resolvin-d1 and Pain

The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.

Topics: Analgesics; Animals; Docosahexaenoic Acids; Humans; Inflammation Mediators; Lipid Metabolism; Lipoxins; Neuroimmunomodulation; Pain; Pain Management; Vagus Nerve Stimulation

Endogenous pain-inhibitory substances have rarely been found. A group of powerful pain suppressor molecules that are endogenously generated are now emerging: resolvins and related compounds including neuroprotectins and maresins. These molecules began to be unveiled in a series of inflammation studies more than a decade ago, rapidly shifting the paradigm that explains the mechanism for the inflammatory phase switch. The resolution phase was considered a passive process as proinflammatory mediators disappeared; it is now understood to be actively drawn by the actions of resolvins. Surprisingly, these substances potently affect the pain state. Although this research area is not fully matured, consistently beneficial outcomes have been observed in a various in vivo and in vitro pain models. Furthermore, multiple hypotheses on the neuronal and molecular mechanisms for alleviating pain are being tested, deriving inspiration from existing inflammation and pain studies. This paper serves as a brief summary of the proresolving roles of resolvins and related lipid mediators in inflammation and also as a review for accumulated information of their painkilling actions. This also includes potential receptor-mediated mechanisms and discusses future scientific perspectives. Further diverse approaches will help to construct a hidden axis of natural protection principles and establish proofs of concept for pain relief.

Topics: Calcium Channels; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Nerve Tissue Proteins; Pain; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Resolvins, including D and E series resolvins, are endogenous lipid mediators generated during the resolution phase of acute inflammation from the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Resolvins have potent anti-inflammatory and pro-resolution actions in several animal models of inflammation. Recent findings also demonstrate that resolvin E1 and resolvin D1 can each potently dampen inflammatory and postoperative pain. This review focuses on the mechanisms by which resolvins act on their receptors in immune cells and neurons to normalize exaggerated pain via regulation of inflammatory mediators, transient receptor potential (TRP) ion channels, and spinal cord synaptic transmission. Resolvins may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation.

Topics: Analgesics; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Neurons; Pain; Pain, Postoperative

Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature.. Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1β production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy.. RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1β production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1β production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages.. This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1.

Topics: Animals; Arthritis, Gouty; Calcitonin Gene-Related Peptide; Docosahexaenoic Acids; Hyperalgesia; Inflammation; Macrophage Activation; Male; Mice; Neuroimmunomodulation; Neurons; Nociceptors; Pain; Uric Acid

Topics: Anemia, Sickle Cell; Docosahexaenoic Acids; Humans; Inflammation; Pain

Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 min twice daily reduced inflammation and improved pain, 2 weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch versus no stretch for 48 h, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue.

Topics: Animals; Carrageenan; Connective Tissue; Docosahexaenoic Acids; Inflammation; Macrophages; Mechanical Phenomena; Muscle Stretching Exercises; Neutrophils; Pain; Pain Management; Phagocytosis; Rats

Transient receptor potential ion channel vanilloid 3 (TRPV3) is expressed in skin keratinocytes and plays an important role in thermal and chemical nociceptions in the periphery. The presence of TRPV3 inhibitors would improve our understanding of TRPV3 function and help to develop receptor-specific analgesics. However, little is known about physiological substances that specifically inhibit TRPV3 activity. Here, we investigated whether 17(R)-resolvin D1 (17R-RvD1), a naturally occurring pro-resolving lipid specifically affects TRPV3 activity.. We examined the effect of 17R-RvD1 on sensory TRP channels using Ca(2+) imaging and whole cell electrophysiology experiments in a HEK cell heterologous expression system, cultured sensory neurons and keratinocytes. We also examined changes in sensory TRP agonist-specific acute licking/flicking or flinching behaviours and mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems in the absence and presence of inflammation.. We showed that 17R-RvD1 specifically suppresses TRPV3-mediated activity at nanomolar and micromolar concentrations. The voltage-dependence of TRPV3 activation by camphor was shifted rightwards by 17R-RvD1, which indicates its inhibitory mechanism is as a result of a shift in voltage-dependence. Consistently, TRPV3-specific acute pain behaviours were attenuated by locally injected 17R-RvD1. Moreover, the administration of 17R-RvD1 significantly reversed the thermal hypersensitivity that occurs during an inflammatory response. Knockdown of epidermal TRPV3 blunted these antinociceptive effects of 17R-RvD1.. 17R-RvD1 is a novel natural inhibitory substance specific for TRPV3. The results of our behavioural studies suggest that 17R-RvD1 has acute analgesic potential via TRPV3-specific mechanisms.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Capsaicin; Carrageenan; Cell Line; Docosahexaenoic Acids; Freund's Adjuvant; Ganglia, Spinal; HEK293 Cells; Hot Temperature; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Pain; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; TRPV Cation Channels

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).. 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.. 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.. 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.

Topics: Animals; Arthritis; Chronic Disease; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Freund's Adjuvant; Hot Temperature; Inflammation; Male; Pain; Rats

Inflammatory pain such as arthritic pain is typically treated with opioids and cyclo-oxygenase-2 inhibitors with well known side effects. Transient receptor potential subtype vanilloid 1 (TRPV1) and TRP ankyryn 1 (TRPA1) contribute importantly to the genesis of inflammatory pain via both peripheral mechanisms (peripheral sensitization) and spinal cord mechanisms (central sensitization). Although these TRP channels have been intensively studied, little is known about their endogenous inhibitors. Recent studies have demonstrated that the endogenous lipid mediators resolvins (RvE1 and RvD1), derived from ω-3 unsaturated fatty acids, are potent inhibitors for inflammatory pain, without noticeable side effects. However, the molecular mechanisms underlying resolvins' distinct analgesic actions in mice are unclear. RvD2 is a novel family member of resolvins. Here we report that RvD2 is a remarkably potent inhibitor of TRPV1 (IC(50) = 0.1 nm) and TRPA1 (IC(50) = 2 nm) in primary sensory neurons, whereas RvE1 and RvD1 selectively inhibited TRPV1 (IC(50) = 1 nm) and TRPA1 (IC(50) = 9 nm), respectively. Accordingly, RvD2, RvE1, and RvD1 differentially regulated TRPV1 and TRPA1 agonist-elicited acute pain and spinal cord synaptic plasticity [spontaneous EPSC (sEPSC) frequency increase]. RvD2 also abolished inflammation-induced sEPSC increases (frequency and amplitude), without affecting basal synaptic transmission. Intrathecal administration of RvD2 at very low doses (0.01-1 ng) prevented formalin-induced spontaneous pain. Intrathecal RvD2 also reversed adjuvant-induced inflammatory pain without altering baseline pain and motor function. Finally, intrathecal RvD2 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest distinct roles of resolvins in regulating TRP channels and identify RvD2 as a potent endogenous inhibitor for TRPV1/TRPA1 and inflammatory pain.

Topics: Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Ganglia, Spinal; Inflammation; Male; Mice; Neuronal Plasticity; Neurons; Pain; Spinal Cord; TRPV Cation Channels

Inflammatory pain, such as arthritis pain, is a growing health problem. Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a unique family of lipid mediators, including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, have shown marked potency in treating disease conditions associated with inflammation. Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 in mice potently reduces inflammatory pain behaviors induced by intraplantar injection of formalin, carrageenan or complete Freund's adjuvant (CFA), without affecting basal pain perception. Intrathecal RvE1 injection also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and tumor necrosis factor-alpha (TNF-alpha). RvE1 has anti-inflammatory activity by reducing neutrophil infiltration, paw edema and proinflammatory cytokine expression. RvE1 also abolishes transient receptor potential vanilloid subtype-1 (TRPV1)- and TNF-alpha-induced excitatory postsynaptic current increases and TNF-alpha-evoked N-methyl-D-aspartic acid (NMDA) receptor hyperactivity in spinal dorsal horn neurons via inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, we show a previously unknown role for resolvins in normalizing the spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the potency of resolvins and the well-known side effects of opioids and COX inhibitors, resolvins may represent new analgesics for treating inflammatory pain.

Topics: Analgesics; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Inflammation; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Pain; Posterior Horn Cells

Topics: Analgesics; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Models, Biological; Molecular Structure; Pain