Chronic pain and arthritis – studies of mechanisms in the regulation of hypersensitivity

Chronic pain is one of the most devastating symptoms reported by rheumatoid arthritis (RA) patients. Current treatment strategies are focusing on dampening the inflammatory and immunological aspects of RA, but unfortunately subgroups of patients continue to suffer from pain, even when the disease is adequately controlled. In this thesis, the work is focused on investigating mechanisms underlying arthritis-induced pain using the collagen antibodyinduced arthritis mouse (CAIA) model. In Paper I, we describe 50 peptides that are only expressed, and 38 peptides that are predominantly expressed in the dorsal spinal cord using liquid chromatography mass spectrometry. Intrathecal injection of [des-Ser1]-cerebellin (desCER), one of the peptides predominantly expressed in the spinal dorsal horn, induces a dose-dependent mechanical hypersensitivity but has no effect on thermal sensitivity in mice. We also show that the precursor of desCER is expressed in excitatory interneurons of laminae II/III. This study suggests that desCER is a novel pain modulator, and provides a platform for continued exploration of novel neuropeptides involved in nociception. In Paper II, we report that mice subjected to CAIA display transient inflammation and persistent mechanical hypersensitivity. We find an anti-nociceptive effect of a COX inhibitor, but only in the inflammatory phase of the CAIA model, and a time-dependent spinal glial activation. In Paper III, we report neurochemical changes in dorsal root ganglia (DRGs) and spinal cord after induction of CAIA. In the CAIA DRGs, galanin, voltage-gated calcium channel subunit α2δ1 and the nerve injury markers ATF3 and GAP43 are up-regulated. Taken together, based on the pharmacological and neurochemical profile, our work suggests that antibody-driven joint inflammation lead to a partial neuropathic pain phenotype. Finally, in Paper IV we focus on the role of lysophosphatidic acid (LPA) in arthritis-induced pain. The LPA synthesizing enzyme autotaxin is increased in DRGs from mice subjected to CAIA. Systemic treatment with a monoclonal antibody (Ab) against LPA completely reverses arthritis-induced mechanical and thermal pain-like behavior and also blocks the upregulation of α2δ1 in peripheral sensory neurons of CAIA mice. We also find that the expression of α2δ1 remains at basal levels in Lpa receptor-1 (Lpar1) deficient CAIA mice. These results provide new insights into the role of the LPA1/α2δ1 axis in arthritis-induced pain, suggesting new potential therapeutic targets for pain relief in RA. In summary, we have described a battery of pain-related factors involved in CAIA-induced hypersensitivity. These results lead to a deeper understanding of pain mechanisms in RA and hopefully to new therapeutic approaches to treat the pain component in RA patients. LIST OF PAPERS INCLUDED IN THE THESIS I. Su J*, Sandor K*, Skold K, Hokfelt T, Svensson CI, Kultima K Identification and quantification of neuropeptides in naive mouse spinal cord using mass spectrometry reveals [des-Ser1]-cerebellin as a novel modulator of nociception Journal of Neurochemistry 04/2014; 130(2): 199-214. II. Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, Nandakumar KS, Holmdahl R, Svensson CI Collagen Antibody-Induced Arthritis Evokes Persistent Pain With Spinal Glial Involvement and Transient Prostaglandin Dependency Arthritis & Rheumatology 12/2012; 64(12): 3886-96. III. Su J, Gao T, Shi T, Xiang Q, Xu X, Wiesenfeld-Hallin Z, Hokfelt T, Svensson CI Phenotypic changes in dorsal root ganglion and spinal cord in the collagen antibody-induced arthritis mouse model: Neuronal plasticity in arthritic mice The Journal of Comparative Neurology 01/2015; 523(10): 1505-28. IV. Su J, Barde S, Delaney A, Ribeiro J, Kato J, Agalave N, Wigerblad G, Matteo R, Sabbadini R, Josephson A, Dolphin AC, Chun J, Kultima K, Peyruchaud O, Hokfelt T, Svensson CI Blockade of lysophosphatidic acid by monoclonal antibody reverses arthritis-induced pain via the LPA1/α2δ1 pathway Manuscript * shared first authorship RELATED PUBLICATIONS NOT INCLUDED IN THE THESIS I. Bas DB, Su J, Wigerblad G, Svensson CI Pain in rheumatoid arthritis – models and mechanisms Pain Management, in press. II. Wigerblad G, Bas DB, Fernades-Cerqueira C, Krishnamurthy A,. Nandakumar KS, Rogoz K, Kato J, Sandor K, Su J, Jimenez – Andrade JM, Finn A, Farinotti AB, Amara K, Lundberg K, Holmdahl R, Jakobsson P, Malmstrom V, Catrina AI, Klareskog L, Svensson CI Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism Annals of the Rheumatic Diseases 04/2016; 75(4): 730-8. III. Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundback P, Palmblad K, Andersson U, Harris H, Svensson CI Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis Pain 06/2014; 155(9): 1802-13. CONTENTS