Volume 6 Supplement 3

Global Arthritis Research Network (GARN): 4th World Congress on Arthritis in Montreal

Open Access

Mechanisms of pain in arthritis

  • H-G Schaible1
Arthritis Res Ther20046(Suppl 3):41

https://doi.org/10.1186/ar1376

Published: 13 September 2004

During inflammation in a joint, patients experience hyperalgesia and sometimes resting pain. Hyperalgesia includes stronger pain upon noxious stimulation (e.g. strong pressure or twisting the joint) and the experience of pain when stimuli are applied that are not felt painful under normal conditions (palpation, movements in the working range). Resting pain is felt without intentional stimulation. Neuronal mechanisms involved in arthritic pain are the peripheral sensitization (sensitization of primary afferent fibres supplying the joint) and central sensitization (sensitization of spinal cord neurons). The peripheral sensitization includes the sensitization of so-called polymodal nociceptors (high threshold receptors that are excited under normal conditions by noxious mechanical stimuli) and of silent nociceptors (neurons that are not excited even by noxious mechanical stimuli). When these nociceptors are sensitized in the process of inflammation they are rendered more excitable and then they even respond to normally non-painful stimuli. In addition, the enhanced input from sensitized nociceptors induces hyperexcitability of second-order neurons in the spinal cord. This central sensitization is an increased gain in the spinal nociceptive processing, and sensitized spinal cord neurons show stronger responses to stimulation of inflamed tissue but also to stimulation of adjacent and even remote healthy tissue. Thus the whole pain pathway is sensitized and this explains why, in the inflamed tissue, pain is evoked by stimuli that do not elicit pain under normal conditions [1].

Numerous mediators and ion channels are involved in the activation and sensitization of nociceptive neurons [1]. Importantly, some mediators that are involved in the pathophysiology of inflammation are also involved in the generation of peripheral and central sensitization (e.g. prostaglandins). Cyclooxygenases and prostaglandins in the periphery and in the spinal cord have been important topics in pain research [2]. During development of an acute inflammation in the knee joint, prostaglandin E2 release in the spinal cord is significantly enhanced. This is in part due to an upregulation of cyclooxygenase-2 in the spinal cord that is already seen within 3 hours of inflammation [3]. The application of prostaglandin E2 to the spinal cord produces hyperexcitability of spinal cord neurons similar to peripheral inflammation. When indomethacin is applied to the spinal cord before and during the development of joint inflammation, the development of central sensitization is significantly attenuated [4]. These findings show the importance of spinal prostaglandins in the generation of inflammation-evoked spinal hyperexcitability. However, the spinal administration of indomethacin to the spinal cord after establishment of inflammation did not reduce responses of spinal cord neurons to mechanical stimulation of the inflamed joint, raising the question of how important spinal prostaglandins are in the maintenance of spinal hyperexcitability [4]. Prostaglandin E2 acts through EP1, EP2, EP3 and EP4 receptors. The generation of spinal hyperexcitability by spinal prostaglandin E2 can be mimicked by spinal application of agonists at the EP1, EP2 and EP4 receptors. When the joint is inflamed and hyperexcitability is established, EP2 and EP4 receptor agonists fail to change responses of spinal cord neurons to mechanical stimulation of the joint. Interestingly, however, the spinal application of an agonist at the EP3 alpha receptor even reduced responses although it had no effect under normal conditions [5]. Thus considerable plasticity of EP receptor activation seems to determine the precise role of spinal prostaglandins in different phases of inflammation.

Declarations

Acknowledgement

The work was supported by the Deutsche Forschungsgemeinschaft (Scha 404/11-1 and 11-2).

Authors’ Affiliations

(1)
Department of Physiology, Friedrich Schiller University of Jena

References

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Copyright

© BioMed Central Ltd 2004

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