Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation.

OBJECTIVE: In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation. METHODS: Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. RESULTS: Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. CONCLUSION: Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation.

Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis.

Inflammation causes sensitization of peripheral and central nociceptive neurons. Pharmacological modulation of the latter has successfully been used for clinical pain relief. In particular, inhibitors of the NMDA glutamate receptor such as ketamine and agonists at the mu-opioid receptor such as morphine are broadly used. Besides driving the propagation of pain signals, spinal mechanisms are also discussed to modulate inflammation in the periphery. Here, we tested the hypothesis that intrathecally applied ketamine or morphine not only reduce pain-related behavior, but also attenuate induction and maintenance of the inflammatory response in a model of chronic antigen-induced arthritis (AIA). Ketamine, morphine or vehicle was applied to the spinal cords of anesthesized animals with AIA. Swelling and histopathological changes were assessed after 6h (acute phase). Intrathecal catheters were implanted in another set of animals with AIA and substances were applied continuously. During the observation period of 21 days, inflammation and pain-related behavior were assessed. Ketamine and morphine significantly reduced arthritis severity as indicated by reduced joint swelling, but even more intriguingly by reduced infiltration with inflammatory cells and joint destruction in the acute and the chronic phase of arthritis. Morphine showed strong antinociceptive effects in the acute phase only, while the newly established effective dose for ketamine in a continuous application design reduced hyperalgesia in the acute and the chronic stage. In conclusion, both compounds exhibit anti-inflammatory effects during induction and maintenance of arthritis when applied intrathecally. These data thus propose a role of spinal NMDA- and opioid-receptors in the neuronal control of immune-mediated inflammation.

Gait abnormalities differentially indicate pain or structural joint damage in monoarticular antigen-induced arthritis.

Gait abnormalities have been suggested to provide an objective measure for joint pain in animal models. Here, we aimed to assess whether parameters of gait analysis correlate with measures of pain-related behavior in experimental monoarthritis. For this purpose, antigen-induced arthritis was induced in the left knee joints of 68 female Lewis rats, of which 30 were treated with tumor necrosis factor-alpha(TNF)-neutralizing compounds. During the course of arthritis, paw print analysis parameters and measures for mechanical and thermal hyperalgesia were obtained. Knee joints harvested on either day 3 or day 21 were scored histologically for signs of inflammation and cartilage and bone destructions. Data were compared to those obtained from 33 immunized control rats and correlated for days 3 and 21. Arthritic rats showed distinct asymmetric gait abnormalities. In the acute stage of antigen-induced arthritis, but not in the chronic phase, there was a significant correlation between the gait parameter 'left-right distance' and measures of primary and secondary hyperalgesia. Both in the acute and chronic phases, however, the gait parameter 'angle between paws' indicating outward rotation of paws mainly correlated with joint destruction as assessed using histology. Etanercept treatment exhibited pronounced anti-nociceptive and pro-locomotional effects, but the described correlations remained. In conclusion, some parameters of gait analysis may represent a good measure for arthritis pain, mainly in acute inflammation, while others are increasingly influenced by mechanical joint deformation as indicated by cartilage and bone destructions. Thus, gait abnormalities may not unequivocally be suitable for objective pain assessment in all stages of experimental arthritis.