Footshock Research Articles

Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress

Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.

Early postnatal stress alters the extinction of context-dependent conditioned fear in adult rats

Fear extinction is hypothesized to be a learning process based on a new inhibitory memory. The present study was conducted to elucidate the effect of early postnatal stress on the extinction of context-dependent fear memory in adult rats, with a focus on the serotonergic system. Extinction was estimated by the expression of freezing behavior during repeated extinction trials (i.e., repeated exposure to contextual fear conditioning) on consecutive days. The decrease in fear expression was attenuated in adult rats that had been subjected to footshock (FS) at the third postnatal week (3wFS), but not in those exposed to footshock at the second postnatal week (2wFS). The decreased attenuation of freezing behavior observed in 3wFS was abolished by repeated treatment with the partial N-methyl- d-aspartate receptor agonist d-cycloserine (15 mg/kg, i.p., for 4 days), which has been shown to facilitate cue-dependent extinction. Repeated treatment with the serotonin 5-hydroxytryptamine-1A (5-HT 1A) receptor agonist tandospirone (1 mg/kg, i.p., for 4 days) prevented the expression of freezing behavior in 3wFS, whereas diazepam treatment (1 mg/kg, i.p., for 4 days) in 3wFS did not. These results suggest that exposure to early postnatal stress at the third week is responsible for attenuating extinction of contextual fear conditioning and is mediated by a serotonergic 5-HT 1A receptor mechanism. In other words, exposure to traumatic events during the early postnatal period might precipitate long-lasting alterations in synaptic function that underlie extinction processes of context-dependent fear memory.

Early postnatal stress affects the serotonergic function in the median raphe nuclei of adult rats

Recent studies have focused on the serotonergic mechanism mediated via serotonin (5-HT) receptors underlying regulation of emotional stress during the developmental period. The present study was undertaken to elucidate whether early postnatal stress affects rat brain development and influences the serotonergic function in the midbrain median raphe nuclei (MRN) and dorsal raphe nuclei (DRN) in the adult, focusing on the response to unconditioned fear stress. Rats received aversive foot shock (FS) stimuli at the third week of the postnatal period (3wFS), but not those at the second week (2wFS), had increased percentage of time spent on open arms, estimated by the elevated plus maze test, at the postadolescent period (10–12 weeks old). The anxiolytic behavior observed in 3wFS was similar to that in rats having electrolytic lesion of the MRN, but not the DRN. In addition, the number of MRN 5-HT-immunoreactive cells in 3wFS remarkably was reduced compared to the non-FS control and 2wFS groups. These data suggest that aversive stress at the third week is attributable to the serotonergic function in the MRN underlying regulation of unconditioned fear stress. In other words, the “critical period” appears to be the time of neural circuit development of the MRN serotonergic system, which may be implicated in lifelong susceptibility to emotional stress.

The expression of an intraspecific aggressive reaction in the face of a stressor agent alters the immune response in rats

The repercussion on the immune response of the expression of intraspecific aggressiveness in the face of a stressor agent was investigated in rats. Ninety-day-old animals were divided into three groups: the control group (only immunological measurements were performed), the foot-shock (FS) (animals individually receiving FS), and the intraspecific aggressive response (IAR) group (animals receiving FS and presenting IAR). For immunological measurements, blood samples were collected promptly at 7 and 15 days after FS or IAR. The FS reduced the total leukocyte amount presented. However, aggressiveness triggered not only reduction of the leukocytes, but also lymphocyte decrease and neutrophil increase. Moreover, an elevation in total leukocytes associated with an increase in the humoral immune response was also observed one week after IAR. In this study, the expression of intraspecific aggressiveness in the face of a stressor seemed to activate the immune system and to potentiate the antigen specific humoral response.

Pretreatment With Footshock Alters Some Effects Of Subsequent Organophosphate Exposure

Pre-exposure to non-chemical stressors may alter a subject's vulnerability to chemical stressors. We found recently that rats given a subtoxic dose of chlorfenvinphos (CVP), an organophosphorus pesticide, develop behavioral hyposensitivity to amphetamine (AMPH). The present experiments were performed in order to find out whether pre-exposure to a non-chemical stressor several days prior to CVP exposure could influence this effect of the pesticide. In experiment 1 adult male Wistar rats were subjected once to either a short, 5 min (SFS) or long, 20 min (LFS) series of unavoidable footshocks (FS). Twenty-four hours or 14 days after the FS, their open field behavior was tested before and after a test dose of AMPH (0.5 mg/kg. i.p). In experiment 2, the rats were subjected to LFS and 14 days later they were injected intraperitoneally with CVP (1.0 mg/kg) or vehicle (corn oil). In both experiments, serum corticosterone (CORT) levels were determined in separate groups of rats in order to assess the magnitude of the stress response induced by the applied stressors. It was found that: (i) the rise in serum CORT concentration after SFS or LFS was similar in magnitude, while that following LFS was more persistent; (ii) exposure to LFS, but not to SFS, resulted in a decreased response to AMPH on day 14 after the experience; (iii) in rats not pretreated with LFS, CVP exposure resulted in a profound increase in serum CORT concentration. In LFS pretreated rats, however, this effect was significantly reduced; (iv) three weeks after the exposure to CVP, the psychomotor response to AMPH was diminished in control rats but was normal in LFS pretreated animals. The results indicate that pretreatment with a non-chemical stressor may protect the rat against at least some of the effects of an organophosphate pesticide.

Early postnatal stress alters the 5-HTergic modulation to emotional stress at postadolescent periods of rats

Several lines of evidence have shown that traumatic events during the early postnatal stage might precipitate long-lasting alteration in the functional properties underlying emotional expression. The aim of the present study was to examine whether the early postnatal stress alters the 5-HTergic mechanism underlying regulation of emotional stress, focusing on the 5-HT(1A) receptor-mediated synaptic responses in adult rats. Pups were exposed to aversive stimulus, footshock (FS) at the postnatal period of the second (2W) and the third week (3W). At postadolescent period (10-12-week-old), electrophysiological and behavioral studies were performed. The 5-HT(1A) receptor agonist tandospirone (10 mg/kg body wt, i.p.) blocked the long-term potentiation (LTP) in the hippocampal CA1 field of 3W-FS, as well as non-FS control, whereas this inhibition was not observed in 2W-FS group. Fear-related freezing behavior observed during exposure to contextual fear conditioning markedly attenuated in 2W-FS, but not in 3W-FS. These data suggest that aversive stress exposed at 2W is attributable to changes in the 5-HT(1A) receptor-mediated synaptic plasticity, which may be responsible for the attenuation of freezing behavior. Thus, 5-HT(1A) receptors appear to play a key role in the 5-HTergic mechanism underlying regulation of emotional stress on the postnatal development of the brain. In other words, the second postnatal week may be the "critical period" for establishing proper behavioral responses to emotional stress in adult rats. (c) 2005 Wiley-Liss, Inc.

Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats

Lactoferrin (LF) is known as an iron-binding glycoprotein. It has been shown that bovine LF (bLF) is transported into cerebrospinal fluid via blood although its physiological effects in the central nervous system (CNS) are still unclear. In this study, a suppressive effect of bLF on psychological distress was investigated in adult rats. Intraperitoneal injection of bLF (100 mg/kg) reduced stressful behaviors in a conditioned fear-induced freezing test and an elevated plus-maze test. Interestingly, the suppressive effect of bLF was enhanced by pretreatment with electric foot-shock (FS). This suppressive effect of bLF in the elevated plus-maze test was reversed by pretreatment with naloxone, an opioid receptor antagonist, at a dose of 1 mg/kg (ip). N ω-nitro- l-arginine methyl ester ( l-NAME), a nitric oxide synthase (NOS) inhibitor, also blocked the suppressive effect of bLF and foot-shock. In addition, combined application of a low dose of bLF (30 mg/kg, ip) and l-arginine (30 and 100 mg/kg, ip) showed significant potentiated effects on psychological stress. These results suggest that bLF has suppressive effects on psychological distress, especially under the condition of moderate stress. Furthermore, it is suggested that bLF possibly activates an endogenous opioidergic system via nitric oxide synthase activation.

Serotonergic modulation of psychological stress-induced alteration in synaptic plasticity in the rat hippocampal CA1 field

In order to elucidate possible involvement of the serotonergic neuronal system in the stress-induced alteration in synaptic plasticity, the effects of contextual fear conditioning (CFC) on long-term potentiation (LTP) in the hippocampal CA1 field were examined in 5-HT-depleted rats by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 200 μg/rat, i.c.v.). LTP induction was suppressed by footshock (FS) stimulation in 5-HT-lesioned rats and vehicle-treated controls. When rats were exposed to CFC, which was received 24 h after FS stimulation, LTP was also blocked in both-treated groups. CFC-induced impairment of LTP, however, significantly attenuated in 5-HT-lesioned rats when compared with that in controls. Fear-related freezing behavior after FS stimulation occurred similarly in both treated groups, whereas the behavior observed during exposure to CFC significantly reduced in 5-HT-lesioned rats. These results suggest that the serotonergic mechanism is involved in the psychological stress-induced alteration in synaptic plasticity, which appears to be associated with fear-related behavior.

Anxiety-related behavior in juvenile stroke-prone spontaneously hypertensive rats — an animal model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (AD/HD) is defined as a developmental disorder, manifested by deficit sustained attention (inattention), and/or hyperactivity-motor impulsiveness. Neuropsychological evidence indicates the comorbidity of anxiety disorder with AD/HD. The aim of the present study was to characterize anxiety-related behavior of the juvenile stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of AD/HD, and compare with genetic and/or normotensive controls. Our hypothesis, that low susceptibility to fear/anxiety stimuli might underlie impulsive behavior in juvenile SHRSP, was assessed by a contextually conditioned fear paradigm. In order to examine whether contextual fear stimuli would affect the synaptic efficacy in the hippocampus, changes in field potentials of perforant path-dentate gyrus (DG) synapses were recorded in the freely behaving rat. Aversive footshock (FS) stimuli elicited intense freezing behavior in genetic and/or normotensive controls. Re-exposing to the FS chamber in the 30-min retention period also produced freezing behavior, as contextually conditioned fear response, in genetic and/or normotensive controls. In contrast, SHRSP exhibited a significant attenuation in freezing behavior both in the 5-min post FS period (immediately after FS) and in the 30-min retention period (24 hours after FS) as compared to genetic and/or normotensive controls. Pain perception as measures of behavioral responses to electric FS, jumping and/or vocalization, indicated that less anxiety-related response in SHRSP did not simply result from low susceptibility to FS stimuli. During the re-exposure to contextual fear stimuli, SHRSP and a normotensive control rat exhibited a decrease in the amplitude of the evoked population spikes in perforant path-DG synapses, accompanying freezing behavior. The synaptic response in this hippocampal subfield was mimicked by low frequency stimulation (1 Hz). These synaptic responses induced by behavioral and electrophysiological manipulations, freezing and LFS, were less pronounced in SHRSP than those in the control. Our findings indicate that the impaired responsiveness to contextually conditioned fear stimuli, less anxiety-related freezing behavior, in juvenile SHRSP, might explain the impulsive behavior in this AD/HD animal model.

The stress experience dependent long-term depression disassociated with stress effect on spatial memory task

Behavioral stress can either block or facilitate memory and affect the induction of long-term potentiation (LTP) and long-term depression (LTD). However, the relevance of the stress experience-dependent long-term depression (SLTD) to spatial memory task is unknown. Here we have investigated the effects of acute and sub-acute elevated platform (EP) and foot shock (FS) stress on LTD induction in CA1 region of the hippocampus of anesthetized rats and spatial memory in Morris water maze. We found that LTD was facilitated by acute EP stress, but not by sub-acute EP stress that may be due to the fast adaptation of the animals to this naturalistic mild stress. However, FS stress, an inadaptable strong stress, facilitated LTD induction both in acute and sub-acute treatment. In addition, with the same stress protocols, acute EP stress impaired spatial memory but the sub-acute EP stressed animals performed the spatial memory task as well as the controls, may due to the same reason of adaptation. However, acute FS stress slightly impaired learning but sub-acute FS even enhanced memory retrieval. Our results showed that SLTD was disassociated with the effect of stress on memory task but might be related to stress experience-dependent form of aberrant memory.

Conditioned-fear stress increases Fos expression in monoaminergic and GABAergic neurons of the locus coeruleus and dorsal raphe nuclei.

Many studies have demonstrated that physical or psychological stress can increase Fos expression in brainstem monoaminergic nuclei. Little is known, however, about the extent to which stress increases the expression of Fos in monoaminergic and nonmonoaminergic neurons in the brainstem. We examined the effects of conditioned-fear (CF) stress following mild footshock (FS) as unconditioned stress on Fos expression in the monoaminergic and GABAergic neurons of the ventral tegmental area (VTA), locus coeruleus (LC), and dorsal raphe nucleus (DR) in rats. The CF stress significantly increased the number of Fos-positive (Fos+) cells in both the LC and DR, whereas it did not increase the number in the VTA. Using a double-labeling technique, we combined Fos immunostaining with that for tyrosine hydroxylase (TH), serotonin (5-HT), or GABA for histochemical identification of the CF stress-induced Fos+ neurons. The percentage of TH/Fos double-labeled cells resulting from CF stress was 63% of the Fos+ cells in the LC, whereas 52% of the Fos+ cells contained 5-HT in the DR. We also found that approximately 60% of the CF stress-induced Fos+ cells were GABAergic neurons in these brain regions. These results indicate that CF stress induces intense Fos expression in the noradrenergic LC and serotonergic DR neurons, but not in the dopaminergic VTA neurons. They also indicate that not only monoaminergic neurons but also GABAergic neurons within the LC and DR are activated by the stress.

Effects of stress on allergic reaction

The purpose of the present study was to investigate the effects of stress on allergic reaction. We studied changes in the contact hypersensitivity reaction (CHR) of mice exposed to foot shock (FS) stress or psychological (PSY) stress induced by the communication box. CHR was elicited by applying antigen (2,4-dinitrofluorobenzene, DNFB) to the ear of the mice at 4 days after DNFB sensitization. In acute stress experiments, DNFB-sensitized mice were exposed for 2 h to FS or PSY stress after contact challenge with DNFB. Acute FS stress significantly inhibited CHR immediately after the end of the stress period (3 h after DNFB-challenge), and a significant enhancement of the CHR was observed at 5 h after DNFB-challenge. The concentration of the serum corticosterone level of the mice exposed to acute FS stress significantly increased compared to the control mice, immediately after stress loading. Both CHR and serum corticosterone levels after acute PSY stress loading were almost the same as those of the control groups. The temporary decrease of the inflammatory reaction at CHR caused by acute FS stress loading may have been correlated with serum corticosterone produced by the stress, and the increase of corticosterone may act as a trigger of enhancement of the CHR (delayed-type hypersensitivity). Chronic stress experiments were designed to expose mice to FS or PSY stress 2 h daily after sensitization with DNFB. These chronic stresses caused a significant reduction in the body weight of mice. The temporary decrease effect on the CHR of chronic FS stress-loaded mice was similar to the acute FS stress-loaded mice. In contrast, no significant enhancement of the CHR (late phase) at 24 h and 48 h after challenge was observed. Although the changes in body weight suggested that mice were influenced by chronic PSY stress, no significant difference from the control group for the CHR of mice exposed to chronic PSY stress was found, as in the case of acute PSY stress loading. The correlation between chronic PSY stress and CHR remains to be ascertained.

Roles of central interleukin-1 on stress-induced-hypertension and footshock-induced-analgesia in rats

Central interleukin-1 (IL-1) plays an important role in mediating the neural, endocrine, and behavioral responses to stressors. Here we tested whether central IL-1 is involved in stress-induced hypertension or footshock (FS)-induced-analgesia. We observed that: (1) intracerebral ventricular injection of (ICV) IL-1β induced pressor responses; (2) hypertension induced by IL-1β was blocked by ICV an IL-1 antagonist, IL-1ra; (3) ICV IL-1ra attenuated the pressor response induced by FS but intravenous injection of IL-1ra did not significantly reduce this response; (4) the hypertensive response to conditioned fear stimuli was reversed by ICV IL-1ra; (5) FS-induced-analgesia was attenuated by ICV IL-1ra and this effect disappeared 15 min after ICV IL-1ra. These results suggest that both the pressor response to FS or conditioned fear stimuli and short lasting analgesia induced by FS are mediated by central IL-1.

Enhancement of sensitization to nicotine-induced ambulatory stimulation by psychological stress in rats

1. 1. The authors investigated the influence of psychological stress (PSY-stress) on sensitization to nicotine (0.5 mg/Kg S.c.)-induced ambulatory stimulation. 2. 2. Rats were exposed to the emotional responses of animals which received foot-shock (FS), which they, themselves, did not receive. Ten daily exposures to PSY-stress for 20 min enhanced sensitization to the nicotine-induced ambulatory stimulation compared to that in non-stress rats. 3. 3. However, the increased serum corticosterone levels following nicotine (0.5 mg/Kg S.c.) administered 24 hr after the tenth injection of nicotine in the behavioral study was almost the same in the rats exposed to PSY-stress as compared to non-stress rats. 4. 4. These results suggest that PSY-stress may promote sensitization to nicotine-induced ambulatory stimulation and that the combined effect of PSY-stress and nicotine would facilitate the development of sensitization to nicotine.

Effects of Tyr-MIF-1 on Stress-Induced Analgesia and the Blockade of Development of Morphine Tolerance by Stress in Mice

The role of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in biological responses to stress exposure was examined in mice. Intraperitoneal or intracerebroventricular administration of Tyr-MIF-1 attenuated not only footshock (FS)- and forced swimming (SW)-stress-induced analgesia (SIA) but also socio-psychological (PSY)-SIA that, when using the communication box, is produced without any direct physical nociceptions. Tyr-MIF-1 also disrupted the suppressive effect of concurrent exposure to FS- and PSY-stress on the development of morphine antinociceptive tolerance. In elevated-plus-maze tests, mice treated with Tyr-MIF-1 tended to spend more time in the open arms compared with the control group, suggesting the anxiolytic properties of the peptide. Thus, the finding that Tyr-MIF-1 modulates these stress responses suggests that the peptide regulates an endogenous biological alert system responding to stress exposure, perhaps, counteracting the excessive response of the system. Furthermore, Tyr-MIF-1, in the case of PSY-stress, through the attenuation of emotional factors such as fear and anxiety, may suppress PSY-SIA and inhibition by PSY-stress of the development of morphine tolerance.

Characterization of Socio-psychological Stress-Induced Antinociception in the Formalin Test in Mice

The antinociceptive effect induced by exposure to socio-psychological (PSY) stress using a communication box was assessed by the formalin test in mice, compared with those by exposure to foot-shock (FS) stress and forced swimming (SW) stress. After the termination of stress exposure, whereas exposure to FS- and SW-stress resulted in the attenuation of the formalin-induced biphasic pain response over 15 min, no appreciable antinociceptive effect was found in the case of PSY stress. When exposure to PSY stress was started during the period of early or late phase of pain after the formalin injection, the antinociceptive effect was maintained for 5–15 min; however, further exposure to PSY stress was not effective for producing antinociception. In the tail-pinch test, likewise, exposure to PSY stress longer than 5 min rather decreased the intensity of antinociception. We conclude that PSY stress in this tonic pain paradigm produces antinociception, but further continuous exposure to the emotional stress caused mice to become recuperative even in such a fear-inducing situation.

Learning/memory processes under stress conditions

Using mice, changes in the learning/memory processes under various stress conditions were investigated in one-trial step-through type passive avoidance learning task. Pre-, post-training and pre-test foot shock (FS)-stress induced long-lasting, at least 96 h, facilitation of test trial latencies. Pre-training psychological (PSY)stress induces facilitation and pre-test swimming (SW)-stress provokes impairment of test trial latencies. These effects of FS-, PSY- and SW-stress are all dependent on the timing of their exposure and due to their acute effect. Intraperitoneal administration of 1 mg/kg scopolamine 30 min pre-training caused impairment of test latencies in naive and pre-test FS-stressed animals but failed to affect both pre- and post-training FS-induced enhancement. Taken all these data together, it seems that cholinergic mechanism is partly involved in the FS-stress induced facilitation of test latencies, though the research on the changes in ACh levels at the action site in brain after FS-stress exposure is necessary for a definite conclusion.

FS stress induces long-lasting memory facilitation: Involvement of cholinergic pathways

We tested in vivo the hypothesis that foot-shock (FS) stress-induced prolongation of latencies in the one-trial step-through passive avoidance learning task in mice occurred through a long-term facilitation process. Whereas behavioral responses in control mice lasted for 24 h, decreasing progressively in the subsequent days, FS-stress exposure for 15 min before training (pretraining), immediately after training (posttraining), or 15 min before the test (pretest) resulted in a profound and sustained enhancement of test latencies that lasted for at least 96 h. These facilitating effects disappeared when FS exposure was delivered with a 2- or 3-h difference with respect to the training trial. Scopolamine (Scop) (1 mg/kg, intraperitoneally) 30 min before the training session caused impairment of test latencies in control and pretest stressed animals, but failed to affect both pre- and posttraining FS stress-induced enhancement. Our working hypothesis is that FS stress may increase the levels of acetylcholine in the presynaptic terminal or the firing rate of cholinergic input. Animals pretreated with FS stress daily for 1 or 4 days followed by the acute schedule described above showed no enhancements of test latencies. Pretraining Scop impaired test latencies in pre- and posttraining and pretest stressed animals, suggesting that unpredictability is a critical factor in activating behavioral long-term facilitation.

Effects of footshock-, psychological- and forced swimming-stress on the learning and memory processes: involvement of opioidergic pathways.

Modulation of learning and memory acquisition, retention and retrieval in the one trial passive avoidance learning task in mice by three inescapable stresses, i.e., footshock (FS), psychological (PSY) and forced swimming (SW) were investigated. Pre-, post-training and pre-test FS-stress (2 mA, 0.2 Hz, 1 sec for 30 min) and pre-training PSY-stress (communication box, 5 min) resulted in enhanced test latencies. On the contrary, SW-stress (20 degrees C, 5 min) immediately or 1 hr after training impaired retention latencies that tended to recover after 2 hr post-training SW-stress, suggesting that at least 2 hr are required to consolidate newly acquired information. In contrast, pre-stress naloxone (Nx), which did not affect FS- and PSY-stress induced facilitatory effects, returned to control levels the impaired retention latencies induced by SW-stress. Taken collectively, these results imply the involvement of an opioid-dependent mechanism in the modulation of memory by SW-stress and non-opioid in the case of FS- and PSY-stress. Furthermore, they suggest that different mechanisms are involved in stress-induced memory modifications and the production of stress-induced analgesia (SIA) since in the latter, FS and PSY but not SW stress produce Nx-sensitive antinociception.

A novel long-latency response of locus coeruleus neurons to noxious stimuli: mediation by peripheral C-fibers.

1. Extracellular recordings were obtained from single presumed noradrenergic neurons in the nucleus locus coeruleus (LC) in response to percutaneous electrical foot shock (FS) stimulation in the rat. We employed long-duration stimulus pulses to examine the possible contribution of peripheral C-fibers to evoked activity in LC. 2. As in previous studies, 0.5-ms FS stimuli produced a short-latency excitatory response (onset 20.8 ms) followed by a prolonged postactivation inhibition. However, 2.0- or 5.0-ms FS stimuli yielded an additional late excitatory response. 3. The onset and termination latency of this late excitatory response were approximately 200 and 400 ms, respectively, after the FS. The conduction velocity for this late response (peripheral plus central pathway) was estimated to be < 1.2 m/s. 4. The percentages of LC neurons that exhibited a significant late response was 4% (3/85) with 0.5-ms stimuli, 53% (31/59) with 2.0-ms stimuli, and 73% (47/64) with 5.0-ms FS stimuli. 5. The average number of spikes evoked per FS stimulus (presented at 0.5 Hz) increased from the 1st to the 21st FS stimulus. This increased response occurred selectively in the late, not in the early, response. This result was interpreted to represent a "windup" phenomenon reflected at the level of LC. 6. Direct application of capsaicin onto the sciatic nerve reduced the average magnitude of the late response of LC neurons to 17% of control 42.5 min after application. The magnitude of the short-latency response components showed little or no change. 7. Averaged compound action potential (cAP) recordings from the sciatic nerve revealed that C-fiber responses were more consistently observed and much larger with 5.0-ms compared with 0.5-ms FS stimuli. 8. C-fiber cAPs were reduced or eliminated after application of capsaicin distal to the recording site with a time course similar to that of the late response of LC neurons, with little or no effect on A-fiber cAPs. 9. These data show that a previously undescribed long-latency response of LC neurons to noxious FS stimulation in rat results from C-fiber activation in the sciatic nerve. This late response may be involved in generating descending noradrenergic analgesia induced by electrical stimulation of the foot pad or other body regions. Future studies of the pharmacology of this late response to noxious stimuli in LC may aid in developing new therapies for the treatment of acute or chronic pain.