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#142 Interleukin-1 signaling is involved in stress-induced analgesia
Abstracts / Brain, Behavior, and Immunity 19 (2005) e43–e74
#142 Interleukin-1 signaling is involved in stress-induced analgesia Gilly Wolf a, Raz Yirmiya a, Tirzah Kreisel a, Josef Weidenfeld b, Yehuda Shavit a a
Department of Psychology, The Hebrew University, Jerusalem 91905, Israel b Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel The proinflammatory cytokine interleukin-1 (IL-1) is involved in the neural, endocrine, and behavioral responses to stress. Various stressors increase the production and secretion of IL-1, within the CNS and in the periphery, and this increase is associated with activation of the HPA axis. We have recently shown that mice with impaired IL-1 signaling display diminished corticosterone secretion after exposure to mild stress compared with their wild type (WT) controls. Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed Ôstress-induced analgesiaÕ (SIA). Since IL-1 also plays a role in pain modulation (impaired IL-1-signaling is associated with decreased basal pain sensitivity, and with prolonged and potentiated opiate analgesia), we hypothesized that IL-1 plays a modulatory role in SIA. To test this hypothesis, we used two mouse models of impaired IL-1-signaling: Targeted deletion of the IL-1 receptor type I (IL-1rKO), or transgenic overexpression of the IL-1 receptor antagonist within the CNS (IL1raTG). Mutant mice were compared with their WT controls. Mice were exposed to one of two forms of stress: swimming for 2 min at 32 C (mild stress) or at 15 C (severe stress). They were then allowed to dry for 2 min, and tested for pain sensitivity using the hot-plate test immediately after drying. Mild stress induced significant analgesia in the two WT strains, but not in the mutant strains. In contrast, both WT and mutant strains displayed similar analgesic response following severe stress. In separate groups of IL-1raTG and their WT controls, corticosterone levels were assessed following exposure to either type of stress (mild or severe). Corticosterone levels were elevated following both types of stress in WT mice, but only following the severe stress in IL-1raTG mice. These findings appear to be somewhat inconsistent with our recent studies on the role of IL-1 in pain sensitivity, which demonstrated that in the mutant mice the analgesic response to morphine is potentiated. We reasoned that such potentiation was not observed following exposure to the mild and/or severe stress because in animals deficient in IL-1 signaling the mild stress was not stressful, whereas following severe stress the potentiation was most likely masked by the fact that the analgesic response nearly reached cut-off in all animals. To test the hypothesis that SIA can be potentiated by the blockade of IL-1 signaling, hot plate latency was tested in IL-1rKO mice and their WT controls following exposure to a moderate form of swim stress n˜ swimming at 23 C. While both IL-1rKO and WT mice displayed analgesic response to moderate
e73
stress, this analgesia was markedly potentiated in the mutant strain. These results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to more severe stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the antianalgesic role of IL-1 in several pain modulatory conditions, including SIA. doi:10.1016/j.bbi.2005.10.149
#143 Age-dependent changes in NF-jB binding activity in response to acute psychosocial stress Jutta M. Wolf a, Nicolas Rohleder a, Angelika Bierhaus b, Dimitri Petrov b, Peter P. Nawroth b, Clemens Kirschbaum a a
Biopsychology, TU Dresden, Germany Department of Medicine I, University of Heidelberg, Germany b
We previously showed that the nuclear transcription factor NF-jB is rapidly activated by psychosocial stress in healthy subjects and that norepinephrine is able to induce this activation. Additionally, NF-jB mediates immune suppressive effects of cortisol. Based on these findings we hypothesized that in response to psychosocial stress norepinephrine leads to a rapid immune activation through induction of NF-jB, whereas cortisol leads to delayed suppression of this immune activation. Since NF-jB activity also seems to play a role in immune senescence we were additionally interested in the effects of age on this model. In the present study, we therefore investigated 44 healthy female and male subjects with ages ranging from 20 to 59 years. All subject were exposed to the psychosocial stress paradigm ‘‘Trier social stress test’’ (TSST). Salivary free cortisol levels (CORT), plasma norepinephrine (NE) levels, and NF-jB-DNA-binding activity were determined before and repeatedly after TSST. To test for effects of age, two groups were formed (young group: 20–30 years, older group: 31–59 years). We found significant stress effects on CORT (p < .001) and NE (p < .001) but not on NF-jB activity (p = .668). Nevertheless the stress-induced increases in CORT and NF-jB correlated significantly (r = .393; p = .047) thereby supporting the hypothesized model. The missing effect of stress on NF-jB activity can be explained by taking into account age as an intervening variable: testing for age effects revealed significant group differences for NF-jB activity (p = .039). As expected, NF-jB activity increased after TSST in the young group. The older subjects, in contrast, showed a decrease in NF-jB activity, which is in accordance with findings regarding its role in immune senescence. Interestingly, the older subjects also showed a trend to both elevated CORT (p = .084) and elevated NE (p = .082) levels compared with younger subjects.
#142 Interleukin-1 signaling is involved in stress-induced analgesia Gilly Wolf a, Raz Yirmiya a, Tirzah Kreisel a, Josef Weidenfeld b, Yehuda Shavit a a
Department of Psychology, The Hebrew University, Jerusalem 91905, Israel b Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel The proinflammatory cytokine interleukin-1 (IL-1) is involved in the neural, endocrine, and behavioral responses to stress. Various stressors increase the production and secretion of IL-1, within the CNS and in the periphery, and this increase is associated with activation of the HPA axis. We have recently shown that mice with impaired IL-1 signaling display diminished corticosterone secretion after exposure to mild stress compared with their wild type (WT) controls. Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed Ôstress-induced analgesiaÕ (SIA). Since IL-1 also plays a role in pain modulation (impaired IL-1-signaling is associated with decreased basal pain sensitivity, and with prolonged and potentiated opiate analgesia), we hypothesized that IL-1 plays a modulatory role in SIA. To test this hypothesis, we used two mouse models of impaired IL-1-signaling: Targeted deletion of the IL-1 receptor type I (IL-1rKO), or transgenic overexpression of the IL-1 receptor antagonist within the CNS (IL1raTG). Mutant mice were compared with their WT controls. Mice were exposed to one of two forms of stress: swimming for 2 min at 32 C (mild stress) or at 15 C (severe stress). They were then allowed to dry for 2 min, and tested for pain sensitivity using the hot-plate test immediately after drying. Mild stress induced significant analgesia in the two WT strains, but not in the mutant strains. In contrast, both WT and mutant strains displayed similar analgesic response following severe stress. In separate groups of IL-1raTG and their WT controls, corticosterone levels were assessed following exposure to either type of stress (mild or severe). Corticosterone levels were elevated following both types of stress in WT mice, but only following the severe stress in IL-1raTG mice. These findings appear to be somewhat inconsistent with our recent studies on the role of IL-1 in pain sensitivity, which demonstrated that in the mutant mice the analgesic response to morphine is potentiated. We reasoned that such potentiation was not observed following exposure to the mild and/or severe stress because in animals deficient in IL-1 signaling the mild stress was not stressful, whereas following severe stress the potentiation was most likely masked by the fact that the analgesic response nearly reached cut-off in all animals. To test the hypothesis that SIA can be potentiated by the blockade of IL-1 signaling, hot plate latency was tested in IL-1rKO mice and their WT controls following exposure to a moderate form of swim stress n˜ swimming at 23 C. While both IL-1rKO and WT mice displayed analgesic response to moderate
e73
stress, this analgesia was markedly potentiated in the mutant strain. These results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to more severe stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the antianalgesic role of IL-1 in several pain modulatory conditions, including SIA. doi:10.1016/j.bbi.2005.10.149
#143 Age-dependent changes in NF-jB binding activity in response to acute psychosocial stress Jutta M. Wolf a, Nicolas Rohleder a, Angelika Bierhaus b, Dimitri Petrov b, Peter P. Nawroth b, Clemens Kirschbaum a a
Biopsychology, TU Dresden, Germany Department of Medicine I, University of Heidelberg, Germany b
We previously showed that the nuclear transcription factor NF-jB is rapidly activated by psychosocial stress in healthy subjects and that norepinephrine is able to induce this activation. Additionally, NF-jB mediates immune suppressive effects of cortisol. Based on these findings we hypothesized that in response to psychosocial stress norepinephrine leads to a rapid immune activation through induction of NF-jB, whereas cortisol leads to delayed suppression of this immune activation. Since NF-jB activity also seems to play a role in immune senescence we were additionally interested in the effects of age on this model. In the present study, we therefore investigated 44 healthy female and male subjects with ages ranging from 20 to 59 years. All subject were exposed to the psychosocial stress paradigm ‘‘Trier social stress test’’ (TSST). Salivary free cortisol levels (CORT), plasma norepinephrine (NE) levels, and NF-jB-DNA-binding activity were determined before and repeatedly after TSST. To test for effects of age, two groups were formed (young group: 20–30 years, older group: 31–59 years). We found significant stress effects on CORT (p < .001) and NE (p < .001) but not on NF-jB activity (p = .668). Nevertheless the stress-induced increases in CORT and NF-jB correlated significantly (r = .393; p = .047) thereby supporting the hypothesized model. The missing effect of stress on NF-jB activity can be explained by taking into account age as an intervening variable: testing for age effects revealed significant group differences for NF-jB activity (p = .039). As expected, NF-jB activity increased after TSST in the young group. The older subjects, in contrast, showed a decrease in NF-jB activity, which is in accordance with findings regarding its role in immune senescence. Interestingly, the older subjects also showed a trend to both elevated CORT (p = .084) and elevated NE (p = .082) levels compared with younger subjects.