Yoshiyuki Oi

Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the nucleus accumbens with the mu-, delta(1)- and delta(2)-opioid receptor agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), [D-Pen(2,5)]-enkephalin (DPDPE) and [D-Ser(2)]Leu-enkephalin-Thr(6), respectively, significantly enhanced the extracellular amount of accumbal dopamine in a dose-related manner (5.0 nmol and 50.0 nmol). However, the highest concentration tested (50.0 nmol) of DAMGO induced a biphasic effect, i.e. a rapid onset increase lasting for 75 min followed by a slower onset gradual and prolonged increase. The mu-opioid receptor antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) (0.15 nmol) primarily reduced the DAMGO-induced second component. The delta(1)-opioid receptor antagonist (E)-7-benzylidenenaltrexone (0.15 nmol) significantly reduced the first component and abolished the second component induced by DAMGO, while the delta(2)-opioid receptor antagonist naltriben (1.5 nmol) significantly reduced only the first component. The DPDPE (50.0 nmol)-induced dopamine increase was almost completely abolished by (E)-7-benzylidenenaltrexone, but only partially reduced by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and naltriben. The [D-Ser(2)]Leu-enkephalin-Thr(6) (50.0 nmol)-induced dopamine increase was almost completely abolished by naltriben, but not at all by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and (E)-7-benzylidenenaltrexone. The non-selective opioid receptor antagonist naloxone (0.75 and 1.5 nmol) dose-dependently reduced the effects of DAMGO, DPDPE and [D-Ser(2)]Leu-enkephalin-Thr(6) but only to about 10-25% of the control values. Moreover, perfusion with the sodium channel blocker tetrodotoxin (0.1 nmol) reduced the DAMGO-induced dopamine increase by 75%, while it almost completely abolished the increase induced by DPDPE or [D-Ser(2)]Leu-enkephalin-Thr(6). The results show that stimulation of mu-opioid receptors or, to a lesser degree, delta(1)-opioid receptors results in a large naloxone-sensitive increase and a small naloxone-insensitive increase of extracellular dopamine. It is suggested that the naloxone-insensitive component is also tetrodotoxin-insensitive. Furthermore, it is hypothesized that stimulation of mu-opioid receptors activates delta(1)-receptors, which in turn activate delta(2)-opioid receptors, thereby giving rise to a rapid onset increase of extracellular dopamine. In addition, it is hypothesized that stimulation of another group of mu-opioid receptors activates a second group of delta(1)-opioid receptors that is not coupled to delta(2)-opioid receptors and mediates a slow onset increase of extracellular dopamine. Finally, it is suggested that stimulation of delta(1)- or delta(2)-opioid receptors inhibits mu-opioid receptors involved in the slow onset increase in extracellular dopamine, whereas stimulation of delta(1)-, but not delta(2)-, opioid receptors is suggested to activate mu-opioid receptors involved in the rapid increase in extracellular dopamine.

Hypertonic saline-dextran improves intestinal perfusion and survival in porcine endotoxin shock

ObjectiveTo examine the effects of hypertonic (7.5%) saline-6% dextran 70 (HSD) and isotonic (0.9%) saline-6% dextran 70 (ISD) on cardiovascular function and intestinal perfusion in experimental endotoxin shock. DesignExperimental, randomized, unblinded, interventional study. SettingUniversity experimental animal laboratory. SubjectsAnesthetized and mechanically ventilated landrace pigs (n = 24). InterventionsInduction of endotoxin (ET) shock by infusion of Escherichia coli lipopolysaccharide endotoxin (serotype 0111: B4) followed by no fluid treatment (control; C) or small-volume (4 mL/kg) treatment with HSD or ISD. Measurements and Main ResultsMean arterial pressure, central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac output, portal vein blood flow, intestinal microcirculation, intramucosal (regional) Pco2, intestinal-arterial gap of CO2, and intramucosal pH were monitored, and blood gases were analyzed. Infusion of ET resulted in hypokinetic shock, which in untreated animals led to cardiovascular deterioration and a survival rate of only 33% at 300 mins after start of ET infusion. ISD treatment transiently improved hemodynamic variables and mucosal blood flow but did not affect the survival rate vs. C. Significant beneficial, long-lasting effects of HSD infusion on hemodynamics, especially on mucosal blood flow and intramucosal pH, were demonstrable, resulting in a survival rate of 86%. The relative risk of death at 300 mins was 1.20 for ISD vs. C and 0.17 for HSD vs. C. ConclusionSmall-volume HSD resuscitation is much more effective than ISD resuscitation. Variables that were improved include cardiac output, portal blood flow, and intestinal mucosal blood flow in ET shock, all of which improve survival. Such beneficial effects of HSD on splanchnic perfusion may be of value in treating critically ill septic patients in the intensive care unit.

Descending aortic blood flow and cardiac output : A clinical and experimental study of continuous oesophageal echo-Doppler flowmetry

Background: Several studies have demonstrated that perioperative optimisation of oxygen delivery and haemodynamics can reduce mortality and morbidity for high‐risk surgical patients. To optimise cardiac output, reliable, continuous and “less invasive” methods for measuring cardiac output are urgently needed.

Predictability of Painful Stimulation Modulates Subjective and Physiological Responses

UNLABELLED Clinical observations suggest that the perceived intensity of a painful event increases as the unpredictability of its occurrence increases. We examined the effect of varying stimulus predictability on the Somatosensory Evoked Potential (SEP), Pupil Diameter Response (PDR), Pain Report (PR), and Fear Report (FR) in 25 healthy female volunteers experiencing repeated noxious fingertip shocks. Each volunteer underwent high- and low-stimulus intensities in 4 stimulus patterns defined by stimulus sequence (SEQ) and interstimulus interval (ISI) as follows: A) serial stimulus intensity SEQ with fixed ISI; B) serial stimulus intensity SEQ with varied ISI; C) random stimulus intensity SEQ with fixed ISI; and D) random stimulus intensity SEQ with varied ISI. Results revealed that: (1) lower stimulus predictability led to higher PR and FR, greater PDR magnitude, and greater SEP amplitude; and (2) the 4 dependent measures showed the same response pattern across levels of stimulus predictability. These findings support the hypothesis that lower stimulus predictability is associated with higher reported pain and fear as well as greater physiological arousal. PERSPECTIVE Patients undergoing painful procedures experience more distress when the occurrence of a painful event is unpredictable. Poor predictability increases pain, fear, and associated physiological arousal. Maximizing the predictability of painful events may improve the quality of patient care by minimizing associated levels of pain and fear.

Presynaptic Interneuron Subtype- and Age-Dependent Modulation of GABAergic Synaptic Transmission by β-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.

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.

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.

The angiotensin II receptor blocker candesartan improves survival and mesenteric perfusion in an acute porcine endotoxin model

Background:  Blockade of the angiotensin II type 1 (AT1) receptor has been demonstrated to ameliorate splanchnic hypoperfusion in acute experimental circulatory failure. This study focused on hemodynamic changes and survival in pigs treated with AT1 blockade prior to or during acute endotoxinemia.

Spatiotemporal profiles of transcallosal connections in rat insular cortex revealed by in vivo optical imaging.

The gustatory cortex (GC), a part of the insular cortex (IC), receives gustatory inputs from the parvicellular part of the ventroposteromedial thalamic nucleus (VPMpc). Transcallosal projections from the contralateral GC modulate neural responses to gustatory stimulation. However, the spatiotemporal dynamics of the amplitude and area of excitation induced by contralateral GC stimulation remain unclear. First, we demonstrated the distribution patterns of neurons projecting to the GC by injecting the anterograde tracer, biotinylated dextranamine (BDA), and retrograde tracer, Fluorogold (FG), into the unilateral putative GC throughout the layers in five male Sprague-Dawley and two vesicular GABA transporter-Venus rats. FG-labeled pyramidal neurons were found in the contralateral GC and ipsilateral VPMpc. The contralateral GC and ipsilateral VPMpc received BDA-positive fibers, suggesting that the GCs of both hemispheres are reciprocally connected. Second, the spatiotemporal profiles of neural responses evoked by five train pulses of electrical stimulation (50 Hz) were quantified by in vivo optical imaging with a voltage-sensitive dye in male Sprague-Dawley rats (n=56). Stimulation of the ipsilateral VPMpc evoked potent GC activation that was followed by propagation to the surrounding IC; this propagation was similar to that following ipsilateral GC stimulation. Contralateral stimulation of the somatosensory area I, dorsal IC, and ventral IC evoked excitation in the ipsilateral each corresponding area, suggesting that transcallosal fibers are symmetrically connected. Contralateral GC stimulation induced a similar spatial profile of excitation as ipsilateral GC stimulation; however, the latency was longer (~20 ms), and the excitation was frequently followed by a GABA(B) receptor antagonist-sensitive inhibitory signal. Excitation by ipsilateral GC stimulation was potentiated by simultaneous contralateral GC stimulation, especially in cases where the amplitude of the response to ipsilateral stimulation was small. These results suggest that the transcallosal projection may support the detection of gustatory inputs by potentiating weak gustatory signals in the GC.

Endothelin-1 blockade corrects mesenteric hypoperfusion in a porcine low cardiac output model.

ObjectiveTo study the importance of endothelin-1-induced vasoconstriction in a model of acute and maintained low cardiac output, by investigating regional changes within the mesenteric and particularly the intestinal mucosal circulation. DesignProspective, controlled animal study. SettingUniversity-affiliated research laboratory. SubjectsThirteen fasted, anesthetized, mechanically ventilated landrace pigs. Measurements and Main Results Cardiac output, portal venous blood flow, renal arterial flow, jejunal mucosal microcirculation by laser Doppler flowmetry, jejunal capnotonometry (Pco2 gap), and jejunal mucosal oxygenation (tPo2) were monitored. Cardiac tamponade was established to reduce portal venous blood flow to a preset end point at two thirds of baseline. Measurements were made at baseline, after 90 mins of cardiac tamponade, and 90 mins after the administration of the combined endothelinA/endothelinB antagonist tezosentan at 1 mg·kg−1·hr−1 during tamponade in seven animals. Six animals served as time controls and received only the vehicle. Cardiac tamponade decreased portal venous blood flow, renal arterial flow, and laser Doppler flowmetry, whereas the Pco2 gap increased. The change in tPo2 failed to gain statistical significance (p = .08). Administration of tezosentan during tamponade restored portal venous blood flow and laser Doppler flowmetry to baseline values, increased tPo2 above baseline, and decreased Pco2 gap. No effect on renal arterial flow was observed. Investigated variables remained unchanged in control animals after induction of cardiac tamponade. ConclusionsEndothelin-1 blockade in acute cardiac failure improves mesenteric, but not renal, perfusion, illustrating the regional importance of endothelin-1-induced vasoconstriction. Importantly, endothelin-1 blockade restored mucosal blood flow and oxygenation, which might be particularly interesting considering the implications for maintenance of mucosal barrier integrity in low output states.