Kazuo Shindo

Responses of Plasma Adrenocorticotropic Hormone, Cortisol, and Cytokines during and after Upper Abdominal Surgery

There is currently accumulating evidence for bidirectional communication between the neuroendocrine and immune systems. Various cytokines have been suggested to be involved in the stimulation of stress hormone secretion during the times of infection and inflammation. To assess the possible involvement and pathophysiologic significance of cytokines in the mechanisms responsible for the perioperative stress response of the hypothalamo-pituitary-adrenal axis, we observed the changes of plasma adrenocorticotropic hormone and cortisol levels together with those of plasma endotoxin and cytokine levels. In patients undergoing pancreatoduodenectomy, perioperative stimulation of adrenocorticotropic hormone and cortisol secretion was accompanied by a significant elevation of plasma cytokine levels. Application of epidural block up to the upper thoracic levels failed to suppress this stress response effectively. In patients undergoing unilateral total hip replacement, the response of plasma hormone levels was smaller and briefer with no significant increase of plasma cytokine levels. Application of epidural block up to the lower thoracic levels suppressed this hormonal response almost completely. In patients undergoing pancreatoduodenectomy, a significant elevation of plasma endotoxin level was followed by a gradual but significant elevation of plasma tumor necrosis factor alpha and interleukin-6 levels. It seems likely that the stimulatory effects of these cytokines on the secretion of adrenocorticotropic hormone and cortisol might be involved in the development of the greater and more prolonged stress response of hypothalamo-pituitary-adrenal axis. Our present study suggests that not only neural input from the surgical wound but also stimulation of cytokine production were responsible for the development of the stress response of the hypothalamo-pituitary-adrenal axis during and after upper abdominal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional localization of pain perception in the human brain studied by PET.

TO elucidate the functional localization and somatotopic organization of pain perception in the human cerebral cortex, we studied the regional cerebral blood flow using positron emission tomography during selective painful stimulation in six normal subjects. Response to a painful stimulus was elicited using a special CO2 laser, which selectively activates nociceptive receptors, to the hand and foot. Multiple brain areas, including bilateral secondary somatosensory cortices (SII) and insula, and the frontal lobe and thalamus contralateral to the stimulus side, were found to be involved in the response to painful stimulation. While our data indicate that the bilateral SII play an important role in pain perception, they also indicate that there is no pain-related somatotopic organization in the human SII or insula.

Pain-related and cognitive components of somatosensory evoked potentials following CO2 laser stimulation in man

We recorded cortical potentials evoked by painful CO2 laser stimulation (pain SEP) employing an oddball paradigm in an effort to demonstrate event-related potentials (ERP) associated with pain. In 12 healthy subjects, frequent (standard) pain stimuli (probability 0.8) were delivered to one side of the dorsum of the left hand while rare (target) pain stimuli (probability 0.2) were delivered to the other side of the same hand. Subjects were instructed to perform either a mental count or button press in response to the target stimuli. Two early components (N2 and P2) of the pain SEP demonstrated a Cz maximal distribution, and showed no difference in latency, amplitude or scalp topography between the oddball conditions or between response tasks. In addition, another positive component (P3) following the P2 was recorded maximally at Pz only in response to the target stimuli with a peak latency of 593 msec for the count task and 560 msec for the button press task. Its scalp topography was the same as that for electric and auditory P3. The longer latency of pain P3 can be explained not only by its slower impulse conduction but also by the effects of task difficulty in the oddball paradigm employing the pain stimulus compared with electric and auditory stimulus paradigms. It is concluded that the P3 for the pain modality is mainly related to a cognitive process and corresponds to the P3 of electric and auditory evoked responses, whereas both N2 and P2 are mainly pain-related components.

Effects of interleukins on plasma arginine vasopressin and oxytocin levels in conscious, freely moving rats

To elucidate whether interleukins are involved in vasopressin or oxytocin release during cytokine-related stressful conditions, we examined the effects of human interleukin-1 beta and interleukin-6 on plasma vasopressin and oxytocin levels in rats. Interleukin-1 beta administrated intravenously stimulated both the vasopressin and oxytocin secretion in dose-dependent manners. Neither hormone release was observed following interleukin-6 administration. Pretreatment with aspirin significantly attenuated the effects of interleukin-1 beta on both the vasopressin and oxytocin levels. SC-19220, a prostaglandin E2 receptor antagonist, did not affect the interleukin-1 beta-induced increase of plasma oxytocin levels, but almost completely abolished its effect on plasma vasopressin levels. These results suggest that under certain stressful conditions which accompany the stimulation of cytokine production, interleukin-1 is involved in the increase of plasma vasopressin and oxytocin levels and, moreover, different kinds of prostaglandins are suggested to participate in these interleukin-1-induced hormone release.

Generator mechanism of pain-related evoked potentials following CO2 laser stimulation of the hand: scalp topography and effect of predictive warning signal.

In order to clarify the generator mechanism of pain-related evoked potentials (pain EPs), we studied the scalp topography of the pain EPs following CO2 laser stimulation of hand dorsum by using balanced sternovertebral electrodes as the noncephalic reference in 11 normal volunteers. We also examined the effects of predictive warning signal (light-emitting diode) on the pain EPs. In both the warned and unwarned conditions, all of the 22 hand stimulations showed a large negative component (N2) at the peak latency of about 213 ms followed by a large positive component (P2) at the peak latency of about 329 ms. A preceding small negative component (N1) at the peak latency of about 148 ms was detected in 12 of the 22 hand stimulations in the warned condition and in 13 of the 22 hand stimulations in the unwarned condition. P2 was significantly larger and occurred earlier in the warned condition than in the unwarned condition, whereas other components did not differ between the two conditions, suggesting that an increased attention of the subject to the stimulus influenced the generator mechanism of the P2 component. With regards to the scalp topography, N2 was maximal at Cz and widespread transversely to both sides, whereas P2 was maximal at Cz or Pz and spread more posteriorly than N2. These findings suggest that P2 is generated by a different mechanism from N2 and is most likely associated with pain-related cognitive function. N1 was localized to the contralateral central and midtemporal areas, confirming that the nociceptive inputs are perceived in the sensory cortex in humans. The question as to whether the N1 component is generated in the hand area of the primary somatosensory cortex or in the secondary somatosensory cortex, or in both areas, remains to be solved.

Pain-related somatosensory evoked potentials can quantitatively evaluate hypalgesia in Wallenberg's syndrome.

In 6 patients with Wallenbergs syndrome who showed a dissociated loss of pain sense, we recorded pain‐related somatosensory evoked potentials following CO2 laser stimulation of the hand dorsum (pain SEPs). Two components, N2 and P2, were recorded by stimulation of the unaffected hand, whereas on the affected side they were absent or decreased in proportion to the severity of hypalgesia which was evaluated by both needle test and CO2 laser stimulation. Latency of either component, if appeared, was longer in the affected hand stimulation than that in the unaffected one. In contrast, N20 of the conventional electrically‐stimulated SEPs (electric SEPs) showed no difference between the two sides. It is concluded that, unlike other electrophysiological methods, pain SEPs following CO2 laser stimulation can quantitatively evaluate functional impairment of the spinothalamic tract in Wallenbergs syndrome.

Cortical mechanisms underlying point localization of pain spot as studied by event-related potentials following CO2 laser stimulation in man

Abstract To elucidate cortical mechanisms underlying point localization of a pain spot, we investigated event-related potentials (ERPs) while using a CO2 laser beam to apply a pain stimulus to the hand dorsum in 16 healthy men. The stimulus spot (pain spot) was shifted for each stimulus, while the subject was requested to identify the stimulated spot as accurately as possible and to use a pointer in the non-stimulated hand to indicate the corresponding spot on a figure of a hand that was projected onto a screen (localization condition). For the control condition, the subject pointed to a single predetermined spot, regardless of the location of the stimulation (control motor task condition). Electroencephalograms were recorded from 21 electrodes, referenced to the linked earlobes, and were averaged time-locked to the stimulus onset for each task separately. Under the control rest condition (neither point localization nor motor task), only two early components (N2 and P2) were recorded. During the control motor task condition (no point localization), in addition to N2 and P2, a steep negative-going slope was recorded at the fronto-central region. Exclusively during the localization condition, a positive peak (647 ms, 5.6 µV for the left and 634 ms, 5.7 µV for the right hand stimulation) was identified; this was maximal at the midline centro-parietal area and distributed symmetrically over the scalp. It is suggested that the late positive component detected exclusively during the localization task is related to the somatotopic point localization of the pain spot. From the distribution of this ERP, the task most likely involves bilateral activation of the superior parietal cortices.

Effects of acupuncture on somatosensory evoked potentials: a review.

Although acupuncture has a long history of analgesic effects, the mechanisms underlying its effects are still unclear. Somatosensory evoked potential (SEP) methodology has been adopted in the research of acupuncture since the 1970s. In research on the effects of acupuncture on the conventional SEP, variable results have been observed, and two different opinions concerning the presence or absence of acupuncture effects on the conventional SEP are discussed. Since the conventional SEP is mediated mainly by fast conducting sensory nerve fibers, the conventional SEP methodology, especially that for recording short-latency SEP, may be inadequate for studying acupuncture mechanisms. In the case of the long-latency cortical SEP, there are too few data available to judge the effects of acupuncture analgesia (AA). Studies on the effects of AA on pain SEPs demonstrated that AA has a suppressive effect on amplitude of the pain SEP (and affecting the latency as well in some experiments) in both animals and humans, being accompanied by increased pain threshold. Thus, acupuncture seems to have analgesic effects that are probably related to activation of the antinociceptive system, and application of the pain SEP methodology to the study of mechanisms of AA may be promising.

Brief A morphological filter for extracting waveform characteristics of single-sweep evoked potentials

A morphological filter was designed for extracting the waveform characteristics of pain SEP from the single-sweep record. The properties of the basic operations for the morphological filter; erosion, dilation, opening and closing were clarified in order to design an appropriate filter. The morphological filter was designed by selecting the structuring elements, which represented the features of the pain SEP waveform. The designed morphological filter was evaluated using the simulation data, and applied to the pain SEP data obtained from a normal adult with satisfactory results.

Possible Role of Cytokines in the Stress Response of the Hypothalamo-Pituitary-Adrenal Axis During Upper Abdominal Surgery

It is well known that surgical invasion activates the hypothalamo-pituitary-adrenal (H-P-A) axis and induces marked elevation in plasma adrenocorticotropic hormone (ACTH) and Cortisol levels during and after surgery. The stress response of plasma ACTH and Cortisol levels cannot be totally suppressed by epidural [1] or subarachnoid anesthesia [2], especially in upper abdominal surgery [3], which suggests the involvement of some factor(s) other than afferent neural output arising from the injury site [4]. Some cytokines have recently been suspected to play important roles in the activation of the H-P-A axis at the times of infectious challenge and other stressful conditions [5–7]. To assess the possible involvement and role of cytokines in the stress response of the H-P-A axis during surgical procedures, we observed changes in the levels of plasma ACTH, Cortisol, endotoxin, tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in patients undergoing upper abdominal surgery. We then investigated the ACTH-releasing activities of these cytokines using an in vivo experimental system.