Masahiro Umino

The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability.

Heart rate (HR) and arterial blood pressure (BP) changes have been reported during conscious sedation with propofol and midazolam. One potential mechanism to explain these changes is that propofol and midazolam affect HR and BP via changes in the cardiac autonomic nervous system. Two specific hypotheses were tested by HR variability analysis: 1) propofol induces predominance of parasympathetic activity, leading to decreased HR and BP, and 2) midazolam induces predominance of sympathetic activity, leading to increased HR and decreased BP. Thirty dental patients were included in a prospective, randomized study. HR, BP, low frequency (LF), high frequency (HF), and entropy were monitored during the awake, sedation, and recovery periods and depth of sedation was assessed using the Observer’s Assessment of Alertness/Sedation score. Propofol induced a significant decrease in total power (503 ± 209 ms2/Hz versus 162 ± 92 ms2/Hz) and LF/HF ratio (2.5 ± 1.2 versus 1.0 ± 0.4), despite the absence of any change in HR during the sedation period compared with baseline. Midazolam decreased normalized HF (34 ± 10% versus 10 ± 4%) but did not significantly change LF/HF ratio (2.3 ± 1.1 versus 2.2 ± 1.4) and increased HR in the sedation period. Compared with baseline, propofol was associated with a significant increase in normalized HF in the recovery period (34 ± 11% versus 44 ± 12%) and a significant decrease in HR, whereas midazolam was associated with an increase in LF/HF ratio (2.3 ± 1.1 versus 3.7 ± 1.8) with no change in HR. These results indicated a dominant parasympathetic effect of propofol and a dominant sympathetic effect of midazolam in both periods. These results should be considered during conscious sedation, especially in patients at risk of cardiovascular complications.

Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: Diffuse noxious inhibitory controls in the trigeminal nerve territory

The purpose of this study was to determine whether the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and pain intensity are inhibited by heterotopic ischemic stimulation. The tourniquet pressure with 50 mmHg greater than the individuals systolic pressure was applied to the left upper arm for 10 min as ischemic conditioning stimulation. The late component of SEP and visual analogue scale (VAS) were recorded at 4 times and both were significantly decreased when ischemic conditioning stimulation was applied. The maximum reductions in SEP amplitude and the VAS value were 26.1% and 21.2%, respectively, during ischemic conditioning stimulation. After‐effect was observed 5 min after removal of the conditioning stimulation. The present study revealed that heterotopic ischemic stimulation attenuated the late component of SEP induced by electrical tooth stimulation, triggering diffuse noxious inhibitory controls (DNIC) and after‐effects in the trigeminal nerve territory. It was also suggested that the DNIC effect differs, depending on the intensity, kind, and quality of the test and conditioning stimuli.

Prolonged rhythmic gum chewing suppresses nociceptive response via serotonergic descending inhibitory pathway in humans.

&NA; Serotonergic (5‐HT) neurons are implicated in modulating nociceptive transmission. It is established that 5‐HT neuronal activity is enhanced by rhythmic behaviors such as chewing and locomotion in animals. We thus hypothesized that 5‐HT descending inhibitory pathways may be enhanced by rhythmic behavior of gum chewing in humans. To evaluate this idea, we examined nociceptive flexion reflex (NFR), while a subject chewed gum rhythmically for 20 min. NFR was elicited by electrical stimulation of the sural nerve, and the evoked potential was recorded from the biceps femoris muscle. Visual analogue scale (VAS) was also obtained. To assess 5‐HT activity, we determined 5‐HT levels quantitatively in platelet poor plasma (PPP) and whole blood (WB) using HPLC system. Both NFR area and VAS were significantly decreased at 5 min after the onset of chewing and these reductions persisted until cessation of chewing. There were no significant changes in NFR and VAS while resting without chewing. The PPP 5‐HT level increased significantly just after cessation of chewing and had returned to the pre‐chewing level by 30 min after cessation of chewing. The WB 5‐HT level obtained 30 min after cessation of chewing was significantly greater than the pre‐chewing level. Serotonin transporters have recently been discovered at the blood–brain barrier, suggesting that the rise in blood 5‐HT may possibly reflect an increase in 5‐HT level within the brain. The present results support our hypothesis that the rhythmic behavior of chewing suppresses nociceptive responses via the 5‐HT descending inhibitory pathway.

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain

In an attempt to clarify whether glial cell line‐derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal‐transducing receptor Ret after nerve injury in two rat models of neuropathic pain. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. In CCI‐treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL‐treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI‐treated rats at 7 and 14 postoperative days and in SNL‐treated rats at 14 days. In CCI‐ or SNL‐treated rats, continuous intrathecal administration of GDNF (12 μg day−1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.

Expression changes of cation chloride cotransporters in the rat spinal cord following intraplantar formalin.

Cation chloride cotransporters, K(+)-Cl(-) cotransporter 2 (KCC2) and Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) are reported to be expressed in the neurons in the spinal cord and regulate intracellular Cl(-) concentration. Evidence has been accumulating that the expression of cation chloride cotransporters changes in inflammatory or neuropathic pain, and such changes take a part in pathophysiology of the persistent pain states. However, it is largely unknown how these cotransporters contribute to hyperalgesia in the acute pain state. We, therefore, investigated expression changes of KCC2 and NKCC1 in the spinal dorsal horn of the rat after the intraplantar injection of formalin as an acute nociceptive stimulus. The rats showed two phases (phases 1 and 2) of increase in pain-related behavior in response to formalin. We found that expression of KCC2-like immunoreactivity (IR) was reduced in lamina I and II in the lumbar spinal cord on the stimulated side in phase 1, and then recovered gradually. In contrast, the number of NKCC1-like IR-positive cells was unchanged over the period examined. These results suggest that KCC2, rather than NKCC1, mainly contributes to modulating excitability of the dorsal spinal cord neurons in the initial stage of formalin-evoked hyperalgesia.

Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism.

Several clinical reports have suggested that there is a hyperactivation of the dopaminergic system in people with autism. Using rats exposed prenatally to valproic acid (VPA) as an animal model of autism, we measured dopamine (DA) levels in samples collected from the frontal cortex (FC) using in vivo microdialysis and HPLC. The basal DA level in FC was significantly higher in VPA-exposed rats relative to controls. Since the mesocortical DA system is known to be sensitive to physical and psychological stressors, we measured DA levels in FC before, during, and after a 60-min forced swim test (FST). There were further gradual increases in FC DA levels during the FST in the VPA-exposed rats, but not in the control rats. Behavioral analysis during the last 10 min of the FST revealed a significant decrease in active, escape-oriented behavior and an increase in immobility, which is thought to reflect the development of depressive behavior that disengages the animal from active forms of coping with stressful stimuli. These results suggest that this rodent model of autism exhibits a hyperactive mesocortical DA system, which is exaggerated by swim stress. This abnormality may be responsible for depressive and withdrawal behavior observed in autism.

Heterotopic painful stimulation decreases the late component of somatosensory evoked potentials induced by electrical tooth stimulation.

The purpose of this study was to determine the relationship between the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and subjective pain estimation when heterotopically painful stimulation was delivered to humans. The noxious electrical conditioning stimuli were applied to the left median nerve in noxious session I and the right median nerve in noxious session II for 10 min. The amplitude of the late component and visual analogue scale (VAS) value were both decreased significantly by conditioning stimuli in both sessions. The maximum decreases in SEP amplitude and VAS value induced by conditioning stimuli were respectively 40.2 and 37.2% in noxious session I and 49.3 and 42.3% in noxious session II. After-effect was observed 5 min after removal of the conditioning stimuli. The rates of decrease were thus nearly the same and independent of the site of conditioning stimulation in noxious sessions I and II. The SEP amplitude was significantly correlated with VAS values. The present study revealed that SEP amplitude and subjective pain intensity estimated by VAS following electrical tooth stimulation can be decreased by noxious stimuli to hand. This finding that heterotopic painful stimulation attenuates experimentally-induced tooth pain suggests a triggering of diffuse noxious inhibitory control (DNIC) with after-effect in trigeminal region.

Long-term pain control in trigeminal neuralgia with local anesthetics using an indwelling catheter in the mandibular nerve.

ObjectiveThe authors sought to determine the usefulness of long-term continuous trigeminal nerve block with local anesthetics using an indwelling catheter in a patient with trigeminal neuralgia. DesignThe study design included pain control in a patient with trigeminal neuralgia until the time of neurosurgical operation. SettingThe study was conducted in the Dental Hospital of Tokyo Medical and Dental University. PatientThe patient was a 78-year-old woman with trigeminal neuralgia in the right maxillary region. Her pain could not be controlled by carbamazepine and was unbearable. InterventionThe authors estimated the patients pain intensity, quality, and locality using a visual analog scale to determine the effectiveness of continuous nerve block. Outcome MeasuresVisual analog scores were measured during treatment. The treatment term was divided into three periods according to the difference of the catheter location and injection protocol (premandibular nerve block, infuser injection, and patient-controlled analgesia [PCA] pump injection). The authors also examined the patients general condition and blood concentration of drugs. ResultsThe visual analog values were 44.8 ± 3.6, 26.7 ± 3.5, and 11.9 ± 3.1 mm in each period, respectively. The value in the PCA pump infusion period was significantly lower than that in the other periods. No side effects of the local anesthetics were observed on the patients systemic condition. ConclusionsThe authors controlled trigeminal neuralgia pain by blocking the mandibular nerve with local anesthetics administered through an indwelling catheter. Because the continuous nerve block with local anesthetics is reversible and only mildly toxic, this method is beneficial for pain control in patients with trigeminal neuralgia scheduled to undergo microvascular decompression.

A mechanism of the high frequency AC iontophoresis

The efficiency and the voltage dependence of the AC iontophoresis were studied in vitro. Two cylindrical glass cells separated by a cellophane film were used, where the donor cell was filled with the solution of target electrolytes and the receptor cell with distilled water. The sinusoidal AC voltage with a frequency of 1 kHz was applied between the two platinum plates located at the opposite ends of two cells. The time variation of the ion concentration was evaluated by measuring the impedance of the solution in the receptor cell. The transportation velocity of the ions increased with the amplitude of the voltage applied between two platinum plate electrodes apart 20 mm up to approximately 15 V, and leveled off above approximately 15 V. A theoretical model is proposed on the AC iontophoresis, where each ion moves together with the surrounding water molecules when it is hydrated. The effective Stokes radius of an ion is assumed to be half of the whole size of the ion with hydrating water molecules. When the external alternating electric field strongly vibrates the ion, the ion-dipole interactions between the ion and water molecules are broken, resulting in the reduced effective Stokes radius, which leads to the increase of the diffusion efficiency.

Diffuse noxious inhibitory controls triggered by heterotopic CO2 laser conditioning stimulation decreased the SEP amplitudes induced by electrical tooth stimulation with different intensity at an equally inhibitory rate.

&NA; The purpose of this study was to investigate (1) whether selective Aδ‐fiber stimulation with CO2 laser produces a diffuse noxious inhibitory controls (DNIC) effect in the trigeminal nerve territory; and (2) whether the DNIC effect differs depending on test stimulus intensities under constant conditioning stimuli. To examine whether the CO2 laser radiation on the dorsum of the hand selectively stimulates Aδ‐fibers, laser evoked potentials (LEP) were recorded. The mean peak latency of LEP was 381.4 ms. The findings revealed that the CO2 laser selectively stimulated Aδ‐fibers. Electrical tooth stimuli with 3 levels of intensities (1.2, 1.4, 1.6 times the pain threshold) were applied to subjects as test stimulation in randomized order, with a CO2 laser stimulus of 18 mJ/mm2 applied to the dorsum of the hand for 4 min as the noxious conditioning stimulus. Somatosensory evoked potentials (SEP) induced by electrical tooth stimulation were recorded and tooth pain intensity was evaluated using a visual analogue scale (VAS). The amplitudes of the SEP late component and VAS values were significantly decreased only during the conditioning stimuli without aftereffect. The inhibitory rates of the amplitudes ranged from 31.3% to 34.6% and the VAS values from 29.0% to 31.2%. There were no significant differences in their inhibitory rates between the 3 test stimulus intensities. The result indicated that selective Aδ‐fiber stimulation with the CO2 laser produces a DNIC effect in the trigeminal nerve territory and suggested that the DNIC effect does not depend on the intensity of the test stimuli.