Background/Purpose:

Induction of K/BxN serum transfer arthritis and collagen antibody-induced arthritis (CAIA) leads to transient joint inflammation but persistent mechanical hypersensitivity lasting at least 2 weeks after the inflammation has resolved (late phase). While mechanical hypersensitivity during the inflammatory phase is reversed by analgesics such as ketorolac/diclofenac (cyclooxygenase inhibitors) and gabapentin (calcium channel blocker), only gabapentin has effect in the late phase. Assessment of mechanical hypersensitivity is based on a stimulus-evoked response. Non-evoked or “ongoing pain” is another aspect of pain in RA that is more difficult to monitor in animal models. A current question is if changes in spontaneous behavior can be used as a measure of ongoing pain-like behavior. The aim of this study was to examine if K/BxN and CAIA which induce mechanical hypersensitivity also induce changes in locomotor activity and condition place preference (CPP) and if those are similarly sensitive to treatment with cyclooxygenase inhibitors and/or gabapentin.

Methods:

K/BxN arthritis was induced in C57BL/6 mice by i.p. injection of 100 μl K/BxN serum and CAIA in BALB/c and B10.RIII mice by i.v. injection of 4 mg collagen type II antibody cocktail. Joint inflammation was assessed by visual scoring and mechanical hypersensitivity by von Frey filaments. Locomotor activity was recorded overnight using a Comprehensive Lab Animal Monitoring System. CPP was assessed by monitoring the number of crossings between distinctly different chambers (wall pattern and floor texture). CPP paradigm: 2 days adaptation with free access to all chambers, 2 days conditioning with restriction to one chamber (vehicle in morning and drug in afternoon), preference testing on day 5 with free access to all chambers. Effects of gabapentin (50 or 100 mg/kg) and cyclooxygenase inhibitors (ketorolac: 15 mg/kg; diclofenac: 30 mg/kg; naproxen 30 mg/kg) were assessed.

Results:

Gabapentin reversed mechanical hypersensitivity during both phases of the K/BxN and CAIA models. Ketorolac and diclofenac only attenuated mechanical hypersensitivity during ongoing inflammation in the K/BxN and the CAIA model, respectively, and had no effect in the late phase in both models. Ketorolac did not reduce CAIA-induced mechanical hypersensitivity. Locomotor activity was reduced in the early phase in the CAIA model (not assessed in the K/BxN model), which was normalized by naproxen, but not by gabapentin. Diclofenac reduced locomotion in naïve mice. A significant preference for both the gabapentin and ketorolac-paired compartment was observed in the early phase of the K/BxN model, while in the late phase only gabapentin treatment resulted in CPP. In the CAIA model, gabapentin produced a preference in the early phase and a trend in the late phase, whereas ketorolac was ineffective in both phases.

Conclusion:

We found that the K/BxN and the CAIA models induce changes in spontaneous behavior. Locomotor activity was affected by sedative side effects of the drugs. While somewhat different responses to cyclooxygenase inhibitors were noted in the two arthritis models, there was correspondence between the anti-hyperpathic pharmacology as defined by thresholds and CPP.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-gabapentin-and-cyclooxygenase-inhibitors-on-evoked-and-ongoing-pain-like-behavior-in-two-arthritis-models-in-mice/