Background & Aims
Chronic pain is a hallmark of joint diseases and a significant number of arthritis patients experience severe persistent pain and anxio-depressive comorbidities that are not adequately managed with current treatments. Whether these comorbidities are the direct results of the more obvious sensory and functional symptoms of joint pain is poorly understood and this likely contributes to the difficulty in treating these conditions. Through recent studies, we have detected a predictive role of functional impairment in the early stages of the disease on later development of anxio-depressive outcomes in mice exposed to models of joint pain (Hestehave 2023). Here we aim to 1) expand on those findings by focusing on the model producing the most prominent deficits, and 2) explore the effects of pharmacological intervention in the early stages on pain and comorbidities in the late disease stage, using a novel FKBP51-inhibitor with promising effects against persistent pain (Maiaru 2016 & 2018).
Methods
Study 1; Male and female mice (C57/BL from CRL) were exposed to a model of unilateral arthritis (MIA knee-injection), or un-injured control. For up to 3 months following injury, mice were assessed on a number of parameters; mechanical threshold (von Frey filaments), functional impairment (weight bearing), anxiety- (Open Field Test) and anhedonia/depressive-like behavior (Sucrose Preference Test). Study 2; male and female mice were treated with either the FKBP51-antagonist, SAFit2 (Gaali, et al. 2015), in a gel (VPG) providing 7 days of slow release, or vehicle, before being exposed to the MIA-injury. The treatment was repeated to provide effects during the first two weeks after injury, where the weight bearing deficits from the MIA-model are most prominent.
Results
Study 1; MIA-injection resulted in robust and immediate sensory and functional changes. While the tactile allodynia was stable from the first day, the functional deficits reached a prominent maximum around one week after injury, after which it was stable from 2 weeks to 3 months. Anxiety- and depressive-like behaviors did not develop until 3 months after injury, but correlated with the early sensory and functional changes (first 2 weeks after injury). Study 2; Administration of SAFit2-VPG during the induction stage of the joint disease reduced both sensory- and functional-impairment, not only in the early phase while the compound was active, but also in the late stage of the disease, at least 3 months after treatment. Most crucially, the development of anxiety- and depressive-like behavior at 3 months was prevented, and there were clear correlations between the sensory- and functional outcomes in the early phase, and the development of anxiety- and depressive-like behavior at 3 months.
Conclusions
The functional and sensory outcomes measured in the early stages of the disease stage clearly correlated with sensory and emotional profiles at 3 months, suggesting that early measures may be used as predictors of the long-term symptoms associated with persistent joint pain. This confirms our recent findings (Hestehave 2023). In addition, provision of the FKBP51-inhibitor, SAFit2 in the early stages, significantly improved the pain-outcomes in the phase with the most prominent deficits, and thereby improved both pain- and emotional-related outcomes in the late stages.
In conclusion, the predictive value of early measures of the functional impact of joint disease could prove useful in the clinical settings for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.
References
Gaali, S. et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol 11, 33-37, doi:10.1038/nchembio.1699 (2015).
Hestehave, S. et al. Predicting hypersensitivity and comorbid depressive-like behavior in late stages of joint disease using early weight bearing deficit. bioRxiv, 2023.2011.2029.569246, doi:10.1101/2023.11.29.569246 (2023).
Maiaru, M. et al. The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling. Sci Transl Med 8, 325ra319, doi:10.1126/scitranslmed.aab3376 (2016).
Maiaru, M. et al. The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes. Pain 159, 1224-1234, doi:10.1097/j.pain.0000000000001204 (2018).
Presenting Author
Sara Hestehave
Poster Authors
Topics
- Models: Chronic Pain - Inflammatory