). In joints, selective peptide ligands that bind to PAR-4 cause sensitization of joint nociceptors and impart a marked pain response. Furthermore, blockade of PAR-4 with the antagonist pepducin p4Pal10 has been shown to reduce peripheral sensitization and joint pain, as well as ameliorating physiological signs of inflammation in an acute synovitis model.

Neurophysiological assessment of joint nociceptors in the rat medial meniscus transection model of post-traumatic osteoarthritis

Meniscal injury is a common prelude to post-traumatic osteoarthritis (PTOA). Joint nerves can become damaged in arthritic joints leading to the manifestation of neuropathic pain. Both PTOA and neuropathic pain are more common in females; however, it is unknown whether the neural processing of joint pain is sex-specific. Male and female Wistar rats (230-286g) underwent unilateral medial meniscus transection (MMT) and allowed to recover for 28 days. Pain development was assessed over the time course by von Frey hair algesiometry and dynamic weight bearing. Recordings from joint primary afferents was carried out by electrophysiology at end-stage disease. Nerve damage and β-endorphin levels were also compared between MMT and sham operated animals. Male MMT rats exhibited significant pain behaviour compared to sham control. Evoked afferent firing rate was heightened in male MMT animals. Female PTOA rats did not show signs of pain behaviour on each of the test days and the neurophysiological properties of their nociceptors was not different from control. Peripheral neuropathy was observed in about 30% of axons from male MMT animals compared to 15% in females. Systemic β-endorphin levels in female PTOA rats was 91.0±10.4pg/mL and only 49.0±5.0pg/mL in males. Secondary allodynia and joint pain were observed in male but not female MMT rats. Joint nociceptors were sensitized in PTOA males but not in females. This lack of pain in females may be due to the absence of a peripheral neuropathy and greater endogenous opioid production.

Sensory Ganglia-Specific TNF Expression Is Associated With Persistent Nociception After Resolution of Inflammation.

Joint pain is a distressing symptom of arthritis, and it is frequently persistent even after treatments which reduce local inflammation. Continuous production of algogenic factors activate/sensitize nociceptors in the joint structures and contribute to persistent pain, a challenging and difficult condition to treat. TNF is a crucial cytokine for the pathogenesis of several rheumatic diseases, and its inhibition is a mainstay of treatment to control joint symptoms, including pain. Here, we sought to investigate the inflammatory changes and the role of TNF in dorsal root ganglia (DRG) during persistent hypernociception after the resolution of acute joint inflammation. Using a model of antigen-induced arthritis, the peak of joint inflammation occurred 12–24 h after local antigen injection and was characterized by an intense influx of neutrophils, pro-inflammatory cytokine production, and joint damage. We found that inflammatory parameters in the joint returned to basal levels between 6 and 8 days after antigen-challenge, characterizing the resolving phase of joint inflammation. Mechanical hyperalgesia was persistent up to 14 days after joint insult. The persistent nociception was associated with the inflammatory status of DRG after cessation of acute joint inflammation. The late state of neuroinflammation in the ipsilateral side was evidenced by gene expression of TNF, TNFR2, IL-6, IL-1β, CXCL2, COX2, and iNOS in lumbar DRG (L3-L5) and leukocyte adhesion in the lumbar intumescent vessels between days 6 and 8. Moreover, there were signs of resident macrophage activation in DRG, as evidenced by an increase in Iba1-positive cells. Intrathecal or systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism.

Peripheral Nociception Is Associated with Voluntary Activation Deficits and Quadriceps Weakness Following Total Knee Arthroplasty.

Quadriceps weakness is a hallmark of total knee arthroplasty and is driven by reduced voluntary muscle activation following the surgical procedure. The mechanisms underlying postoperative activation deficits are not well established, although nociception has been implicated via both spinal reflex and supraspinal pathways. The purpose of this study was to assess the role of nociception in postoperative recovery of strength and activation. A total of 53 participants were assessed prior to total knee arthroplasty and at 6 weeks postoperatively. Quadriceps strength was measured by maximum voluntary isometric contraction, and activation was measured by the doublet interpolation technique. The pressure-pain threshold was used to measure local sensitization (at the knee joint) and systemic sensitization (at the forearm). Changes in outcomes (strength and activation) were regressed against pressure-pain threshold measurements. Mediation analyses were planned for significant associations to investigate whether deficits in voluntary activation were implicated on a causal pathway between pressure-pain threshold measures and postoperative strength loss. Knee pressure-pain threshold measures were significantly associated with reduced voluntary quadriceps activation (beta = -0.04; p = 0.009) and diminished quadriceps strength after total knee arthroplasty (beta = -0.07; p = 0.001). There was also a mediation effect of voluntary activation on the relationship between the knee pressure-pain threshold and quadriceps strength. After correcting for multiple comparisons, relationships between the forearm pressure-pain threshold and strength and activation did not reach significance. The measures of local nociceptor sensitization were related to reduced strength and activation following total knee arthroplasty. This is consistent with a causal pathway linking increased firing of knee joint nociceptors to reduced activation and reduced strength. Future randomized studies should investigate whether peripherally directed pain therapies reduce pain while also promoting the recovery of quadriceps strength via an improved capacity for voluntary activation. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Inflammation and osteoarthritis-related pain

Osteoarthritis (OA) is one of the major causes of chronic pain. Although OA has long been considered anon-inflammatory "wear and tear" disease leading to loss of articular cartilage, recent findings provide convincing evidence that inflammatory mechanisms play apivotal role in the pathophysiology of OA. In OA mononuclear cells (e. g. T‑cells and macrophages) infiltrate the synovial membrane and the levels of pro-inflammatory cytokines in peripheral blood and synovial fluid samples are elevated. Increased release of inflammatory mediators including interleukin (IL) IL-1β, IL-6, IL-8, IL-15 und tumor necrosis factoralpha (TNF‑α) induces the expression of proteolytic enzymes such as matrix metalloproteinases resulting in cartilage breakdown. Molecular and cellular interactions between the immune and nervous system are also involved in the development of OA-related pain. Inflammatory mediators including IL-6 und TNF‑α lead to peripheral sensitization of joint nociceptors and growth factors (e. g. NGF) trigger the expression of TRPV1 channels in primary afferents. Moreover, neuropeptides reduce the threshold of nociceptors of OA joints. The current review highlights the role of inflammatory mechanisms in OA-induced joint pain considering clinical signs of inflammation and major inflammatory pathways.

An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2.

Pain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by cleavage mediated by a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS-4) or ADAMTS-5 in the interglobular domain (E373-374A). Further cleavage by MMPs (N341-342F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We found that the 32-mer excites dorsal root ganglion nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced expression of the proalgesic chemokine CCL2. These effects were mediated through TLR2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer fragment provoked knee hyperalgesia in WT but not Tlr2-null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

Distance-based permutation of inter-meal differences as a sensitive test of temporomandibular joint nociception in rats.

Compare non-parametric permutation method using intr-meal rate as endpoint to existing ANOVA method that uses average daily meal duration as an endpoint for detection of chronic pain in Sprague-Dawley rats. Nociception following bilateral temporomandibular joint (TMJ) injection of high-dose of Complete Freunds Adjuvant (CFA, 250 μg/50 μL per side) could be detected in young adult male Sprague-Dawley rats using average daily meal durations as a measure of nociception for up to 19 days (Kramer, Kerins, Schneiderman, & Bellinger, 2010) using ANOVA and multiple comparisons range tests. In this study, we reanalyzed the data using a non-parametric permutation procedure based on absolute differences between intra-meal feeding rate curves. In addition, to that experiment, we injected bilaterally the TMJ of naive rats with either a low-dose CFA (15 μg/50 μL per side, n=6) or saline (50 μL of 0.9%, n=4) and monitored the animals for 7 days. The permutation test of the intra-meal feeding rate detected the presence of nociception in the high-dose CFA treatment group for up to 40 days or twice as long as when using ANOVA on average daily meal durations. The permutation method also detected the low-dose CFA induced nociception with ten-times lower p-values and for several days longer than ANOVA of changes in meal durations. CFA-induced injury resulted in even reduction of intra-meal feeding rate and lengthening of the meals in both high- and low-dose CFA-injected animals. The rate analysis also showed when the rats first started a meal they were experiencing the same level of nociception as at the end of the meal. This demonstrated that intra-meal chewing itself did not alter the level of nociception. These results suggest that permutation tests based on differences in intra-meal feeding rates can be used as a sensitive test to determine and study the temporal patterns of TMJ nociception.

Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis.

Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines.

Coactivation of μ- and κ-Opioid Receptors May Mediate the Protective Effect of Testosterone on the Development of Temporomandibular Joint Nociception in Male Rats.

To investigate whether the protective effect of testosterone on the development of temporomandibular joint (TMJ) nociception in male rats is mediated by the activation of central opioid mechanisms. Experiments were performed on 156 male Wistar rats. A pharmacologic approach was used to assess the ability of opioid receptor antagonists infused into the dorsal portion of the brainstem and adjacent to the caudal component (subnucleus caudalis) of the spinal trigeminal nucleus to block the protective effect of testosterone in male rats. The TMJ injection of 0.5% formalin was used as a nociceptive stimulus. One-way or two-way ANOVA was used for data analyses. The injection of 0.5% formalin into the TMJ induced a significant nociceptive behavior in gonadectomized male rats (P < .05), but not in naïve, sham, and testosterone-replaced gonadectomized rats, confirming that testosterone prevents the development of TMJ nociception. The injection of either the nonselective opioid receptor antagonist naloxone (15 μg) or the simultaneous injection of the μ-opioid receptor antagonist Cys2, Tyr3, Orn5, Pen7amide (CTOP, 30 μg) and the κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI, 90 μg) significantly increased the 0.5% formalin-induced behavioral response in sham and testosterone-replaced gonadectomized rats (P < .05) but had no effect in gonadectomized rats. However, the injection of each selective opioid receptor antagonist alone or the simultaneous injection of μ- or κ- and δ-opioid receptor antagonists had no effect. These findings indicate that the protective effect of endogenous testosterone on the development of TMJ nociception in male rats is mediated by the activation of central opioid mechanisms. Furthermore, the coactivation of central μ- and κ-opioid receptors is necessary for testosterone to protect male rats from developing TMJ nociception.

Reduction of joint nociception induced by formalin in rats treated ith low level laser therapy 670 or 830 nm

Study design: experimental study of cross-cutting nature. Objective: To evaluate the low level laser therapy (LLLT) effects, with a wavelength of 670 and 820nm, in nociception of Wistar rats submitted to hypernociception in his right knee. Methods: 18 Wistar rats, separated into 3 groups: G1 – untreated; G2 – treated with LBP 670 nm; G3 – treated with LBP 830 nm. For the hypernociception induction was injected into the tibiofemoral articular space 100 µL of 5% formalin. To evaluate nociception was used digital von Frey filament, both with pressure on the knee, as in the plantar region. The evaluations occurred: pre-injury (EV1), 15 (EV2), 30 (EV3) and 60 (EV4) minutes after hypernociception induction. For the treatment with LBP was used to 8 J/cm2, after EV2. Results: the withdrawal threshold, when the pressure was held at the knee, showed that 670 nm produced threshold elevation in EV3 and EV4, returning to values similar to those of EV1. For the plantar region, only 830 nm showed restoration of values in EV4, and was higher in EV3 when comparing with G1. Conclusion: Both wavelengths produced raising the paw withdrawal threshold in rats with knee hypernociception

Physiology in Perspective: Why Do We Continue to Ignore Sex Differences?

In 2001, the Institute of Medicine (IOM) of the National Academy of Sciences issued a report in which they highlighted the importance of exploring sex differences in biomedical research and medical practice. The IOM report recognized the obvious biological fact that sex, as defined by the presence

ASICs Mediate Pain and Inflammation in Musculoskeletal Diseases.

Chronic musculoskeletal pain is debilitating and affects ∼ 20% of adults. Tissue acidosis is present in painful musculoskeletal diseases like rheumatoid arthritis. ASICs are located on skeletal muscle and joint nociceptors as well as on nonneuronal cells in the muscles and joints, where they mediate nociception. This review discusses the properties of different types of ASICs, factors affecting their pH sensitivity, and their role in musculoskeletal hyperalgesia and inflammation.

Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice.

The assessment of articular nociception in experimental animals is a challenge because available methods are limited and subject to investigator influence. In an attempt to solve this problem, the purpose of this study was to establish the use of dynamic weight bearing (DWB) as a new device for evaluating joint nociception in an experimental model of antigen-induced arthritis (AIA) in mice. AIA was induced in Balb/c and C57BL/6 mice, and joint nociception was evaluated by DWB. Western Blotting and real-time PCR were used to determine protein and mRNA expression, respectively. DWB detected a dose- and time-dependent increase in joint nociception during AIA and was able to detect the dose-response effects of different classes of analgesics. Using DWB, it was possible to evaluate the participation of spinal glial cells (microglia and astrocytes) and cytokines (IL-1β and TNFα) for the genesis of joint nociception during AIA. In conclusion, the present results indicated that DWB is an effective, objective and predictable test to study both the pathophysiological mechanisms involved in arthritic nociception in mice and for evaluating novel analgesic drugs against arthritis.

Joint production of IL-22 participates in the initial phase of antigen-induced arthritis through IL-1β production.

IntroductionRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by neutrophil articular infiltration, joint pain and the progressive destruction of cartilage and bone. IL-22 is a key effector molecule that plays a critical role in autoimmune diseases. However, the function of IL-22 in the pathogenesis of RA remains controversial. In this study, we investigated the role of IL-22 in the early phase of antigen-induced arthritis (AIA) in mice.MethodsAIA was induced in C57BL/6, IL-22−/−, ASC−/− and IL-1R1−/− immunized mice challenged intra-articularly with methylated bovine serum albumin (mBSA). Expression of IL-22 in synovial membranes was determined by RT-PCR. Articular hypernociception was evaluated using an electronic von Frey. Neutrophil recruitment and histopathological analyses were assessed in inflamed knee joint. Joint levels of inflammatory mediators and mBSA-specific IgG concentration in the serum were measured by ELISA.ResultsThe IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA. In addition, pharmacological inhibition (anti-IL-22 antibody) and genetic deficiency (IL-22−/− mice) reduced articular pain and neutrophil migration in arthritic mice. Consistent with these findings, recombinant IL-22 joint administration promoted articular inflammation per se in WT mice, restoring joint nociception and neutrophil infiltration in IL-22−/− mice. Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice. Corroborating these results, the exogenous administration of IL-22 into the joints induced IL-1β production in WT mice and reestablished IL-1β production in IL-22−/− mice challenged with mBSA. Additionally, IL-1R1−/− mice showed attenuated inflammatory features induced by mBSA or IL-22 challenge. Articular nociception and neutrophil migration induced by IL-22 were also reduced in ASC−/− mice.ConclusionsThese results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0759-2) contains supplementary material, which is available to authorized users.

Calcitonin gene-related peptide in the joint: contributions to pain and inflammation.

Arthritis is the commonest cause of disabling chronic pain, and both osteoarthritis (OA) and rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute neurogenic inflammation. Contributions of CGRP to the pain and inflammation of chronic arthritis, however, are only recently being elucidated. Animal models of arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both arthritis and pain. Peripheral actions of CGRP in the joint might contribute to both inflammation and joint afferent sensitization. CGRP and its specific receptors are expressed in joint afferents and up-regulated following arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitization seen in arthritic joints. Increased mechanosensitivity in OA knees and pain behaviour can be reduced by peripherally acting CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitization rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent synovitis, and the progression from nociception to sensitization. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early arthritis, or suppress them in established disease, might prevent persistent inflammation and relieve arthritis pain.