Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically inflammatory swelling lasts about three weeks. Pain-related behaviors were monitored for 84 days after AIA induction. Unbiased cluster analysis of intra-group-differences at day 84 of AIA revealed that about one third of the rats (cluster 1) showed persistent mechanical hyperalgesia at the injected knee joint, whereas the other rats (cluster 2) had recovered from pain. Retrograde analysis of pain-related behaviors revealed that cluster 1 rats exhibited more severe mechanical hyperalgesia at the injected knee from day 3 of AIA, and mechanical hyperalgesia at the contralateral knee. Cluster 1 and 2 rats did not show different inflammatory swelling, secondary mechanical and thermal hyperalgesia at the ipsilateral hindpaw, guarding score and asymmetry of weight bearing during AIA. Thus in particular early severe mechanical hyperalgesia in the inflamed joint and segmental contralateral mechanical hyperalgesia seem to be a risk factor for the development of persistent mechanical hyperalgesia pointing to the importance of spinal mechanisms. However, none of the rats showed an expression of ATF3 in DRG neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in DRG neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.
