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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The effect of preventive administration of a single intraperitoneal dose of dimethylsulfoxide (DMSO) at various concentrations (10, 30 and 50%; 10 mL/kg) on the nociceptive response in mice induced by local and systemic activation of TRPV1 ion channels by the TRPV1 agonist capsaicin was studied. DMSO (50%) significantly reduced (by 73.1%) the latency of the response to injection of capsaicin solution into the metatarsus. DMSO in the tail-flick test did not significantly affect the thermal pain threshold, which was elevated after a single subcutaneous injection (above the shoulder blades) of capsaicin at a dose of 1 mg/kg. However, DMSO (30 and 50%) per se raised the pain threshold of mice in the tail-flick test. Because externally applied DMSO enhanced the effect of capsaicin in the capsaicin test, the demonstrated analgesic effect of a single intraperitoneal injection of DMSO in the capsaicin test and tail-flick test in mice was due to its central action rather than to its effect on afferent innervation. [ABSTRACT FROM AUTHOR]

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Resumen: 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. Métodos: Se 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. Resultados: Los 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. Conclusiones: El 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. Abstract: 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 5.33 seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). 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.

Abstract 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.

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,β-methylene-ATP (α,β-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,β-meATP upwards, with an increase of 31.57 ± 6.81% in the maximal current response to α,β-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,β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary 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. Graphical Abstract Highlights • The nociceptive responses of Kif26a −/− mice are abnormally prolonged • Kif26a −/− DRG axons are hyperbranched, and their Ca transients are prolonged • KIF26A sequesters FAK on microtubules and increases Ca pump activity • The SFK inhibitor PP2 reverses Kif26a −/− phenotypes in vitro and in vivo Wang et al. establish a mouse model of pain by deleting the Kif26a gene, which encodes an atypical kinesin. The nociceptive response of this model is abnormally prolonged. KIF26A sequesters FAK onto cytoplasmic microtubules and facilitates Ca pump activity, which leads to prolonged pain response. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2) was significantly increased in cannulated (Cn) rats, compared with naive (Nv) or sham-operated (Sh) rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%). The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

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 (6–15 min post formalin injection) and phase 2 (16–75 min 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. [ABSTRACT FROM AUTHOR]

Low-intensity high-frequency stimulation (HFS) delivered to the basolateral nuclei of the amygdala (BLAs) induced anti-nociceptive effects and reduced spontaneous motor activities in freely moving rats. Stimulation (20 μA, 100 sec-1, 200 μsec square, for 30 sec) was applied through electrodes implanted bilaterally in the BLA. Pain behavioral responses were inhibited by HFS in the formalin test but not in the plantar test. Spontaneous motor activities were also reduced by HFS delivered to the BLAs. Intrathecal injection of naloxone failed to block the analgesic effects of HFS, suggesting the descending opiate system to be minimally involved. We previously reported that HFS delivered to the BLA inhibited nociceptive responses recorded in the prefrontal cortex. Here, we demonstrate that such stimulation under the same conditions also induces analgesic effects in behavior studies. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the ability of SC indexes in discriminating acute responses to different heel prick procedures. Methods: Observational cohort study of a systematic, convenience sample of neonates with clinical indication of capillary blood sampling by heel prick, either for glycaemia or for blood gas analysis. The Neonatal Infant Pain Scale (NIPS) was used to confirm the painful nature of the stimuli. NIPS assessment and SC measurement (Med-Storm Pain Monitor™) were simultaneously performed by two independent observers before, during and after blood sampling. Results: Sixty-eight heel prick procedures (46 for glycaemia and 22 for blood gas analysis) were applied to 16 infants. Both NIPS scores and SC peaks/s index were significantly higher during blood sampling than before or thereafter (Wilcoxon Signed Ranks, p < 0.001). There was no significant difference in NIPS score and SC peaks/s between the different heel prick procedures. Significantly higher SC area under low peaks index (Mann-Whitney, p = 0.001) and lower SC average rise time index (Mann-Whitney, p = 0.037) were registered when blood was drawn for blood gas analysis than for glycaemia, related to a sustained acute nociceptive response to a more prolonged stimulus. Conclusion: Using the conjunction of available SC indices, SC seems able to differentiate the nociceptive response to acute pain of different durations. [ABSTRACT FROM AUTHOR]

Abstract: The contribution of central PGE2 levels to the nociceptive response in rats was assessed and the effects of the selective cPLA2α inhibitor efipladib, and pain therapies of different classes on these responses was determined. An inflammatory pain model was optimized in rats so that PGE2 levels in the cerebrospinal fluid (CSF) could be directly correlated to the nociceptive response. Since efipladib appears to have limited permeation of the blood–brain barrier, we used this compound to determine the extent of pain reversal resulting primarily from peripheral, but not central, inhibition of the arachidonic acid (AA) pathway. The nociceptive response was significantly inhibited by orally administered efipladib, yet spinal fluid levels of PGE2 and temperature measurements were unaffected compared to vehicle-treated animals. Conversely, intrathecal (IT) administration of efipladib reduced PGE2 levels in the CSF by 45–60%, yet there was no effect on the nociceptive response. With COX-2 selective inhibitors and ibuprofen, a return of the nociceptive response developed over time, despite complete inhibition of PGE2 in the spinal fluid. The opposite was true with low doses of indomethacin: inhibition of the nociceptive response was observed despite the lack of effect on central PGE2 levels. Our results demonstrate that levels of PGE2 in the spinal fluid do not directly correlate with the nociceptive response and that blocking cPLA2α in the periphery significantly decreases inflammatory pain. [Copyright &y& Elsevier]

Lampreys are one of the most primitive vertebrates still living today. They attach themselves to the body surface of the host fish through their sucker-like mouths and suck blood of the host for days. Recent fossil evidence has indicated that morphology of lampreys in the late Devonian period, over 360 million years ago, already possessed the present day major characteristics, suggesting the evolutionary stability of a highly specialized parasitic feeding habit. Obviously, nociceptive responses and hemostasis of the host are two major barriers to long-term feeding of the parasitic lamprey. It has been found, to counteract hemostasis of the host, that paired buccal glands of lampreys secrete antihemostatic compounds to prevent blood of the host from coagulation. However, it is not known how lampreys make the host lose nociceptive responses. Here, we prepared components of the crude extract from the buccal glands of the lampreys ( Lampetra japonica). Then, we show that crude extract and one of its purified components reduce the firing frequency of neuronal action potentials probably through inhibiting the voltage-dependent Na+ channels. As the voltage-gated Na+ channels are highly conserved throughout evolution, we argue that the secretion of the lampreys could exert the similar effect on the Na+ channels of their host fish as well. Therefore, together with its antihemostatic effect, the secretion due to its inhibitory effect on neuronal excitability might provide a mechanism for the parasitic lampreys to keep their evolutionary stability. [ABSTRACT FROM AUTHOR]

Abstract: Zaltoprofen, a preferential COX-2 inhibitor, exhibited a potent inhibitory action on the nociceptive responses induced by a retrograde infusion of bradykinin into the right common carotid artery in rats. However, other COX-2 preferential inhibitors such as meloxicam and etodolac did not exhibit any apparent action, and also, preferential COX-1 inhibitors mofezolac and indomethacin, COX-1 and COX-2 inhibitor loxoprofen sodium showed a weak effect. These non-steroidal anti-inflammatory drugs (NSAIDs) except for zaltoprofen, strongly inhibited an acetic acid-induced writhing response related to PGs based on COX-1, at lower doses. Zaltoprofen had a moderate inhibitory effect compared with those of the above-mentioned NSAIDs. These results suggest that the inhibitory effect of zaltoprofen on bradykinin-induced nociceptive responses is not explainable by the inhibition of cyclooxygenase (COX). So, we examined the inhibitory effect of zaltoprofen on bradykinin-induced nociceptive responses by performing several in vitro experiments. Zaltoprofen did not bind to B1 and B2 receptors in a radio-ligand binding assay. In the cultured dorsal root ganglion cells of mature mice, zaltoprofen completely inhibited the bradykinin-induced increase of [Ca2+]i, which was inhibited by B2 antagonist D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin, but not by B1 antagonist. In addition, the inhibition of zaltoprofen on the increase of [Ca2+]i was observed even under extracellular Ca2+-free conditions. The above results suggest that zaltoprofen produces an analgesic action on bradykinin-induced nociceptive responses by blocking the B2 receptor-mediated pathway in the primary sensory neurons. Taken together, these results suggest that zaltoprofen may serve as a potent and superior analgesic for the treatment of pain. [Copyright &y& Elsevier]

Abstract: Intrathecal injection of histamine elicited behavioral responses consisting of scratching, biting and licking in conscious mice. To study the participation of histamine in pain perception, histidine decarboxylase knockout mice were examined for pain threshold by means of three different kinds of noxious stimuli: thermal nociception (hot-plate, tail-flick, and paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (formalin test and capsaicin test). Mutant mice lacking histidine decarboxylase showed significantly fewer nociceptive responses to the hot-plate, tail-flick, paw-withdrawal, tail-pressure, formalin and capsaicin tests. Sensitivity to noxious stimuli in the histidine decarboxylase knockout mice was significantly lower when compared to the wild-type mice. The intrathecally-administered histamine (400 pmol) significantly shortened the latency in the histidine decarboxylase knockout mice, but not in the wild-type mice in tail-flick tests. Pyrilamine, a histamine H1 receptor antagonist, but not ranitidine, a histamine H2 receptor antagonist, produced inhibition of the induced behavioral responses in the tail-flick test when co-administered with histamine. Sendide, a tachykinin NK1 receptor antagonist, inhibited histamine-induced nociceptive behavior in the histidine decarboxylase knockout mice. In contrast, the treatment with d-(−)-2 amino-5-phosponovaleric acid (d-APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, did not prevent the induction of the behavioral responses by histamine. These studies substantiate the evidence that nociceptive behavior induced by intrathecal injection of histamine is largely mediated through tachykinin NK1 and histamine H1 receptors in the spinal cord. [Copyright &y& Elsevier]

The formalin test was used to elicit acute and chronic pain in rats, and antisense oligodeoxynucleotide (AS-ODN) was used as a tool to modulate the expression of nociceptive behavioral and nuerochemical responses. AS-ODN complementary to c-Fos mRNA was administered intrathecally (i.t.) 4 h before formalin injection in the experimental group. Normal saline or reverse AS-ODN was pre-administered i.t. at the same time in two control groups (saline and reverse AS-ODN). The results showed that the acute phase of nociceptive behavior showed no change by AS-ODN administration, whereas the tonic phase of nociceptive licking and biting behavior was significantly suppressed by AS-ODN as compared with the saline or the reverse AS-ODN group, respectively (p < .05 and p < .01) in the AS-ODN group as compared with that in two control groups. The results indicate that the long-lasting nociceptive responses elicited by sustained noxious inputs are based on the up-regulation of c-Fos gene expression, which in turn induces the upregulation of Dyn A production. It is proposed that intensified Dyn A production in the dorsal horn may be pivotal for the appearance of chronic pain. [ABSTRACT FROM AUTHOR]

Intrathecal (i.t.) injection of nociceptin elicited a behavioral response mainly consisting of biting and licking, which were eliminated by the i.t. co-administration of opioid receptor-like-1 (ORL-1) receptor antagonists. The behavioral response induced by nociceptin was characteristically similar to that by i.t.-administered histamine, and was attenuated by i.t. co-administration of the H1 receptor antagonists, but not by the H2 receptor antagonists, whereas the H3 receptor antagonist promoted the nociceptin-induced behavior. H1 receptor knockout (H1R-KO) mice did not show the nociceptin-induced nociceptive behavior, which was observed in wild-type mice. Pretreatment with a histamine antiserum or a histidine decarboxylase inhibitor resulted in a significant reduction of the response to nociceptin. The previous studies showed that NK1 receptor antagonists and a novel substance P (SP)-specific antagonist given i.t. could reduce the behavioral response to nociceptin and histamine. On the other hand, the nociceptive response induced by nociceptin, but not histamine, was completely attenuated by the i.t. co-administration of agonists for GABAA and GABAB receptors. In contrast, the antagonists for GABAA and GABAB receptors injected i.t. showed same nociceptive response with nociceptin and histamine, and their nociceptive responses were significantly blocked by the i.t. co-administration of the H1 receptor antagonists, but not H2 receptor antagonists or ORL-1 receptor antagonists. The present results suggest that the activation of the ORL-1 receptor by nociceptin may induce the disinhibition of histaminergic neuron and enhance the release of histamine, which subsequently acts on the H1 receptor located on the SP-containing neurons to produce the spinal cord-mediated nociceptive response. [Copyright &y& Elsevier]

The experience of pain is highly variable among individuals, which may be due in part to the effects of genetic factors on the central transmission and modulation of noxious inputs. This study examined behavioral responses and the expression of preprodynorphin (PPD) mRNA at the spinal level during complete Freund''s adjuvant-induced inflammation of the unilateral hind paw in male Fischer 344 (F344), Sprague–Dawley (SD), and Lewis (LEW) rats. Experiments showed that F344 rats exhibited stronger hind paw hyperalgesia and greater spinal PPD mRNA induction than SD or LEW rats. These results indicate that genetic factors that determine the spinal PPD mRNA and dynorphin production underlie strain-dependent differences in pain perception. [Copyright &y& Elsevier]

Results of previous studies have shown that nociceptive sensitivity in male C57 mice is enhanced by exposure to a regular 37 Hz or an irregularly varying (<1 Hz) electromagnetic field. In order to test whether these fields affect more generally mouse behaviour, we placed Swiss CD-1 mice in a novel environment (open field test) and exposed them for 2 h to these two different magnetic field conditions. Hence, we analysed how duration and time course of various behavioural patterns (i.e. exploration, rear, edge chew, self-groom, sit, walk and sleep) and nociceptive sensitivity had been affected by such exposure.Nociceptive sensitivity was significantly greater in magnetically treated mice than in controls. The overall time spent in exploratory activities was significantly shorter in both magnetically treated groups (<1 Hz, 33% and 37 Hz, 29% of total time), than in controls (42%). Conversely, the time spent in sleeping was markedly longer in the treated groups (both 27% of total time) than in controls (11%). These results suggest that exposure to altered magnetic fields induce a more rapid habituation to a novel environment. [Copyright &y& Elsevier]

Intrathecal injection of histamine elicited a behavioral response consisting of scratching, biting and licking in conscious mice. Here, we have examined the involvement of substance P (SP) by using intrathecal injection of tachykinin neurokinin (NK)1 receptor antagonists and SP antiserum. Histamine-induced behavioral response was evoked significantly 5–10 min after intrathecal injection and reached a maximum at 10–15 min. Dose-dependency of the induced response showed a bell-shaped pattern from 200 to 3200 pmol, and maximum effect was observed at 800–1000 pmol. The H1 receptor antagonist, d-chlorpheniramine and pyrilamine but not the H2 receptor antagonists, ranitidine and zolantidine, inhibited histamine-induced behavioral response. The NK1 receptor antagonists, CP-99,994, RP-67580 and sendide, inhibited histamine-induced behavioral response in a dose-dependent manner. A significant antagonistic effect of [d-Phe7, d-His9]SP (6–11), a selective antagonist for SP receptors, was observed against histamine-induced response. The NK2 receptor antagonist, MEN-10376, had no effect on the response elicited by histamine. Pretreatment with SP antiserum resulted in a significant reduction of the response to histamine. No significant reduction of histamine-induced response was detected in mice pretreated with NK A antiserum. The present results suggest that elicitation of scratching, biting and licking behavior induced by intrathecal injection of histamine may be largely mediated by NK1 receptors via H1 receptors in the spinal cord. [Copyright &y& Elsevier]

The aim of this study was to assess the cell-type and distribution of highly activated neurons in rat spinal cord underlying nociceptive responses induced by scorpion BmK venom using Fos immunohistochemistry. BmK venom was intraplantarly injected into one hind paw of a conscious rat. Fos-like immunoreactive neurons were found to predominantly distribute at L4–5 segments in the rat spinal cord after BmK venom application. c-Fos labeling was most dense in the medial half portion of laminae I–II, moderately dense in laminae V–VI and less dense in laminae III–IV, VII–X. c-Fos labeling could be detected at 0.5 h, reached the peak at 2 h, decreased steeply from 4 h and then almost disappeared at 24 h. Ten to fifty micrograms of BmK venom was deemed to be a sufficient dosage to evoke c-Fos expression. On the other hand, c-Fos expression induced by BmK venom could be suppressed partially by systemic morphine in a dose-dependent manner. The results suggest that the different extent of activities of neuronal subpopulation in the spinal cord involved in nociceptive transmission manifesting as c-Fos expression, were mainly correlated with mechanisms underlying the generation, maintenance and/or modulation of spontaneous pain and hyperalgesia evoked by BmK venom. [Copyright &y& Elsevier]

The present study examines the effects of dopaminergic system modulation on nociceptive response time in male diabetic rats. In this study, diabetes was induced by streptozotocin (STZ, 45 mg/kg) in adult male Sprague–Dawley rats. Insulin replacement therapy was initiated 6 weeks after the induction of diabetes for one-half of the diabetic group (1.5–2.5 IU/12 h/rat) and was continued throughout the duration of the study (up to 14 weeks). After 6 weeks of daily insulin replacement therapy, eight rats from each experimental group (STZ-diabetic, STZ-diabetic+insulin and nondiabetic control) were injected with either bromocriptine (BROM, 3 mg/kg/12 h), haloperidol (HALO, 1.5 mg/kg/12 h) or vehicle. Nociceptive response was measured by the hot plate (HP) latency test before the induction of diabetes (baseline), every 3 weeks for the first 12 weeks and then on days 5, 9 and 14 of treatment with dopaminergic agents. Animals were sacrificed 3 or 4 days after the last HP test and the brain, blood, spinal cord (SC), pituitary and adrenal glands (AD) were dissected for Met-enkephalin (ME) assay. The results show that nociceptive response of untreated diabetic animals increased gradually and significantly over the duration of this study. Administration of BROM and HALO significantly decreased and increased the nociceptive response, respectively, in all groups. However, the response of the diabetic group was more pronounced than that of the other two groups, especially for those treated with BROM. Daily insulin administration normalized nociceptive response to that of the nondiabetic controls. Diabetic animals receiving insulin replacement+BROM also showed normalized nociceptive response while the diabetic animals+HALO did not. Moreover, the administration of HALO and BROM resulted in an increase and decrease ME concentrations, respectively, in most tissues and brain regions examined. The effect of these dopaminergic agents on ME levels was greater in brain regions and tissues of the diabetic rats than in the diabetic groups receiving vehicle or in the nondiabetic control receiving these two agents. These data suggest that diabetes alters the sensitivity of the dopaminergic receptors and that altered response of the dopaminergic system could be indirectly involved in the modulation of nociception in diabetic rats possibly through the enhancement and/or deactivation of the endogenous Met-enkephalinergic system. [Copyright &y& Elsevier]

The purpose of this study was to determine the mechanisms of nitrous oxide (N2O) antinociception at the spinal level with yohimbine (an α2-adrenergic antagonist) and flumazenil (a specific benzodiazepine antagonist) using chemonociceptive stimuli in spinal dorsal horn neurons in the cat. A lumbar laminectomy extending from L4 to L6 was performed to allow insertion of a extracellular recording device via a microelectrode. Additional laminectomy was performed at the T12 level to transect the spinal cord. As a noxious stimulus, bradykinin (BK) was injected via the cannula inserted into the femoral artery. Animals were divided into four treatment groups for subsequent experiments: N2O+flumazenil, N2O+yohimbine, flumazenil (alone), and yohimbine (alone). N2O suppressed BK-induced nociceptive responses in transected feline spinal cords. The BK-induced neuronal firing rates were significantly suppressed: to 69.2%, 61.8%, and 52.2% of the baseline firing rate at 10, 20, and 30 min, respectively, after N2O administration. The 47.8% suppression on BK-induced neuronal responses at 30 min after N2O administration was reversed 5 min after administration of yohimbine (25.2% suppression). Similarly, N2O suppression (42.5%) on chemically induced neuronal responses was reversed by flumazenil (24.9% suppression) at identical postadministration intervals. These data imply that N2O suppresses the nociceptive responses in part probably through its agonistic binding activity to the α2-adrenergic, γ-aminobutyric acid (GABA)-benzodiazepine, or both receptor systems in dorsal born neurons of the feline spinal cord. [ABSTRACT FROM AUTHOR]

Effects of naloxone and flumazenil on isoflurane activities were examined on dorsal horn neurons in cats. Isoflurane suppressed bradykinin-induced nociceptive responses in transected feline spinal cords. The bradykinin-induced neuronal firing rates were significantly suppressed by 60.0%, 35.3% and 32.2% at 10, 20 and 30 min after isoflurane administration, respectively. The 32.2% suppression on bradykinin-induced neuronal responses at 30 min after isoflurane administration was not reversed 5 min after administration of naloxone (36.4% suppression). The suppressive effects of isoflurane were not reversed by naloxone (0.2 mg·kg, i.v. Similarly, the benzodiazepine antagonist, flumazenil (0.2 mg·kg i.v., did not affect the suppressive effects of isoflurane. Failure of naloxone and flumazenil to reverse the suppressive effects of isoflurane suggests that isoflurane interacts with neither opioid nor benzodiazepine receptors in producing its suppressive action on nociceptive responses in dorsal horn neurons of the feline spinal cord. [ABSTRACT FROM AUTHOR]

Interactions among antagonists acting at different regulatory sites within the N-methyl- D-aspartate (NMDA) receptor-channel complex on the evoked responses to noxious thermal stimuli of wide dynamic range (WDR) neurons in spinal dorsal horn were studied on 21 adult anesthetized and spinalized cats. The responses of nociceptive spinal dorsal horn neurons to noxious heating (45–55°C) of the glabrous skin of the unilateral hind paw were reduced markedly by iontophoretically applied antagonists. The specific recognition site antagonist, DL-2-amino-5-phosphonovaleratic acid (APV), the strychnine-insensitive glycine site antagonist 7-chlorokynurenic acid (7CKA), the polyamine site antagonist ifenprodil (IFEN), and the phencyclidine (PCP) site antagonists ketamine (KET) and MK-801 (40–100 nA) significantly reduced ( t-tests, P < 0.01) the noxious thermal stimulus-evoked responses in about 70% of the neurons by (mean ± SE) 54.1±5.8% (n=19), 80.8 ± 4.7% ( n = 16), 51.1 ± 6.4% ( n = 10), 77 ± 4.9% ( n = 16) and 81.2 ± 8.1% ( n = 5), respectively. APV and IFEN were less effective in blocking noxious thermal stimuli-evoked responses than 7CKA, KET and MK-801 (ANOVA, P < 0.05). The responses were completely inhibited in some neurons. After co-administration of the antagonists, APV + 7CKA, APV + IFEN, 7CKA + IFEN, APV + KET and APV + MK-801, all at the subthreshold ejection current, the responses were reduced markedly in 13 of 16, 7 of 10, 5 of 10, 3 of 6 and 3 of 5 neurons, respectively. The present study suggests that blockage of any component of the NMDA receptor-channel complex antagonizes the NMDA receptor-mediated response, and that there are the cooperative interactions among the various regulatory sites within the NMDA receptor-channel complex in the transmission or modulation of spinal nociceptive thermal information. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2018 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)