Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models

Abstract

BackgroundHarnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects.MethodsPain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl).ResultsAT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase-activating protein (FLAP) and a decrease in 15-lipoxygenase (15-LOX) mRNA in the ipsilateral spinal cord of the carrageenan group, compared to controls.ConclusionsOur data suggest that peripheral inflammation-mediated changes in spinal FLAP expression may contribute to the novel inhibitory effects of spinal AT-RvD1 on WDR neuronal excitability, which are mediated by FPR2/ALX receptors. Inflammatory-driven changes in this pathway may offer novel targets for inflammatory pain treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0676-6) contains supplementary material, which is available to authorized users.

Spinal neuronal excitability and neuroinflammation in a model of chemotherapeutic neuropathic pain: targeting the resolution pathways

“…The lack of effect of AT-RvD1 on WDR neuronal responses to higher weight mechanical stimuli suggests that treatments acting through the resolvin pathways are unlikely to modulate normal physiological high-intensity nociceptive processing, ensuring that this major protective pathway remains intact and functional. Indeed, our previous study reported no effect of AT-RvD1 on electrically evoked C-fibre responses of WDR neurones in naïve rats [22] and behavioural studies reported no change in baseline threshold responses following spinal RvD1 treatment [61]. Our data build upon the recent report that intrathecal injection of RvD1 attenuates mechanical hypersensitivity in PCX-treated mice [21], and provides neurophysiological mechanisms underlying these antihyperalgesic effects seen in models of CINP.…”

“…Sexual dimorphism was reported for some of the resolvins in this previous study, specifically for RvD5, but not RvD1 or RvD2-mediated analgesia in the PCX model [ 21 ]. Previously, we reported that spinal administration of AT-RvD1 has robust inhibitory effects on noxious-evoked responses of spinal neurones in a model of acute inflammatory pain, but does not alter somatosensory processing in the spinal cord in naïve rats [ 22 ]. Here, we hypothesised that the sensitisation of spinal neuronal activity in the PCX model would be associated with changes in the spinal expression of genes encoding key neuroinflammatory markers and enzymes involved in the generation/catabolism of the resolvins, and that PCX-induced changes in spinal neuronal excitability would be responsive to spinal treatment with AT-RvD1.…”

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

“…AT-RvD1 reduces osteoarthritic pain (139), as does precursor 17-HDHA (140), prompting validation of their receptors (ALX/ FPR2 and ERV/CMKLR1) in rat models of osteoarthritis pain (141). Plasma RvD2 levels correlate with reduction in astrogliosis in spinal cord (141).…”

Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation

“…Aspirin‐triggered epimer AT‐RvD1 reduces osteoarthritic pain , as does its precursor, 17‐HDHA . Some SPM receptors (ALX/FPR2 and ERV/CMKLR1) are validated in murine osteoarthritic pain .…”