Tsutomu Shichino

Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats.

UNLABELLED Xenon (Xe) suppresses wide dynamic range neurons in cat spinal cord to a similar extent as nitrous oxide (N2O). The antinociceptive action of N2O involves the descending inhibitory system. To clarify whether the descending inhibitory system is also involved in the antinociceptive action of Xe, we compared the effects of Xe on the spinal cord dorsal horn neurons with those of N2O in spinal cord-transected cats anesthetized with alpha-chloralose and urethane. We investigated the change of wide dynamic range neuron responses to touch and pinch by both anesthetics. Seventy percent Xe significantly suppressed both touch- and pinch-evoked responses in all 12 neurons. In contrast, 70% N2O did not show significant suppression in touch- and pinch-evoked responses. These results suggest that the antinociceptive action of Xe might not be mediated by the descending inhibitory system, but instead may be produced by the direct effect on spinal dorsal horn neurons. IMPLICATIONS Xenon (Xe) is an inert gas with anesthetic properties. We examined the antinociceptive effects of Xe and nitrous oxide (N2O) in spinal cord-transected cats. Our studies indicate that Xe has a direct antinociceptive action on the spinal cord that is greater than that of N2O.

Nitric Oxide Synthase Inhibitor Does Not Reduce Minimum Alveolar Anesthetic Concentration of Halothane in Rats

Nitric oxide (NO) synthase inhibitor (Nω-nitro-L-arginine methyl ester [L-NAME]) has been reported to reduce minimum alveolar anesthetic concentration (MAC) of halothane when administered intravenously (IV) and to reduce thermal hyperalgesia, or produce antinociception in the formalin test, when administered intracerebroventricularly (ICV) or intrathecally (IT). This study attempts to identify the site(s) in the central nervous system (CNS) where L-NAME acts to reduce the halothane MAC. For this purpose, we examined the effects of IV, ICV, and IT administration of L-NAME on the halothane MAC in rats. In contrast to an earlier study, we did not observe any decrease in the halothane MAC after IV (10–30 mg/kg) administration of L-NAME. ICV (100 pg) and IT (100 pg and 1 mg) administration of L-NAME also did not alter the halothane MAC. These findings indicate that the L-arginine-NO pathway is not involved in the mechanism of action of halothane to suppress mechanical nociceptive response or in the nociceptive neural mechanism of mechanical stimulation.

Chronic Treatment with Nitric Oxide Synthase (NOS) Inhibitor Profoundly Reduces Cerebellar NOS Activity and Cyclic Guanosine Monophosphate but Does Not Modify Minimum Alveolar Anesthetic Concentration

We previously found that acute administration of a nitric oxide synthase (NOS) inhibitor (Nomega-nitro-L-arginine methyl ester [L-NAME]) does not reduce the minimum alveolar anesthetic concentration (MAC) of halothane in rats. However, a recent study has suggested that brain NOS activity could not be inhibited by more than approximate equals 50% by acute administration of L-NAME. To investigate the effect of marked inhibition of NOS activity on the MAC of halothane, we measured cerebellar NOS activity, cerebellar cyclic guanosine monophosphate (cGMP) levels, and halothane MAC in rats chronically treated with L-NAME and compared the results to those of the saline-treated control group. Although the cerebellar NOS activity and cGMP levels were significantly decreased (14% and 2.7% of control, respectively) by L-NAME, the value of the halothane MAC was not significantly affected. These results suggest that the anesthetic action of halothane, as measured by its MAC in rats, is not related to NOS activity or cGMP levels in the brain. (Anesth Analg 1995;81:862-5)

Activity of the serotonergic system during isoflurane anesthesia

BACKGROUND:Microdialysis studies have demonstrated that the release of serotonin (5-hydroxytryptamine, 5-HT) in the serotonergic projection areas increases during waking and decreases during sleep in rat and cat, suggesting that 5-HT plays an important role in modulation of sleep. Although it might be expected that 5-HT release is also decreased during general anesthesia, the functional contribution of serotonergic neurons in pharmacological effects of volatile anesthetics has not been fully investigated. METHODS:Using an in vivo microdialysis technique, we measured extracellular 5-HT in rat frontal cortex during waking, slow-wave sleep, and isoflurane anesthesia. To assess the involvement of the serotonergic system in the hypnotic action of isoflurane, the concentration of isoflurane required for loss of righting reflex was determined with or without pretreatment of fluoxetine hydrochloride, a selective 5-HT reuptake inhibitor. RESULTS:During slow-wave sleep and isoflurane anesthesia (0.1–1.5 MAC), 5-HT release decreased to 21%–44% of that during the waking state. Loss of righting reflex occurred at significantly higher isoflurane concentrations in fluoxetine-treated rats (0.76% ± 0.03% [n = 8]) than in control rats (0.60% ± 0.01% [n = 8]). CONCLUSIONS:It is suggested that a change in the activity of the serotonergic system in the brain is involved in the hypnotic action of isoflurane.

Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background Ketamine, a noncompetitive N‐methyl‐D‐aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N‐methyl‐D‐aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c‐fos protein (c‐Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established. Methods The effects of diazepam and halothane on c‐Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c‐Fos expression was detected using immunohistochemical methods. Results Ketamine induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices in a dose‐dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose‐dependent manner, leaving the thalamus relatively unaffected. Conclusion Halothane and diazepam inhibited ketamine‐induced c‐Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.

Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum.

Background: Acetylcholine (ACh) is one of the major excitatory neurotransmitters in the central nervous system, and changes in neural activity induced by anesthesia alter the release of ACh. However, the effects of isoflurane, one of the most widely used volatile anesthetics, on ACh release are not known. The present study attempts to clarify the dose–effect relationship of isoflurane on the in vivo release of ACh in rat brains.

Dopamine D2-like receptor in the nucleus accumbens is involved in the antinociceptive effect of nitrous oxide.

BACKGROUND:The mechanism of the antinociceptive effects of nitrous oxide (N2O) has not been completely elucidated. On the other hand, numerous studies have indicated that mesolimbic dopaminergic neurons, which are thought to be involved in rewarding and reinforcement processes, play important roles in the supraspinal pain-suppression system. We hypothesized that the mesolimbic dopaminergic system is involved in the antinociceptive effect of N2O. METHODS:Adult male Fischer rats were used in this study. To examine whether the dopaminergic system is activated by N2O, frozen sections of the ventral tegmental area of rats exposed to 75% N2O were double-stained for c-Fos and tyrosine hydroxylase. To clarify whether the dopaminergic system is involved in the antinociceptive action of N2O, saline or raclopride, a dopamine D2-like receptor antagonist, was injected into the nucleus accumbens (NAc) shell region. After exposure to 25% oxygen–75% nitrogen or 25% oxygen–75% N2O for 30 min, rats were subjected to formalin test, and the spinal cord was examined immunohistochemically. RESULTS:Exposure to 75% N2O increased c-Fos expression in tyrosine hydroxylase-positive cells in the ventral tegmental area. Raclopride, injected into the NAc shell region, attenuated the antinociceptive effect of N2O in the formalin test, and blocked the suppressive effect of N2O on the formalin-induced c-Fos expression in the dorsal horn of the spinal cord by N2O. CONCLUSION:It is possible that inhalation of N2O activates mesolimbic dopaminergic neurons, and that the antinociceptive effect of N2O is at least partially mediated by dopamine D2-like receptors in the NAc shell region.

Perioperative plasma concentrations of endothelin and natriuretic peptides in children undergoing living-related liver transplantation

To investigate the clinical significance of endothelin (ET), natriuretic peptides, and the renin-angiotensin-aldosterone system in pediatric liver transplantation, we measured plasma levels of ET, atrial and brain natriuretic peptides (ANP, BNP), aldosterone, and plasma renin activity in 18 patients (aged 0.5-12 yr; median 1 yr) undergoing living-related liver transplantation due to congenital biliary atresia and severe liver cirrhosis. Before transplantation, the plasma ET level (28.9 +/- 2.5 [mean +/- SEM] pg/mL) was increased compared with that of healthy children (10-18 pg/mL), but decreased during the anhepatic phase (22.5 +/- 1.6 pg/mL). It increased again after reperfusion and remained at high levels in the early postoperative period (postoperative day 3, 27.8 +/- 3.0 pg/mL). Plasma levels of ANP and BNP and aldosterone and plasma renin activity were also high before surgery. Plasma ANP and BNP did not change significantly during surgery. After transplantation, plasma BNP significantly increased, and plasma ANP tended to increase. Plasma aldosterone increased markedly during the anhepatic phase, although plasma renin activity decreased. After transplantation, plasma aldosterone and plasma renin activity both decreased to within normal levels. Mean arterial blood pressure increased gradually after reperfusion and surgery (postoperative day 3, 35.7 +/- 5.2% increase). No substantial differences in these variables occurred between the younger (<or=to1.0 yr, n = 9) and older patients (>1.0 yr, n = 9). These results suggest that ET production in the cirrhotic liver is augmented and ET, natriuretic peptides, and the renin-angiotensin-aldosterone system all play some role in the circulatory regulation during perioperative periods of pediatric liver transplantation. (Anesth Analg 1996;82:235-40)

Omission of fentanyl during sevoflurane anesthesia decreases the incidences of postoperative nausea and vomiting and accelerates postanesthesia recovery in major breast cancer surgery

PurposeOur purpose was to investigate the effect of omission of fentanyl during sevoflurane anesthesia on the incidences of postoperative nausea and vomiting and on postanesthesia recovery in female patients undergoing major breast cancer surgery.MethodsFemale patients (American Society of Anesthesiologists [ASA] physical status [PS] class I-II; age, 28–84 years) undergoing major breast cancer surgery were randomized to one of two anesthesia maintenance groups: sevoflurane-fentanyl anesthesia (SF; n = 25) or fentanyl-free sevoflurane anesthesia (S; n = 26). All patients were administered with propofol 2 mg·kg−1 intravenously for anesthesia induction, a laryngeal mask airway was placed, and they received rectal diclofenac and local infiltration anesthesia. Anesthesia was maintained with sevoflurane in oxygen-air and they breathed spontaneously. The patients in group SF received fentanyl 0.1 mg intravenously and those in group S received normal saline during anesthesia.ResultsGroup SF revealed higher incidences of postoperative nausea (68% vs 27%) and vomiting (32% vs 8%) in the first 24 postoperative hours than group S. The median (25th–75th percentile) length of time from postanesthesia care unit (PACU) admission to ambulation was significantly longer in group SF (n = 23) at 195 min (158–219 min), than in group S, at 141 min (101–175 min). Two patients in group SF could not walk during the PACU stay.ConclusionOmission of fentanyl during sevoflurane anesthesia, combined with diclofenac and local infiltration anesthesia, decreases the incidences of postoperative nausea and vomiting and accelerates postanesthesia recovery in patients undergoing major breast cancer surgery.

The involvement of the nociceptin receptor in the antinociceptive action of nitrous oxide

Nociceptin and its receptor are widely expressed in the central nervous system and are involved in the modulation of nociception. We have previously reported that the minimum anesthetic alveolar concentrations for volatile anesthetics do not differ between nociceptin receptor knockout (NOP−/−) mice and wild-type (NOP+/+) mice. In the present study, we investigated whether the nociceptin system is involved in the antinociceptive action of nitrous oxide. Using the acetic acid-induced writhing test, we showed that nitrous oxide had significantly less analgesic action in NOP−/− mice than in NOP+/+ mice. Furthermore, when anesthetized with a mixture of halothane and nitrous oxide (70%), intraperitoneal injection of acetic acid resulted in an increase of plasma adrenocorticotropic hormone concentrations in NOP−/− mice but not in NOP+/+ mice. An immunohistochemical study showed that nitrous oxide exposure induced c-Fos expression in the spinal cords of NOP+/+ mice but not in those of NOP−/− mice. These results together suggest that the antinociceptive action of nitrous oxide is, at least partly, mediated by the nociceptin system.