During inflammation in the joint, normal joint movements are usually painful. A neuronal mechanism for this form of mechanical hyperalgesia is the persistent sensitization of joint nociceptors to mechanical stimuli. Because tumor necrosis factor (TNF) is a major mediator of joint inflammation, we undertook the present study both to explore the potential of TNF to sensitize joint nociceptors to mechanical stimuli and to address the cellular mechanism involved.
In anesthetized rats, action potentials (APs) were recorded from sensory nociceptive Aδ fibers and C fibers supplying the knee joint. We monitored responses to rotation of the knee joint at innocuous and noxious intensities. TNF, etanercept, and a p38 inhibitor were injected into the knee joint, and the cyclooxygenase (COX) inhibitor diclofenac was administered intraperitoneally. APs were also recorded in isolated cultured dorsal root ganglion (DRG) neurons in order to test for changes in neuronal excitability induced by TNF.
A single application of TNF into the normal knee joint caused a significant persistent sensitization of nociceptive sensory fibers to mechanical stimuli applied to the joint. This effect was dose dependent. It was prevented by coadministration of etanercept or by an inhibitor of p38, and it was attenuated by systemic application of a COX inhibitor. Patch clamp recordings from isolated DRG neurons showed a rapid increase in neuronal excitability induced by TNF.
TNF can induce a long-lasting sensitization of joint nociceptors to mechanical stimuli and thus can induce long-lasting mechanical hyperalgesia in joints. TNF can act directly on neurons, underscoring its role as a sensitizing pain mediator.