Noriya Hirose

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.

Fentanyl increases dopamine release in rat nucleus accumbens: involvement of mesolimbic mu- and delta-2-opioid receptors

The effects of the mu-receptor agonist fentanyl on extracellular levels of dopamine in rat nucleus accumbens were studied in awake animals by in vivo brain microdialysis. Fentanyl dose-dependently increased the levels of dopamine when given intravenously (microg/kg) or via a microdialysis probe placed into the ventral tegmental area or the nucleus accumbens (nmol). The effect of fentanyl given into the nucleus accumbens was blocked by systemic administration of the non-selective opioid receptor antagonist naloxone and by accumbens administration of D-Phe-Cys-Tyr-D-Trp-Om-Thr-Phe-Thr-NH2 (nmol), a mu-opioid receptor antagonist, and naltrindole (nmol), a non-selective delta-opioid receptor antagonist, in a dose-dependent manner. The delta2-opioid receptor antagonist, naltriben (nmol), also blocked the effects of fentanyl, whereas the delta1-opioid receptor antagonist, (E)-7-benzylidenenaltrexone (nmol), was ineffective. When marginally effective doses of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 and naltriben were given simultaneously, the effect of fentanyl was nearly fully blocked; the pretreatment itself had no effect. Administration of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (nmol), the delta1-opioid receptor agonist [D-Pen2,5]-enkephalin (nmol) or the delta2-opioid receptor agonist [D-Ala2,Glu4]-deltorphin (nmol) into the nucleus accumbens enhanced the amount of accumbal dopamine. This study provides evidence that not only activation of delta1- and delta2-opioid receptors, but also activation of mu-opioid receptors in the nucleus accumbens increases the release of accumbal dopamine in freely moving rats. We suggest that the effect of intra-accumbens administration of fentanyl upon accumbal release of dopamine is either due to the simultaneous activation of mu-opioid receptors and delta2-opioid receptors or due to activation of mu-opioid receptors that interact with delta2-opioid receptors in a complex manner.

Effects of chronic haloperidol and clozapine on vacuous chewing and dopamine-mediated jaw movements in rats: evaluation of a revised animal model of tardive dyskinesia.

Summary. Rats received haloperidol (1.0 mg/kg i.p.) or clozapine (10 mg/kg i.p.), twice daily for 4 weeks: vacuous chewing -recorded 26 h after the final injection- similarly increased in both groups. Three h later, the rats were challenged with dopaminomimetics, and automatically recorded jaw movements were analysed. Both apomorphine and a mixture of D1 and D2 receptor agonists (SKF 38393 resp. quinpirole) increased jaw movements in haloperidol-treated, but not clozapine-treated rats; SKF 38393 or quinpirole remained ineffective, when given alone. A fixed dose of quinpirole together with increasing doses of SKF 38393, but not a fixed dose of SKF 38393 together with increasing doses of quinpirole, produced a dose-dependent increase in jaw movements in otherwise non-treated rats, suggesting that the noted haloperidol-induced increase was due to a shift in the D1–D2 receptor balance towards a predominance of D1 receptors. This study presents a new animal model of tardive dyskinesia with predictive validity, good reliability and, especially, great efficiency.

The Different Effects of Midazolam and Propofol Sedation on Dynamic Cerebral Autoregulation

BACKGROUND: Although midazolam and propofol reduce cerebral blood flow (CBF) similarly, they generate different effects on the autonomic nervous system and endothelium-induced relaxation. Midazolam induces sympathetic dominance, whereas propofol induces parasympathetic dominance. Midazolam has no effect on endothelium-dependent relaxation, whereas propofol suppresses endothelium-dependent relaxation. Moreover, midazolam apparently constricts cerebral arterioles. We therefore hypothesized that midazolam and propofol have different effects on dynamic cerebral autoregulation. METHODS: Ten healthy male subjects received midazolam, propofol, and placebo administrations in a randomized, single-blind, crossover study. The modified Observers Assessment of Alertness/Sedation scale was used to assess sedation depth. After reaching a target depth of sedation (Observers Assessment of Alertness/Sedation scale score 3, responds only after name is called loudly and/or repeatedly) or after 15 minutes of normal saline administration as placebo, dynamic cerebral autoregulation was evaluated by spectral and transfer function analyses between mean arterial blood pressure variability in the radial artery measured by tonometry, and CBF velocity variability in the middle cerebral artery measured by transcranial Doppler ultrasonography. RESULTS: Steady-state CBF velocity decreased significantly with midazolam and propofol administration (significant interaction effects, P = 0.024). However, transfer function gain in the low-frequency range decreased significantly only with midazolam administration (significant interaction effects, P = 0.015), suggesting a reduced magnitude of transfer from mean arterial blood pressure oscillations to CBF fluctuations during midazolam sedation. CONCLUSION: Our results suggest that midazolam and propofol sedation have different effects on dynamic cerebral autoregulation despite causing equivalent decreases in steady-state CBF velocity. Only midazolam sedation is likely to improve dynamic cerebral autoregulation.

The effects of age on maintenance of intense neuromuscular block with rocuronium.

Increasing age is associated with a longer duration of action of neuromuscular block. The aim of this study was to determine the influence of ageing on the recovery of the post‐tetanic count (PTC) from rocuronium‐induced neuromuscular block.

Effect of spinal anesthesia for elective cesarean section on cerebral blood oxygenation changes: comparison of hyperbaric and isobaric bupivacaine.

We used near-infrared spectroscopy (NIRS) to evaluate cerebral blood oxygenation changes in subjects undergoing cesarean section under spinal anesthesia (SP) with hyperbaric bupivacaine (group H, 27 subjects) or isobaric bupivacaine (group I, 15 subjects). In group H, total-Hb, oxy-Hb, and mean blood pressure (MBP) within 20 min after SP were significantly lower than the baseline values. In contrast, there was no significant change from baseline in total-Hb, oxy-Hb, or MBP in group I after SP. Total-Hb and MBP in group H were significantly lower than those in group I within 10 min after SP. There was no significant change of deoxy-Hb, tissue oxygen index, or heart rate from baseline in either of the groups. These results suggest that isobaric bupivacaine may be superior to hyperbaric bupivacaine for preventing a decrease of maternal cerebral blood flow after SP for cesarean section.

Changes in Cerebral Blood Flow and Oxygenation During Induction of General Anesthesia with Sevoflurane Versus Propofol

Sevoflurane and propofol are widely used for induction and maintenance of general anesthesia. Although the effects of sevoflurane and propofol on cerebral hemodynamics during maintenance of general anesthesia have been demonstrated, the effects during induction of general anesthesia have still not been clarified. We therefore compared changes in cerebral blood flow (CBF) and oxygenation (CBO) during induction of anesthesia using sevoflurane (group S: n=9) or propofol (group P: n=9). CBF and CBO were evaluated using the following variables: oxy-, deoxy-, and total-hemoglobin (Hb) concentrations and tissue oxygen index (TOI), measured on the forehead by near-infrared spectroscopy. The variables were recorded immediately before administration of sevoflurane or propofol and at every 10 s for 4 min after administration of the induction agent. Patients received 8% sevoflurane in 100% oxygen via an anesthesia mask in group S, and an IV bolus of 2 mg/kg of propofol during oxygenation in group P. We found that oxy-Hb, total-Hb, and TOI were significantly higher in group S than in group P (P>0.05). Changes in deoxy-Hb, MBP, and HR did not differ between the groups. The results of the present study demonstrated that sevoflurane increases CBF and CBO during induction of general anesthesia.

Clinical course of pain in a patient with neuropathic pain induced by ligation of an intercostal nerve

A patient with severe right chest pain and mechanical allodynia induced by an intercostal drainage tube to his chest is presented. It was not relieved by treatment with diclofenac sodium and was worsened by movement and touch to the right chest wall. Mechanical allodynia was also present. The patients wrenching pain disappeared immediately after stitch removal, but the dull pain and mechanical allodynia persisted, gradually decreasing to zero in 7 days.

Oxygen Supplementation is Effective in Attenuating Maternal Cerebral Blood Deoxygenation After Spinal Anesthesia for Cesarean Section.

The purpose of this study was to measure changes in maternal cerebral blood oxygenation using near-infrared spectroscopy (NIRS) for 15 min after spinal anesthesia performed for cesarean section, and to determine the efficacy of supplemental oxygen in maintaining maternal cerebral blood oxygenation. Thirty patients were randomly assigned to either receive 100% oxygen via a facemask at a constant flow rate of 3 l/min throughout the study (O2 group), or were evaluated without supplemental oxygen (Air group). Changes in cerebral blood oxygenation were evaluated using the following parameters: oxy-hemoglobin (Hb), deoxy-Hb, and total-Hb concentrations, as well as tissue oxygen index (TOI), measured over the forehead by NIRS. Mean arterial pressure (MAP) and heart rate (HR) were also recorded throughout the study. Mean oxy-Hb, total-Hb, TOI, and MAP in both groups decreased significantly from baseline values (P<0.05). The reduction in oxy-Hb and TOI in the Air group was significantly greater than that in the O2 group (oxy-Hb: -4.72 vs. -2.96 μmol/l; P<0.05, TOI: -6.82 vs. -1.68%; P<0.01); however, there were no significant differences in the reduction of total-Hb and MAP between the groups. Mean deoxy-Hb in the Air group was significantly higher than that in the O2 group (0.02 vs. -1.01 μmol/l; P<0.05). The results of the present study demonstrate that oxygen supplementation attenuates cerebral blood deoxygenation secondary to the reduction in cerebral blood flow following spinal anesthesia.

Antagonistic effect of flumazenil after midazolam sedation on arterial-cardiac baroreflex.

Flumazenil is generally administered to antagonise the sedative effect of midazolam. However, although flumazenil completely antagonises the sedative effect of midazolam, a few effects remain unantagonised. Hence, it is unclear whether flumazenil restores the attenuation of the arterial‐cardiac baroreflex (i.e. arterial‐heart rate reflex) induced by midazolam. We investigated the antagonistic effect of flumazenil administered after midazolam on cardiac baroreflex, to reveal whether complete recovery from midazolam‐induced sedation by flumazenil administration is accompanied by restoration of midazolams attenuating effects on the cardiac baroreflex.