Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heatevoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32°C. However, the cytokines IL-1␤, tumor necrosis factor (TNF)-␣, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC 50 for IL-1␤ of 2.7 ng/ml and for TNF-␣ of 3.1 ng/ml. The maximum IL-1␤ effect reached almost 600% of the heat-evoked release, and the maximum TNF-␣ effect induced a rise in CGRP release of 350%. In contrast to IL-1␤ and TNF-␣, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1␤ and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.

Involvement of the proinflammatory cytokines tumor necrosis factor‐alpha, IL‐1 beta, and IL‐6 but not IL‐8 in the development of heat hyperalgesia: effects on heat‐evoked calcitonin gene‐related peptide release from rat. (Friedrich‐Alexander‐Universität Erlangen‐Nürnberg, Erlangen, Germany) J Neurosci 2000;20:6289–6293. In this study, the rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heat‐evoked release of calcitonin gene‐related peptide (CCRP) from nociceptors in vivo. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any CCRP release at normal skin temperature of 32°C. However, the cytokines IL‐1β, tumor necrosis factor (TNF)‐α, and IL‐6 but not IL‐8 induced a pronounced and transient sensitization of the heat‐evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC50 for IL‐1β of 2.7 ng/mL and for TNF‐α of 3.1 ng/mL. The maximum IL‐1β effect reached almost 600% of the heat‐evoked release, and the maximum TNF‐α effect induced a rise in CGRP release of 350%. In contrast to IL‐1β and TNF‐α, IL‐6 did not induce heat sensitization when applied alone, but was only effective in the presence of soluble IL‐6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL‐1β and the signal transduction molecule gp 130, but not IL‐6 receptor or IL‐8 receptor. Furthermore, the acute cytokine signaling observed was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Conclude that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy. Comment by Marshall Devor, PhD. Impulses in nociceptive afferents signal pain to a conscious brain, but in addition, they have an efferent, effector role in peripheral tissue. Specifically, impulses arriving at a sensory ending may cause the release of various peptides and other potential inflammatory mediators, affecting local tissue circulation and the trophic state of the tissue. Oprée and Kress show that specific cytokines can facilitate this release by lowering the temperature required to evoke release of the calcitonin gene‐related peptide. If the temperature required were lowered to basal tissue temperature, a real possibility, then the peptides would be released on a tonic basis at normal body temperature. This could be a mechanism for the disruption of normal tissue integrity in chronic inflammatory conditions such as rheumatoid arthritis.