Fast-spiking Interneurons Contribute to Propofol-induced Facilitation of Firing Synchrony in Pyramidal Neurons of the Rat Insular Cortex.

BACKGROUND: The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. METHODS: Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 µM propofol application. RESULTS: Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. CONCLUSIONS: These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.

Loss of Dec1 prevents autophagy in inflamed periodontal ligament fibroblast.

Periodontal ligament fibroblasts (PDLFs) are integral to the homeostasis of periodontal tissue. The transcription factor Dec1 functions to modulate Porphyromonas gingivalis-induced periodontal inflammation. Here, we aimed to characterize the Dec1-mediated autophagy in PDLFs under inflammatory conditions. Human PDLFs were subjected to an inflammatory environment using P. gingivalis Lipopolysaccaride (LPS) along with Dec1 siRNA in vitro. Quantitative real-time polymerase chain reaction and Western blot analyses were used to evaluate the expression levels of autophagy-related genes and their upstream AKT/mTOR signaling pathways. An experimental P. gingivalis-treated Dec1 knockout (Dec1KO) mouse model was used to confirm the expression of autophagy in PDLFs in vivo. Treatment with P. gingivalis LPS induced the expression of ATG5, Beclin1 and microtubule-associated protein 1 light chain 3 (LC3) and elevated the expression of pro-inflammatory cytokine IL-1ß and Dec1 in human PDLFs. Knockdown of Dec1 partly reversed the detrimental influences of LPS on these autophagy markers in human PDLFs. The inhibition of autophagy with Dec1 siRNA suppressed the inflammatory effect of AKT/mTOR signaling pathways following treatment with P. gingivalis LPS. P. gingivalis-treated Dec1KO mice partly reduced autophagy expression. These findings suggest that a Dec1 deficiency can modulate the interaction between autophagy and inflammation in PDLFs.

Propofol decreases spike firing frequency with an increase in spike synchronization in the cerebral cortex.

Little is known about how propofol modulates the spike firing correlation between excitatory and inhibitory cortical neurons in vivo. We performed extracellular unit recordings from rat insular cortical neurons, and classified neurons with high spontaneous firing frequency, bursting, and short spike width as high frequency with bursting neurons (HFB; pseudo fast-spiking GABAergic neurons) and other neurons with low spontaneous firing frequency and no bursting were classified as non-HFB. Intravenous administration of propofol (12 mg/kg) from the caudal vein reduced the firing frequency of HFB, whereas propofol initially increased (within 30 s) and then decreased the firing frequency of non-HFB. Both HFB and non-HFB spontaneous action potential discharge was depressed by propofol with a greater depression seen for HFB. Cross-correlograms and auto-correlograms demonstrated propofol-induced increases in the ratio of the peak, which were mostly observed around 0-10 ms divided to baseline amplitude. The analysis of interspike intervals showed a decrease in spike firing at 20-100 Hz and a relative increase at 8-15 Hz. These results suggest that propofol induces a larger suppression of firing frequency in HFB and an enhancement of synchronized neural activities in the α frequency band in the cerebral cortex (192 words).

Fast-spiking cell to pyramidal cell connections are the most sensitive to propofol-induced facilitation of GABAergic currents in rat insular cortex.

BACKGROUND: Propofol facilitates γ-aminobutyric acid-mediated inhibitory synaptic transmission. In the cerebral cortex, γ-aminobutyric acidergic interneurons target both excitatory pyramidal cells (Pyr) and fast-spiking (FS) and non-FS interneurons. Therefore, the propofol-induced facilitation of inhibitory transmission results in a change in the balance of excitatory and inhibitory inputs to Pyr. However, it is still unknown how propofol modulates γ-aminobutyric acidergic synaptic transmission in each combination of Pyr and interneurons. METHODS: The authors examined whether propofol differentially regulates inhibitory postsynaptic currents (IPSCs) depending on the presynaptic and postsynaptic cell subtypes using multiple whole cell patch clamp recording from γ-aminobutyric acidergic interneurons and Pyr in rat insular cortex. RESULTS: Propofol (10 µM) consistently prolonged decay kinetics of unitary IPSCs (uIPSCs) in all types of inhibitory connections without changing paired-pulse ratio of the second to first uIPSC amplitude or failure rate. The FS→Pyr connections exhibited greater enhancement of uIPSC charge transfer (2.2 ± 0.5 pC, n = 36) compared with that of FS→FS/non-FS connections (0.9 ± 0.2 pC, n = 37), whereas the enhancement of charge transfer in non-FS→Pyr (0.3 ± 0.1 pC, n = 15) and non-FS→FS/non-FS connections (0.2 ± 0.1 pC, n = 36) was smaller to those in FS→Pyr/FS/non-FS. Electrical synapses between FS pairs were not affected by propofol. CONCLUSIONS: The principal inhibitory connections (FS→Pyr) are the most sensitive to propofol-induced facilitation of uIPSCs, which is likely mediated by postsynaptic mechanisms. This preferential uIPSC enhancement in FS→Pyr connections may result in suppressed neural activities of projection neurons, which in turn reduces excitatory outputs from cortical local circuits.

Sedation outcomes for remimazolam, a new benzodiazepine.

Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is expected to be safe and effective for a wide range of patients undergoing intravenous sedation for dental procedures. The aim of this literature review was to evaluate clinical and sedation outcomes for remimazolam, including method of administration, level of sedation at the dose required, and clinical adverse events. An electronic literature search of databases was conducted, and eight articles were selected for inclusion in this review. Onset time from drug administration to optimal sedation level was faster for remimazolam (around 1.5-6.4 min) than for midazolam. Recovery time was significantly shorter for remimazolam than for midazolam and propofol. A study comparing various doses of remimazolam with midazolam found no significant difference in safety. Comparison of a remimazolam group with a propofol group showed that incidences of hypotension (13.0% vs 42.9%, respectively) and respiratory depression (1.1% vs 6.9%, respectively) were significantly lower for remimazolam. Remimazolam appears to be an ideal sedative.

Presynaptic interneuron subtype- and age-dependent modulation of GABAergic synaptic transmission by beta-adrenoceptors in rat insular cortex.

beta-Adrenoceptors play a crucial role in the regulation of taste aversion learning in the insular cortex (IC). However, beta-adrenergic effects on inhibitory synaptic transmission mediated by gamma-aminobutyric acid (GABA) remain unknown. To elucidate the mechanisms of beta-adrenergic modulation of inhibitory synaptic transmission, we performed paired whole cell patch-clamp recordings from layer V GABAergic interneurons and pyramidal cells of rat IC aged from postnatal day 17 (PD17) to PD46 and examined the effects of isoproterenol, a beta-adrenoceptor agonist, on unitary inhibitory postsynaptic currents (uIPSCs). Isoproterenol (100 microM) induced facilitating effects on uIPSCs in 33.3% of cell pairs accompanied by decreases in coefficient of variation (CV) of the first uIPSC amplitude and paired-pulse ratio (PPR) of the second to first uIPSC amplitude, whereas 35.9% of pairs showed suppressive effects of isoproterenol on uIPSC amplitude obtained from fast spiking (FS) to pyramidal cell pairs. Facilitatory effects of isoproterenol were frequently observed in FS-pyramidal cell pairs at > or =PD24. On the other hand, isoproterenol suppressed uIPSC amplitude by 52.3 and 39.8% in low-threshold spike (LTS)-pyramidal and late spiking (LS)-pyramidal cell pairs, respectively, with increases in CV and PPR. The isoproterenol-induced suppressive effects were blocked by preapplication of 100 microM propranolol, a beta-adrenoceptor antagonist. There was no significant correlation between age and changes of uIPSCs in LTS-/LS-pyramidal cell pairs. These results suggest the presence of differential mechanisms in presynaptic GABA release and/or postsynaptic GABA(A) receptor-related assemblies among interneuron subtypes. Age- and interneuron subtype-specific beta-adrenergic modulation of IPSCs may contribute to experience-dependent plasticity in the IC.

A Case of Successful Tracheal Tube Exchange With McGrath MAC for Tube Damage During Oral Surgery.

A patient undergoing a bilateral sagittal split and LeFort 1 maxillary osteotomy performed under general anesthesia required emergent intraoperative exchange of a potentially damaged nasotracheal tube. This exchange was smoothly performed under constant indirect visualization using the McGrath MAC video laryngoscopy system. After the exchange, ventilation of the patient dramatically improved. The removed endotracheal tube was torn 19 cm from the distal tip. The McGrath MAC was useful for visualizing the glottis and confirming the entire course of the tube exchange despite the patient's having a difficult airway (Cormack-Lehane grade 3).

Orexin facilitates GABAergic IPSCs via postsynaptic OX1 receptors coupling to the intracellular PKC signalling cascade in the rat cerebral cortex.

Orexin has multiple physiological functions including wakefulness, appetite, nicotine intake, and nociception. The cerebral cortex receives abundant orexinergic projections and expresses both orexinergic receptor 1 (OX1R) and 2 (OX2R). However, little is known about orexinergic regulation of GABA-mediated inhibitory synaptic transmission. In the cerebral cortex, there are multiple GABAergic neural subtypes, each of which has its own morphological and physiological characteristics. Therefore, identification of presynaptic GABAergic neural subtypes is critical to understand orexinergic effects on GABAergic connections. We focused on inhibitory synapses at pyramidal neurons (PNs) from fast-spiking GABAergic neurons (FSNs) in the insular cortex by a paired whole-cell patch-clamp technique, and elucidated the mechanisms of orexin-induced IPSC regulation. We found that both orexin A and orexin B enhanced unitary IPSC (uIPSC) amplitude in FSN→PN connections without changing the paired-pulse ratio or failure rate. These effects were blocked by SB-334867, an OX1 receptor (OX1R) antagonist, but not by TCS-OX2-29, an OX2R antagonist. [Ala11, D-Leu15]-orexin B, a selective OX2R agonist, had little effect on uIPSCs. Variance-mean analysis demonstrated an increase in quantal content without a change in release probability or the number of readily releasable pools. Laser photolysis of caged GABA revealed that orexin A enhanced GABA-mediated currents in PNs. Downstream blockade of Gq/11 protein-coupled OX1Rs by IP3 receptor or protein kinase C (PKC) blockers and BAPTA injection into postsynaptic PNs diminished the orexin A-induced uIPSC enhancement. These results suggest that the orexinergic uIPSC enhancement is mediated via postsynaptic OX1Rs, which potentiate GABAA receptors through PKC activation.

Role of GABA B receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats.

In vivo microdialysis was used to study the effects of the locally applied GABA B receptor antagonist 2-hydroxysaclofen and GABA B receptor agonist baclofen on the basal dopamine efflux as well as on the endomorphin-1- and endomorphin-2-induced dopamine efflux in the nucleus accumbens of freely moving rats. 2-Hydroxysaclofen (100 and 500 nmol) increased basal dopamine efflux. Baclofen (2.5 and 5 nmol) failed to affect basal dopamine efflux. 2-Hydroxysaclofen (1 and 10 nmol) which did not alter the basal dopamine efflux, enhanced the endomorphin-1 (25 nmol)-induced dopamine efflux. Baclofen (2.5 and 5 nmol) failed to affect endomorphin-1 (25 nmol)-induced dopamine efflux, but it counteracted the 2-hydroxysaclofen-induced increase of the endomorphin-1-elicited dopamine efflux. Neither 2-hydroxysaclofen (10 nmol) nor baclofen (5 nmol) affected the endomorphin-2 (25 nmol)-induced dopamine efflux. The doses mentioned are the total amount of drug over the infusion period that varied across the drugs (25 or 50 min). These results suggest that accumbal GABA B receptor plays an inhibitory role on the basal as well as the endomorphin-1-elicited accumbal dopamine efflux. The present results support our earlier reported notion that endomorphin-1 and endomorphin-2 increase accumbal dopamine efflux by different mechanisms. Finally, it is suggested that a decrease of endogenous accumbal GABA reduces the accumbal GABA B receptor-mediated GABA-ergic inhibition, enhancing thereby the accumbal dopamine efflux.

Role of GABAA receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats.

In vivo microdialysis was used to study the effects of the locally applied GABA(A) receptor agonist muscimol and GABA(A) receptor antagonist bicuculline on the basal dopamine efflux as well as on the endomorphin-1- and endomorphin-2-induced dopamine efflux in the nucleus accumbens of freely moving rats. Muscimol (2500 pmol) and bicuculline (5 and 10 nmol) increased basal dopamine efflux. Bicuculline (50 pmol) inhibited the muscimol (2500 pmol)-induced dopamine efflux. Muscimol (250 pmol), but not bicuculline (50 and 500 pmol), enhanced the endomorphin-1 (25 nmol)-induced dopamine efflux. Bicuculline (50 pmol) counteracted the muscimol (250 pmol)-induced increase of the endomorphin-1-elicited dopamine efflux. Neither muscimol (25 and 250 pmol) nor bicuculline (50 and 500 pmol) affected the endomorphin-2 (25 nmol)-induced dopamine efflux. The doses mentioned are the total amount of drug over the infusion period (25 or 50 min) that varied across the drugs. The finding that muscimol and bicuculline increased basal dopamine efflux may imply that these drugs acted at different sites. It is suggested that (1) muscimol acts at GABA(A) receptors on GABA-ergic neurons that exert an inhibitory control of dopaminergic neurons and, accordingly, disinhibits these dopaminergic neurons, and that (2) bicuculline acts directly at GABA(A) receptors on dopaminergic neurons and, accordingly, removes the inhibitory control of these dopaminergic neurons. The finding that an agonist, but not antagonist, of GABA(A) receptors enhanced the endomorphin-1's effects might indicate that endomorphin-1 produced a floor effect at the level of GABA(A) receptors located on presynaptic, dopaminergic terminals. Finally, the present results support our earlier reported notion that endomorphin-1 and endomorphin-2 increase accumbal dopamine efflux by different mechanisms.

Pupil dilation response to noxious stimulation: effect of varying nitrous oxide concentration.

OBJECTIVE: This report examines the pain-related pupil dilation response (PDR), tracking it across mixture concentrations of nitrous oxide (N(2)O) in oxygen (O(2)) and relating its variation to change in long latency somatosensory evoked potentials (SEPs) and visual analogue scale (VAS) pain report. METHODS: We varied mixture concentrations of N(2)O in O(2) (0%, 10%, 30%, and 50%), measuring PDR, SEP and VAS responses to painful electrical fingertip stimulation at high and low intensities in 15 volunteers. RESULTS: Mixed effect model statistical analyses revealed that: (1) PDR increased significantly with stimulus intensity and constricted significantly with mixture concentration; (2) SEP and VAS decreased significantly with increasing mixture concentration; (3) PDR correlated with SEP amplitude and VAS across mixture concentrations; (4) subjects differed significantly in: (a) baseline PDR and SEP amplitudes, (b) rate of change of these measures across mixture concentrations; and (5) VAS increased significantly with stimulus intensity and decreased significantly with mixture concentration without significant individual differences. CONCLUSIONS: The findings support the hypothesis that the pain-related PDR is a complex brain-mediated response rather than a simple sympathetic reflex. SIGNIFICANCE: PDR may provide a useful indicator for studying the central processing of noxious stimuli and the effects of analgesic interventions.

Hydroxyethyl starch: the effect of molecular weight and degree of substitution on intravascular retention in vivo.

BACKGROUND: Hydroxyethyl starch (HES) solution is characterized by its mean molecular weight (MW), concentration, and degree of substitution (DS). This character varies worldwide. METHODS: After binding fluorescein-isothiocyanate (FITC-HES), we evaluated the retention rate of three types of 6% HES in the A2 and V2 blood vessels of rat cremaster muscles using intravital microscopy in a mild hemorrhage model (10% of total blood volume). After blood withdrawal, we infused three types of FITC-HES: HES-A (MW 150-200 kDa, DS 0.6-0.68), HES-B (MW 175-225 kDa, DS 0.45-0.55), or HES-C (MW 550-850 kDa, DS 0.7-0.8) before determining the FITC-HES retention rate in the intravital microscope. RESULTS: For V2, the FITC-HES retention rates 120 min after the start of the infusion were 27% +/- 7.2% of baseline values (HES-A), 65% +/- 9.1% (HES-B), and 86% +/- 9.6% (HES-C); for A2 they were 27% +/- 6.6%, 73% +/- 10.2%, and 89% +/- 8.7%, respectively. HES-B and HES-C were retained in the vessels longer than HES-A (P = 0.028 for V2, P = 0.038 for A2 between HES-B and HES-A; P = 0.022 for V2, P = 0.037 for A2 between HES-C and HES-A). There was no difference in the rate of disappearance from the vessels between HES-B and HES-C. CONCLUSIONS: HES-B and HES-C are equally retained in the blood vessels. Middle-sized HES-B with low DS and middle substitution pattern stayed in the blood vessels as long as the large-sized HES. HES solutions of varying characters should be examined to optimize HES infusion.

Actions of Propofol on Neurons in the Cerebral Cortex.

Propofol is primarily a hypnotic, and is widely used for induction and maintenance of anesthesia, as well as for sedation in various medical procedures. The exact mechanisms of its action are not well understood, although its neural mechanisms have been explored in in vivo and in vitro experiments. Accumulating evidence indicates that one of the major targets of propofol is the cerebral cortex. The principal effect of propofol is considered to be the potentiation of GABAA receptor-mediated inhibitory synaptic currents, but propofol has additional roles in modulating ion channels, including voltage-gated Na+ channels and several K+ channels. We focus on the pharmacological actions of propofol on cerebrocortical neurons, particularly at the cellular and synaptic levels.

The effect of sevoflurane on dynamic cerebral blood flow autoregulation assessed by spectral and transfer function analysis.

Sevoflurane reduces autonomic neural control, which plays a significant role in cerebral autoregulation. Therefore, we hypothesized that sevoflurane influences cerebral autoregulation. We investigated the effects of sevoflurane on dynamic cerebral blood flow (CBF) autoregulation by using spectral and transfer function analysis between blood pressure variability and CBF velocity variability. Eleven healthy male subjects received 0.5%, 1.0%, and 1.5% sevoflurane via facemask. Dynamic cerebral autoregulation was evaluated by transfer function gain, phase, and coherence between CBF velocity in the middle cerebral artery measured by transcranial Doppler, and blood pressure in the radial artery. Coherence in the very low-frequency range (0.02-0.07 Hz) increased above 0.5 during administration of 0.5% and 1.0% sevoflurane. Transfer function gain in this frequency range (0.02-0.07 Hz), as an index of dynamic cerebral autoregulation, increased significantly with 0.5% and 1.0% sevoflurane. Transfer function gain and coherence in the low- and high-frequency ranges, however, remained unchanged during administration of sevoflurane. These results suggest that sevoflurane impairs dynamic cerebral autoregulation in the very-low-frequency range even with small concentrations, whereas dynamic cerebral autoregulation in the low- and high-frequency ranges remained unchanged.

Different effects on circulatory control during volatile induction and maintenance of anesthesia and total intravenous anesthesia: autonomic nervous activity and arterial cardiac baroreflex function evaluated by blood pressure and heart rate variability analysis.

STUDY OBJECTIVE: To evaluate the different effects on autonomic circulatory control during volatile induction/maintenance of anesthesia (VIMA) vs total intravenous anesthesia (TIVA). DESIGN: Prospective study. SETTING: Operating theater of a university hospital. PATIENTS: Twenty patients, with American Society of Anesthesiologists physical status of I or II, were randomly allocated into the VIMA group (n = 10) or the TIVA group (n = 10). INTERVENTIONS: In the VIMA group, anesthesia was induced with 5% sevoflurane and 60% N2O in oxygen and maintained with 2% sevoflurane and 60% N2O in oxygen. In the TIVA group, anesthesia was induced with propofol 2.0 mg/kg intravenously by bolus injection and fentanyl 2 microg/kg, and maintained with an intravenous infusion of propofol 5 mg/kg.per hour and air-oxygen mixture. MEASUREMENTS: Monitoring included recordings of electrocardiographic and arterial blood pressure waveforms. Autonomic nervous activity and arterial cardiac baroreflex function were evaluated by analysis of blood pressure variability, heart rate variability, and transfer function analysis between these 2 variables. MAIN RESULTS: In the VIMA group, the low-frequency component of blood pressure variability (LF(SBP)) and low- and high-frequency components of the R-R interval variability (LF(RR) and HF(RR)) decreased significantly during anesthesia. In the TIVA group, LF(SBP) and LF(RR) decreased significantly. The degree of reduction in LF(SBP) was greater in the VIMA group than in the TIVA group. However, changes in R-R interval variability and cardiac baroreflex indices were not significantly different between the 2 groups. CONCLUSIONS: Our results demonstrated that although reductions in autonomic nervous modulation to the heart might not be so different between the 2 groups, reduction in sympathetic nervous modulation to peripheral vasculature is greater in the VIMA group than in the TIVA group.

Propofol-induced spike firing suppression is more pronounced in pyramidal neurons than in fast-spiking neurons in the rat insular cortex.

Propofol is a major intravenous anesthetic that facilitates GABAA receptor-mediated inhibitory synaptic currents and modulates inward current (Ih), K+, and voltage-gated Na+ currents. This propofol-induced modulation of ionic currents changes intrinsic membrane properties and repetitive spike firing in cortical pyramidal neurons. However, it has been unknown whether propofol modulates these electrophysiological properties in GABAergic neurons, which express these ion channels at different levels. This study examined whether pyramidal and GABAergic neuronal properties are differentially modulated by propofol in the rat insular cortical slice preparation. We conducted multiple whole-cell patch-clamp recordings from pyramidal neurons and from GABAergic neurons, which were classified into fast-spiking (FS), low threshold spike (LTS), late-spiking (LS), and regular-spiking nonpyramidal (RSNP) neurons. We found that 100µM propofol hyperpolarized the resting membrane potential and decreased input resistance in all types of neurons tested. Propofol also potently suppressed, and in most cases eliminated, repetitive spike firing in all these neurons. However, the potency of the propofol-induced changes in membrane and firing properties is particularly prominent in pyramidal neurons. Using a low concentration of propofol clarified this tendency: 30µM propofol decreased the firing of pyramidal neurons but had little effect on GABAergic neurons. Pre-application of a GABAA receptor antagonist, picrotoxin (100µM), diminished the propofol-induced suppression of neural activities in both pyramidal and FS neurons. These results suggest that GABAergic neurons, especially FS neurons, are less affected by propofol than are pyramidal neurons and that propofol-induced modulation of the intrinsic membrane properties and repetitive spike firing are principally mediated by GABAA receptor-mediated tonic currents.

Opposite effects of mu and delta opioid receptor agonists on excitatory propagation induced in rat somatosensory and insular cortices by dental pulp stimulation.

The insular cortex (IC) contributes to nociceptive information processing. IC neurons express opioid receptors, including the mu (MOR), kappa (KOR), and delta (DOR) subtypes. Opioidergic agonists suppress excitatory synaptic transmission in the cerebral cortex. In addition, morphine injection into the IC reduces responses to noxious thermal stimuli. However, the mechanisms of the opioid-dependent modulation of cortical excitation at the macroscopic level, which bridge the cellular and behavioral findings, have remained unknown. The present in vivo optical imaging study aimed to examine the effects of the agonists of each subtype on cortical excitatory propagation in the IC and the neighboring cortices, the primary (S1) and secondary somatosensory (S2) areas. To assess the opioidergic effects on the cortical circuits, we applied electrical stimulation to the maxillary 1st molar pulp, which induced excitation in the ventral part of S1 and the S2/insular oral region (IOR). The initial excitatory response was observed 10-14ms after stimulation, and then excitation propagated concentrically. DAMGO (10-100µM), an MOR agonist, suppressed the amplitude of cortical excitation and shrank the maximum excitation areas in S1 and S2/IOR. In contrast, 10-100µM DPDPE, a DOR agonist, increased the amplitude of excitation and expanded the area of maximum excitation. U50488 (10-100µM), a KOR agonist, had little effect on cortical excitation. These results suggest that MOR-induced suppression of excitatory propagation in the IC is an underlying mechanism of the powerful analgesic effects of MOR agonists. In contrast, DOR may play a minor role in suppressing acute pain.

Opioid subtype- and cell-type-dependent regulation of inhibitory synaptic transmission in the rat insular cortex.

The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC. Pyramidal and GABAergic neurons in the rat IC were recorded by a multiple whole-cell patch-clamp technique. [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin acetate salt (DAMGO), an MOR agonist, reduced uIPSC amplitude by 74% in fast-spiking GABAergic interneuron (FS)→FS connections without a significant effect on FS→pyramidal cell (Pyr) connections. These effects of DAMGO were also observed in non-FS→FS and non-FS→Pyr connections: DAMGO reduced the uIPSC amplitude in non-FS→FS but not in non-FS→Pyr connections. DAMGO-induced depression of uIPSCs was blocked by the MOR antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2. The DOR agonist, [D-Pen2,5]-Enkephalin hydrate (DPDPE), reduced uIPSC amplitude by 39% in FS→FS and by 49% in FS→Pyr connections, which was antagonized by the DOR antagonist, naltrindole. However, DPDPE had little effect on non-FS→FS/Pyr connections. (±)-trans-U-50488 methanesulfonate salt (U50488), a KOR agonist, had little effect on uIPSC in FS→FS/Pyr connections. These results suggest that MOR-induced uIPSC depression in FS→FS and non-FS→FS, but not FS→Pyr and non-FS→Pyr connections, results in the depression of excitatory propagation in the IC, which may be an underlying mechanism of the powerful analgesic effects of MOR agonists.

Three cases of retroesophageal right subclavian artery.

We have experienced three cases of retroesophageal right subclavian artery. Two cases were cadavers, and one case was a live human. In the two cadavers of a 68-year-old and a 76-year-old, respectively Japanese and European males, the right subclavian artery originated from the aorta after the aorta branched the right carotid artery, the left carotid artery and the left subclavian artery. The right carotid artery immerged solely from the aorta. Where the right subclavian artery originated from the aorta, the artery took a dorsal direction. It passed between the esophagus and the vertebral column. The esophagus was compressed from the dorsal side by the right subclavian artery. The structural anomaly of the right subclavian artery accompanied the cephalad recurrence of the branch from the right vagal nerve toward the larynx. In the live human case, we obtained CT views. The patient was a 41-year-old Japanese, who complained of dysphagia lusoria. We found that the right subclavian artery was anomalous and originated from the aorta as the last cardinal branch in the thorax.

Postoperative mental disorder following prolonged oral surgery.

A prolonged period of oral surgery is a potential risk factor of postoperative mental disorders although no such report has been published to date. We retrospectively studied perioperative features in 36 patients who underwent prolonged (10 hours or more) of oral surgery. Patients were categorized as pre-delirium (Pre-D) when they manifested 1 or 2 symptoms and delirium (D) when they showed more than 2 symptoms, according to the modified International Classification of Diseases, 10th edition. Of the 36 patients who returned to a normal mental state without drug therapy, 13 were classified as D and 14 were Pre-D. A number of patients had moderate complications preoperatively, and massive hemorrhaging occurred during the operation in some Pre-D and D patients. Age was greater in D (62.0 +/- 9.9 years) than in Pre-D (56.0 +/- 13.8 years) patients. Propofol-based general anesthesia was most commonly employed. The time prior to appearance of pre-delirium was significantly shorter in D (30.0 +/- 16.7 hours) than in Pre-D (55.0 +/- 35.0 hours) group patients. Our results indicate that, in general, patients predisposed to postoperative mental disorders have moderate complications preoperatively, are generally older than 50-years-old, receive propofol-based general anesthesia and/or experience a massive hemorrhage during the operation.