Nitroxidative Signaling Mechanisms in Pathological Pain

Grace, Peter M.; Gaudet, Andrew D.; Staikopoulos, Vasiliki; Maier, Steven F.; Hutchinson, Mark R.; Salvemini, Daniela; Watkins, Linda R.

doi:10.1016/j.tins.2016.10.003

Cited by 92 publications

(91 citation statements)

References 213 publications

(241 reference statements)

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“…Numerous studies have convincingly shown that an increase in neuroinflammation in the dorsal spinal cord importantly contributes to allodynia following sciatic CCI (Grace et al, 2016a, 2014). One of the major neuroinflammatory mediators within spinal cord implicated in creating allodynia is following injury to peripheral sensory/motor mixed nerves is IL-1beta (Grace et al, 2016a, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…One of the major neuroinflammatory mediators within spinal cord implicated in creating allodynia is following injury to peripheral sensory/motor mixed nerves is IL-1beta (Grace et al, 2016a, 2014). In contrast, IL-1 has never been implicated in allodynia induced as a consequence of injury to motor axons, either spinally or supraspinally.…”

Section: Resultsmentioning

confidence: 99%

“…IL-1 may have a common role in mediating nociceptive hypersensitivity after craniofacial and sciatic nerve injury (Grace et al, 2014), unlike IL-6 (Latrémolière et al, 2008). There are several known mechanisms by which IL-1 may increase neuronal excitability in nociceptive pathways (Grace et al, 2016a, 2014), including phosphorylation of postsynaptic NR1 NMDA receptor subunits (Zhang et al, 2008), and down-regulation of both the astrocyte glutamate transporter GLT-1 (Yan et al, 2014) and neuronal G protein-coupled receptor kinase 2 (an enzymatic regulator of G protein-coupled receptor homologous desensitization, that protects against overstimulation) (Kleibeuker et al, 2008). IL-1 is elevated in the brainstem and contributes to extra-territorial pain after trigeminal nerve injury (Chai et al, 2012; Takahashi et al, 2011), and this report adds to others demonstrating a causal role for this cytokine in craniofacial neuropathic pain (Won et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies have revealed that selective lesion of spinal motor neurons by L5 ventral root transection induces nociceptive hypersensitivity and microglia activation in the spinal dorsal horn, which are both dependent on tumor necrosis factor (TNF) signaling (Li et al, 2002; Sheth et al, 2002; Xu et al, 2006, 2007). Such neuroimmune signaling has a well-documented role in the development of neuropathic pain after injury to mixed (sensory and motor) peripheral nerves (Grace et al, 2016a, 2014). Furthermore, injury of the gastrocnemius-soleus (predominantly motor) nerve results in nociceptive hypersensitivity, and both induces ectopic activity and amplifies evoked action potentials of sciatic nerve and DRG neurons (Kirillova et al, 2011; Michaelis et al, 2000; Zhou et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia

Lewis

Grace

Hutchinson

et al. 2017

Brain, Behavior, and Immunity

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Despite pain being a sensory experience, studies of spinal cord ventral root damage have demonstrated that motor neuron injury can induce neuropathic pain. Whether injury of cranial motor nerves can also produce nociceptive hypersensitivity has not been addressed. Herein, we demonstrate that chronic constriction injury (CCI) of the buccal branch of the facial nerve results in long-lasting, unilateral allodynia in the rat. An anterograde and retrograde tracer (3000MW tetramethylrhodamine-conjugated dextran) was not transported to the trigeminal ganglion when applied to the injury site, but was transported to the facial nucleus, indicating that this nerve branch is not composed of trigeminal sensory neurons. Finally, intracisterna magna injection of interleukin-1 (IL-1) receptor antagonist reversed allodynia, implicating the pro-inflammatory cytokine IL-1 in the maintenance of neuropathic pain induced by facial nerve CCI. These data extend the prior evidence that selective injury to motor axons can enhance pain to supraspinal circuits by demonstrating that injury of a facial nerve with predominantly motor axons is sufficient for neuropathic pain, and that the resultant pain has a neuroimmune component.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia

Lewis

Grace

Hutchinson

et al. 2017

Brain, Behavior, and Immunity

Self Cite

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“…When reacting with NO • , O 2 •− forms ONOO − , which initiates lipid peroxidation and thus leads to acute or chronic inflammatory responses (Yang et al ., ). There are evidences that NO • and O 2 •− can directly increase the excitability of nociceptive neurons, activating calcium/calmodulin‐dependent protein kinase II in glutamatergic spinal neurons (Grace et al ., ). On the other hand, although it is not the unique mechanism, oxidative stress can cause endothelial dysfunctions such as increase of capillary permeability and recruitment of cells, which contribute to edema formation (Bielli et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Chemical Composition and Antioxidant, Antinociceptive, and Anti‐inflammatory Activities of Four Amazonian Byrsonima Species

Guilhon-Simplicio

Machado

Nascimento

et al. 2017

Phytotherapy Research

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Species of the Byrsonima genus are widely used in Brazil, especially for the treatment of gastrointestinal disorders. However, species from the Amazonian region are still poorly studied. Thus, we studied the antioxidant, antinociceptive, and anti-inflammatory activities of for Amazonian species, Byrsonima crispa, Byrsonima duckeana, Byrsonima garcibarrigae, and Byrsonima incarnata. Phenolic composition was determined by chemical and chromatographic methods. The aqueous extracts were evaluated in DPPH , ABTS , and superoxide (O ) tests, LPS-activated macrophage assay, and formalin test. All species contained a high phenolic and flavonoid content. We identified 15 phenolic compounds, including phenolic acids, hydroxycinnamic acids, flavonoids, and catechins. The extracts showed high antioxidant activity and were more active than quercetin at inhibiting nitric oxide release in the LPS-activated macrophage assay. B. duckeana and B. garcibarrigae showed higher in vivo antinociceptive and anti-inflammatory activities. B. garcibarrigae presented significant effect on the early phase of the formalin test, pointing to an antinociceptive mechanism distinct from traditional anti-inflammatory medicines. In conclusion, the pharmacological potential of these species is closely related to their flavonoid-rich chemical composition, which seems to act through antioxidant mechanisms. Copyright © 2017 John Wiley& Sons, Ltd.

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Antihypersensitivity effect of betanin (red beetroot extract) via modulation of microglial activation in a mouse model of neuropathic pain

Kwankaew

Okuda

Aye-Mon

et al. 2021

European Journal of Pain

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Background: Neuropathic pain (NeP) medications have several side effects that affect NeP patients' quality of life. Betanin, the most common betacyanin pigment, has been shown to have potent antioxidant and anti-inflammatory properties in vivo; thus, it has potential as a healthcare treatment. In this study, we focused on betanin (red beetroot extract) as a potential therapy for NeP. Methods: Mice model of NeP were made by chronic constriction injury (CCI), and the development of mechanical hypersensitivity was confirmed using the von Frey test. Motor coordination and locomotor activity were assessed using open field tests and rotarod tests, respectively. The expression level of glial markers in the spinal cords was analyzed by immunostaining. The direct effects of betanin on microglial cells were investigated using primary cultured microglial cells. Results: In CCI model mice, repeated betanin treatment, both intraperitoneally and orally, attenuated developing mechanical hypersensitivity in a dose-dependent manner without impairing motor coordination. Betanin treatment also attenuated mechanical hypersensitivity that had developed and prevented the onset of mechanical hypersensitivity in CCI mice. Microglial activation in the spinal cord is known to play a key role in the development of NeP; betanin treatment reduced CCI-induced microglial activation in the spinal cord of model mice. Moreover, in primary microglia cultured cells, the activation of microglia by lipopolysaccharide application was suppressed by betanin treatment. Conclusion: Betanin treatment appears to ameliorate mechanical hypersensitivity related to CCI-induced NeP in mice by inhibiting microglial activation. Significance: This article supports findings of the effect of betanin on NeP and provides a potential therapeutic candidate for NeP. Furthermore, elucidating the underlying mechanism of the effect of betanin on microglial activation could assist the development of new treatments for chronic pain. How to cite this article: Kwankaew N, Okuda H, Aye-Mon A, et al. Antihypersensitivity effect of betanin (red beetroot extract) via modulation of microglial activation in a mouse model of neuropathic pain.

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Nitroxidative Signaling Mechanisms in Pathological Pain

Cited by 92 publications

References 213 publications

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia

Chemical Composition and Antioxidant, Antinociceptive, and Anti‐inflammatory Activities of Four Amazonian Byrsonima Species

Antihypersensitivity effect of betanin (red beetroot extract) via modulation of microglial activation in a mouse model of neuropathic pain

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