Peripheral Interaction of Resolvin D1 and E1 with Opioid Receptor Antagonists for Antinociception in Inflammatory Pain in Rats

Abstract

Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund’s adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.

Kinetic Analysis of the Early Signaling Steps of the Human Chemokine Receptor CXCR4

“…5B ), whereas this was not the case for the norepinephrine/ α 2A -AR axis ( Fig. 5C ) or other ligand/receptor pairs tested using these same G protein sensors ( van Unen et al, 2016 ; Oehler et al, 2017 ; Grundmann et al, 2018 ). The nature of this observation is currently unknown to us, but several factors might play a role in this process.…”

Immunoresolvents Support Skeletal Myofiber Regeneration via Actions on Myeloid and Muscle Stem Cells

“…Moreover, the ability of daily dosing with RvD1 throughout the entire time-course of recovery from injury to ultimately improve muscle regeneration rather than compromise it, as is the case with daily systemic NSAID treatment (20)(21)(22)(23)(24)(25), is in itself novel. This clear advantage of RvD1 treatment compared with NSAIDs is of great clinical importance given that such frequent repeated dosing would likely be required to effectively exploit the analgesic potential of SPMs for pain management (99,100), which is a key therapeutic goal in the clinical treatment of soft tissue injuries. An additional novel finding of the current study is the demonstration for the first time that SPM biosynthetic circuits are also locally induced in response to overload of skeletal muscle, in close association with intramuscular immune cell transitions and the onset of the adaptive hypertrophy of pre-existing myofibers.…”

Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives

“…OxPAPC as well as its corresponding metabolites excite nociceptors and pain behaviour in different models for inflammatory pain ( 10 , 11 , 14 , 15 , 28 , 29 ). Specific OxPAPC components such as PGPC and POVPC as well as the OxPL degradation product lysophosphatidylcholine (LPC) are increased in chloroform-based lipid extracts from inflamed tissue by MALDI-TOF ( 10 ).…”

“…This is not easy to understand but points to a different mechanism of how OxPL activate TRP channels. For instance, TRPA1 activation by OxPL via an interaction with cysteines in the TRP N-terminus requires an electrophilic substance, similar to activation by the mustard oil compound AITC or 4-HNE or electrophilic OxPAPC compounds ( 28 , 32 , 33 ). Electrophilic compounds such as 4-HNE covalently bind via Michael addition and Schiff base formation to histidine, lysine, and cysteine residues, a key mechanism of TRPA1 activation.…”