The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats

Abstract

BACKGROUND AND PURPOSE Resolution of inflammation is mediated by endogenous molecules with anti‐inflammatory and pro‐resolving activities and they have generated new possibilities for the treatment of inflammatory diseases. Here, we have investigated the possible anti‐hyperalgesic effects of two lipids, aspirin‐triggered resolvin D1 (AT‐RvD1) and its precursor, 17(R)‐hydroxy‐4Z,7Z,10Z,13Z,15E,17R,19Z‐docosahexaenoic acid (17(R)HDoHE). EXPERIMENTAL APPROACH The anti‐hyperalgesic effects of both lipid mediators were evaluated, using mechanical and thermal stimuli, at different time‐points in adjuvant‐induced arthritis in rats. Cytokine levels were measured, and immunohistochemistry and real‐time PCR for pro‐inflammatory mediators were also performed. KEY RESULTS The precursor of resolvin D series, 17(R)HDoHE, given systemically, inhibited the development and the maintenance of mechanical hyperalgesia in acute inflammation. Such effects were likely to be associated with modulation of both NF‐κB and COX‐2 in dorsal root ganglia and spinal cord. 17(R)HDoHE was also effective against sub‐chronic pain. Unexpectedly, repeated treatment with 17(R)HDoHE did not modify paw and joint oedema in the sub‐chronic model, while joint stiffness was prevented. Notably, AT‐RvD1 exhibited marked anti‐hyperalgesic effects in acute inflammation when given systemically. The efficacy of long‐term treatment with either 17(R)HDoHE or AT‐RvD1 was partly related to decreased production of TNF‐α and IL‐1β in rat hind paw. CONCLUSIONS AND IMPLICATIONS Our findings provide fresh evidence for the anti‐hyperalgesic properties of 17(R)HDoHE and its pro‐resolution metabolite AT‐RvD1. Such lipid mediators might be useful for treating pain associated with acute or chronic inflammation. LINKED ARTICLE This article is commented on by Xu and Ji, pp. 274–277 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01348.x

Activation of Spinal NF‐κB/p65 Contributes to Peripheral Inflammation and Hyperalgesia in Rat Adjuvant‐Induced Arthritis

“…In the rat chronic constriction injury (CCI) model, we previously observed extensive colocalization of NF-B/p65 with TNF␣ in the spinal dorsal horn (36), and down-regulation of spinal NF-B/ p65 expression significantly attenuated sciatic nerve ligation-induced mechanical and thermal hyperalgesia (19). In addition, spinal NF-B is also activated following injection of CFA or formalin into the footpad, and spinal application of an NF-B inhibitor reduces painrelated behavior (18,37,38). Similar to the findings in these studies, the present results show that peripheral inflammation resulting from AIA led to the activation of NF-B/p65 in the spinal cord, and a spinally delivered inhibitor of NF-B/p65 expression, the lentiviral vector LV-shNF-B/p65, significantly attenuated the inflammation-induced hyperalgesia in this rat model of arthritis.…”

“…Measurements were obtained at baseline (1 day before CFA injection), and day 0 was the time point of CFA injection. Measurements were also obtained on days 6,8,10,12,14,16,18, and 20 following CFA injection.…”

“…Thermal thresholds (paw withdrawal latency) were detected using a BME-410A thermal dolorimeter (Biomedical Engineering Institute of the Chinese Academy of Medical Sciences), according to the methods described previously (24). Tests were performed at different times (6,8,10,12,14,16,18, and 20 days) following CFA injection. All groups were evaluated 1 day before the injection of CFA in order to determine the baseline mechanical and thermal thresholds.…”

“…Previous studies have indicated that activation of spinal NF-B/p65 occurs in peripheral tissue damage or inflammation (17,18). Findings in a recent study from our group showed that intrathecal injection of a lentiviral vector, LV-shNF-B/p65, an inhibitor of NF-B/ p65 that encodes short hairpin RNAs (shRNAs) targeting NF-B/p65, significantly reduced the expression of spinal NF-B/p65 and also reduced mechanical and thermal hyperalgesia following peripheral nerve injury (19).…”

Resolvins D1, D2, and Other Mediators of Self-Limited Resolution of Inflammation in Human Blood following n-3 Fatty Acid Supplementation

“…RvD1 reduces inflammatory and postoperative pain in rodent models (29,30 ), has been shown to inhibit transient receptor potential ankyryn 1 (TRPA1) in the dorsal root ganglion (31 ), and is an effective antihyperalgesic agent in a rat model of adjuvant-induced arthritis (13,32 ). In mice, RvD2 is a potent inhibitor of TRPV1 (transient receptor potential subtype vanilloid) and TRPA1, 2 types of TRP channels that are strongly implicated in the genesis of inflammatory pain.…”