Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen‐induced arthritis: Evidence of a neuronal target

Abstract

Objective. The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor ␣ (TNF␣) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy.Methods. Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent A␦ fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/ carrageenan-induced inflammation).Results. In rats with AIA, both etanercept and infliximab significantly decreased inflammationinduced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI-and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint. Conclusion. Overall, these data show the pronounced antinociceptive effects of TNF␣ neutralization, thus suggesting that reduction of the effects of TNF␣ on pain fibers themselves significantly contributes to pain relief.

IL-4, JAK-STAT signaling, and pain

“…The same study provided electrophysiological recordings performed in anesthetized rats showing reduced responses to noxious outward rotation of inflamed knees after etanercept treatment. 34 As mentioned above and shown in Figure 1B, TNF-α enhances the production and release of several other proinflammatory cytokines and factors like IL-6, IL-8, IL-1β, NGF, and prostaglandins and by that amplifies the inflammatory response. The injection of TNF-α into healthy tissue of rats locally elevated the levels of IL-1β and NGF and produced a transient, dose-dependent mechanical hyperalgesia.…”

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

“…For technical reasons (e.g., to monitor painrelated behavior in unrestrained animals), we measured secondary hyperalgesia in the hind paws after induction of AIA in the knee joint. This is valid because primary hyperalgesia in the inflamed knee is usually accompanied by secondary hyperalgesia in the paws (23,24). At 2 time points before AIA induction (baseline), as well as on days 1, 3, 7, 14, and 21 of AIA, secondary mechanical hyperalgesia was determined on ipsilateral and contralateral hind paws, using a dynamic plantar esthesiometer (Ugo Basile).…”

“…Secondary thermal hyperalgesia was assessed in the hind paws with an algesiometer (Ugo Basile) as described elsewhere (23). After accommodation of the animals to the testing device, 3 consecutive radiant-heat stimuli were applied to the hind paws with at least 1-minute intervals between stimuli.…”

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

“…In contrast to the well-documented role of TNF-α as a proinflammatory cytokine, its role as a mediator of pain is incompletely characterized. It is known that both receptors for TNF-α are expressed in dorsal root ganglion neurons and that intra-articular injection of TNF-α blocking agents reduces nociception elicited by joint inflammation (10). TNF-α is also involved in development of mechanical hyperalgesia following injury (11,12).…”