Modulation of spinal glial reactivity by intrathecal PPF is not sufficient to inhibit mechanical allodynia induced by nerve crush

Gallo, Alessandro; Dimiziani, Andrea; Damblon, Jonathan; Michot, B.; Rieux, Anne des; Kock, Marc De; Hermans, Emmanuel; Deumens, Ronald

doi:10.1016/j.neures.2015.02.004

Cited by 7 publications

(7 citation statements)

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“…4f , h ). These findings are supportive to the studies that reported the disassociation between microglial inhibition (indicated by microglial markers such as Iba1) and analgesic outcomes [ 39 – 41 ]. This finding also implies that the hypersensitivity later than 1 day after PSL may not solely depend on microglial activation.…”

Section: Discussionsupporting

confidence: 91%

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

Tang

Wang

et al. 2016

J Neuroinflammation

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BackgroundIt is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain.MethodsNeuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC−/− (histidine decarboxylase gene knockout) and IL-1R−/− (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1β production, respectively.ResultsHistidine (100 mg/kg, i.p.) administered throughout days 0–3, 0–7, or 0–14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2–3, 4–7, and 8–14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1β upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC−/− mice and IL-1R−/− mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia.ConclusionsThese results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1β production in the spinal cord following nerve injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0637-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

Tang

Wang

et al. 2016

J Neuroinflammation

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“…In our study, also a marked reduction in nerve injury‐induced reactivity of spinal glial cells was noted after spinal RGS4 inhibition. These glial cells are strongly implicated in neuropathic pain (Scholz and Woolf, ; Zhuang et al ., ) even though there is not always an evident link between glial reactivity states and neuropathic pain symptoms such as allodynia (Gallo et al ., ; Leinders et al ., ). It remains to be determined whether the effect of spinal RGS4 inhibition on glial reactivity is directly or indirectly linked to the anti‐hyperalgesic effects in our investigation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB₁ receptor signalling

Bosier

Brolet

Muccioli

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSERegulators of G protein signalling (RGS) are major determinants of metabotropic receptor activity, reducing the lifespan of the GTP-bound state of G proteins. Because the reduced potency of analgesic agents in neuropathic pain may reflect alterations in RGS, we assessed the effects of CCG 63802, a specific RGS4 inhibitor, on pain hypersensitivity and signalling through cannabinoid receptors, in a model of neuropathic pain. EXPERIMENTAL APPROACHThe partial sciatic nerve ligation (PSNL) model in male Sprague Dawley rats was used to measure paw withdrawal thresholds to mechanical (von Frey hairs) or thermal (Hargreaves method) stimuli, during and after intrathecal injection of CCG 63802. HEK293 cells expressing CB 1 receptors and conditional expression of RGS4 were used to correlate cAMP production and ERK phosphorylation with receptor activation and RGS4 action. KEY RESULTSTreatment of PSNL rats with CCG 63802, twice daily for 7 days after nerve injury, attenuated thermal hyperalgesia during treatment. Spinal levels of anandamide were higher in PSNL animals, irrespective of the treatment. Although expression of CB 1 receptors was unaffected, HU210-induced CB 1 receptor signalling was inhibited in PSNL rats and restored after intrathecal CCG 63802. In transfected HEK cells expressing CB 1 receptors and RGS4, inhibition of cAMP production, a downstream effect of CB 1 receptor signalling, was blunted after RGS4 overexpression. RGS4 expression also attenuated the CB 1 receptor-controlled activation of ERK1/2. CONCLUSIONS AND IMPLICATIONSInhibition of spinal RGS4 restored endogenous analgesic signalling pathways and mitigated neuropathic pain. Signalling through CB 1 receptors may be involved in this beneficial effect

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“… 2007 ), propentofylline (Gallo et al. 2015 ) as well as blockade of the microglial receptors P2X4R (Zhou et al. 2014 ; Jurga, Piotrowska, et al.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

Jurga

Rojewska

Makuch

et al. 2018

Pharmaceutical Biology

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Context: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception.Objective: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed.Materials and methods: Behavioural (von Frey’s/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 μG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7.Results: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy.Conclusions: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.

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Modulation of spinal glial reactivity by intrathecal PPF is not sufficient to inhibit mechanical allodynia induced by nerve crush

Cited by 7 publications

References 28 publications

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB₁ receptor signalling

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

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Modulation of spinal glial reactivity by intrathecal PPF is not sufficient to inhibit mechanical allodynia induced by nerve crush

Cited by 7 publications

References 28 publications

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB1 receptor signalling

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

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Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB₁ receptor signalling