Females show enhanced susceptibility to develop nerve injury and constant joint pain compared to males in a mouse model of knee joint pain

Arthritis is a leading cause of diminished quality of life from chronic pain and disability and is more severe in female patients. Arthritis pain is difficult to manage due to its heterogeneous nature. Patients report joint pain during use that dissipates with joint rest, however some patients also report constant joint pain that fails to abate with rest. A murine model of osteoarthritis knee joint pain was used to explore the hypothesis that constant joint pain is associated with increased nerve injury, and females develop constant pain and nerve injury at earlier stages of joint damage compared to males. Monosodium iodoacetate (MIA) was injected into the intra-articular space of the knee joint followed by analysis of weight asymmetry and analgesia-induced conditioned place preference (CPP) 2 weeks later. Knee joints and dorsal root ganglia (DRG) were collected following behavioral analyses to assess joint pathology, changes in innervation, and nerve injury. Females developed analgesia-induced CPP at a 5-fold lower concentration of MIA (16 mg/mL) compared to males (80 mg/mL), while males treated with 16 mg/mL MIA only developed weight asymmetry. Equivalent joint pathology and changes in innervation were observed in males and females treated with 16 mg/mL MIA despite differences in pain-like behaviors. Increased expression of activating transcription factor-3 (ATF3) mRNA, a marker of nerve injury, was only observed in DRG L2-L5 of females and males with analgesia-induced CPP. These observations indicate that females have increased susceptibility to arthritis associated nerve injury that likely contributes to sex differences in joint pain.