The nitroxyl donor, Angeli's salt, reduces chronic constriction injury-induced neuropathic pain.
Chronic pain is a major health problem worldwide. We have recently demonstrated the analgesic effect of the nitroxyl donor, Angeli's salt (AS) in models of inflammatory pain. In the present study, the acute and chronic analgesic effects of AS was investigated in chronic constriction injury of the sciatic nerve (CCI)-induced neuropathic pain in mice. Acute (7th day after CCI) AS treatment (1 and 3 mg/kg; s.c.) reduced CCI-induced mechanical, but not thermal hyperalgesia. The acute analgesic effect of AS was prevented by treatment with 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor), KT5823 (an inhibitor of protein kinase G [PKG]) or glibenclamide (GLB, an ATP-sensitive potassium channel blocker). Chronic (7-14 days after CCI) treatment with AS (3 mg/kg, s.c.) promoted a sustained reduction of CCI-induced mechanical and thermal hyperalgesia. Acute AS treatment reduced CCI-induced spinal cord allograft inflammatory factor 1 (known as Iba-1), interleukin-1β (IL-1β), and ST2 receptor mRNA expression. Chronic AS treatment reduced CCI-induced spinal cord glial fibrillary acidic protein (GFAP), Iba-1, IL-1β, tumor necrosis factor-α (TNF-α), interleukin-33 (IL-33) and ST2 mRNA expression. Chronic treatment with AS (3 mg/kg, s.c.) did not alter aspartate aminotransferase, alanine aminotransferase, urea or creatinine plasma levels. Together, these results suggest that the acute analgesic effect of AS depends on activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Moreover, chronic AS diminishes CCI-induced mechanical and thermal hyperalgesia by reducing the activation of spinal cord microglia and astrocytes, decreasing TNF-α, IL-1β and IL-33 cytokines expression. This spinal cord immune modulation was more prominent in the chronic treatment with AS. Thus, nitroxyl limits CCI-induced neuropathic pain by reducing spinal cord glial cells activation.
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380, Cx. Postal 10.011, 86057-970, Londrina, Parana, Brazil.
Daniela T
DT
Longhi-Balbinot
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380, Cx. Postal 10.011, 86057-970, Londrina, Parana, Brazil.
Ana C
AC
Rossaneis
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380, Cx. Postal 10.011, 86057-970, Londrina, Parana, Brazil.
Felipe A
FA
Pinho-Ribeiro
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380, Cx. Postal 10.011, 86057-970, Londrina, Parana, Brazil.
Mariana M
MM
Bertozzi
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14049-900, São Paulo, Brazil.
Fernando Q
FQ
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14049-900, São Paulo, Brazil.
José C
JC
Alves-Filho
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14049-900, São Paulo, Brazil.
Thiago M
TM
Cunha
Department of Immunology, Institute of Biomedical Sciences, Ed. Biomédicas IV, University of Sao Paulo, Av. Prof. Dr. Lineu Prestes, 1730, 05508-900, São Paulo, Brazil.
Jean P S
JP
Peron
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
Katrina M
KM
Miranda
Department of Pharmaceutical Sciences, University Hospital (Health Science Centre), Av. Robert Koch, 60, 86038-350, State University of Londrina, Parana, Brazil.
Rubia
R
Casagrande
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380, Cx. Postal 10.011, 86057-970, Londrina, Parana, Brazil. Electronic address: waverri@uel.br.
Waldiceu A
WA
Verri
D000255:Adenosine Triphosphate / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000235:genetics; D000067596:Interleukin-33 / Q000235:genetics; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D012584:Sciatic Nerve / Q000187:drug effects* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000700:Analgesics; D053583:Interleukin-1beta; D000067596:Interleukin-33; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D017869:Cyclic GMP-Dependent Protein Kinases; C039900:nitroxyl; D006152:Cyclic GMP
Astrocytes; Cytokines; Microglia; Neuropathic pain; Nitroxyl donor