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-Cre;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.

Macrophages and Schwann cell TRPA1 mediate chronic allodynia in a mouse model of complex regional pain syndrome type I / de Logu, Francesco; Dal-Toé De Prá, Samira; Tatiane de David Antoniazzi, Caren; Qader Kudsi, Sabrina; Ronsani Ferro, Paula; Landini, Lorenzo; Karine Rigo, Flávia; de Bem Silveira, Gustavo; Cesar Lock Silveira, Paulo; Marchesan Oliveira, Sara; Marini, Matilde; Mattei, Gianluca; Ferreira, Juliano; Geppetti, Pierangelo; Nassini, Romina; Trevisan, Gabriela. - In: BRAIN BEHAVIOR AND IMMUNITY. - ISSN 0889-1591. - ELETTRONICO. - (2020), pp. ---. [10.1016/j.bbi.2020.04.037]

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

de Logu, Francesco;Landini, Lorenzo;Marini, Matilde;Mattei, Gianluca;Ferreira, Juliano;Geppetti, Pierangelo;Nassini, Romina;Trevisan, Gabriela
2020

Abstract

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-Cre;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.
2020
-
-
de Logu, Francesco; Dal-Toé De Prá, Samira; Tatiane de David Antoniazzi, Caren; Qader Kudsi, Sabrina; Ronsani Ferro, Paula; Landini, Lorenzo; Karine Rigo, Flávia; de Bem Silveira, Gustavo; Cesar Lock Silveira, Paulo; Marchesan Oliveira, Sara; Marini, Matilde; Mattei, Gianluca; Ferreira, Juliano; Geppetti, Pierangelo; Nassini, Romina; Trevisan, Gabriela
File in questo prodotto:
File Dimensione Formato  
De Logu Trevisan.bbi.2020.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 2.63 MB
Formato Adobe PDF
2.63 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1190645
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 39
  • ???jsp.display-item.citation.isi??? 39
social impact