Leishmania (L). amazonensis induces hyperalgesia in balb/c mice: Contribution of endogenous spinal cord TNF alpha and NF kappa B activation

作者：Borghi Sergio M; Fattori Victor; Ruiz Miyazawa Kenji W; Miranda Sapla Milena M; Casagrande Rubia; Pinge Filho Phileno; Pavanelli Wander R; Verri Waldiceu A Jr

来源：Chemico-Biological Interactions, 2017, 268: 1-12.

DOI：10.1016/j.cbi.2017.02.009

• L. (L.) amazonensis
• TNF alpha
• NF kappa B
• Spinal cord
• Pain
• Hyperalgesia

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 TNF alpha, TNFR1 and TNFR2 mRNA expression, and NF kappa B activation were evaluated. The effects of intrathecal (i.t.) injection of morphine, TNF alpha, TNF alpha inhibitors (etanercept and adalimumab) and NF kappa B 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 TNF alpha mRNA expression increased in a time-dependent manner, peaking between 30 and 40 days after infection. At the peak of TNF alpha mRNA expression (day 30), there was a concomitant increase in TNFR1 and TNFR2 mRNA expression. TNF alpha i.t. injection enhanced L. (L.) amazonensis- induced hyperalgesia. Corroborating a role for TNF alpha in L. (L.) amazonensis-induced hyperalgesia, i.t. treatment with the TNF alpha inhibitors, etanercept and adalimumab inhibited the hyperalgesia. L. (L.) amazonensis also induced spinal cord activation of NF kappa B, and PDTC (given i.t.), also inhibited L. (L.) amazonensis-induced hyperalgesia, and spinal cord TNF alpha, TNFR1 and TNFR2 mRNA expression. Moreover, L. (L.) amazonensis-induced spinal cord activation of NF kappa B was also inhibited by etanercept and adalimumab as well as PDTC i.t. treatment. These results demonstrate that endogenous spinal cord TNF alpha and NF kappa B activation contribute to L. (L.) amazonensis-induced hyperalgesia in mice. Thus, spinal cord TNF alpha and NF kappa B are potential therapeutic targets for Leishmania infection-induced pain.

• 出版日期2017-4-25