resiniferatoxin and Arthritis--Rheumatoid

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, "black box" period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Capsaicin; Diterpenes; Male; Mice; Mice, Inbred BALB C; Neurogenic Inflammation; Neuropeptides; Reactive Oxygen Species; Sensory System Agents

The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis.. Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis.. Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups.. This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.

Topics: Animals; Ankle; Arthritis, Rheumatoid; Capsaicin; Cartilage; Disease Models, Animal; Diterpenes; Female; Hindlimb; Mice; Mice, Inbred BALB C; Neurotoxins; Peptides; Proteoglycans; Reactive Oxygen Species; Sensory System Agents; Sensory Thresholds; Severity of Illness Index; Spine

The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology.. Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed.. In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice.. Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Capsaicin; Disease Models, Animal; Diterpenes; Edema; Hindlimb; Hyperalgesia; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Nociceptors; Pain Threshold; Peroxidase; Reactive Oxygen Species; Sensory System Agents; Somatostatin; Tarsus, Animal; TRPV Cation Channels; X-Ray Microtomography

The transient receptor potential (TRP) channels are important membrane sensors, responding to thermal, chemical, osmotic, or mechanical stimuli by activation of calcium and sodium fluxes. In this study, three distinct TRP channels were detected and their role established in mediating cytosolic free calcium concentration ([Ca(2+)](cyt)) response in tumor-derived SW982 synoviocytes and primary cultures of human synovial cells from patients with inflammatory arthropathies. As shown by fura-2 ratio measurements while cells were incubated in a temperature-regulated chamber, significant [Ca(2+)](cyt) elevation was elicited by rapid changes in bath temperature, application of TRPV1 receptor agonists capsaicin and resiniferatoxin, or a cold receptor stimulator, icilin. Temperature thresholds for calcium response were determined to be 12 +/- 1 degrees C for cold and 28 +/- 2 degrees C for heat activation. Temperature increases or decreases beyond these thresholds resulted in a significant rise in the magnitude of [Ca(2+)](cyt) spikes. Observed changes in [Ca(2+)](cyt) were completely abolished in calcium-free medium and thus resulted from direct calcium entry through TRP channels rather then by activation of voltage-dependent calcium channels. Two heat sensitive channels, TRPV1 and TRPV4, and a cold-sensitive channel, TRPA1, were detected by RT-PCR. Minimal mRNA for TRPV3 or TRPM8 was amplified. The RT-PCR results support the data obtained with the [Ca(2+)](cyt) measurements. We propose that the TRP channels are functionally expressed in human synoviocytes and may play a critical role in adaptive or pathological changes in articular surfaces during arthritic inflammation.

Topics: Arthritis, Rheumatoid; Calcium; Calcium Channels; Calcium Signaling; Capsaicin; Cell Line, Tumor; Cells, Cultured; Chondrocalcinosis; Cytosol; Diterpenes; Hot Temperature; Humans; Inflammation; Nerve Tissue Proteins; Pyrimidinones; RNA, Messenger; Synovial Membrane; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; TRPV Cation Channels