Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model

TY - JOUR

T1 - Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model

AU - Clark, Anna K.

AU - Grist, John

AU - Al-Kashi, Adam

AU - Perretti, Mauro

AU - Malcangio, Marzia

PY - 2012/6

Y1 - 2012/6

N2 - Objective: The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain.  Methods: Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization.  Results: Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA.  Conclusion The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX3CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA.

AB - Objective: The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain.  Methods: Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization.  Results: Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA.  Conclusion The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX3CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA.

U2 - 10.1002/art.34351

DO - 10.1002/art.34351

M3 - Article

SN - 0004-3591

VL - 64

SP - 2038

EP - 2047

JO - Arthritis & Rheumatism

JF - Arthritis & Rheumatism

IS - 6

ER -