New method for postoperative pain relief using a combination of noxious and non-noxious stimuli after impacted wisdom tooth extraction.

Although in clinical dentistry the major method used for pain relief is oral administration of analgesics, alternative methods are available, such as transcutaneous electrical nerve stimulation (TENS), acupuncture, vibration and conditioned pain modulation (CPM), formerly termed diffuse noxious inhibitory control. The aim of the present study was to investigate the combined effects of non-noxious (TENS) and noxious (CPM) stimuli on postoperative pain after extraction of an impacted wisdom tooth. The study involved 44 patients who were scheduled to undergo impacted wisdom tooth extraction. The patients were randomly allocated into four groups: noxious stimuli, non-noxious stimuli, combined noxious and non-noxious stimuli, and a sham group. On the day after tooth extraction, stimulation procedures for pain relief were performed and changes in the level of perceived pain were scored using a visual analog scale (VAS). The combination of non-noxious and noxious stimuli decreased the VAS scores by 63.7%, indicating a more potent analgesic effect than that in the non-noxious, noxious, and sham groups. This method of analgesia using a combination of non-noxious and noxious stimuli can be applied to patients who are unable to tolerate analgesics, such as those with allergy, hypersensitivity or digestive disorders, and those who are pregnant.

Enhancement of Analgesic Effect by Combination of Non-Noxious Stimulation and Noxious Stimulation in Humans.

The aim of the this study was to investigate the combined effects of heterosegmental non-noxious and noxious stimulation on electrically induced tooth pain. The late component of somatosensory-evoked potentials (SEP), induced by electrical tooth stimulation and pain intensity, were examined under electrical stimulation to forearms. Noxious, non-noxious, and combined non-noxious and noxious electrical stimulation were applied to median nerves on the forearms. Four experimental sessions (ie, control session, combined non-noxious and noxious stimulation session, non-noxious stimulation session, and noxious stimulation session were performed for each subject at each 10-minute interval for 30 minutes. The amplitudes of the SEP and VAS scores in the combined stimulation session decreased significantly compared with those in the control session and the reduction rates were 51.1% (13.4 µV) and 41.0% (23.5 mm), respectively. These results show that the combined stimulation has a more potent analgesic effect than that of either the non-noxious or the noxious stimulation. It is suggested that a potent analgesia was produced by an activated central mechanism, including endogenous opioid and descending pain inhibitory systems due to combined non-noxious and noxious stimulation.

The effect of alternating current iontophoresis on rats with the chronic constriction injury to the infraorbital nerve.

This study aimed to examine the effect of AC iontophoresis on rats with the chronic constriction injury (CCI) to the infraorbital nerve by animal experiments. CCI model rats were divided into four groups, namely, rats that received general anesthesia for 60 min except AC IOP (CCI: n = 5), AC IOP with 0.9% physiological saline for 60 min (CCI + saline AC IOP: n = 5), AC IOP with 4% lidocaine hydrochloride for 60 min (CCI + lidocaine AC IOP: n = 5), and attachment of two electrodes soaked with 4% lidocaine hydrochloride to the facial skin for 60 min (CCI + attach lidocaine: n = 5). In the CCI + lidocaine AC IOP group, an elevated withdrawal threshold was observed after AC IOP, and the duration of efficacy was longer compared with that in the CCI + saline AC IOP and CCI + attached lidocaine groups. A significant decrease in the number of Fos-like immunoreactive (LI) cells was observed in the CCI + lidocaine AC IOP group compared with that in the CCI group. These findings suggest that the effect of CCI + lidocaine AC IOP group may be caused by active permeation of lidocaine into the facial skin and electrical stimulation of the trigeminal nucleus.

In vitro evaluation of calcium alginate gels as matrix for iontophoresis electrodes.

Calcium alginate gel has some unique properties, such as the capability to keep the drugs, bioadhesiveness, safety, and low cost. The purpose of this study is to determine whether calcium alginate gel can be used as a matrix of electrodes for iontophoresis (IOP). We measured the concentration of lidocaine transported from calcium alginate gels with various concentrations of alginic acid using an in vitro experimental cell with square-wave alternating current (AC) application. Temperature and pH changes were also determined during AC-IOP. The results revealed that lidocaine was released from calcium alginate gels at concentrations nearly 1.71-fold larger at 5 V, 60 min after AC application than in the case of passive diffusion. Lidocaine transport depended on the alginic acid concentration in the gels. Although there were slight increases in temperature and pH, chemical and thermal burns were not severe enough to be a concern. In conclusion, the calcium alginate gel can be used as a possible matrix for IOP electrodes.

The relation between the duty cycle and anesthetic effect in lidocaine iontophoresis using alternating current.

We assessed the effect of the duty cycle on the anesthetic effect during lidocaine alternating current (AC) iontophoresis. A solution of 2% lidocaine was delivered to the medial antecubital skin for 20 minutes using AC iontophoresis with a duty cycle of 60%, 70%, or 80%. The von Frey test was then performed to evaluate the anesthetic effect. In the groups treated with a duty cycle of 80% or 70% the touch thresholds (TT) were significantly elevated from 0 minutes to 30 minutes and from 0 minutes to 20 minutes. TT were significantly elevated at 0 minutes in the group treated with a 60% duty cycle. The anesthetic effect was significantly enhanced in a duty cycle-dependent manner.

Prolonged gum chewing evokes activation of the ventral part of prefrontal cortex and suppression of nociceptive responses: involvement of the serotonergic system.

We have proposed a concept that prolonged rhythmic gum chewing causes a suppressed nociceptive flexion reflex via the serotonergic (5-HT) descending inhibitory pathway. However, the mechanism of activation of the 5-HT system by gum chewing remains undetermined. Several human and animal studies have reported that a direct connection exists between the prefrontal cortex (PFC) and 5-HT neurons in the dorsal raphe nucleus; therefore, we hypothesized that activation of the PFC region might be responsible for augmented 5-HT activity. To evaluate this hypothesis, oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin concentrations in the PFC were measured in the PFC during a 20-min time period of gum chewing using 24-channel near-infrared spectroscopy. A significant increase in oxyHb level was observed in the ventral part of PFC compared with the dorsal part of PFC. We confirmed the previous results in that the nociceptive flexion reflex was significantly suppressed and the 5-HT level in blood was significantly increased following prolonged gum chewing. These results support the hypothesis that activation of the ventral part of PFC during gum chewing evokes augmented activity of 5-HT neurons in the dorsal raphe nucleus, which in turn suppress nociceptive responses.

Heterotopic CO2 laser stimulation inhibits tooth-related somatosensory evoked potentials.

BACKGROUND: The diffuse noxious inhibitory control (DNIC) effect is the neurophysiological basis for the phenomenon that heterotopic "pain inhibits pain" in remote areas of the body. The effect of DNIC is mediated by spino-bulbo-spinal loops and a final postsynaptic inhibitory mechanism. The DNIC effect depends on intensity, duration, quality, and application site of conditioning stimulation and stimulated nerve fiber-type. DNIC induced by CO(2) laser conditioning stimulation has, however, not yet been investigated, and the present study was designed to examine this. METHODS: As the indicator of test stimulation, the late component of somatosensory evoked potentials (SEPs) induced by electrical tooth stimulation and pain intensity were examined under CO(2) laser conditioning stimulation. As the conditioning stimuli, CO(2) laser energy (lambda = 10.6 microm, spot size Ø = 2 mm) was applied to the dorsum of the left hand. RESULTS: The maximum reductions in SEP amplitude and pain intensity evaluated using a visual analog scale were 34.7% and 28.7%, respectively during CO(2) laser conditioning stimulation. No aftereffect was observed. CONCLUSION: The present study revealed that CO(2) laser radiation attenuated the late component of SEPs induced by electrical tooth stimulation, triggering the DNIC effect but with no aftereffect.

Phenylephrine suppresses the pain modulation of diffuse noxious inhibitory control in rats.

BACKGROUND: Diffuse noxious inhibitory control (DNIC) is a phenomenon whereby wide dynamic range neurons are selectively and powerfully inhibited through the central nervous system by noxious stimuli heterotopically applied to a body area distant from their excitatory receptive fields. Previous work has shown that systemic administration of an alpha1-adrenoceptor agonist, phenylephrine (PE), blocked the DNIC. We hypothesized that descending inhibitory pathways mediate the DNIC mechanism and that the neural network of the DNIC loop exists in the middle brainstem, likely in a more rostral part than formerly assumed, possibly the nucleus raphe magnus (RMg). The aim of this study was to determine whether DNIC is directly modulated by PE when administered close to the RMg. METHODS: The experiments were performed on anesthetized male Sprague-Dawley rats. For administration of different drugs close to the RMg, the tip of a 33-gauge cannula was placed into an area close to the RMg as determined using the atlas of Paxinos and Watson. Single square-wave electrical stimuli were applied to the digits of the left hindpaw. The C-fiber reflex response elicited by electrical stimulation within the receptive field of the ipsilateral sural nerve was recorded from the biceps femoris muscle in the absence and presence of noxious tail immersion in warm water at 50 degrees C. The DNIC effect was calculated from a recorded electromyogram as the "inhibition rate." Saline (0.05 microL) or PE (0.05 microg/0.05 microL) was microinjected close to the RMg through the cannula. The C-fiber reflex evoked by electromyographic activity was recorded the same way. The inhibition rate of the C-fiber reflex was compared before and after administration of drugs. A paired t test was used for statistical comparison between same drug administration groups, and 1-way analysis of variance and Bonferroni multiple comparison were used for statistical analysis between different drugs. At the end of all experiments, the tissue-contacting end of the cannula tip was cauterized with an electric current to localize the drug administration site. The brain was removed, sliced in coronal sections, and stained with hematoxylin and eosin. RESULTS: The C-fiber reflex inhibited by noxious thermal stimuli (DNIC) was significantly blocked after the injection of PE close to the RMg. CONCLUSION: Direct administration of PE close to the RMg inhibited DNIC, thereby affecting and modulating the intrinsic pain inhibition system. These findings suggest that the RMg may be involved in the regulation of DNIC.

Effects of alpha-adrenergic agonists on pain modulation in diffuse noxious inhibitory control.

BACKGROUND: Diffuse noxious inhibitory control (DNIC) is thought to be mediated by neural networks in supraspinal brain structures. The descending antinociceptive system (DAS) is an important component of the DNIC neural network, but the precise structure of the neural network and the related neurotransmitters have not been examined. METHODS: The study was designed to examine whether systemic administration of the adrenergic agonists dexmedetomidine (DEX) and phenylephrine (PE) influences DNIC in the rat. Changes in the C-fiber reflex evoked by electromyographic activity were recorded following noxious tail immersion in hot water. RESULTS: Inhibition of the C-fiber reflex by the conditioning stimuli was reduced from 77.1 +/- 22.6% to 26.6 +/- 38.2% with continuous administration of DEX, and restored to 58.3 +/- 29.2% by intramuscular injection of atipamezole hydrochloride(APZ), a selective alpha 2-adrenoceptor antagonist. Inhibition of the C-fiber reflex was reduced from 75.6 +/- 25.8% to 22.7 +/- 38.9% with continuous administration of PE, and restored to 84.9 +/- 9.7% by intramuscular injection of phentolamine mesylate (PT), an alpha-adrenoceptor antagonist. CONCLUSION: The results show that clinical doses of DEX and PE inhibit DNIC, thereby affecting and modulating the intrinsic pain inhibition system. These findings suggest that adrenergic neurons are involved in DNIC.

Lidocaine transport through a cellophane membrane by alternating current iontophoresis with a duty cycle.

The purpose of this study was to determine whether lidocaine can be efficiently transported across a cellophane membrane using a square-wave alternating current (AC) with an adjusted duty cycle. Three voltages at 1 kHz with 6 duty cycles were applied for 60 min to the diffusion cells on both sides of the cellophane membrane. The donor chamber was filled with 1% lidocaine hydrochloride solution. The transport of lidocaine was enhanced in a voltage-, and duty cycle-dependent manner. These findings indicate that voltage and the direct current (DC) component of the square-wave AC play important roles in generating the driving force necessary for lidocaine delivery. Additionally, the periodic polarity alteration could reduce the electrode polarization. The higher voltages and duty cycles induced a pH change. The practical electrical conditions which are preferable for clinical application were 10 V with a 70% duty cycle or 20 V with a 60% duty cycle.

The relation between epinephrine concentration and the anesthetic effect of lidocaine iontophoresis.

We assessed the effect of epinephrine at various concentrations on the anesthetic effect during lidocaine iontophoresis. A solution of 2% lidocaine with epinephrine in concentration of 1:80,000, 1:160,000, 1:320,000, 2% lidocaine plain and normal saline control was delivered to the medial antecubital skin for 10 minutes by iontophoresis with 1.0 mA of direct current. The pinprick test and the von Frey test were conducted to evaluate anesthetic effect. Pricking pain using visual analogue scale was significantly lower throughout the entire experiment compared with the baseline values and lasted for 60 minutes in groups with 1:80,000 and 1:160,000 epinephrine. The pressure pain thresholds (PPT) and the touch thresholds (TT) were significantly elevated in groups with 1:80,000 and 1:160,000 epinephrine compared with the baseline values. No significant elevations in the PPT and TT values were observed in the other groups. The present study revealed that the anesthetic effect was significantly enhanced in an epinephrine dose-related manner and the anesthetic effect of 2% lidocaine with 1:160,000 epinephrine was equivalent to the same anesthetic with 1:80,000 epinephrine.

Occurrence of intermittent Wolff-Parkinson-White syndrome during intravenous sedation.

Patients with intermittent Wolff-Parkinson-White (WPW) syndrome, defined as intermittent loss of the delta waves, can show occasional conduction through the accessory pathway. WPW syndrome often causes paroxysmal supraventricular tachycardia or atrial fibrillation. However, it may be difficult to identify the abnormalities preoperatively because of their only intermittent occurrence. We report a case in which exogenously administered epinephrine and an autonomic imbalance may have precipitated the abrupt occurrence and disappearance of the delta waves.

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.

Pentazocine transport by square-wave AC iontophoresis with an adjusted duty cycle.

So far, pentazocine iontophoresis has never been studied, although pentazocine is widely used in pain management. The purpose of this study was to determine whether pentazocine transportation through a cellophane membrane could be enhanced using square-wave alternating current (AC) iontophoresis with an adjusted duty cycle and dependence on the voltage and the duty cycle. Voltages of 10, 25 and 40 V with duty cycles of 50%, 51%, 52%, 53%, 54% and 55% were applied for 60 minutes at a high frequency of 1 MHz to diffusion cells on both sides of a cellophane membrane. The donor compartment was filled with a solution containing pentazocine. Square-wave AC iontophoresis with an adjusted duty cycle enhanced pentazocine transportation at higher voltages and duty cycles. These results suggested that the direct current (DC) component of the square-wave AC played an important role in enhancing pentazocine transportation despite changes in polarity at very high frequency of 1 MHz. The higher voltages and duty cycles induced a pH change. The practical electrical conditions that could be applied clinically were 25 V with a 54% duty cycle or 40 V with a 53% duty cycle.

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.

The purpose of this study was to investigate (1) whether selective Adelta-fiber stimulation with CO(2) 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 CO(2) laser radiation on the dorsum of the hand selectively stimulates Adelta-fibers, laser evoked potentials (LEP) were recorded. The mean peak latency of LEP was 381.4 ms. The findings revealed that the CO(2) laser selectively stimulated Adelta-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 CO(2) laser stimulus of 18 mJ/mm(2) 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 Adelta-fiber stimulation with the CO(2) 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.

General anesthesia for dental treatment in a Williams syndrome patient with severe aortic and pulmonary valve stenosis: suspected episode of postoperatively malignant hyperthermia.

A 28-month-old boy (height, 76 cm; weight, 9.4 kg) diagnosed as having Williams syndrome presented for dental care. We report a case of postoperatively suspected malignant hyperthermia after the administration of general anesthesia for dental treatment in this patient with severe supravalvular aortic stenosis and pulmonary artery hypoplasia. Anesthesia was maintained through the inhalation of nitrous oxide and sevoflurane with oxygen. The patient was hemodynamically stable and no other abnormalities were observed. After the completion of the dental treatment, he was transferred to the pediatric ward. On arrival at the ward, the patient's core temperature increased to 39.5 degrees C and tachypnea (RR, 30 breaths/min) was observed. The SPO2 during inhalation was slightly low (92%-93%). Serum biochemistry revealed an elevated CK level (1345 U/L) but no other abnormal findings. Twelve hours after the dental treatment, the patient's core temperature fell to 37.4 degrees C. After hospitalization for 4 days, the patient was discharged in good condition. In the present case, general anesthesia was employed for dental treatment despite severe supravalvular aortic stenosis and peripheral pulmonary artery hypoplasia, because conventional dental therapy was very difficult as a result of the patient's mental retardation and hyperkinesia. The present case suggests that the use of volatile agents that could trigger malignant hyperthermia should be avoided wherever possible.

Vasovagal syncope with asystole associated with intravenous access.

Two cases of vasovagal syncope (VVS) during venous access are reported. Both patients had a history of fainting episodes and experienced bradycardia with asystole, hypotension, and fainting. Pain and phobic stress during venous access triggered an increase in parasympathetic tone, resulting in bradycardia with asystole and hypotension in both cases. Hypotension and bradycardia likely caused cerebral hypoperfusion, leading to fainting. The intense parasympathetic tone triggered by somatic or emotional stress was likely responsible for directly depressing the sinus node, leading to asystole and bradycardia. Bradycardia with asystole progressing to syncope is a potentially fatal dysrhythmia in patients with cardiovascular disease or older patients with decreased cardiac function. Appropriate treatment for VVS includes the administration of intravenous fluids, vagolytics, ephedrine, and the rapid use of the Trendelenburg position. Intravenous fluids and atropine were used to treat the present patients.

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.

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 individual's 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.