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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Postoperative hyperthermia of unknown origin treated with dantrolene sodium.

An 11-year-old girl was scheduled for alveolar cleft bone grafting with an iliac bone under general anesthesia. Anesthesia was performed with 70% nitrous oxide, 30% oxygen, and propofol. On the first and second postoperative day, persistent hyperthermia was observed. Because the administration of diclofenac sodium had not been effective for the hyperthermia, dantrolene sodium was given. Her body temperature gradually dropped and returned to normal level on the fifth postoperative day. The hyperthermia in the present case might have been caused by a rapidly elevated muscle metabolism in response to pain and stress after the propofol anesthesia. The oral administration of dantrolene sodium successfully lowered the patient's high body temperature.

A new method of recording somatosensory evoked potentials by randomized electrical tooth stimulation with 6 levels of intensity.

Dental somatosensory evoked potentials (SEPs) corresponding to the stimulus intensity levels were recorded at 6 different levels of intensity presented in a randomized order. The relationships between the amplitude of the late SEP component with latency between 150 and 300 msec and each stimulus intensity level were also compared in conditions of randomized intensity and constant intensity. The amplitude of the late component increased significantly with the increased stimulus intensity both in the randomized and constant intensity stimulation. The amplitude of the late component in the randomized stimulation with a 1-sec interstimulus interval (ISI) increased in the same manner as that in the constant intensity condition with a 1-sec ISI. The randomized stimulation with the prolonged ISI increased the amplitude of the late component. The latency of the late positive component significantly increased with the randomized stimulation with a 3-sec ISI. This phenomenon might be attributable to the psychological contamination. SEP recording in the randomized dental stimulation with a 1-sec ISI may have applications in neuropharmacological research or physiological research on pain and evaluation of the effects of analgesics, anesthetics, acupuncture and transcutaneous electrical nerve stimulation (TENS).

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

1. 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. 2. 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. 3. 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. 4. 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. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. 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.

An experimental system for a heterotopic pain stimulation study in humans.

So far heterotopic pain stimulation study has been performed in humans. Many studies have examined changes in subjective pain threshold and nociceptive somatic reflex. However, there are few studies using somatosensory evoked potentials (SEPs) for heterotopic pain stimulation study. Here we describe a new experimental system for a heterotopic pain stimulation study in humans. This system consists of three subsystems including the electrical test stimulation for teeth, the recording of SEP induced by electrical tooth stimulation and conditioning nerve stimulation. The preliminary experiment performed in eight healthy subjects indicated that the electrical test stimulation subsystem with the SEP recording subsystem is also very well indicated for subjective and objective pain evaluation, including VAS estimation and the amplitude of the SEP late component induced by electrical tooth stimulation. Under the experimental system in the present study, electrical median nerve stimulation as conditioning stimulation significantly decreased both the SEP amplitude induced by electrical tooth simulation and subjective pain expressed by the VAS. These results revealed that our experimental system works well and it is very suitable and useful for the study of the pain mechanism under heterotopic stimulation in humans.

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

OBJECTIVE: The 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. DESIGN: The study design included pain control in a patient with trigeminal neuralgia until the time of neurosurgical operation. SETTING: The study was conducted in the Dental Hospital of Tokyo Medical and Dental University. PATIENT: The 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. INTERVENTION: The authors estimated the patient's pain intensity, quality, and locality using a visual analog scale to determine the effectiveness of continuous nerve block. OUTCOME MEASURES: Visual 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 patient's general condition and blood concentration of drugs. RESULTS: The 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 patient's systemic condition. CONCLUSIONS: The 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.

Comparison of topical anesthesia of 20% benzocaine and 60% lidocaine gel.

OBJECTIVE: The purpose of this study was to determine the efficacies of 2 topical anesthetics commonly used in dentistry. STUDY DESIGN: The alveolar mucosa of the upper incisor apices of 20 healthy male volunteers was applied for 20 minutes with either 20% benzocaine gel or nothing as a control. The second part of experiment was done with 60% lidocaine gel and vehicle as control. Three methods of stimulation were given, and the pain rating score and visual analog scale were measured after each stimulation. RESULTS: Twenty percent benzocaine did not significantly alter pain perception as measured by the pain rating score and visual analog scale with these 3 methods of stimulation. In contrast, 60% lidocaine significantly reduced pain perception according to these measurements. We conclude that 60% lidocaine gel is effective for topical anesthesia before infiltration anesthesia.