Neuronal Injury Marker ATF-3 Is Induced in Primary Afferent Neurons of Monoarthritic Rats

Activating transcription factor 3 (ATF-3) expression has been associated with several signaling pathways implicated in cellular stress response in many cell types and is usually regarded as a neuronal damage marker in dorsal root ganglia (DRG). We investigated ATF-3 expression in primary afferents in the monoarthritic (MA) model of chronic inflammatory joint pain. Immunohistochemistry revealed that ATF-3 is highly induced mainly in small and medium neurons, especially at 2 and 4 days of MA in L(5) DRGs. Colocalization with calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) demonstrated that ATF-3-immunoreactive cells are mainly peptidergic. The lack of significant differences in ATF-3 and pAkt colocalization indicated that ATF-3 is probably not involved in a pAkt-mediated survival pathway. Anti-inflammatory (ketoprofen) administration failed to reverse ATF-3 induction in MA rats, but significantly increased CGRP expression. These data suggest that ATF-3 expression is definitely involved in MA, actually marking injured neurons. Some degree of neuronal damage seems to occur right from the first days of disease, mainly affecting small-to-medium peptidergic neurons. The intra-articular injection of complete Freund's adjuvant and the generation of a neuroinflammatory environment seem to be the plausible explanation for the local nerve damage.