Macrophages and Schwann cell TRPA1 mediate chronic allodynia in a mouse model of complex regional pain syndrome type I

• Published in: Brain, behavior, and immunity Vol. 88; pp. 535 - 546
• Main Authors: De Logu, Francesco, De Prá, Samira Dal-Toé, de David Antoniazzi, Caren Tatiane, Kudsi, Sabrina Qader, Ferro, Paula Ronsani, Landini, Lorenzo, Rigo, Flávia Karine, de Bem Silveira, Gustavo, Silveira, Paulo Cesar Lock, Oliveira, Sara Marchesan, Marini, Matilde, Mattei, Gianluca, Ferreira, Juliano, Geppetti, Pierangelo, Nassini, Romina, Trevisan, Gabriela
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-08-2020
• Subjects: 4-HNE; A-967079; Allodynia; Animals; Complex Regional Pain Syndromes; HC-030031; Hyperalgesia; Macrophage; Macrophages; Mice; Mice, Inbred C57BL; Nociception; Schwann Cells; TRPA1 Cation Channel; Nociception; Allodynia; 4-HNE; Schwann cells; HC-030031; Macrophage; A-967079
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2020.04.037

•TRPA1 mediates allodynia in a mouse model of complex regional pain syndrome type I.•Allodynia is associated with macrophage accumulation in the injured tibial nerve.•Allodynia is dependent of TRPA1 agonists production by macrophage accumulation.•Schwann cell TRPA1 is essential to sustain neuroinflammation and allodynia.
Complex regional pain syndrome type I (CRPS-I) is characterized by intractable chronic pain. Poor understanding of the underlying mechanisms of CRPS-I accounts for the current unsatisfactory treatment. Antioxidants and antagonists of the oxidative stress-sensitive channel, the transient receptor potential ankyrin 1 (TRPA1), have been found to attenuate acute nociception and delayed allodynia in models of CRPS-I, evoked by ischemia and reperfusion (I/R) of rodent hind limb (chronic post ischemia pain, CPIP). However, it is unknown how I/R may lead to chronic pain mediated by TRPA1. Here, we report that the prolonged (day 1–15) mechanical and cold allodynia in the hind limb of CPIP mice was attenuated permanently in Trpa1−/− mice and transiently after administration of TRPA1 antagonists (A-967079 and HC-030031) or an antioxidant (α-lipoic acid). Indomethacin treatment was, however, ineffective. We also found that I/R increased macrophage (F4/80+ cell) number and oxidative stress markers, including 4-hydroxynonenal (4-HNE), in the injured tibial nerve. Macrophage-deleted MaFIA (Macrophage Fas-Induced Apoptosis) mice did not show I/R-evoked endoneurial cell infiltration, increased 4-HNE and mechanical and cold allodynia. Furthermore, Trpa1−/− mice did not show any increase in macrophage number and 4-HNE in the injured nerve trunk. Notably, in mice with selective deletion of Schwann cell TRPA1 (Plp1-CreERT;Trpa1fl/fl mice), increases in macrophage infiltration, 4-HNE and mechanical and cold allodynia were attenuated. In the present mouse model of CRPS-I, we propose that the initial oxidative stress burst that follows reperfusion activates a feed forward mechanism that entails resident macrophages and Schwann cell TRPA1 of the injured tibial nerve to sustain chronic neuroinflammation and allodynia. Repeated treatment one hour before and for 3 days after I/R with a TRPA1 antagonist permanently protected CPIP mice against neuroinflammation and allodynia, indicating possible novel therapeutic strategies for CRPS-I.