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The Journal of Neuroscience, August 15, 2000, 20(16):6289-6293
Involvement of the Proinflammatory Cytokines Tumor Necrosis
Factor- , IL-1 , and IL-6 But Not IL-8 in the Development of Heat
Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide
Release from Rat Skin
A.
Oprée and
M.
Kress
Institut für Physiologie und Experimentelle Pathophysiologie,
Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054
Erlangen, Germany
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
heat-evoked 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 EC50 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.
Key words:
nociception; heat sensitization; inflammation; neuropeptides; sensory neurons; interleukin
Copyright © 2000 Society for Neuroscience 0270-6474/00/20166289-05$05.00/0
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