Effect of dexmedetomidine constant rate infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study.

The aim of this study was to evaluate whether a constant rate infusion of dexmedetomidine could prolong the analgesic effect of peripheral nerve blocks. Twenty client-owned dogs were enrolled and randomly divided into 2 groups. The DEX group received dexmedetomidine infusion at 1 mcg kg-1 h-1, and the NaCl group received an equivalent volume infusion of saline. Infusions were started after securing vascular access and continued for 10 min, after which intravenous (IV) methadone at 0.2 mg kg-1 and propofol to effect were administered. All animals were maintained with isoflurane in 70% oxygen. Sciatic, saphenous and obturator nerve blocks were performed using 0.1 mL kg-1 0.5% ropivacaine/block. Intraoperative fentanyl was administered if the heart rate and/or mean arterial pressure (MAP) increased > 15% from the previous measurement, and vasopressors were administered if MAP was ≤ 70 mmHg. Postoperative pain was assessed every hour using the Glasgow Composite Pain Scale (GCPS) until the first rescue analgesia administration. Postoperative rescue analgesia (methadone (0.2 mg kg-1 IV) and carprofen (2 mg kg-1 IV)) was administered if the pain score was higher than 6/24 or 5/20. Duration of analgesia was defined as the time between the nerve block procedure and initial postoperative rescue analgesia. Ambulation, proprioception, and skin sensitivity were evaluated to assess the duration of the motor and sensory block. A Student T and chi-square test were used to compare groups for duration of postoperative analgesia and intraoperative fentanyl and vasopressor use, respectively (p values ≤ 0.5 considered significant). A greater number of dogs in the NaCl group required fentanyl (5/10 p = 0.03) and vasopressors (8/10, p = 0.02) than did those in the DEX group (0/10 and 2/10, respectively). The duration of postoperative analgesia was significantly longer (604 ± 130 min) in the DEX group than in the NaCl group (400 ± 81 min, p = 0.0005).Dexmedetomidine infusion at 1 mcg kg-1 h-1 delays the time to first administration of rescue analgesia and reduces intraoperative analgesic and vasopressor requirements during Tibial Tuberosity Advancement surgery.

Inferior alveolar nerve block anesthesia in children: The effect of ibuprofen and phentolamine mesylate on pain perception.

CONTEXT: For successfully managing pediatric dental patients, local anesthesia is essential to eliminate pain during or after the operative period. An early recovery from soft-tissue anesthesia after an inferior alveolar nerve block (IANB) should benefit a young child patient by avoiding the risk of inadvertently biting the soft tissues. AIMS: Hence, the purpose of the study was to (1) evaluate and compare the efficacy of pre- and postoperative ibuprofen on pain perception in children who undergo IANB anesthesia with or without the use of PM and (2) evaluate the average time required for reversal of anesthesia symptoms using phentolamine mesylate. METHODS: The present study was a randomized, clinical trial performed among 60 children between 6 and 8 years of age using a convenient sampling method. The children were randomly assigned into four equal groups of 15 each using the computer-generated randomization sequence. IANB anesthesia was performed using 2% lignocaine with 1:100,000 epinephrine, and a mandibular primary molar pulpotomy was performed on each group. Group 1: the ibuprofen tablet was taken 1 h before the onset of the procedure. Group 2: ibuprofen tablet 30 min after the pulpotomy procedure. Group 3: the ibuprofen tablet was taken 1 h before the onset of the procedure, and the Phentolamine mesylate (PM) injection was administered. Group 4: immediately after the pulpotomy, the PM injection was administered, and an ibuprofen tablet was taken 30 min after the pulpotomy procedure. All children were assessed for the duration of soft-tissue anesthesia, their behavior scores and pain rating, as well as the incidence of postoperative self-inflicted injuries. STATISTICAL ANALYSIS USED: A one-way ANOVA was used to compare the average time needed for the reversal of anesthetic symptoms between groups. The effects of phentolamine, local anesthetics, and ibuprofen on the child's behavior and pain scores were compared using the Student's t-test. For the study, P < 0.05 was accepted as statistically significant. RESULTS: The time needed for the full reversal of anesthetic symptoms to manifest on the tongue and lip was substantially reduced by the injection of phentolamine (P < 0.001). The use of phentolamine for reversal or the intake of ibuprofen pre- or postoperatively did not exhibit any significant variation in the behavior, pain experience, or incidence of self-inflicted injuries in the child. CONCLUSION: It is evident that although phentolamine injections shorten the duration of anesthesia, the adjunctive use of pre- or postoperative ibuprofen did not significantly alter pain scores.

Dexmedetomidine as a Short-Use Analgesia for the Immature Nervous System.

Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain.

Low doses of acetaminophen produce antidepressive-like effects through the opioid system in mice.

Acetaminophen (paracetamol) is one of the most popular analgesics for the management of fever and pain but few reports have investigated its antidepressant-like effect. Moreover, the role of the opioidergic pathway has been indicated in depression pathophysiology. This study aimed to examine the involvement of the opioid receptors in the antidepressant-like effect of acetaminophen after acute and sub-chronic administration using mice forced swimming test (FST). Our finding showed that administration of acetaminophen (50 and 100 mg/kg, i.p.) 30 min before the FST produced an antidepressant effect which was reduced by naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). Moreover, we observed that acetaminophen in higher doses (200 and 400 mg/kg) was ineffective. Also, the response of the non-effective dose of acetaminophen (25 mg/kg) was potentiated by the non-effective dose of morphine (0.1 mg/kg) in the FST that was antagonized by naloxone. Also, in contrast to morphine (10 mg/kg), acetaminophen (100 mg/kg, i.p.) induced neither tolerance to the anti-immobility behavior nor withdrawal syndrome after repeated administration. In addition, RT-PCR showed that hippocampal mu- and kappa-opioid receptor mRNA expression increased in mice after repeated administration of acetaminophen; however, morphine therapy for 6 days did not affect kappa-opioid receptor expression. Our findings demonstrated that acetaminophen in lower doses but not high doses revealed an antidepressant-like activity without inducing tolerance and withdrawal syndromes. Moreover, the observed effect of acetaminophen may be via altering the opioid system, particularly hippocampal mu- and kappa-receptors.

Acetaminophen induces mitochondrial apoptosis through proteasome dysfunctions.

Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.

Antinociceptive effects of fentanyl and nonopioid drugs in methocinnamox-treated rats.

BACKGROUND: A single administration of the opioid receptor antagonist methocinnamox (MCAM) antagonizes the antinociceptive effects of µ-opioid receptor agonists for 2 weeks or longer. Such a long duration of antagonism could necessitate the use of nonopioid drugs for treating pain in patients receiving MCAM for opioid use disorder (OUD). METHODS: The antinociceptive effects of fentanyl and nonopioid drugs were assessed in 24 male Sprague Dawley rats using a complete Freund's adjuvant (CFA) model of inflammatory pain. Twelve rats received 10mg/kg MCAM and 12 received vehicle; half (n=6) of the animals from each treatment group were treated (intraplantar) with CFA or saline. Hypersensitivity to mechanical stimulation was measured using a von Frey anesthesiometer. Fentanyl (0.01-0.1mg/kg), ketamine (17.8-56mg/kg), gabapentin (32-100mg/kg), meloxicam (3.2-10mg/kg), and ∆9-tetrahydrocannabinol (THC, 1-10mg/kg) were administered intraperitoneally and tested every 3 days in a pseudorandom order. Next, the same drugs were studied for effects on motor performance using a rotarod apparatus. RESULTS: CFA-induced hypersensitivity was attenuated by fentanyl in vehicle- but not MCAM-treated rats. THC, ketamine, and gabapentin attenuated (up to 82, 66, and 46 %, respectively) CFA-evoked mechanical hypersensitivity in both MCAM- and vehicle-treated rats. Meloxicam failed to alter CFA-evoked mechanical hypersensitivity in either group. Fentanyl, THC, gabapentin, and meloxicam did not affect motor performance in either group whereas ketamine impaired motor performance in both groups (up to 71 % reduction in latency to fall). CONCLUSIONS: These data suggest that ketamine, gabapentin, and THC could be effective for treating inflammatory pain under conditions of long term µ-opioid receptor antagonism.

A triple cysteine motif as major determinant of the modulation of neuronal KV7 channels by the paracetamol metabolite N-acetyl-p-benzo quinone imine.

BACKGROUND AND PURPOSE: The analgesic action of paracetamol involves KV7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H2O2, or nitric oxide has been found to modulate currents through KV7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal KV7 channels might be responsible for the effects of NAPQI. EXPERIMENTAL APPROACH: To address this question, we used a combination of perforated patch-clamp recordings, site-directed mutagenesis, and mass spectrometry applied to recombinant KV7.1 to KV7.5 channels. KEY RESULTS: Currents through the cardiac subtype KV7.1 were reduced by NAPQI. Currents through all other subtypes were increased, either by an isolated shift of the channel voltage dependence to more negative values (KV7.3) or by such a shift combined with increased maximal current levels (KV7.2, KV7.4, KV7.5). A stretch of three cysteine residues in the S2-S3 linker region of KV7.2 was necessary and sufficient to mediate these effects. CONCLUSION AND IMPLICATION: The paracetamol metabolite N-acetyl-p-benzo quinone imine (NAPQI) modifies cysteine residues of KV7 subunits and reinforces channel gating in homomeric and heteromeric KV7.2 to KV7.5, but not in KV7.1 channels. In KV7.2, a triple cysteine motif located within the S2-S3 linker region mediates this reinforcement that can be expected to reduce the excitability of nociceptors and to mediate antinociceptive actions of paracetamol.

Synergistic interaction of guanfacine or dexmedetomidine coadministered with lidocaine for cutaneous analgesia in rats.

BACKGROUND: This study examined the cutaneous analgesic effects of lidocaine co-injected with guanfacine and its comparison with dexmedetomidine. METHODS: Cutaneous analgesic effects are quantified through the blocking effects of the cutaneous trunci muscle reflex against skin pinpricks in rats. The dose-response curves of guanfacine, dexmedetomidine, and lidocaine were constructed and drug-drug interactions were analyzed by the ED50 isobologram. RESULTS: Subcutaneous injections of guanfacine, dexmedetomidine, and lidocaine produced dose-dependently nociceptive/sensory blockade. On the ED50 (50% effective dose) basis, the potency rankings of the drug are dexmedetomidine (0.09 [0.08-0.11] µmol/kg) > guanfacine (3.98 [2.96-5.34] µmol/kg) > lidocaine (25.40 [23.51-27.44] µmol/kg) (p < 0.01). On their equipotent doses (ED25, ED50, and ED75), the duration of sensory blockade induced by guanfacine or dexmedetomidine was longer than lidocaine's (p < 0.01). Both guanfacine and dexmedetomidine showed synergistic effects with lidocaine. CONCLUSIONS: We showed that guanfacine elicits dose-dependent cutaneous analgesia when administered subcutaneously. Lidocaine is less potent than guanfacine or dexmedetomidine. Both guanfacine and dexmedetomidine enhance the potency and duration of lidocaine. Better synergistic responses we are getting with guanfacine plus lidocaine.

Comparing the efficacy of intravenous morphine versus ibuprofen or the combination of ibuprofen and acetaminophen in patients with closed limb fractures: a randomized clinical trial.

INTRODUCTION: This study aims to investigate the effectiveness of intravenous ibuprofen or intravenous ibuprofen plus acetaminophen compared to intravenous morphine in patients with closed extremity fractures. METHODS: A triple-blinded randomized clinical trial was conducted at a tertiary trauma center in Iran. Adult patients between 15 and 60 years old with closed, isolated limb fractures and a pain intensity of at least 6/10 on the visual analog scale (VAS) were eligible. Patients with specific conditions or contraindications were not included. Participants were randomly assigned to receive intravenous ibuprofen, intravenous ibuprofen plus acetaminophen, or intravenous morphine. Pain scores were assessed using the visual analog scale at baseline and 5, 15, 30, and 60 min after drug administration. The primary outcome measure was the pain score reduction after one hour. RESULTS: Out of 388 trauma patients screened, 158 were included in the analysis. There were no significant differences in age or sex distribution among the three groups. The pain scores decreased significantly in all groups after 5 min, with the morphine group showing the lowest pain score at 15 min. The maximum effect of ibuprofen was observed after 30 min, while the ibuprofen-acetaminophen combination maintained its effect after 60 min. One hour after injection, pain score reduction in the ibuprofen-acetaminophen group was significantly more than in the other two groups, and pain score reduction in the ibuprofen group was significantly more than in the morphine group. CONCLUSION: The study findings suggest that ibuprofen and its combination with acetaminophen have similar or better analgesic effects compared to morphine in patients with closed extremity fractures. Although morphine initially provided the greatest pain relief, its effect diminished over time. In contrast, ibuprofen and the ibuprofen-acetaminophen combination maintained their analgesic effects for a longer duration. The combination therapy demonstrated the most sustained pain reduction. The study highlights the potential of non-opioid analgesics in fracture pain management and emphasizes the importance of initiation of these medications as first line analgesic for patients with fractures. These findings support the growing trend of exploring non-opioid analgesics in pain management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05630222 (Tue, Nov 29, 2022). The manuscript adheres to CONSORT guidelines.

Efficacy and safety of intravenous fosphenytoin for patients with acute herpes zoster-associated pain: A placebo-controlled randomized trial.

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 µg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor.

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α2A-adrenergic receptor (α2AAR), seeking new α2AAR agonists chemotypes that lack the sedation conferred by known α2AAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Gi and Go signaling. Experimental structures of α2AAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC50) of 52 nanomolar] and two analogs, '7075 and PS75 (EC50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

Restoration Algorithm-Based Ultrasound Image in Evaluating the Effect of Dexmedetomidine on Patients with Neurological Disorder Anesthetized by Sevoflurane.

The study focused on the application value of ultrasound images processed by restoration algorithm in evaluating the effect of dexmedetomidine in preventing neurological disorder in patients undergoing sevoflurane anesthesia. 90 patients undergoing tonsillectomy anesthesia were randomly divided into normal saline group, propofol group, and dexmedetomidine group. The ultrasound images were processed by restoration algorithm, and during the postoperative recovery period, ultrasound images were used to evaluate. The results showed that the original ultrasonic image was fuzzy and contained interference noise, and that the image optimized by restoration algorithm was clear, without excess noise, and the image quality was significantly improved. In the dexmedetomidine group, the extubation time was 10.6 ± 2.3 minutes, the recovery time was 8.4 ± 2.2 minutes, the average pain score during the recovery period was 2.6 ± 0.7, and the average agitation score was 7.2 ± 2.4. Of 30 patients, there were 13 cases with vertigo and 1 case with nausea and vomiting. The vascular ultrasound imaging showed that, in the dexmedetomidine group, the peak systolic velocities (PSV) of the bilateral vertebral arteries during the recovery period were 67.7 ± 14.3 and 67.9 ± 15.2 cm/s, respectively; the end-diastolic velocities (EDV) of the bilateral vertebral arteries were 27.8 ± 6.7 and 24.69 ± 5.9 cm/s, respectively; the PSV in bilateral internal carotid artery systolic peak velocities were 67.2 ± 13.9 and 67.8 ± 12.7 cm/s, respectively; the EDV in bilateral internal carotid arteries were 27.7 ± 5.3 and 26.9 ± 4.9 cm/s, respectively; bilateral vertebral artery resistance indexes (RIs) were 0.6 ± 0.02 and 0.71 ± 0.08, respectively; the bilateral internal carotid artery RIs were 0.57 ± 0.04 and 0.58 ± 0.06, respectively, all better than the normal saline group (12.1 ± 2.5 minutes, 10.1 ± 2.3 minutes, 3.9 ± 0.6, 10.6 ± 3.7, 15 cases, 11 cases, 81.5 ± 13.6, 80.7 ± 11.6 cm/s, 29.3 ± 6.8, 28.9 ± 6.7 cm/s, 74.3 ± 10.2, 73.9 ± 12.5 cm/s, 29.1 ± 4.3, 29 ± 4.5 cm/s, 0.84 ± 0.06, 0.83 ± 0.05, 0.8 ± 0.04, and 0.81 ± 0.05) and the propofol group (11.4 ± 2.1 minutes, 9.0 ± 2.1 minutes, 3.4 ± 0.8, 8.5 ± 2.3, 12 cases, 9 cases, 72.5 ± 12.9, 73.4 ± 11.8 cm/s, 28.6 ± 5.4, 26.5 ± 5.1 cm/s, 72.1 ± 11.4, 73.5 ± 10.6 cm/s, 28.8 ± 5.6, 27.3 ± 4.7 cm/s, 0.78 ± 0.07, 0.82 ± 0.06, 0.76 ± 0.03, and 0.78 ± 0.05), and the differences were statistically significant (P < 0.05). In conclusion, ultrasound images processed by restoration algorithm have high image quality and high resolution. The dexmedetomidine can prevent neurological disorder in patients with sevoflurane anesthesia and is suggested in postoperative rehabilitation.

Analgesic Action of Acetaminophen via Kv7 Channels.

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

ɑO-Conotoxin GeXIVA isomers modulate N-type calcium (CaV 2.2) channels and inwardly-rectifying potassium (GIRK) channels via GABAB receptor activation.

αO-Conotoxin GeXIVA is a 28 amino acid peptide derived from the venom of the marine snail Conus generalis. The presence of four cysteine residues in the structure of GeXIVA allows it to have three different disulfide isomers, that is, the globular, ribbon or bead isomer. All three isomers are active at α9α10 nicotinic acetylcholine receptors, with the bead isomer, GeXIVA[1,2], being the most potent and exhibiting analgesic activity in animal models of neuropathic pain. The original report of GeXIVA activity failed to observe any effect of the isomers on high voltage-activated (HVA) calcium channel currents in rat dorsal root ganglion (DRG) neurons. In this study, we report, for the first time, the activity of globular GeXIVA[1,3] at G protein-coupled GABAB receptors (GABAB R) inhibiting HVA N-type calcium (Cav2.2) channels and reducing membrane excitability in mouse DRG neurons. The inhibition of HVA Ba2+ currents and neuroexcitability by GeXIVA[1,3] was partially reversed by the selective GABAB R antagonist CGP 55845. In transfected HEK293T cells co-expressing human GABAB R1 and R2 subunits and Cav2.2 channels, both GeXIVA[1,3] and GeXIVA[1,4] inhibited depolarization-activated Ba2+ currents mediated by Cav2.2 channels, whereas GeXIVA[1,2] had no effect. The effects of three cyclized GeXIVA[1,4] ribbon isomers were also tested, with cGeXIVA GAG being the most potent at human GABAB R-coupled Cav2.2 channels. Interestingly, globular GeXIVA[1,3] also reversibly potentiated inwardly-rectifying K+ currents mediated by human GIRK1/2 channels co-expressed with GABAB R in HEK293T cells. This study highlights GABAB R as a potentially important receptor target for the activity of αO-conotoxin GeXIVA to mediate analgesia.

Dexmedetomidine attenuates haemorrhage-induced thalamic pain by inhibiting the TLR4/NF-κB/ERK1/2 pathway in mice.

BACKGROUND: Thalamic pain, a neuropathic pain syndrome, frequently occurs after stroke. This research aimed to investigate the effect of dexmedetomidine (DEX) on thalamic pain. METHODS: The cellular localization of the TLR4 protein was determined by immunostaining. The expression of Iba1, GFAP and protein associated with the TLR4/NF-κB/ERK1/2 pathway was measured by Western blotting. Continuous pain hypersensitivity was evaluated by behavioural tests. The results were analysed by one-way ANOVA, two-way ANOVA and Tukey's post hoc test. RESULTS: The results demonstrated that DEX obviously alleviated thalamic pain induced by haemorrhage on the ipsilateral side and delayed the development of pain hypersensitivity. Furthermore, the expression levels of Iba1, GFAP and proteins associated with the TLR4/NF-κB/ERK1/2 signalling pathway were greatly increased in mice with thalamic pain, but these effects were reversed by DEX. CONCLUSION: Our findings suggest that DEX alleviates the inflammatory response during thalamic pain through the TLR4/NF-κB/ERK1/2 signalling pathway and might be a potential therapeutic agent for thalamic pain.

No antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol in male and female rats with persistent inflammatory pain.

Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.