title: Leishmania (L). amazonensis induces hyperalgesia in balb/c mice: Contribution of endogenous spinal cord TNFα and NFκB activation.
abstract: Cutaneous leishmaniasis (CL) is the most common form of the leishmaniasis in humans. Ulcerative painless skin lesions are predominant clinical features of CL. Wider data indicate pain accompanies human leishmaniasis, out with areas of painless ulcerative lesions per se. In rodents, Leishmania (L.) major infection induces nociceptive behaviors that correlate with peripheral cytokine levels. However, the role of the spinal cord in pain processing after Leishmania infection has not been investigated. Balb/c mice received intraplantar (i.pl.) injection of Leishmania (L). amazonensis and hyperalgesia, edema, parasitism, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression, and NFκB activation were evaluated. The effects of intrathecal (i.t.) injection of morphine, TNFα, TNFα inhibitors (etanercept and adalimumab) and NFκB inhibitor (PDTC) were investigated. The present study demonstrates that Leishmania (L.) amazonensis infection in balb/c mice induces chronic mechanical and thermal hyperalgesia in an opioid-sensitive manner. Spinal cord TNFα mRNA expression increased in a time-dependent manner, peaking between 30 and 40 days after infection. At the peak of TNFα mRNA expression (day 30), there was a concomitant increase in TNFR1 and TNFR2 mRNA expression. TNFα i.t. injection enhanced L. (L.) amazonensis-induced hyperalgesia. Corroborating a role for TNFα in L. (L.) amazonensis-induced hyperalgesia, i.t. treatment with the TNFα inhibitors, etanercept and adalimumab inhibited the hyperalgesia. L. (L.) amazonensis also induced spinal cord activation of NFκB, and PDTC (given i.t.), also inhibited L. (L.) amazonensis-induced hyperalgesia, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression. Moreover, L. (L.) amazonensis-induced spinal cord activation of NFκB was also inhibited by etanercept and adalimumab as well as PDTC i.t.
  
  
  METHODS
  These results demonstrate that endogenous spinal cord TNFα and NFκB activation contribute to L. (L.) amazonensis-induced hyperalgesia in mice. Thus, spinal cord TNFα and NFκB are potential therapeutic targets for Leishmania infection-induced pain.
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Borghi
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Fattori
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Kenji W
authors.initials: KW
authors.lastname: Ruiz-Miyazawa
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Milena M
authors.initials: MM
authors.lastname: Miranda-Sapla
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Hospital Universitário, Universidade Estadual de Londrina, Av. Robert Koch, 60, 86038-350 Londrina, Paraná, Brazil.
authors.forename: Rúbia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Phileno
authors.initials: P
authors.lastname: Pinge-Filho
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil.
authors.forename: Wander R
authors.initials: WR
authors.lastname: Pavanelli
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970 Londrina, Paraná, Brazil. Electronic address: waldiceujr@yahoo.com.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000068879:Adalimumab / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000068800:Etanercept / Q000008:administration & dosage / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology* / Q000503:physiopathology; D007894:Leishmania mexicana / Q000502:physiology*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology* / Q000503:physiopathology; D008297:Male; D008807:Mice, Inbred BALB C; D009020:Morphine / Q000627:therapeutic use; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059208:Parasite Load; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology*; D013859:Thiocarbamates / Q000008:administration & dosage / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013859:Thiocarbamates; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D009020:Morphine; D000068879:Adalimumab; D000068800:Etanercept
keywords: Hyperalgesia; L. (L.) amazonensis; NFκB; Pain; Spinal cord; TNFα