Immune Cytokines and Their Receptors in Inflammatory Pain

There is a significant unmet clinical need to understand the induction and persistence of pain in inflammatory conditions such as arthritis. Primary afferent neurons are specialized neurons that are important for pain induction due to the activation/sensitization of nociceptors by many potential stimuli. Under pathological conditions, one of the most important forms of responsiveness of primary sensory neurons (nociceptors) clinically is to a wide range of chemical stimuli, including many substances released from damaged tissues such as cytokines. Potentially, neurons can either be directly activated by cytokines binding to cell surface receptors or be sensitized directly or indirectly by cytokines, leading to increased responsiveness to stimulation. However, whether certain immune cytokines can act directly via specific receptors on neurons is often unclear, sometimes as a result of flawed approaches. There is also debate as to whether certain immune cytokines can initiate pain without the indirect action on neurons of downstream mediators. There is burgeoning interest in the interaction between the immune and nervous systems. Pain is mediated by primary sensory neurons (nociceptors) that can respond to a variety of thermal, mechanical and chemical signals. Cytokines are now recognized as important mediators of inflammatory pain. They can induce nociceptor sensitization indirectly via mediators, wherein neurons become primed and thus become more responsive to stimulation; alternatively, there is also evidence that cytokines can directly activate neurons via their specific receptors present on the neuronal cells. We review here the evidence for and against these respective mechanisms, focusing on arthritis and inflammatory skin models. A number of striking inconsistencies amongst the conclusions made in the literature are highlighted and discussed. There is burgeoning interest in the interaction between the immune and nervous systems. Pain is mediated by primary sensory neurons (nociceptors) that can respond to a variety of thermal, mechanical and chemical signals. Cytokines are now recognized as important mediators of inflammatory pain. They can induce nociceptor sensitization indirectly via mediators, wherein neurons become primed and thus become more responsive to stimulation; alternatively, there is also evidence that cytokines can directly activate neurons via their specific receptors present on the neuronal cells. We review here the evidence for and against these respective mechanisms, focusing on arthritis and inflammatory skin models. A number of striking inconsistencies amongst the conclusions made in the literature are highlighted and discussed.