Vanilloid receptor TRPV1-mediated phosphorylation of ERK in murine adjuvant arthritis

SummaryObjectiveThe vanilloid receptor transient receptor potential vanilloid 1 (TRPV1), expressed by sensory neurons that innervate joints, is implicated in arthritis but the mechanisms are not fully understood. One possibility is that downstream effects of activation of TRPV1 are mediated by the extracellularly-regulated kinase (ERK). ERK is phosphorylated (p-ERK) in sensory neurons in response to noxious stimuli and its inhibition has been found to be antinociceptive in several pain models. We here wanted to ascertain whether TRPV1 may contribute to the pain hypersensitivity and inflammation of arthritis via an ERK-mediated pathway.MethodsWe used a model of adjuvant-induced arthritis (AIA) of the ankle and investigated the changes in expression of p-ERK in sensory afferent neurons in dorsal root ganglia (DRG) and spinal dorsal horn of TRPV1-knockout (KO) mice, compared to wild-type (WT) mice of the same genetic background, using multiple immunofluorescence.ResultsTwo to three weeks after inducing AIA in mice, the number of neurons in DRG and spinal cord that expressed p-ERK was significantly higher on the side of AIA than on the contralateral, vehicle-injected side. The fraction of p-ERK-positive neurons in the DRG that also expressed TRPV1 was increased, indicating that activation of ERK occurred preferentially in TRPV1-positive neurons. Moreover, TRPV1-KO mice had reduced activation of ERK in sensory neurons, compared to WT mice. These changes in expression of p-ERK correlated with changes in pain behavior and joint histopathology: TRPV1-KO mice had reduced nociceptive behavior and severity of arthritis, compared to WT mice.ConclusionOur results support the idea that activation of ERK in primary afferent neurons is mediated, at least in part, by TRPV1. In the absence of TRPV1, the signs of arthralgia and histopathology in the mouse model of AIA are reduced. We conclude that TRPV1, expressed by neurons in the articular afferent pathway, contributes to the pathogenesis of arthritis via an ERK-mediated pathway.