Stability and variability of synapses in the adult molluskan CNS

Synaptic transmission was examined between identified neurons in the central nervous system (CNS) of the freshwater mollusk, Lymnaea stagnalis. Four identified neurons were used: Right Pedal Dorsal one (RPeD1; a dopaminergic respiratory interneuron), Visceral Dorsal two and three (VD2/3), and Visceral Dorsal four (VD4; a cardiorespiratory interneuron). Neuron RPeD1 synapses onto both VD2/3 and VD4, while VD4 makes a reciprocal synapse onto RPeD1. When compared from animal to animal, the connections were variable in sign. Previously, we demonstrated that, in a given animal, the RPeD1 --> VD4 synapse could be either inhibitory, biphasic, or undetectable. The present study now expands this concept of variability by showing that the RPeD1 --> VD2/3 synapse was either excitatory or undetectable from animal to animal, while the synapse from VD4 to RPeD1 was observed as inhibitory, biphasic, depolarizing, excitatory, or undetectable. Next, we used 1-day organ culture to determine if the variability observed between animals is a product of ongoing change to the sign of these identified synapses and whether or not the extent of change could be influenced by the culture conditions. Changes to the sign of transmission occurred within minutes and, more commonly, after 24-h organ culture. All three synapses were investigated before and after 1-day organ culture, in either defined medium (DM) or brain-conditioned medium (CM). Regardless of culture conditions, the RPeD1 --> VD2/3 synapse showed no change of sign, i.e., it was relatively stable. However, the synapses between RPeD1 and VD4 did change sign, and when cultured in CM, the VD4 --> RPeD1 synapse changed significantly more than in DM. These data indicate that variability of some synapses reflects changes at these synapses. This is the first report that specific synapses in an adult CNS can change sign, and that the sign of transmission can be modulated by environmental conditions.     

Localization,physiology, and modulation of a molluskan dopaminergic synapse

We investigated the location, physiology, and modulation of an identified synapse from the central nervous system (CNS) of the mollusk Lymnaea stagnalis. Specifically, the excitatory synapse from interneuron right pedal dorsal one (RPeD1) to neurons visceral dorsal two and three (VD2/3) was examined. The gross and fine morphology of these neurons was determined by staining with Lucifer yellow or sulforhodamine. In preparations where RPeD1 was stained with Lucifer yellow and VD2/3 with sulfo-rhodamine, the axon collaterals occupied similar regions, suggesting that these neurons make physical contact in the CNS. Digital confocal microscopy of these preparations revealed that presynaptic varicosities made apparent contact (synapses) with smooth postsynaptic axon collaterals. The number of putative synapses per preparation was about five to 10. Regarding physiology, the synaptic latency was moderately rapid at 24.1 ± 5.2 ms. Previous work indicated that RPeD1 uses dopamine as a neurotransmitter. The RPeD1 → VD2/3 excitatory postsynaptic potential (EPSP) and the VD2/3 bath-applied dopamine (100-μM) response displayed a similar decrease in input resistance and a similar predicted reversal potential (−31 vs. −26 mV), indicating that the synapse and exogenous dopamine activate the same conductance. Finally, bath-applied serotonin (10 μM) rapidly and reversibly depressed the RPeD1 → VD2/3 synapse but did not affect the VD2/3 bath-applied dopamine (100-μM) response, suggesting a presynaptic locus of action for serotonin. The effect of serotonin was not associated with any changes to the pre- or postsynaptic membrane potential and input resistance, or the presynaptic action potential half-width. The RPeD1 → b3 VD2/3 synapse provides an opportunity to examine the anatomy and physiology of transmission, and is amenable to the study of neuromodulation. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 247–264, 1997     

Target cell contact suppresses neurite outgrowth from soma-soma paired Lymnaea neurons

Neurite extension from developing and/or regenerating neurons is terminated on contact with their specific synaptic partner cells. However, a direct relationship between the effects of target cell contact on neurite outgrowth suppression and synapse formation has not yet been demonstrated. To determine whether physical/synaptic contacts affect neurite extension from cultured cells, we utilized soma-soma synapses between the identified Lymnaea neurons. A presynaptic cell (right pedal dorsal 1, RPeD1) was paired either with its postsynaptic partner cells (visceral dorsal 4, VD4, and Visceral dorsal 2, VD2) or with a non-target cell (visceral dorsal 1, VD1), and the interactions between their neurite outgrowth patterns and synapse formation were examined. Specifically, when cultured in brain conditioned medium (CM, contains growth-promoting factors), RPeD1, VD4, and VD2 exhibited robust neurite outgrowth within 12-24 h of their isolation. Synapses, similar to those seen in vivo, developed between the neurites of these cells. RPeD1 did not, however, synapse with its non-target cell VD1, despite extensive neuritic overlap between the cells. When placed in a soma-soma configuration (somata juxtaposed against each other), appropriate synapses developed between the somata of RPeD1 and VD4 (inhibitory) and between RPeD1 and VD2 (excitatory). Interestingly, pairing RPeD1 with either of its synaptic partner (VD4 or VD2) resulted in a complete suppression of neurite outgrowth from both pre- and postsynaptic neurons, even though the cells were cultured in CM. A single cell in the same dish, however, extended elaborate neurites. Similarly, a postsynaptic cell (VD4) contact suppressed the rate of neurite extension from a previously sprouted RPeD1. This suppression of the presynaptic growth cone motility was also target cell contact specific. The neurite suppression from soma-soma paired cells was transient, and neuronal sprouting began after a delay of 48-72 h. In contrast, when paired with VD1, both RPeD1 and this non-target cell exhibited robust neurite outgrowth. We demonstrate that this neurite suppression from soma-soma paired cells was target cell contact/synapse specific and Ca(2+) dependent. Specifically, soma-soma pairing in CM containing either lower external Ca(2+) concentration (50% of its control level) or Cd(2+) resulted in robust neurite outgrowth from both cells; however, the incidence of synapse formation between the paired cells was significantly reduced. Taken together, our data show that contact (physical and/or synaptic) between synaptic partners strongly influence neurite outgrowth patterns of both pre- and postsynaptic neurons in a time-dependent and cell-specific manner. Moreover, our data also suggest that neurite outgrowth and synapse formation are differentially regulated by external Ca(2+) concentration.     

Pronase modifies synaptic transmission and activity of identifiedLymnaea neurons

Proteolytic enzymes can have significant effects on the physiological properties of neurons. Although several actions of proteolytic enzymes on the physiology of single neurons have been described, the effects of these enzymes on network properties in the central nervous system (CNS) have received less attention. The effects of bath-applied pronase (0.05%) on synaptic connections and spontaneous activity in theLymnaea CNS were examined. Brief application (i.e. 2–3 min) of pronase modified some, but not all, synapses in the CNS. For example, the chemical synapse between two interneurons, RPeD11 and RPeD1, and between the interneuron, RPeD1, and RPA motoneurons were examined. Both these synapses were either biphasic or monophasic (depolarizing) under control conditions. Pronase exposure eliminated the depolarizing phase of the RPeD11→RPeD1 synapse, but had no effect on the connection between RPeD1 and RPA neurons. In addition, the effects of pronase on electrical-coupling between two peptidergic neurons, VD1 and RPD2, in the CNS were investigated. Pronase decreased the total network input resistance and cell input resistances as well as the steady-state coupling ratio. Furthermore, exposure to pronase induced various changes (i.e. depolarization, hyperpolarization, bursting patterns and afterdischarges) in the activity pattern of different identified neurons in the CNS. Collectively, these data show that even brief exposure to a low concentration of pronase can acutely modify both synapses and neuronal activity.     

Target cell contact suppresses neurite outgrowth from soma–soma paired Lymnaea neurons

Neurite extension from developing and/or regenerating neurons is terminated on contact with their specific synaptic partner cells. However, a direct relationship between the effects of target cell contact on neurite outgrowth suppression and synapse formation has not yet been demonstrated. To determine whether physical/synaptic contacts affect neurite extension from cultured cells, we utilized soma–soma synapses between the identified Lymnaea neurons. A presynaptic cell (right pedal dorsal 1, RPeD1) was paired either with its postsynaptic partner cells (visceral dorsal 4, VD4, and Visceral dorsal 2, VD2) or with a non‐target cell (visceral dorsal 1, VD1), and the interactions between their neurite outgrowth patterns and synapse formation were examined. Specifically, when cultured in brain conditioned medium (CM, contains growth‐promoting factors), RPeD1, VD4, and VD2 exhibited robust neurite outgrowth within 12–24 h of their isolation. Synapses, similar to those seen in vivo, developed between the neurites of these cells. RPeD1 did not, however, synapse with its non–target cell VD1, despite extensive neuritic overlap between the cells. When placed in a soma–soma configuration (somata juxtaposed against each other), appropriate synapses developed between the somata of RPeD1 and VD4 (inhibitory) and between RPeD1 and VD2 (excitatory). Interestingly, pairing RPeD1 with either of its synaptic partner (VD4 or VD2) resulted in a complete suppression of neurite outgrowth from both pre‐ and postsynaptic neurons, even though the cells were cultured in CM. A single cell in the same dish, however, extended elaborate neurites. Similarly, a postsynaptic cell (VD4) contact suppressed the rate of neurite extension from a previously sprouted RPeD1. This suppression of the presynaptic growth cone motility was also target cell contact specific. The neurite suppression from soma–soma paired cells was transient, and neuronal sprouting began after a delay of 48–72 h. In contrast, when paired with VD1, both RPeD1 and this non‐target cell exhibited robust neurite outgrowth. We demonstrate that this neurite suppression from soma–soma paired cells was target cell contact/synapse specific and Ca²⁺ dependent. Specifically, soma–soma pairing in CM containing either lower external Ca²⁺ concentration (50% of its control level) or Cd²⁺ resulted in robust neurite outgrowth from both cells; however, the incidence of synapse formation between the paired cells was significantly reduced. Taken together, our data show that contact (physical and/or synaptic) between synaptic partners strongly influence neurite outgrowth patterns of both pre‐ and postsynaptic neurons in a time‐dependent and cell‐specific manner. Moreover, our data also suggest that neurite outgrowth and synapse formation are differentially regulated by external Ca²⁺ concentration. © 2000 John Wiley & Sons, Inc. J Neurobiol 42: 357–369, 2000     

The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.     

异丙酚对正常大鼠脊髓背角感觉神经元反应性的抑制作用

脊髓背角感觉神经元不仅在感觉信息的传递和调节中起到重要作用,也是各种内源性和外源性药物的作用靶位.为了解静脉麻醉剂异丙酚是否对背角感觉神经元的反应性具有调节作用,本实验采用在体单细胞胞外记录技术,观察了脊髓背表面直接滴注0.5 μmol异丙酚对戊巴比妥钠麻醉大鼠脊髓背角广动力域(WDR)神经元和低阈值机械感受型(LTM)神经元反应性的影响.实验发现,异丙酚能抑制背角WDR神经元由施加于外周感受野伤害性热刺激(45、47、49和53℃,15 s)和夹捏机械刺激(10 s)诱发的反应性,与DMSO对照组比较具有显著性统计学差异(P＜0.05);同样,异丙酚对非伤害性机械刺激诱发的WDR或LTM神经元的反应性也具有显著的抑制作用(P＜0.05).本结果提示,异丙酚可直接作用于正常大鼠脊髓背角神经元,对由非伤害性和伤害性纤维介导的神经元反应性均产生抑制作用,因此异丙酚的脊髓抗伤害作用可能不是特异性的.     

Electrical Activity of Identified Neurons in the Central Nervous System of a Mollusk Lymnaea stagnalis under Acute Hyperglycemia

Journal of Evolutionary Biochemistry and Physiology - Rapid responses of the key interneurons identified in the respiratory (RPeD1), locomotor (LPeD1) and cardioregulatory (VD1/RPaD2) networks of...     

Neural correlates of swimming behavior in Melibe leonina

The nudibranch Melibe leonina swims by rhythmically bending from side to side at a frequency of 1 cycle every 2-4 s. The objective of this study was to locate putative swim motoneurons (pSMNs) that drive these lateral flexions and determine if swimming in this species is produced by a swim central pattern generator (sCPG). In the first set of experiments, intracellular recordings were obtained from pSMNs in semi-intact, swimming animals. About 10-14 pSMNs were identified on the dorsal surface of each pedal ganglion and 4-7 on the ventral side. In general, the pSMNs in a given pedal ganglion fired synchronously and caused the animal to flex in that direction, whereas the pSMNs in the opposite pedal ganglion fired in anti-phase. When swimming stopped, so did rhythmic pSMN bursting; when swimming commenced, pSMNs resumed bursting. In the second series of experiments, intracellular recordings were obtained from pSMNs in isolated brains that spontaneously expressed the swim motor program. The pattern of activity recorded from pSMNs in isolated brains was very similar to the bursting pattern obtained from the same pSMNs in semi-intact animals, indicating that the sCPG can produce the swim rhythm in the absence of sensory feedback. Exposing the brain to light or cutting the pedal-pedal connectives inhibited fictive swimming in the isolated brain. The pSMNs do not appear to participate in the sCPG. Rather, they received rhythmic excitatory and inhibitory synaptic input from interneurons that probably comprise the sCPG circuit.     

Nitric oxide selectively enhances cAMP levels and electrical coupling between identified RPaD2/VD1 neurons in the CNS of Lymnaea stagnalis (L.)

The isolated CNS of the freshwater mollusc Lymnaea stagnalis was used as a model to study the role of cAMP in NO-mediated mechanisms. The NO donor, DEA/NO (10(-5)-10(-3) M) increased cAMP concentrations in the cerebral, pedal, pleural, parietal and visceral ganglia. In contrast, in the buccal ganglia the same doses of DEA/NO decreased the level of cAMP production. The NOS inhibitor, L-NNA (10(-4) M) increased cAMP concentrations in all areas of the CNS. L-arginine (1 mM), a metabolic precursor of NO, mimicked the action of the NO-donor. The coefficient of electrical coupling between two viscero-parietal peptidergic neurons (VD1/RPaD2) was enhanced by both DEA/NO (10(-4) M) and 8-Br-cAMP (10(-4) M) whereas 8-Br-cGMP (2x10(-4) M) reduced the coupling. We suggest that cAMP-dependent mechanisms are involved in neuronal NO signaling in this simpler nervous system.     

Involvement of mu-receptors in the opioid-induced generation of bursting discharges in hippocampal pyramidal cells

Cultured hippocampal pyramidal cells responded to field stimulation with a short latency excitation followed by a long-lasting inhibition. This sequence was transformed into a bursting response by bath application of 10(-8) M FK 33-824, 10(-6) M (D-Ala)2(D-Leu)5-enkephalin and 10(-5) M bremazocine. Bremazocine and ethylketocyclazocine stereospecifically blocked the effects of FK 33-824. The results indicate that the excitatory responses were predominantly mediated by mu-receptors.     

Differential effects of propofol and ketamine on critical brain dynamics

Whether the brain operates at a critical “tipping” point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as “dissociative anaesthesia”). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.     

Effect of acute temperature change on lung respiration of the mollusc Lymnaea stagnalis

• 1.Temperature-dependent effects on respiratory behaviour as well as the corresponding temperature-dependent activities of identified neurons within the respiratory network of the pulmonate snail Lymnaea stagnalis were investigated.
• 2.Lymnaea lung ventilation terminated at low temperatures (under 10 °C) while temperature elevation increased ventilation rates. The respiratory central pattern generator (CPG) functioning was relatively quiescent at temperatures under 12.5±0.44 °C.
• 3.Identified CPG neurons (RPeD1, VD4, VD1/RPaD2) and the respiratory network motor neurons (Vi- and RPa-cells) were found to exhibit varied temperature-dependent electrophysiological parameters (action potential frequency and amplitude, resting potential value) between cell types.
• 4.The observed alterations in the electrical activity of the Lymnaea respiratory network neurons underlie the marked changes of respiratory behaviour observed in the intact animal during temperature changes.

     

Actions of calcitonin gene-related peptide on rat sensory ganglion neurones

The membrane actions of calcitonin gene-related peptide (CGRP) and the effect of CGRP on the Ca-dependent action potential of rat dorsal root ganglion (DRG) neurons have been studied by means of an intracellular recording technique in isolated DRG of 2-3-week-old rats in vitro. Bath application of CGRP (10(-8)-10(-6) M for 1-5 min) elicited a slow reversible hyperpolarization and this hyperpolarizing effect was still observed in the medium containing TTX and TEA. However, about half of the large cells, classified by duration of action potential, were depolarized by CGRP. These membrane effects of CGRP were associated with an increase in membrane input resistance (about 20%). In addition, CGRP increased the duration of Ca-dependent action potentials. Our results are consistent with the role of CGRP as an excitatory neurotransmitter or neuromodulator in DRG-spinal cord.     

Propofol and thiopental attenuate adenosine triphosphate-sensitive potassium channel relaxation in pulmonary veins

Pulmonary veins (PV) make a significant contribution to total pulmonary vascular resistance. We investigated the cellular mechanisms by which the intravenous anesthetics propofol and thiopental alter adenosine triphosphate-sensitive potassium (KATP+) channel relaxation in canine PV. The effects of KATP+ channel inhibition (glybenclamide), cyclooxygenase inhibition (indomethacin), nitric oxide synthase inhibition (L-NAME), and L-type voltage-gated Ca2+ channel inhibition (nifedipine) on vasorelaxation responses to levcromakalim (KATP+ channel activator) alone and in combination with the anesthetics were assessed. The maximal relaxation response to levcromakalim was attenuated by removing the endothelium and by L-NAME, but not by indomethacin. Propofol (10(-5), 3x10(-5), and 10(-4) M) and thiopental (10(-4) and 3x10(-4) M) each attenuated levcromakalim relaxation in endothelium-intact (E+) rings, whereas propofol (3x10(-5) and 10(-4) M) and thiopental (3x10(-4) M) attenuated levcromakalim relaxation in endothelium-denuded (E-) rings. In E+ rings, the anesthesia-induced attenuation of levcromakalim relaxation was decreased after pretreatment with L-NAME but not with indomethacin. In E-strips, propofol (10(-4) M) and thiopental (3x10(-4) M) inhibited decreases in tension and intracellular Ca2+ concentration ([Ca2+]i) in response to levcromakalim, and these changes were abolished by nifedipine. These findings indicate that propofol and thiopental attenuate the endothelium-dependent component of KATP+ channel-induced PV vasorelaxation via an inhibitory effect on the nitric oxide pathway. Both anesthetics also attenuate the PV smooth muscle component of KATP+ channel-induced relaxation by reducing the levcromakalim-induced decrease in [Ca2+]i via an inhibitory effect on L-type voltage-gated Ca2+ channels.     

Potency of propofol, thiopentone and ketamine at various endpoints in New Zealand White rabbits

Effective plasma concentrations of propofol, thiopentone and ketamine were determined at different endpoints in a study with randomized, crossover design in nine New Zealand White rabbits. A continuous infusion was used (30 ml/h) with concentrations of 10 mg/ml for propofol, 25 mg/ml for thiopentone and 20 mg/ml for ketamine. The endpoints were loss of the righting reflex, loss of purposeful reactions to tail clamping (as an example of a peripheral pain stimulus) or to intranostril insufflation of ammonia vapour (as an example of a central reflex stimulus), and the recovery of these reflexes and reactions. According to the ED50 values the potency ratios of propofol, thiopentone and ketamine were at the loss of righting reflex 1:1.8:1.2, at the loss of reaction to ammonia vapour 1:1.5:1.6, and at the loss of reaction to tail clamping 1:1.5:3.9, respectively. Recovery was significantly faster after propofol than after thiopentone and ketamine. Measuring the effective plasma concentrations of intravenous anaesthetics provides a method of relating dose to effect, but there still remains a variable gap between plasma concentration and effect.     

Influence of different anaesthetics on pro-inflammatory cytokine expression in rat spleen

We examined the effect of five anaesthetic drugs commonly used in laboratory animal research (tribromoethanol, ketamine/xylazine, chloral hydrate, pentobarbital, and urethane) on the expression of four pro-inflammatory cytokines. The anaesthetic agents were applied at dosages normally used for deep surgical anaesthesia. Semiquantitative image analysis of interleukin (IL)-1beta, IL-2, IL-6, and tumour necrosis factor alpha (TNFalpha) mRNA expression in the spleen of male Wistar rats 4 h after application of the anaesthetic drugs showed that these had moderate immunomodulatory effects. Ketamine/xylazine, chloral hydrate, and pentobarbital enhanced the basal expression of IL-1beta and IL-6 mRNA in rat spleen, while urethane reduced splenic IL-1beta mRNA expression. Tribromoethanol, ketamine/xylazine, and urethane reduced the basal TNFalpha mRNA levels, whereas TNFalpha mRNA expression was unaffected by chloral hydrate and by pentobarbital. The data demonstrate that these anaesthetics have slight, but significant, effects on the basal immune status of rats.     

The effects of different anaesthetic treatments on the adreno-cortical functions and glucose levels in NZW rabbits

The effects of five anaesthetics on the corticosterone, cortisol and glucose concentrations were investigated in the NZW rabbit. Sixty animals were assigned to 6 treatment groups (n= 10 per group): control ( iv saline solution injection), ketamine (10 mg/kg iv) with either xylazine (3 mg/kg iv) or diazepam (2 mg/kg iv), pentobarbitone (30 mg/kg iv), thiopentone (20 mg/kg iv) and fentanyl/droperidol (1 mg/kg sc). Plasma glucocorticoids were measured by competitive enzymeimmunoassay EIA and glucose by an autoanalyzer, previously validated for this species in both cases. Blood samples were obtained at 6 time-points: before injection, at 10, 30, 60, 120 min and 24 h after injection of the anaesthetics/saline. A significant decrease of plasma glucocorticoids at 10-60 min was observed in the pentobarbitone and fentanyl/ droperidol groups, whereas the administration of ketamine/diazepam or thiopentone stimulated plasma glucocorticoid release, principally in the recovery period. However, in the ketamine/xylazine group no changes were observed in the glucocorticoid levels, except for a significative increase of cortisol at 60-120 min. Glucose levels significantly increased after ketamine/diazepam administration and principally, after ketamine/xylazine treatment. The present data suggest that ketamine/xylazine has little effect on glucocorticoid levels and provides an adequate level of surgical anaesthesia, hence it would be the anaesthetic of choice, although the hyperglycaemic effect after injection has to be considered for any experimental procedures in rabbits.     

Effects of propofol on the development of cancer in humans

Cancer is one of most the significant threats to human health worldwide, and the primary method of treating solid tumours is surgery. Propofol, one of the most widely used intravenous anaesthetics in surgery, was found to be involved in many cancer‐related pathophysiology processes, mainly including anti‐tumour and minor cancer‐promoting effects in various types of cancer. An increasing number of studies have identified that propofol plays a role in cancer by regulating the expression of multiple signalling pathways, downstream molecules, microRNAs and long non‐coding RNAs. Emerging evidence has indicated that propofol can enhance the anti‐tumour effect of chemotherapeutic drugs or some small molecular compounds. Additionally, in vivo animal models have shown that propofol inhibits tumour growth and metastasis. Furthermore, most clinical trials indicate that propofol is associated with better survival outcomes in cancer patients after surgery. Propofol use is encouraged in cancers that appear to have a better prognosis after its use during surgery. We hope that future large and prospective multicenter studies will provide more precise answers to guide the choice of anaesthetics during cancer surgery.     

Effects of Tramadol on Substantia Gelatinosa Neurons in the Rat Spinal Cord: An In Vivo Patch-Clamp Analysis

Tramadol is thought to modulate synaptic transmissions in the spinal dorsal horn mainly by activating µ-opioid receptors and by inhibiting the reuptake of monoamines in the CNS. However, the precise mode of modulation remains unclear. We used an in vivo patch clamp technique in urethane-anesthetized rats to determine the antinociceptive mechanism of tramadol. In vivo whole-cell recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) were made from substantia gelatinosa (SG) neurons (lamina II) at holding potentials of 0 mV and -70 mV, respectively. The effects of intravenous administration (0.5, 5, 15 mg/kg) of tramadol were evaluated. The effects of superfusion of tramadol on the surface of the spinal cord and of a tramadol metabolite (M1) were further analyzed. Intravenous administration of tramadol at doses >5 mg/kg decreased the sEPSCs and increased the sIPSCs in SG neurons. These effects were not observed following naloxone pretreatment. Tramadol superfusion at a clinically relevant concentration (10 µM) had no effect, but when administered at a very high concentration (100 µM), tramadol decreased sEPSCs, produced outward currents, and enhanced sIPSCs. The effects of M1 (1, 5 mg/kg intravenously) on sEPSCs and sIPSCs were similar to those of tramadol at a corresponding dose (5, 15 mg/kg). The present study demonstrated that systemically administered tramadol indirectly inhibited glutamatergic transmission, and enhanced GABAergic and glycinergic transmissions in SG neurons. These effects were mediated primarily by the activation of μ-opioid receptors. M1 may play a key role in the antinociceptive mechanisms of tramadol.