Reverse Translation to Discover Relevant Targets for Chronic Pain: GFRA3/Artemin

Introduction: Chronic pain is a major health problem posing an enormous economic burden to our society. The lack of therapeutic options is driving the current opioid epidemic in humans. One of the limitations in developing potential therapeutics is a lack of understanding of the precise mechanisms in the target disease condition. To overcome this problem, we use naturally occurring osteoarthritis in pet dogs that are highly phenotyped using validated measures of pain. Analyzing tissues from these subjects, we identify novel targets, then utilize mouse models to further understand the mechanisms involved—a forward and reverse approach from mice to dogs to mice.

Materials and Methods: From mouse RNA-sequencing data we determined the GDNF family receptor α 3 (GFRA3) is highly colocalized with the TRPV1-ion channel and thus possibly connected with pain hypersensitivity. Canine samples collected from highly phenotyped dogs (subjective assessment; ground reaction forces; quantitative sensory testing) were subjected to qRT-PCR (dorsal root ganglia [DRG]) and ELISA (serum).

Results: We found expression of GFRA3-receptor significantly increased in dorsal root ganglia (DRG) serving osteoarthritic (OA) joints (n = 12) compared with normal (p < 0.01) (n = 12). Additionally, using samples from highly phenotyped normal (n = 22) and OA dogs (n = 54) serum artemin (GFRA3 ligand) was significantly elevated in OA dogs (p < 0.05).

Discussion: Our results strongly implicate a role for GFRA3 and its ligand artemin in OA pain. Additional work in a mouse model is being conducted. These results show that samples from well-characterized (phenotyped) canine patients can be used to uncover potential novel mechanisms involved in pain states.

Acknowledgements: Funding: SKM start-up funds; private donations to Comparative Pain Research Program.

No conflict of interest has been declared by the author(s).