ObjectiveAn interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.MethodsAntibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.ResultsMice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.ConclusionsThe data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.

Capsaicin-sensitive, TRPV1 (transient receptor potential vanilloid 1) receptor-expressing primary sensory neurons exert local and systemic efferent effects besides the classical afferent function. The TRPV1 receptor is considered a molecular integrator of various physico-chemical noxious stimuli. In the present study its role was analysed in acute nociceptive tests and chronic neuropathy models by comparison of wild-type (WT) and TRPV1 knockout (KO) mice. The formalin-induced acute nocifensive behaviour, carrageenan-evoked inflammatory mechanical hyperalgesia and partial sciatic nerve lesion-induced neuropathic mechanical hyperalgesia were not different in WT and KO animals. Acute nocifensive behaviour after intraplantar injection of phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), was absent in TRPV1 KO animals showing that PKC activation elicits nociception exclusively through TRPV1 receptor sensitization/activation. Thermal hyperalgesia (drop of noxious heat threshold) and mechanical hyperalgesia induced by a mild heat injury (51 degrees C, 15s) was smaller in KO mice suggesting a pronociceptive role for TRPV1 receptor in burn injury. Chronic mechanical hyperalgesia evoked by streptozotocin-induced diabetic and cisplatin-evoked toxic polyneuropathy occurred earlier and were greater in the TRPV1 KO group. In both polyneuropathy models, at time points when maximal difference in mechanical hyperalgesia between the two groups was measured, plasma somatostatin concentrations determined by radioimmunoassay significantly increased in WT but not in TRPV1 KO mice. It is concluded that sensitization/activation of the TRPV1 receptor plays a pronociceptive role in certain models of acute tissue injury but under chronic polyneuropathic conditions it can initiate antinociceptive counter-regulatory mechanisms possibly mediated by somatostatin released from sensory neurons.

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Objective. Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody-induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored.Methods. CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry.Results. Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity.Conclusion. CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel localized on a subset of primary sensory neurons and can be activated by a wide range of stimuli. The present study investigated the role of this receptor in chronic arthritis evoked by complete Freund's adjuvant (CFA) using TRPV1 receptor gene-deleted (TRPV1 Ϫ/Ϫ ) mice and wildtype counterparts (TRPV1 ϩ/ϩ ). In TRPV1 ϩ/ϩ mice, CFA injected intraplantarly into the left hindpaw and the root of the tail induced swelling of the injected and contralateral paws up to 130 and 28%, respectively, measured by plethysmometry throughout 18 days. Mechanonociceptive threshold measured with dynamic plantar aesthesiometry was decreased by 50 and 18% on the injected and contralateral paws, respectively. Histological examination and scoring of the tibiotarsal joints revealed marked arthritic changes in wild-type mice. In TRPV1 Ϫ/Ϫ animals edema, histological score and mechanical allodynia were significantly smaller. Daily treatment with the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the cyclooxygenase inhibitor indomethacin, the bradykinin B2 receptor antagonist

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We have shown that somatostatin released from activated capsaicin-sensitive nociceptive nerve endings during inflammatory processes elicits systemic anti-inflammatory and analgesic effects. With the help of somatostatin receptor subtype 4 gene-deleted mice (sst4 ؊/؊ ), we provide here several lines of evidence that this receptor has a protective role in a variety of inflammatory disease models; several symptoms are more severe in the sst4 knockout animals than in their wild-type counterparts. Acute carrageenaninduced paw edema and mechanical hyperalgesia, inflammatory pain in the early phase of adjuvant-evoked chronic arthritis, and oxazolone-induced delayed-type hypersensitivity reaction in the skin are much greater in mice lacking the sst 4 receptor. Airway inflammation and consequent bronchial hyperreactivity elicited by intranasal lipopolysaccharide administration are also markedly enhanced in sst 4 knockouts, including increased perivascular/peribronchial edema, neutrophil/macrophage infiltration, mucus-producing goblet cell hyperplasia, myeloperoxidase activity, and IL-1␤, TNF-␣, and IFN-␥ expression in the inflamed lung. It is concluded that during these inflammatory conditions the released somatostatin has pronounced counterregulatory effects through sst4 receptor activation. Thus, this receptor is a promising novel target for developing anti-inflammatory, analgesic, and anti-asthmatic drugs.allergic contact dermatitis ͉ arthritis ͉ capsaicin-sensitive afferents ͉ endotoxin-induced pneumonitis ͉ inflammatory cytokines

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.