Blockage of lysophosphatidic acid reverses arthritis-induced hypersensitivity and Cavα2δ1 and P2X3 expression in dorsal root ganglia.

Aims The lysophosphatidic acid (LPA) is an important mediator involved in neuropathic and bone cancer pain models. We are investigating if LPA is involved in arthritis-induced pain in the collagen antibody-induced arthritis (CAIA) mice model. Methods Arthritis was induced in male CBA mice by injection of 1.5 mg collagen type II antibody cocktail. Mechanical and thermal sensitivity and the degree of arthritis were assessed with von Frey filaments, Hargreaves box (heat), acetone test (cold) and visual scoring, respectively. LPA antibody and control IgG (10mg/kg), or saline was injected s.c. twice a week from day 12 through day 47. qPCR and immunohistochemical studies were undertaken in dorsal root ganglia (DRGs) to explore the expression of pain-related ion channels. Results Administration of LPA antibody treatment reversed CAIA-induced mechanical and thermal hypersensitivity (p < 0.05) while had no effect on the early clinical signs of arthritis (p > 0.05). mRNA levels for the LPA synthesizing enzyme autotaxin were elevated in the CAIA group. On day 48, expression of the voltage-gated calcium channel Cavα2δ1 and the ATP-gated P2X3 receptor were significantly increased in the CAIA DRGs, which were completely prevented by LPA antibody treatment. Of note, based on in vitro experiment, LPA stimulation upregulated Cavα2δ1 and P2X3 expression in primary adult mouse DRG cultures. Conclusions Blocking the action of systemic LPA reverses arthritis-induced hypersensitivity, potentially through regulation of Cavα2δ1 and P2X3 expression in peripheral neurons. Thus, our data point to that LPA may serve as a target for providing pain relief in arthritis.