scholarly journals The Skin-Whitening Effects of Ectoine via the Suppression of α-MSH-Stimulated Melanogenesis and the Activation of Antioxidant Nrf2 Pathways in UVA-Irradiated Keratinocytes

Antioxidants ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 63 ◽  
Author(s):  
You-Cheng Hseu ◽  
Xuan-Zao Chen ◽  
Yugandhar Vudhya Gowrisankar ◽  
Hung-Rong Yen ◽  
Jing-Yuan Chuang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Hacat Cells ◽  
Skin Whitening ◽  
B16f10 Cells ◽  
Kinase C ◽  
Protein Kinase Ckii

Ultraviolet A (UVA)-irradiation induced reactive oxygen species (ROS) production mediates excessive melanogenesis in skin cells leading to pigmentation. We demonstrated the depigmenting and anti-melanogenic effects of Ectoine, a natural bacterial osmolyte, in UVA-irradiated human (HaCaT) keratinocytes, and the underlying molecular mechanisms were elucidated. HaCaT cells were pre-treated with low concentrations of Ectoine (0.5–1.5 μM) and assayed for various depigmenting and anti-melanogenic parameters. This pre-treatment significantly downregulated ROS generation, α-melanocyte-stimulating hormone (α-MSH) production, and proopiomelanocortin (POMC) expression in UVA-irradiated HaCaT cells. Also, antioxidant heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase [quinone 1] (NQO-1), and γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC) protein expressions were mediated via the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) whose knockdown indeed impaired this effect signifying the importance of the Nrf2 pathway. Ectoine was mediating the activation of Nrf2 via the p38, protein kinase B (also known as AKT), protein kinase C (PKC), and casein kinase II protein kinase (CKII) pathways. The conditioned medium obtained from the Ectoine pre-treated and UVA-irradiated HaCaT cells downregulated the tyrosinase, tyrosinase-related protein-1 and -2 (TRP-1/-2), cyclic AMP (c-AMP) protein kinase, c-AMP response element-binding protein (CREB), and microphthalmia-associated transcription factor (MITF) expressions leading to melanoma B16F10 cells having inhibited melanin synthesis. Interestingly, this anti-melanogenic effect in α-MSH-stimulated B16F10 cells was observable only at 50–400 μM concentrations of Ectoine, signifying the key role played by Ectoine (0.5–1 μM)-treated keratinocytes in skin whitening effects. We concluded that Ectoine could be used as an effective topical natural cosmetic agent with depigmenting and anti-melanogenic efficacy.

Heme and Iron Chelators Inhibit HIV-1 Through The Induction Of Heme Oxygenase 1, Ferroportin and IKBα

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2198-2198
Author(s):  
Namita Kumari ◽  
Sergei A Nekhai
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Iron Chelators ◽  
Heme Oxygenase 1 ◽  
Kinase C ◽  
Hiv 1

Abstract Background Recently, HIV-1 infection was shown to be efficiently inhibited in macrophages and T-cells treated with hemin that was added extracellularly 1,2. Hemin administration to humanized transgenic mice significantly reduced HIV-1 viral load 1. Suppression of HIV-1 by hemin was mediated through the induction of (HO-1)1, via a protein kinase C-dependent pathway2. The inhibitory effect of hemin could be reversed by protoporphyrin, an HO-1 inhibitor 2. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1. We recently analyzed the role of HO-1 in protecting LPS-treated human macrophages against HIV-1 infection3. LPS-treated macrophages were negative for mature virions, expressed HO-1 and produced MIP1α, MIP1β and LD78β chemokines which led to a decreased CCR5 expression. Treatment with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) increased HIV-1 replication and decreased secretion of MIP1α, MIP1β, and LD78β chemokines. HO-1 also affects several proteins involved in cell cycle progression, and cell cycle is critical for HIV-1 progression. Hypoxia leads to induction and stabilization of HIF-1α and is inhibitory to HIV-1 replication. NF-kB is important for basal and Tat-activated HIV-1 transcription. Here we analyzed factors involved in HIV-1 transcription affected by HO-1 expression. Results HIV-1 replication was reduced in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication, suggesting that ferroportin plays a key role in the HIV-1 inhibition. Stable ferroportin knock down in THP1 cells led to the inability of hemin to inhibit HIV-1, again suggesting that ferroportin plays a key role in this process. In hemin-treated THP-1 cells, expression of p21, HIF-1α and IKBα mRNA was induced. The expression of IKBα, an inhibitor of NF-kB, reduced the level of p65 subunit of NF-kB. We obtained similar results in THP-1 cell treated with iron chelators, which also induced the expression of IKBα, HIF-1 and p21. THP-1 cells treated with hemin or iron chelators were arrested in G1 phase of cell cycle. Stable HIF-1a knockdown in promonocytic THP-1 cells increased HIV replication suggesting that HIF-1 might be a restriction factor for HIV-1. In contrast to iron chelators that inhibited enzymatic activity of CDK2 without affecting its protein level, hemin treatment reduced CDK2 expression at mRNA and protein levels. Conclusions Induction of HIF-1 regulatory pathway and iron export by ferroportin might protect hemin-treated THP-1 cells from HIV-1 infection. Additional molecular mechanisms of heme-mediated HIV-1 inhibition might also include NF-kB inhibition by IKBα and CDK2 inhibition leading to the inhibition of HIV-1 transcription. Our results point to novel therapeutics, such as the use of hemin and iron chelators, both of which are FDA approved for treatment for acute porphyries and iron overload. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. Literature 1. Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006;176(7):4252-4257. 2. Devadas K, Hewlett IK, Dhawan S. Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction. J Leukoc Biol. 2010;87(5):915-924. 3. Zhou ZH, Kumari N, Nekhai S, et al. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun. 2013;435(3):373-377. Disclosures: No relevant conflicts of interest to declare.

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

2003 ◽  
Vol 285 (2) ◽  
pp. C334-C342 ◽  
Author(s):  
Satoshi Numazawa ◽  
Makie Ishikawa ◽  
Aya Yoshida ◽  
Sachiko Tanaka ◽  
Takemi Yoshida
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Prolonged Exposure ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Kinase Assay ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Kinase C

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of antioxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang HC, Nguyen T, and Pickett CB. J Biol Chem 277: 42769–42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12- O-tetradecanoylphorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKCι activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-green fluorescent protein (GFP) fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by coexpression of aPKCι, but not by a kinase inactive mutant aPKCι(K274W). The activity of an ARE-driven reporter was increased by coexpression of aPKCι, and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by coexpression of aPKCι(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in the nuclear translocation and ARE transactivation of Nrf2 by oxidative stress.

scholarly journals Propofol Inhibits Ischemia/Reperfusion-Induced Cardiotoxicity Through the Protein Kinase C/Nuclear Factor Erythroid 2-Related Factor Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Shengqiang Li ◽  
Zhen Lei ◽  
Meng Zhao ◽  
Yonghao Hou ◽  
Di Wang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
H9c2 Cells ◽  
Nrf2 Pathway ◽  
Kinase C ◽  
Creatine Kinase Mb

Both hydrogen peroxide (H2O2, H) and ischemia/reperfusion (I/R) can damage cardiomyocytes, which was inhibited by propofol (P). The present research was designed to examine whether propofol can reduce myocardial I/R injury by activating protein kinase C (PKC)/nuclear factor erythroid-2-related factor 2 (NRF2) pathway in H9C2 cells and rat Langendorff models. H9C2 cells were disposed of no reagents (C), H2O2 for 24 h (H), propofol for 1 h before H2O2 (H+P), and chelerythrine (CHE, PKC inhibitor) for 1 h before propofol and H2O2 (H+P+CHE). N = 3. The PKC gene of H9C2 was knocked down by siRNA and overexpressed by phorbol 12-myristate 13-acetate (PMA, PKC agonist). The cell viability and the expressions of PKC, NRF2, or heme oxygenase-1(HO-1) were evaluated. Propofol significantly reduced H9C2 cell mortality induced by H2O2, and significantly increased NRF2 nuclear location and HO-1 expression, which were restrained by siRNA knockout of PKC and promoted by PMA. Rat hearts were treated with KrebsHenseleit solution for 120 min (C), with (I/R+P) or without (I/R) propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min, and CHE for 10 min before treated with propofol. N = 6. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and creatine kinase-MB (CK-MB) in perfusion fluid and antioxidant enzymes in the myocardium were assessed. I/R, which increased LDH and CK-MB expression and reduced SOD expression, boosted the pathological damage and infarcts of the myocardium after reperfusion. However, propofol restrained all these effects, an activity that was antagonized by CHE. The results suggest that propofol pretreatment protects against I/R injury by activating of PKC/NRF2 pathway.

Mechanism of Hepatic Heme Oxygenase-1 Induction by Isoflurane

2006 ◽  
Vol 104 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Alexander Hoetzel ◽  
Daniel Leitz ◽  
Rene Schmidt ◽  
Eva Tritschler ◽  
Inge Bauer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase A2 ◽  
Heme Oxygenase ◽  
Kupffer Cell ◽  
Cell Function ◽  
Heme Oxygenase 1 ◽  
Gadolinium Chloride ◽  
Kinase C

Background The heme oxygenase pathway represents a major cell and organ protective system in the liver. The authors recently showed that isoflurane and sevoflurane up-regulate the inducible isoform heme oxygenase 1 (HO-1). Because the activating cascade remained unclear, it was the aim of this study to identify the underlying mechanism of this effect. Methods Rats were anesthetized with pentobarbital intravenously or with isoflurane per inhalation (2.3 vol%). Kupffer cell function was inhibited by dexamethasone or gadolinium chloride. Nitric oxide synthases were inhibited by either N(omega)-nitro-L-arginine methyl ester or S-methyl thiourea. N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1. Protein kinase C and phospholipase A2 were inhibited by chelerythrine or quinacrine, respectively. HO-1 was analyzed in liver tissue by Northern blot, Western blot, immunostaining, and enzymatic activity assay. Results In contrast to pentobarbital, isoflurane induced HO-1 after 4-6 h in hepatocytes in the pericentral region of the liver. The induction was prevented in the presence of dexamethasone (P < 0.05) and gadolinium chloride (P < 0.05). Inhibition of nitric oxide synthases or reactive oxygen intermediates did not affect isoflurane-mediated HO-1 up-regulation. In contrast, chelerythrine (P < 0.05) and quinacrine (P < 0.05) resulted in a blockade of HO-1 induction. Conclusion The up-regulation of HO-1 by isoflurane in the liver is restricted to parenchymal cells and depends on Kupffer cell function. The induction is independent of nitric oxide or reactive oxygen species but does involve protein kinase C and phospholipase A2.

Relationship between aldose reductase enzyme and the signaling pathway of protein kinase C in an in vitro diabetic retinopathy model

2020 ◽  
Vol 98 (4) ◽  
pp. 243-251
Author(s):  
Mutlu Sarikaya ◽  
Nuray Yazihan ◽  
Net Daş Evcimen
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Signaling Molecules ◽  
Protein Levels ◽  
Kinase C ◽  
The Relationship ◽  
And Oxidative Stress ◽  
Expression And Activity

Protein kinase C (PKC) and aldose reductase (AR) enzyme activities are increased in diabetes and complications are include retinopathy, nephropathy, and neuropathy. However, the relationship between PKC and AR and the underlying molecular mechanisms is still unclear. We aimed to evaluate the relationship between these two enzymes and clarify the underlying molecular mechanisms by the related signaling molecules. The effects of hyperglycemia and oxidative stress on AR and PKC enzymes and the signaling molecules such as nuclear factor-kappa B (NF-κB), inhibitor kappa B-alpha (IkB-α), total c-Jun, phospho c-Jun, and stress-activated protein kinases (SAPK)/Jun amino-terminal kinases (JNK) were evaluated in human retinal pigment epithelial cells (ARPE-19). AR, PKC protein levels, and related signaling molecules increased with hyperglycemia and oxidative stress. The AR inhibitor sorbinil decreased PKC expression and activity and all signaling molecule protein levels. Increased AR expression during hyperglycemia and oxidative stress was found to be correlated with the increase in PKC expression and activity in both conditions. Decreased expression and activity of PKC and the protein levels of related signaling molecules with the AR inhibitor sorbinil showed that AR enzyme may play a key role in the expression of PKC enzyme and oxidative stress during diabetes.

scholarly journals Protein Kinase C Signaling Mediates a Program of Cell Cycle Withdrawal in the Intestinal Epithelium

2000 ◽  
Vol 151 (4) ◽  
pp. 763-778 ◽  
Author(s):  
Mark R. Frey ◽  
Jennifer A. Clark ◽  
Olga Leontieva ◽  
Joshua M. Uronis ◽  
Adrian R. Black ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Intestinal Epithelium ◽  
Molecular Mechanisms ◽  
Model Systems ◽  
Intestinal Epithelial ◽  
Kinase C

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G0. PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21waf1/cip1 and p27kip1, thus targeting all of the major G1/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G0 as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKCα alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt–villus axis revealed that PKCα activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit–specific events in situ. Together, these data point to PKCα as a key regulator of cell cycle withdrawal in the intestinal epithelium.

scholarly journals Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 416-424 ◽  
Author(s):  
Olga Konopatskaya ◽  
Sharon A. Matthews ◽  
Matthew T. Harper ◽  
Karen Gilio ◽  
Judith M. E. M. Cosemans ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Thrombus Formation ◽  
Dense Granule ◽  
Molecular Pathway ◽  
Kinase C ◽  
Pkc Isoforms ◽  
Dense Granule Secretion ◽  
Granule Secretion

Abstract Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCα, is a major regulator of platelet granule secretion, but the molecular pathway from PKCα to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in α-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion.

scholarly journals The protein kinase C-related PKC-L(eta) gene product is localized in the cell nucleus.

1992 ◽  
Vol 12 (3) ◽  
pp. 1304-1311 ◽  
Author(s):  
H Greif ◽  
J Ben-Chaim ◽  
T Shimon ◽  
E Bechor ◽  
H Eldar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Nucleus ◽  
Molecular Mechanisms ◽  
Phorbol Esters ◽  
Subcellular Fractionation ◽  
Related Family ◽  
Kinase C ◽  
Human Epidermoid Carcinoma

The tumor promoters phorbol esters are thought to induce changes in cell growth and gene expression by direct activation of protein kinase C (PKC). However, the molecular mechanisms by which PKC molecules transduce signals into the cell nucleus are unknown. In this study, we provide evidence for a direct target for phorbol esters in the nucleus. We demonstrate that the new PKC-related family member, PKC-L, recently isolated by us, is expressed specifically in the cell nucleus. Localization of PKC-L in the cell nucleus is shown both by immunofluorescence staining and by subcellular fractionation experiments of several human cell lines, including the human epidermoid carcinoma line A431. Treatment of these cells by phorbol esters does not induce the down-regulation of PKC-L, in contrast to their effect on classical PKC family members. This is the only PKC isoenzyme described so far that resides permanently and specifically in the cell nucleus. PKC-L may function as an important link in tumor promoting, e.g., as a nuclear regulator of gene expression that changes the phosphorylation state of transcriptional components such as the AP-1 complex.

scholarly journals Lipopolysaccharide-Induced Heme Oxygenase-1 Expression in Human Monocytic Cells Is Mediated via Nrf2 and Protein Kinase C

2005 ◽  
Vol 175 (7) ◽  
pp. 4408-4415 ◽  
Author(s):  
Stuart A. Rushworth ◽  
Xi-Lin Chen ◽  
Nigel Mackman ◽  
Richard M. Ogborne ◽  
Maria A. O’Connell
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Monocytic Cells ◽  
Kinase C

Protein Kinase C γ Interneurons Mediate C-fiber–induced Orofacial Secondary Static Mechanical Allodynia, but Not C-fiber–induced Nociceptive Behavior

2016 ◽  
Vol 124 (5) ◽  
pp. 1136-1152 ◽  
Author(s):  
Cedric Peirs ◽  
Nathalie Bourgois ◽  
Alain Artola ◽  
Radhouane Dallel
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mechanical Allodynia ◽  
Molecular Mechanisms ◽  
Spontaneous Pain ◽  
Secondary Hyperalgesia ◽  
Neuronal Activation ◽  
Kinase C ◽  
C Fiber ◽  
Static Mechanical

Abstract Background Tissue injury enhances pain sensitivity both at the site of tissue damage and in surrounding uninjured skin (secondary hyperalgesia). Secondary hyperalgesia encompasses several pain symptoms including pain to innocuous punctate stimuli or static mechanical allodynia. How injury-induced barrage from C-fiber nociceptors produces secondary static mechanical allodynia has not been elucidated. Methods Combining behavioral, immunohistochemical, and Western blot analysis, the authors investigated the cell and molecular mechanisms underlying the secondary static mechanical allodynia in the rat medullary dorsal horn (MDH) using the capsaicin model (n = 4 to 5 per group). Results Intradermal injection of capsaicin (25 μg) into the vibrissa pad produces a spontaneous pain and a secondary static mechanical allodynia. This allodynia is associated with the activation of a neuronal network encompassing lamina I–outer lamina III, including interneurons expressing the γ isoform of protein kinase C (PKCγ) within inner lamina II (IIi) of MDH. PKCγ is concomitantly phosphorylated (+351.4 ± 79.2%, mean ± SD; P = 0.0003). Mechanical allodynia and innocuous punctate stimulus–evoked laminae I to III neuronal activation can be replicated after intracisternally applied γ-aminobutyric acid receptor type A (GABAA) antagonist (bicuculline: 0.05 μg) or reactive oxygen species (ROS) donor (tert-butyl hydroperoxide: 50 to 250 ng). Conversely, intracisternal PKCγ antagonist, GABAA receptor agonist, or ROS scavenger prevent capsaicin-induced static mechanical allodynia and neuronal activation. Conclusions Sensitization of lamina IIi PKCγ interneurons is required for the manifestation of secondary static mechanical allodynia but not for spontaneous pain. Such sensitization is driven by ROS and GABAAergic disinhibition. ROS released during intense C-fiber nociceptor activation might produce a GABAAergic disinhibition of PKCγ interneurons. Innocuous punctate inputs carried by Aδ low-threshold mechanoreceptors onto PKCγ interneurons can then gain access to the pain transmission circuitry of superficial MDH, producing pain.

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