Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ET<sub>B</sub>Receptors in Rats

Verri, Waldiceu A.; Molina, Rodrigo Otoboni; Schivo, Ieda R. S.; Cunha, Thiago M.; Parada, Carlos A.; Poole, Stephen; Ferreira, Sérgio Henrique; Cunha, Fernando Q.

doi:10.1124/jpet.105.089409

Cited by 44 publications

(34 citation statements)

References 35 publications

(70 reference statements)

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“…*, significant difference from baseline (P Ͻ 0.001); #, significant differences from control mice (P Ͻ 0.001). 1998a), injected subcutaneously into the plantar surface of the hind paw, (Baamonde et al 2004;Balonov et al 2006;Gokin et al 2001;Houck et al 2004;Menendez et al 2003b;Piovezan et al 1998Piovezan et al , 2004Verri et al 2004Verri et al , 2005 or skin of the back (Mujenda et al 2007), and injected into tumor-bearing tissues Schmidt et al 2007;Wacnik et al 2001). In contrast, the newer ET A receptor-selective antagonists have been administered systemically (Chichorro et al 2006a;Klass et al 2005;Matwyshyn et al 2006;Piovezan et al 2000;Trentin et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Injection of ET-1 into the knee or hind paw evokes nocifensive behaviors in animals (Baamonde et al 2004;Balonov et al 2006;De-Melo et al 1998a;Ferreira et al 1989;McKelvy et al 2007;Piovezan et al 1998Piovezan et al , 2004Verri et al 2004Verri et al , 2005. For example, injection of ET-1 into the plantar surface of the hind paw evoked dose-dependent hind paw licking (Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000), and application of ET-1 directly to the sciatic nerve evoked robust hind paw flinching (Davar et al 1998;Fareed et al 2000).…”

Section: Et-1-evoked Nocifensive Behaviors and Hyperalgesiamentioning

confidence: 99%

“…Numerous studies have demonstrated that injection of ET-1 into the knee or hind paw evokes nocifensive behaviors (Baamonde et al 2004;Balonov et al 2006;De-Melo et al 1998a;Ferreira et al 1989;Gokin et al 2001;McKelvy et al 2007;Menendez et al 2003b;Piovezan et al 1998Piovezan et al , 2004Verri et al 2004Verri et al , 2005, tactile allodynia (Balonov et al 2006;McKelvy et al 2007), and mechanical (da Ferreira et al 1989) and heat (Menendez et al 2003b) hyperalgesia through a mechanism involving the ET A receptors located in peripheral tissues (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000). Injection of ET-1 into the skin excites C nociceptors (Gokin et al 2001;Khodorova et al 2002;Namer et al 2007) and likely contributes to ET-1-evoked nocifensive behaviors.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

Hamamoto

Khasabov

Cain

et al. 2008

Journal of Neurophysiology

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Hamamoto DT, Khasabov SG, Cain DM, Simone DA. Tumorevoked sensitization of C nonciceptos: a role for endothelin. J Neurophysiol 100: 2300 -2311, 2008. First published August 6, 2008 doi:10.1152/jn.01337.2007. Primary and metastatic cancers that effect bone are frequently associated with pain. Sensitization of primary afferent C nociceptors innervating tissue near the tumor likely contributes to the chronic pain and hyperalgesia accompanying this condition. This study focused on the role of the endogenous peptide endothelin-1 (ET-1) as a potential peripheral algogen implicated in the process of cancer pain. Electrophysiological response properties, including ongoing activity and responses evoked by heat stimuli, of C nociceptors were recorded in vivo from the tibial nerve in anesthetized control mice and mice exhibiting mechanical hyperalgesia following implantation of fibrosarcoma cells into and around the calcaneus bone. ET-1 (100 M) injected into the receptive fields of C nociceptors innervating the plantar surface of the hind paw evoked an increase in ongoing activity in both control and tumor-bearing mice. Moreover, the selective ET A receptor antagonist, BQ-123 (3 mM), attenuated tumor-evoked ongoing activity in tumor-bearing mice. Whereas ET-1 produced sensitization of C nociceptors to heat stimuli in control mice, C nociceptors in tumor-bearing mice were sensitized to heat, and their responses were not further increased by ET-1. Importantly, administration of BQ-123 attenuated tumor-evoked sensitization of C nociceptors to heat. We conclude that ET-1 at the tumor site contributes to tumor-evoked excitation and sensitization of C nociceptors through an ET A receptor mediated mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Et-1-evoked Nocifensive Behaviors and Hyperalgesiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

Hamamoto

Khasabov

Cain

et al. 2008

Journal of Neurophysiology

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“…We have previously shown that sST2 is a potent inhibitor of collagen-induced arthritis in mice (11), suggesting that the IL-33-ST2 signaling pathway is a key mediator of rheumatoid arthritis (RA). Arthritic lesions are accompanied by movement limitation secondary to articular hyperalgesia, and there is consistent evidence that cytokines induce hypernociception (hyperalgesia and/or allodynia in experimental animals) (12)(13)(14)(15). Therefore, we have investigated the role of IL-33 in immune inflammatory hypernociception in mice.…”

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confidence: 99%

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Verri

Guerrero

Fukada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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163

155

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cytokines ͉ inflammation ͉ pain ͉ rheumatoid arthritis ͉ hyperalgesia I L-33 is a recently described member of the IL-1 family that includes IL-1␤ and IL-18. Like IL-1␤ and IL-18, IL-33 was found to have strong immunomodulatory functions (1). However, unlike IL-1␤ and IL-18, which mainly promote T-helper 1 (Th1)-associated responses, IL-33 predominantly induces the production of Th2 cytokines (IL-5 and IL-13) and increases the levels of serum Ig. IL-33 was recently found to be the ligand for the orphan receptor ST2 (1), which also is known as T1, DER4, or Fit (2-5). The interaction between IL-33 and ST2 was sufficient to trigger the activation of NF-B and all three MAPKs (p38, ERK1/2, and JNK1/2) in a mast cell line. In vitro, IL-33 enhanced IL-5 and IL-13 production by polarized Th2, but not Th1, cell lines. In addition, the administration of human IL-33 into naïve mice provoked innate type 2 cytokine, IgE production, and eosinophilia (1).The ST2 gene encodes two isoforms of ST2 protein: ST2L, a transmembrane form, and soluble ST2 (sST2) (6), a secreted form that can serve as a decoy receptor of IL-33 (1). ST2L is preferentially expressed on Th2, but not Th1, cells (7,8) and can profoundly suppress innate and adaptive immunity (9, 10). ST2 also is expressed on mast cells, macrophages, and fibroblasts. We have previously shown that sST2 is a potent inhibitor of collagen-induced arthritis in mice (11), suggesting that the IL-33-ST2 signaling pathway is a key mediator of rheumatoid arthritis (RA). Arthritic lesions are accompanied by movement limitation secondary to articular hyperalgesia, and there is consistent evidence that cytokines induce hypernociception (hyperalgesia and/or allodynia in experimental animals) (12-15). Therefore, we have investigated the role of IL-33 in immune inflammatory hypernociception in mice.We report here that IL-33 is a key mediator of methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception. IL-33 mediates hypernociception via the sequential TNF␣ 3 IL-1␤ 3 IFN␥ 3 endothelin 1 (ET-1) 3 prostaglandin (PG) E 2 signaling cascade. These results therefore reveal a hitherto uncharacterized important pathway of antigen-induced hypernociception normally associated with Th1 response. Furthermore, our results suggest that IL-33 may be a potential therapeutic target for immune inflammatory hypernociception. Results IL-33Mediates Cutaneous Mechanical Hypernociception. IL-33 intraplantar (i.pl.) injection induced mechanical hypernociception in mice in a dose-and time-dependent manner (Fig. 1A). The response was significant from 0.5 h, reaching maximal response between 3 and 5 h, decreasing thereafter to a control level at 48 h. The IL-33-induced hypernociception was restricted to the ipsilateral paw at the doses used (data not shown), indicating a local effect. A 70 ng per paw dose and readout at 3 h were chosen for subsequent experiments. IL-33-induced cutaneous hypernociception was significantly inhibited by the treatment with sST2-Fc, but not by the Fc control (Fig. 1B...

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“…In this sense, drugs that activate such endogenous opioid mechanisms could represent useful therapeutic approaches (Carvalho et al, 2011;Cunha et al, 2010a;Verri et al, 2006b). Evidence suggests a relationship between opioids and cytokines since opioids inhibit cytokine-induced mechanical hyperalgesia, cytokine production and the consequent recruitment of neutrophils (Clark et al, 2007;Martin et al, 2010;Verri et al, 2004Verri et al, , 2005Verri et al, , 2008bWang et al, 2005). This is an important mechanism since hyperalgesic cytokines such as tumor necrosis factor a (TNFa) and interleukin (IL)-1b are crucial mediators in pain (Cunha et al, 2005(Cunha et al, , 2010b.…”

Section: Introductionmentioning

confidence: 99%

Tephrosia sinapouethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFαand IL-1βproduction

Martínez¹,

Zarpelon²,

Cardoso³

et al. 2013

Pharmaceutical Biology

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Context: Tephrosia toxicaria is currently known as Tephrosia sinapou (Buc'hoz) A. Chev. (Fabaceae) and is a source of compounds such as flavonoids that inhibit inflammatory pain. Objective: To investigate the analgesic effect and mechanisms of the ethyl acetate extract of T. sinapou in inflammatory pain in mice. Materials and methods: Behavioral responses were evaluated using mechanical (1-24 h) and thermal hyperalgesia (0.5-5 h), writhing response (20 min) and rota-rod (1-5 h) tests. Neutrophil recruitment (myeloperoxidase activity), cytokines (tumor necrosis factor [TNF]a and interleukin [IL]-1b), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels were determined by colorimetric assays. Pharmacological treatments were opioid receptor antagonist (naloxone, 0.1-1 mg/kg) and control opioid (morphine, 5 mg/kg). Inflammatory stimuli were carrageenin (100 mg/paw), complete Freund's adjuvant (CFA, 10 ml/paw), prostaglandin E 2 (PGE 2 , 100 ng/paw) and acetic acid (0.8%). Results: The intraperitoneal pre-treatment with extract inhibited in a dose-dependent (30-300 mg/kg) dependent manner the mechanical hyperalgesia induced by carrageenin (up to 93% inhibition). The post-treatment (100 mg/kg) inhibited CFA-induced hyperalgesia (up to 63% inhibition). Naloxone (1 mg/kg) prevented the inhibitory effect of the extract over carrageenin-induced mechanical (100%) and thermal (100%) hyperalgesia, neutrophil recruitment (52%) and TNFa (63%) and IL-1b (98%) production, thermal threshold in naïve mice (99%), PGE 2 -induced mechanical hyperalgesia (88%) and acetic acid-induced writhing response (49%). There was no significant alteration in the rota-rod test, and AST and ALT serum levels by extract treatment. Discussion and conclusion: Tephrosia sinapou ethyl acetate extract reduces inflammatory pain by activating an opioid receptor-dependent mechanism.

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Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ET_BReceptors in Rats

Cited by 44 publications

References 35 publications

Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Tephrosia sinapouethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFαand IL-1βproduction

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Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ETBReceptors in Rats

Cited by 44 publications

References 35 publications

Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Tephrosia sinapouethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFαand IL-1βproduction

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Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ET_BReceptors in Rats