Associations between intraoperative nociceptive response index and early postoperative acute kidney injury in patients undergoing non-cardiac surgery under general anesthesia: a single-center retrospective cohort study.

Both tissue hypoperfusion and elevated surgical stress during surgery are involved in the pathogenesis of postoperative acute kidney injury (AKI). Although intraoperative hypotension, which evokes renal hypoperfusion, has been reported to be associated with the development of postoperative AKI, there is no consensus on the association between surgical stress responses (e.g., hypertension and inflammation) and postoperative AKI. Given that intraoperative values of nociceptive response (NR) index are reportedly associated with surgical stress responses, the present study was performed to assess associations between intraoperative NR index and postoperative AKI in patients undergoing non-cardiac surgery. In this single-institutional retrospective cohort study, data of the highest and lowest values of NR index during surgery were obtained in consecutive adult patients undergoing non-cardiac surgery under general anesthesia from February 2022 to August 2023. Data on highest and lowest mean blood pressure (MBP) during surgery were also obtained. In 5,765 patients enrolled, multivariate regression analysis revealed that the development of early postoperative AKI was significantly associated with highest NR during surgery ≥ 0.920, lowest MBP during surgery < 54 mmHg, age ≥ 48 years, male sex, ASA-PS ≥ III, emergency, and duration of surgery ≥ 226 min. In addition to intraoperative hypotension, a higher level of intraoperative NR index is likely associated with higher incidence of early postoperative AKI in adult patients undergoing non-cardiac surgery under general anesthesia.

Quantitative evaluation of the effects of interscalene block on physiological responses to the balance between nociception and anti-nociception among inpatients undergoing total shoulder arthroplasty under general anesthesia.

Although the suppression of physiological responses to the balance between nociception caused by surgical trauma and anti-nociception due to anesthesia during total shoulder arthroplasty (TSA) is relevant for better perioperative managements, quantitative evaluations of the effects of ultrasound-guided interscalene brachial plexus block (ISB) on physiological responses have not been performed. Physiological responses were assessed using the nociceptive response (NR) index. In this multi-institutional observational study, associations between ISB and NR values were examined among inpatients undergoing TSA under general anesthesia between March 2019 and January 2021. The effects of ISB on acute postoperative pain and major complications within 30 days after surgery were also examined. NR values after skin incision clearly showed significant suppressions of physiological responses in patients undergoing TSA with ISB (n = 60), compared to those without ISB (n = 24). Acute postoperative pain on the day of surgery was also significantly less in patients with ISB than in those without ISB. Postoperative complications, classified by Clavien-Dindo grades, showed no significant differences between patients with and without ISB. A propensity score-matched sensitivity analysis confirmed the same results in patients with (n = 21) and without ISB (n = 21). In conclusion, suppression of physiological responses to the balance between nociception and anti-nociception by ISB can be quantitatively evaluated by NR index during TSA.

TNF-α acutely enhances acid-sensing ion channel currents in rat dorsal root ganglion neurons via a p38 MAPK pathway.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to pain signaling caused by tissue acidosis. It is still unclear whether TNF-α has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-α acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons. METHODS: Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro. RESULTS: A brief (5min) application of TNF-α rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-α (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 0.12 ± 0.01 nM. TNF-α shifted the concentration-response curve of proton upwards with a maximal current response increase of 42.34 ± 7.89%. In current-clamp recording, an acute application of TNF-α also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-α was prevented by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting that p38 MAPK is necessary for this enhancement. Behaviorally, TNF-α exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway. CONCLUSIONS: These results suggest that TNF-α rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-α involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.

Association between intraoperative nociception and surgical invasiveness in patients undergoing non-cardiac surgery under general anesthesia: a retrospective cohort study.

There are several indexes of intraoperative nociception during surgery under general anesthesia. Although a higher degree of surgical invasiveness increases intraoperative nociception, an association between the index of intraoperative nociception and severity of surgical invasiveness has not been reported. We hypothesized that there is associations between averaged values of nociceptive response (NR) throughout surgery (mean NR), as the index of intraoperative nociception, and surgical severity codes in the Surgical outcome risk tool (SORT) or procedure risk codes in the Surgical mortality probability model (S-MPM). The primary outcome was the association between mean NR and severity scores of surgical procedure. Hence, a single institutional retrospective cohort study was performed in consecutive patients undergoing non-cardiac surgery under general anesthesia from June 2018 to May 2019. There were significant increases in the three categories of procedure risk in the S-MPM corresponding to the increase in mean NR values in 5090 patients. In the SORT, the highest intensity in the four categories of surgical severity also significantly correlated with the increase in mean NR values. Increasing intensity of intraoperative nociception is likely associated with higher severity codes of surgical invasiveness in prediction models for postoperative morbidity and mortality.

Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons.

Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid-sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1-100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration-response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETAR), but not endothelin-B receptor (ETBR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETAR. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETAR and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.

Association between intraoperative nociception and postoperative complications in patients undergoing laparoscopic gastrointestinal surgery.

A higher degree of surgical invasiveness, which increases intraoperative nociception, might induce postoperative complications. Although several nociceptive indices for use during surgery are available in clinical practice, association between intraoperative nociception and postoperative complications has not been reported. An index representing intraoperative nociception, which is the averaged value of Nociceptive Response throughout the surgery (mean NR) was applied to examine the association in the present study. The retrospective study evaluated consecutive adult patients undergoing laparoscopic gastrointestinal surgery, American Society of Anesthesiologists-physical status (ASA-PS) I or II, whose preoperative C-reactive protein level was < 0.3 mg dL-1. We first used ordinal logistic analysis to examine the association between preoperative and intraoperative risk factors and complications graded by the Clavien-Dindo classification. Next, we performed propensity score matched analysis to evaluate the effects of mean NR throughout surgery on postoperative complications. Ordinal logistic analysis (n = 158) revealed that duration of surgery (P < 0.001), mean NR during surgery (P = 0.002), and ASA-PS (P = 0.016) were risk factors for postoperative complications. Then all patients were divided into two propensity score matched groups, based on a mean NR of < 0.85 and ≥ 0.85, with matching for age, ASA-PS, body mass index and duration of surgery. The severity of postoperative complications was significantly higher in the high NR group than in the low NR group (P = 0.005). In conclusion, there was likely an association between intraoperative nociception and postoperative complications in patients without serious preoperative conditions and comorbidities.

Inhibitory effects of eugenol on putative nociceptive response in spinal cord preparation isolated from neonatal rats.

Eugenol is contained in several plants including clove and is thought to exert an analgesic effect. It has been suggested that the slow ventral root potential induced by ipsilateral dorsal root stimulation in the isolated (typically lumbar) spinal cord of newborn rats reflects the nociceptive response, and this in vitro experimental model is useful to assess the actions of analgesics. To further elucidate neuronal mechanisms of eugenol-induced analgesia, we examined the effects of extracellularly applied eugenol on the nociceptive spinal reflex response. To evaluate the effects of eugenol on putative nociceptive responses, the ipsilateral fifth lumbar (L5) dorsal root was stimulated using a glass suction electrode, and the induced reflex responses were recorded from the L5 and twelfth thoracic (Th12) ventral roots in spinal cord preparations (Th10-L5) from newborn rats (postnatal day 0-3). We found that eugenol (0.25-1.0 mM) caused dose-dependent attenuation of the reflex response and also depressed spontaneous ventral root activity. We also found that the slow ventral root potential was further divided into two components: initial and late components. A lower concentration of eugenol selectively depressed the late component. The inhibitory effects by 1.0 mM eugenol were not reversed by 10 µM capsazepine (TRPV1 antagonist) or 40 µM HC-030031 (TRPA1 antagonist). The depressive effect of eugenol on the reflex response was also confirmed by optical recordings using voltage-sensitive dye. Our report provides additional evidence on the basic neuronal mechanisms of eugenol to support its clinical use as a potential analgesic treatment.

The Impact of Nociception Monitor-Guided Multimodal General Anesthesia on Postoperative Outcomes in Patients Undergoing Laparoscopic Bowel Surgery: A Randomized Controlled Trial.

BACKGROUND: Excess surgical stress responses, caused by heightened nociception, can lead to elevated levels of postoperative inflammation, resulting in an increased incidence of complications after surgery. We hypothesized that utilizing nociception monitor-guided multimodal general anesthesia would exert effects on postoperative outcomes (e.g., serum concentrations of C-reactive protein (CRP) after surgery, postoperative complications). METHODS: This single-center, double-blinded, randomized trial enrolled ASA class I/II adult patients with normal preoperative CRP levels, scheduled for laparoscopic bowel surgery. Patients were randomized to receive either standard care (control group) or nociception monitor-guided multimodal general anesthesia using the nociceptive response (NR) index (NR group), where NR index was kept below 0.85 as possible. The co-primary endpoint was serum concentrations of CRP after surgery or rates of 30-day postoperative complications (defined as Clavien-Dindo grades ≥ II). MAIN RESULTS: One hundred and four patients (control group, n = 52; NR group, n = 52) were enrolled for analysis. The serum CRP level on postoperative day (POD) 1 was significantly lower in the NR group (2.70 mg·dL-1 [95% confidence interval (CI), 2.19-3.20]) than in the control group (3.66 mg·dL-1 [95% CI, 2.98-4.34], p = 0.024). The postoperative complication rate was also significantly lower in the NR group (11.5% [95% CI, 5.4-23.0]) than in the control group (38.5% [95% CI, 26.5-52.0], p = 0.002). CONCLUSIONS: Nociception monitor-guided multimodal general anesthesia, which suppressed intraoperative nociception, mitigated serum concentrations of CRP level, and decreased postoperative complications after laparoscopic bowel surgery.

Rosacea in East Asian populations: Clinical manifestations and pathophysiological perspectives for accurate diagnosis.

Rosacea is a chronic inflammatory disorder primarily affecting the facial skin, prominently involving the cheeks, nose, chin, forehead, and periorbital area. Cutaneous manifestations encompass persistent facial erythema, phymas, papules, pustules, telangiectasia, and flushing. The pathogenesis of rosacea is associated with various exacerbating or triggering factors, including microbial infestation, temperature fluctuations, sunlight exposure, physical exertion, emotional stress, consumption of hot beverages and spicy foods, and exposure to airborne pollen. These environmental factors interact with genetic predispositions in the development of rosacea. The roles of the lipophilic microbiome, ultraviolet radiation, nociceptive responses, and vascular alterations have been proposed as significant factors in the pathogenesis. These insights contribute to understanding the anatomical specificity of facial involvement and the progressive nature of rosacea. East Asian skin, predominantly classified as Fitzpatrick skin phototypes III to IV, is characterized by relatively diminished skin barrier function and increased sensitivity to irritants. Airborne pollen exposure may particularly act as a trigger in East Asian individuals, possibly mediated through toll-like receptors. The lack of specificity in objective clinical and histopathological findings leads to diagnostic challenges for individuals with colored skin, including East Asians, particularly when erythema is the sole objective manifestation. An alternative diagnostic scheme may thus be necessary. A diagnostic approach emphasizing vascular manifestations and nociceptive symptoms potentially holds promise for individuals with darker skin tones. More research focusing on potential variations in skin physiology across different racial groups is essential to establish more effective diagnostic schemes applicable to both dark and light skin colors.

Evaluation and correlation of nociceptive response index and spectral entropy indices as monitors of nociception in anesthetized patients.

Objectives: During anesthesia, the response to these stimuli depends on the balance between nociception and antinociception. Recently, various monitoring systems based on the variables derived from electroencephalography, plethysmography, autonomic tone, reflex pathways, and composite algorithms have been introduced for monitoring nociception. The main aim of our study was to evaluate and correlate the physiological variables which reflect the autonomic nervous system response to nociception, such as heart rate (HR), systolic blood pressure (SBP), perfusion index (PI), and nociceptive response index (NRI), with the spectral entropy indices response entropy (RE) and RE-state entropy (SE), which reflects electromyographic (EMG) activation as a response to pain. Materials and Methods: This is a retrospective analysis of the data from a prospective study on the hypnotic and analgesic effects and the recovery profile of sevoflurane-based general anesthesia. Eighty-six patients undergoing single-agent sevoflurane anesthesia were recruited in the study. The study parameters, HR, SBP, SE, RE, RE-SE, PI, and NRI, were recorded at predefined time points before and after a standardized noxious stimulus. Correlation between the variables was carried out by applying the Pearson correlation equation for normal and the Spearman correlation equation for non-normally distributed data. Receiver operating characteristic (ROC) graphs were plotted, and the area under the curve was calculated to assess the diagnostic accuracy of post-stimulus NRI in detecting pain which was defined as RE-SE >10. Results: There was a significant increase in the SBP, HR, NRI, RE, SE, and RE-SE and a considerable decrease in PI values during the post-noxious period compared to the pre-noxious period. There was no correlation between the absolute values of NRI and entropy indices at T2. However, among the reaction values, there was a weak correlation between the reaction values of NRI and RE (r = 0.30; P = 0.05). The area under the ROC curve for NRI to detect pain as defined by RE-SE >10 was 0.56. Conclusion: During sevoflurane anesthesia, the application of noxious stimulus causes significant changes in variables reflecting sympathetic response and EMG activity. However, NRI failed to detect nociception, and there was only a weak correlation between the reaction values of NRI and RE-SE.

Tissue sealing versus suture ligation in open canine ovariectomy: Surgical times, intraoperative nociceptive response and frequency of complications.

BACKGROUND: In this study, we compared two different techniques currently used for open canine ovariectomy: traditional method utilising absorbable suture and vessel sealing device (ENSEAL® Ethicon Endo-Surgery, Cincinnati, OH). OBJECTIVES: The aim of this study was to compare the surgical times, intraoperative nociceptive response and the frequency of intraoperative complications in the canine ovariectomy procedure using these two techniques. METHODS: Forty bitches were randomly divided into two groups. The Control Group (C) will use a classic open surgery approach using ligatures with absorbable suture and ovarian resection with a scalpel blade. In the Group E, resection of ovarian structures was performed with ENSEAL® tissue sealer device. For each dog the surgical times, the intraoperative nociceptive response (measuring heart rate, respiratory rate and non-invasive blood pressure) and the intraoperative complications were measured to compare the effectiveness of the two techniques. RESULTS: The results of this study showed that the procedures performed using ENSEAL® were faster than the traditional techniques using surgical suture. Instead, the results regarding the nociception and the safety of the two procedures are similar. CONCLUSIONS: The present study shows that the use of ENSEAL® significantly shortened the surgical time. Meanwhile, its use was found to be similarly safe and efficient in terms of intra-operative nociception, as the classical techniques with absorbable suture. Canine ovariectomy using ENSEAL® device is more practical and faster than the traditional technique; the routine use of this device is considered a useful alternative for the canine neutering.

Acute P38-Mediated Enhancement of P2X3 Receptor Currents by TNF-α in Rat Dorsal Root Ganglion Neurons.

PURPOSE: Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine and involves in a variety of pain conditions. Some findings suggest that TNF-α may act directly on primary afferent neurons to induce acute pain hypersensitivity through non-transcriptional regulation. This study investigated whether TNF-α had an effect on functional activity of P2X3 receptors in primary sensory neurons. Herein, we report that a brief (5 min) application of TNF-α rapidly enhanced the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. METHODS: Electrophysiological recordings were carried out on rat DRG neurons, and nociceptive behavior was quantified in rats. RESULTS: A brief (5 min) exposure of TNF-α rapidly increased P2X3 receptor-mediated and α,ß-methylene-ATP (α,ß-meATP)-evoked inward currents in a dose-dependent manner. The potentiation of P2X3 receptor-mediated ATP currents by TNF-α was voltage-independent. TNF-α shifted the concentration-response curve for α,ß-meATP upwards, with an increase of 31.57 ± 6.81% in the maximal current response to α,ß-meATP. This acute potentiation of ATP currents by TNF-α was blocked by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting involvement of p38 MAPK, but not cyclooxygenase. Moreover, intraplantar injection of TNF-α and α,ß-meATP produced a synergistic effect on mechanical allodynia in rats. TNF-α-induced mechanical allodynia was also alleviated after local P2X3 receptors were blocked. CONCLUSION: These results suggested that TNF-α rapidly sensitized P2X3 receptors in primary sensory neurons via a p38 MAPK dependent pathway, which revealed a novel peripheral mechanism underlying acute mechanical hypersensitivity by peripheral administration of TNF-α.

Determination of the temperature causing a nociceptive response in the tail of albino BALB/c mice.

INTRODUCTION: Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful. METHODS: Eight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13cm. The animals' tails were immersed in the container with a starting temperature of 36°C. The water temperature was raised in 1°C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water. RESULTS: Six of the 8 mice began shaking their tails at the temperature of 51°C. All animals removed their tails from the water at the temperatures of 54°C, 55°C, and 56°C, taking a mean time of 8.54, 7.99, and 5.33seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). CONCLUSIONS: The response time was statistically similar for the temperatures of 54°C, 55°C, and 56°C; however, the data were less dispersed for the latter temperature.

Determination of the temperature causing a nociceptive response in the tail of albino BALB/c mice. / Determinación de la temperatura de respuesta nociceptiva sobre la cola de ratones albinos de la cepa Balb/c.

INTRODUCTION: Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful. METHODS: Eight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13 cm. The animals' tails were immersed in the container with a starting temperature of 36°C. The water temperature was raised in 1°C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water. RESULTS: Six of the 8 mice began shaking their tails at the temperature of 51°C. All animals removed their tails from the water at the temperatures of 54°C, 55°C, and 56°C, taking a mean time of 8.54, 7.99, and 5.33seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). CONCLUSIONS: The response time was statistically similar for the temperatures of 54°C, 55°C, and 56°C; however, the data were less dispersed for the latter temperature.

The Atypical Kinesin KIF26A Facilitates Termination of Nociceptive Responses by Sequestering Focal Adhesion Kinase.

Kinesin superfamily proteins (KIFs) are molecular motors that typically alter the subcellular localization of their cargos. However, the atypical kinesin KIF26A does not serve as a motor but can bind microtubules and affect cellular signaling cascades. Here, we show that KIF26A maintains intracellular calcium homeostasis and negatively regulates nociceptive sensation. Kif26a-/- mice exhibit intense and prolonged nociceptive responses. In their primary sensory neurons, excessive inhibitory phosphorylation of plasma membrane Ca2+ ATPase (PMCA) mediated by focal adhesion kinase (FAK) rendered the Ca transients resistant to termination, and the peripheral axonal outgrowth was significantly enhanced. Upstream, KIF26A is directly associated with a FERM domain of FAK and antagonizes FAK function in integrin-Src family kinase (SFK)-FAK signaling, possibly through steric hindrance and localization to cytoplasmic microtubules.

Altered expression of differential gene and lncRNA in the lower thoracic spinal cord on different time courses of experimental obstructive jaundice model accompanied with altered peripheral nociception in rats.

The spinal origin of jaundice-induced altered peripheral nociceptive response poorly understood. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a jaundice model accompanied by altered peripheral nociceptive response, and then to analyze differential gene and lncRNA expression patterns in the lower thoracic spinal cord on different time courses after BDL operation by using high-throughput RNA sequencing. The differentially expressed genes (DEGs) identified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, followed by clustering analysis, Gene Ontology analysis and pathway analysis. As a result, a total of 2033 lncRNAs were differentially expressed 28d after BDL, in which 1545 probe sets were up-regulated and 488 probe sets were down-regulated, whereas a total of 2800 mRNAs were differentially expressed, in which 1548 probe sets were up-regulated and 1252 probe sets were down-regulated. The RNAseq data of select mRNAs and lncRNAs was validated by RT-qPCR. 28d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated whereas the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down-regulated. 14d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated; the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down-regulated. In conclusion, the present study showed that jaundice accompanied with decreased peripheral nociception involved in the changes of gene and lncRNA expression profiles in spinal cord. These findings extend current understanding of spinal mechanism for obstructive jaundice accompanied by decreased peripheral nociception.

Composition and biological activities of the aqueous extracts of three scleractinian corals from the Mexican Caribbean: Pseudodiploria strigosa, Porites astreoides and Siderastrea siderea.

BACKGROUND: Scleractinian corals (stony corals) are the most abundant reef-forming cnidarians found in coral reefs throughout the world. Despite their abundance and ecological importance, information about the diversity of their toxins and their biological activities is very scarce. In this study, the chemical composition and the biological activities of the aqueous extracts of Pseudodiploria strigosa, Porites astreoides and Siderastrea siderea, three scleractinian corals from the Mexican Caribbean, have been assessed for the first time. METHODS: Toxicity of the extracts was assessed in crickets; the presence of cytolysins was detected by the hemolysis assay; the vasoconstrictor activity was determined by the isolated rat aortic ring assay; the nociceptive activity was evaluated by the formalin test. The presence of phospholipases A2 (PLA2), serine proteases, and hyaluronidases was determined by enzymatic methods. Low-molecular-weight fractions were obtained by gel filtration chromatography and ultrafiltration. RESULTS: Extracts from the three species were toxic to crickets, induced hemolysis in human and rat erythrocytes, produced vasoconstriction on isolated rat aortic rings, and presented phospholipase A2 and serine-protease activity. Despite the fact that these corals are not considered to be harmless to humans, the extracts generated significant nociceptive responses. The matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry analysis of the low-molecular-weight fractions revealed the presence of peptides within a mass range of 3000 to 6000 Da. These fractions were toxic to crickets and two of them induced a transitory vasoconstrictor effect on isolated rat aortic rings. CONCLUSION: This study suggests that scleractinian corals produce low-molecular-weight peptides that are lethal to crickets and induce vasoconstriction.

Determinación de la temperatura de respuesta nociceptiva sobre la cola de ratones albinos de la cepa Balb/c / Determination of the temperature causing a nociceptive response in the tail of albino BALB/c mice

Introducción: Los diseños para determinar la respuesta nociceptiva en roedores son de gran utilidad en neurología y en neurociencias experimentales. El paradigma de inmersión de la cola de ratón en agua temperada es uno de los más empleados para evaluar dicha respuesta; sin embargo, existe amplia variación en la temperatura utilizada en las diversas investigaciones. Resulta sumamente útil determinar la temperatura que produce una mejor respuesta nociceptiva sobre la cola de ratones de la cepa Balb/c.MétodosSe emplearon 8 ratones machos Balb/c de 2 meses de edad. Un beaker de 14 cm de alto se llenó de agua hasta 13 cm. Partiendo desde los 36 °C se empezó a sumergir la cola del animal dentro del recipiente. Se comenzó a elevar en 1 °C el agua hasta encontrar las temperaturas que produzcan las respuestas nociceptivas. Dicha respuesta se determinó contabilizando el tiempo que el ratón tardó en sacudir su cola retirándola del agua.ResultadosLos ratones empezaron a sacudir su cola a los 51 °C (6 de los 8 roedores). El total de la muestra retiró su cola del agua a los 54, 55 y 56 °C en el tiempo promedio de 8,54, 7,99 y 5,33 s, respectivamente. Al aplicar ANOVA a los tiempos de las 3 temperaturas señaladas se obtuvo el valor F = 2,8 y p = 0,123.ConclusionesEl tiempo de respuesta fue similar estadísticamente ante las temperaturas de 54, 55 y 56 °C; sin embargo se encontró menor dispersión de los datos ante esta última. (AU)

Introduction: Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful.MethodsEight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13 cm. The animals’ tails were immersed in the container with a starting temperature of 36 °C. The water temperature was raised in 1 °C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water.ResultsSix of the 8 mice began shaking their tails at the temperature of 51 °C. All animals removed their tails from the water at the temperatures of 54 °C, 55 °C, and 56 °C, taking a mean time of 8.54, 7.99, and 5.33 seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123).ConclusionsThe response time was statistically similar for the temperatures of 54 °C, 55 °C, and 56 °C; however, the data were less dispersed for the latter temperature. (AU)

Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion.

Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. The formalin test revealed that rats with neonatal dopamine depletion exhibited a significant increase in nociceptive response during interphase (6-15min post formalin injection) and phase 2 (16-75min post formalin injection). This increase in nociceptive response to the formalin injection was not reversed by pretreatment with methamphetamine, which ameliorates motor hyperactivity observed in adolescent rats with neonatal 6-OHDA treatment. The von-Frey filament and tail flick tests failed to reveal significant differences in withdrawal thresholds between neonatal 6-OHDA-treated and vehicle-treated rats. The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I-II and V-VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of spontaneous motor hyperactivity induced by neonatal dopamine depletion.

Suppressive action of enflurane on dorsal horn neurons in rabbits.

The neurophysiologic mechanism of the suppressive action of enflurane on spinal nociceptive transmission was examined in rabbits with intact and with transected spinal cords. Enflurane suppressed nociceptive responses in both intact and transected spinal cord groups. The suppressive effects of enflurane were significantly greater in the intact group than in the transected group. The suppressive effects of enflurane were not reversed by the addition of 0.2 mg·kg-1 of naloxone. These results suggest that enflurane suppresses nociceptive responses by activating descending inhibitory systems and directly suppressing activity at the spinal level. This suppressive action of enflurane does not interact with the opioid receptor.