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Treatment with a carbon monoxide-releasing molecule inhibits chronic inflammatory pain in mice: nitric oxide contribution

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Abstract

Rationale

Carbon monoxide synthetized by inducible heme oxygenase (HO-1) exerts potent anti-inflammatory and antinociceptive effects during acute and neuropathic pain, but its role in the modulation of chronic inflammatory pain and the possible involvement of nitric oxide in this action remain unknown.

Objectives and methods

The antiallodynic and antihyperalgesic effects of a carbon monoxide releasing molecule, tricarbonyldichlororuthenium(II) dimer (CORM-2), daily administered from days 4 to 14 after complete Freund's adjuvant (CFA) injection in wild-type (WT), neuronal (NOS1-KO), and inducible (NOS2-KO) nitric oxide synthases knockout mice, were evaluated using von Frey filaments and plantar tests. Effects of CORM-2 treatment on the expression of HO-1, NOS1, and NOS2 at 14 days after inflammation induction were assessed by Western blot.

Results

Main inflammatory pain symptoms induced by CFA in WT, NOS1-KO, and NOS2-KO mice were significantly reduced in a time-dependent manner by CORM-2 treatment. In all genotypes, inflammation increased the dorsal root ganglia and paw expression of HO-1, but CORM-2 treatment only over-expressed this enzyme in the paw of all genotypes. The increased NOS1 expression induced by inflammation in WT mice was abolished by CORM-2 treatment, while there was no effect of the inflammation in neither CORM-2 treatment in the expression of NOS2 in WT and NOS1-KO mice.

Conclusions

CORM-2 treatment inhibits inflammatory pain through enhancing HO-1 paw expression in all genotypes and reducing NOS1 over-expression in WT mice. An interaction between HO-1/carbon monoxide and NOS1/nitric oxide systems was also demonstrated. CORM-2 treatment may represent a new approach for management chronic inflammatory pain.

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References

  • Alcaraz MJ, Habib A, Lebret M, Créminon C, Lévy-Toledano S, Maclouf J (2000) Enhanced expression of heme oxygenase-1 by nitric oxide and antiinflammatory drugs in NIH 3T3 fibroblasts. Br J Pharmacol 130:57–64

    Article  CAS  PubMed  Google Scholar 

  • Bijjem KR, Padi SS, Lal Sharma P (2013) Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats. Naunyn Schmiedebergs Arch Pharmacol 386:79–90

    Article  CAS  PubMed  Google Scholar 

  • Boettger MK, Uceyler N, Zelenka M, Schmitt A, Reif A, Chen Y, Sommer C (2007) Differences in inflammatory pain in nNOS-, iNOS- and eNOS-deficient mice. Eur J Pain 11:810–818

    Article  CAS  PubMed  Google Scholar 

  • Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Boettger MK, Reif A, Schmitt A, Uçeyler N, Sommer C (2010) Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. Mol Pain 6:13

    Article  PubMed Central  PubMed  Google Scholar 

  • Chu YC, Guan Y, Skinner J, Raja SN, Johns RA, Tao YX (2005) Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain. Pain 119:113–123

    Article  CAS  PubMed  Google Scholar 

  • De Alba J, Clayton NM, Collins SD, Colthup P, Chessell I, Knowles RG (2006) GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 120:170–181

    Article  PubMed  Google Scholar 

  • Devesa I, Ferrándiz ML, Terencio MC, Joosten LA, van den Berg WB, Alcaraz MJ (2005) Influence of heme oxygenase 1 modulation on the progression of murine collagen-induced arthritis. Arthritis Rheum 52:3230–3238

    Article  CAS  PubMed  Google Scholar 

  • Fan W, Huang F, Wu Z, Zhu X, Li D, He H (2011) Carbon monoxide: a gas that modulates nociception. J Neurosci Res 89:802–807

    Article  CAS  PubMed  Google Scholar 

  • Foresti R, Clark JE, Green CJ, Motterlini R (1997) Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells: involvement of superoxide and peroxynitrite anions. J Biol Chem 272:18411–18417

    Article  CAS  PubMed  Google Scholar 

  • García-Arnandis I, Guillén MI, Gomar F, Castejón MA, Alcaraz MJ (2011) Control of cell migration and inflammatory mediators production by CORM-2 in osteoarthritic synoviocytes. PLoS ONE 6(9):e24591

    Article  PubMed Central  PubMed  Google Scholar 

  • Guillén MI, Megías J, Clérigues V, Gomar F, Alcaraz MJ (2008) The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes. Rheumatology 47:1323–1328

    Article  PubMed  Google Scholar 

  • Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88

    Article  CAS  PubMed  Google Scholar 

  • Hervera A, Leánez S, Negrete R, Pol O (2009) The peripheral administration of a nitric oxide donor potentiates the local antinociceptive effects of a DOR agonist during chronic inflammatory pain in mice. Naunyn Schmiedebergs Arch Pharmacol 380:345–352

    Article  CAS  PubMed  Google Scholar 

  • Hervera A, Negrete R, Leánez S, Martín-Campos J, Pol O (2010a) The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice. J Pharmacol Exp Ther 334:887–896

    Article  CAS  PubMed  Google Scholar 

  • Hervera A, Negrete R, Leánez S, Martín-Campos JM, Pol O (2010b) The spinal cord expression of neuronal and inducible nitric oxide synthases and their contribution in the maintenance of neuropathic pain in mice. PLoS ONE 5:e14321

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hervera A, Leánez S, Negrete R, Motterlini R, Pol O (2012) Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. PLoS ONE 7:e43693

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leánez S, Hervera A, Pol O (2009) Peripheral antinociceptive effects of mu- and delta-opioid receptor agonists in NOS2 and NOS1 knockout mice during chronic inflammatory pain. Eur J Pharmacol 602:41–49

    Article  PubMed  Google Scholar 

  • Lee SK, Park DY, Lee HJ, Lee J, Choi MK, Jeon BH, Jun CD, Lee SK, Kim EC (2007) Functional interaction between nitric oxide-induced iron homeostasis and heme oxygenase-1 in immortalized and malignant oral keratinocytes. Cancer Lett 249:283–293

    Article  CAS  PubMed  Google Scholar 

  • Maicas N, Ferrándiz ML, Devesa I, Motterlini R, Koenders MI, van den Berg WB, Alcaraz MJ (2010) The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model. Eur J Pharmacol 634:184–191

    Article  CAS  PubMed  Google Scholar 

  • Megías J, Guillén MI, Clérigues V, Rojo AI, Cuadrado A, Castejón MA, Gomar F, Alcaraz MJ (2009) Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E(2) production in osteoarthritic chondrocytes. Biochem Pharmacol 77:1806–1813

    Article  PubMed  Google Scholar 

  • Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, Green CJ (2002) Carbon monoxide-releasing molecules: characterization of biochemical and vascular activitis. Circ Res 90:e17–e24

    Article  CAS  PubMed  Google Scholar 

  • Motterlini R, Haas B, Foresti R (2012) Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs). Med Gas Res 2:28

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nascimento CG, Branco LG (2007) Role of the peripheral heme oxygenase-carbon monoxide pathway on the nociceptive response of rats to the formalin test: evidence for a cGMP signaling pathway. Eur J Pharmacol 556:55–61

    Article  CAS  PubMed  Google Scholar 

  • Negrete R, Hervera A, Leánez S, Martín-Campos JM, Pol O (2011) The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids. PLoS ONE 6:e26688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rosa AO, Egea J, Lorrio S, Rojo AI, Cuadrado A, López MG (2008) Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice. Pain 137:332–339

    Article  CAS  PubMed  Google Scholar 

  • Steiner AA, Branco LG, Cunha FQ, Ferreira SH (2000) Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity. Br J Pharmacol 132:1673–1682

    Article  Google Scholar 

  • Tao F, Tao YX, Mao P, Zhao C, Li D, Liaw WJ, Raja SN, Johns RA (2003) Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase. Neuroscience 120:847–854

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Cao J, Sun BW, Liu DD, Liang F, Gao L (2012) Exogenous carbon monoxide attenuates inflammatory responses in the small intestine of septic mice. World J Gastroenterol 18:5719–5728

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Fondo de Investigación Sanitaria, Madrid [Grant: PS0900968] and the Fundació La Marató de TV3 Barcelona [Grant: 070810], Spain.

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Authors and Affiliations

  1. Grup de Neurofarmacologia Molecular, Institut d’Investigació Biomèdica Sant Pau & Institut de Neurociències, Facultat de Medicina. Edifici M2-115, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain

    Roger Negrete, Arnau Hervera, Sergi Leánez & Olga Pol

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  1. Roger Negrete
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  2. Arnau Hervera
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  3. Sergi Leánez
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  4. Olga Pol
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Correspondence to Olga Pol.

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Negrete, R., Hervera, A., Leánez, S. et al. Treatment with a carbon monoxide-releasing molecule inhibits chronic inflammatory pain in mice: nitric oxide contribution. Psychopharmacology 231, 853–861 (2014). https://doi.org/10.1007/s00213-013-3302-7

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  • DOI: https://doi.org/10.1007/s00213-013-3302-7

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