Substance p expression in the murine lumbar dorsal root ganglia: Effect of chronic inflammatory arthritis knee pain and treatment with IA vanilloids

Abstract

Purpose: Joint pain is the earliest symptom of osteoarthritis (OA) although clinical data suggest that it poorly correlates with OA radiological features. Interestingly, recent studies show that OA pain is driven by both nociceptive and neuropathic mechanisms. CR4056 is a promising analgesic drug that binds to imidazoline-2 receptors and that was previously reported to be effective in several animal models of inflammatory, neuropathic, and postoperative pain. The aim of this study was to evaluate the effect of CR4056 in a well-established model of OA pain mimicking the painful components of human OA. The model consisted in the injection of monosodium iodoacetate (MIA) into the knee joint of rats, which produces cartilage degeneration and pain. Methods: Unilateral pain was induced by a single intra-articular injection of 1mg/50ml MIA in the infrapatellar area of the right knee of male Wistar rats (6 animals/group). Pain thresholds were determined as mechanical allodynia (Dynamic Plantar Aesthesiometer -electronic Von Frey test) and mechanical hyperalgesia (Pressure Application Measurement -PAM device) on day 1 before MIA injection, and on day 7, 14 and 21 after MIA injection. CR4056 (2, 6 mg/kg) or 10 mg/kg naproxen were administered orally, as single treatment on day 7 post injury and from day 14 to day 21, once daily, as sub-chronic treatments. Statistical analysis was performed by Two-way RM ANOVA, followed by Dunnett's multiple comparisons test. Results: Intra-articular injection of MIA induced both mechanical allodynia of the ipsilateral paw and mechanical hyperalgesia of the ipsilateral knee, either compared with the contralateral paw and knee or the saline control. Since 7 days after the induction with MIA the difference of pain behaviour between sham and arthritic rats was highly statistically significant both for allodynia (mean ± sem, 36.4 ± 0.82 g vs. 26.5 ± 0.98 g, respectively) and for hyperalgesia (1086 ±13.3 g vs. 692 ± 26.6 g, respectively). The difference between sham and MIA rats remained constant throughout the study. Acute oral administration of CR4056, 7 days after MIA, induced a dose-dependent reversal of MIA induced pain behaviours evaluated 90 minutes after treatment, that attained statistical significance (p<0.05) for the 6 mg/kg dose (40% and 33% reversal for allodynia and hyperalgesia, respectively). Naproxen at 10 mg/kg produced a lower and non-significant analgesia. Even more interestingly, as illustrated in the Figure, subacute treatment from days 14 to 21 after MIA with CR4056 (both doses) and naproxen, showed statistically significant anti-hyperalgesic effects (90' after treatment). Subacute 10 mg/kg Naproxen and 6 mg/kg CR4056 were also significantly effective against allodynia. Moreover, the rats treated for 7 days with 6 mg/kg CR4056 showed a significant reduction of both basal pain behaviours (allodynia and hyperalgesia), demonstrating either a long lasting effect or, even, a true symptom modifying effect. A similar effect was observed after naproxen, but this was only limited t...