Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

UNASSIGNED: Despite this growing interest, there remains a lack of comprehensive and systematic bibliometric analyses of ketamine research. This study aimed to summarize the progress in ketamine research through bibliometric analysis, providing insights into the development and direction of the field.
UNASSIGNED: Publications related to ketamine were retrieved from the Web of Science Core Collection (WoSCC) database on February 15, 2024. In conducting a comprehensive bibliometric analysis, a variety of bibliographic elements were meticulously collected to map the landscape of research within a specific field.
UNASSIGNED: Between January 1, 2014, and December 31, 2023, a total of 10,328 articles on ketamine research were published across 1,752 academic journals by 45,891 authors from 8,914 institutions in 128 countries. The publication volume has shown a steady increase over this period. The United States of America (USA) and the People\'s Republic of China lead in both publication and citation counts. The National Institute of Mental Health (NIMH) and Yale University emerge as the most active institutions in this research domain. Carlos Zarate of the NIH National Institute of Mental Health was noted for the highest number of significant publications and received the most co-citations. The analysis revealed key research themes including mechanism of action, adverse events, psychiatric applications, and perioperative implications.
UNASSIGNED: This study provided comprehensive bibliometric and knowledge mapping analysis of the global ketamine research landscape, offering valuable insights into the trends, key contributors, and thematic focus areas within the field. By delineating the evolution of ketamine research, this study aims to guide future scholarly endeavors and enhance our understanding of ketamine\'s therapeutic potential.

UNASSIGNED: Drawing on the principles of wrist-ankle acupuncture (WAA), our research team has developed a portable device for WAA point compression, termed the acupressure wrist-ankle strap (AWA). The current study aims to evaluate the efficacy of the AWA in alleviating pain associated with primary dysmenorrhea.
UNASSIGNED: A single-blind, randomized clinical trial was conducted from April 1, 2019, to December 31, 2019. 78 participants with primary dysmenorrhea were recruited from Shanghai University of Traditional Chinese Medicine. All participants were treated on the first day of menstruation for 30 min. Participants in the AWA group used the AWA, the internal side of which is equipped with a tip compression component, while participants in the non-acupressure wrist-ankle acupuncture(NAWA)group used the NAWA, with the inside tip pressing parts removed. The main outcome was the difference in visual analogue scale (VAS) score between baseline and 30 minutes after randomization.
UNASSIGNED: A total of 78 participants aged 18 to 30 years were included in the intention-to-treat analyses. The VAS scores (mean [standard deviation]) in the AWA group were significantly lower than those in the NAWA group at each time point of intervention (5 minutes: 95% CI, [-1.27 to -0.68], p < 0.001; 10 minutes: 95% CI, [-2.34 to -1.51], p < 0.001; 30 minutes: 95% CI, [-3.74 to -2.72], p < 0.001). In the AWA group, 16 participants reported \"obvious relief\" of dysmenorrhea pain while 23 did not; the average onset time of analgesia they reported were (21.50 ± 3.65) min, while no subjects in NAWA group reported obvious pain relief. The pain threshold (mean [standard deviation]) at SP9 of both sides in AWA group decreased significantly after intervention that in NAWA group (Left: 95% CI, [-5.02 to -1.81], p < 0.001; Right: 95% CI, [-7.67 to -4.24], p < 0.001). There was no significant change in the temperature at CV4 in either group (95% CI, [-0.63 to -0.66], p = 0.970).
UNASSIGNED: This trial substantiates our hypothesis that the AWA provides immediate analgesic effects. The AWA represents an effective and safe non-invasive physical therapy option, which patients can self-administer to alleviate abdominal pain.

Neuropathic pain is chronic pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain, with a high incidence and complex pathogenesis, is one of the most significant areas of clinical medicine and basic research. Currently, prescribed treatments are still unsatisfactory or have limited effectiveness. A medicinal preparation is required that relieves the neuropathic pain and prolongs action time, which has not yet been discovered. In this study, MIL-101 (Fe) was employed as a drug carrier to regulate the release of diclofenac sodium, thereby achieving the effect of analgesia and sustained release. The release curves demonstrated that diclofenac sodium could be continuously released from MIL-101 (Fe) for more than 48 h. There was no toxicity in vitro and in vivo, and the safety of MIL-101 (Fe) was confirmed by hematoxylin and eosin as well as ELISA tests in vivo. The results of behavioral testing, pharmacokinetics, and RNA sequencing analysis showed that MIL-101 (Fe) loaded with diclofenac sodium could enhance the mechanical withdrawal threshold and alleviate cold allodynia induced by Spared Nerve Injury, prolonging the work time by three days. The results indicated that MIL-101 (Fe) exhibited excellent biocompatibility, while the MIL-101 (Fe)-DS demonstrated analgesic and controlled-release properties. These findings provide a scientific foundation for the clinical management of neuropathic pain and the development of a novel formulation.

Chronic pain is a prevalent and persistent ailment that affects individuals worldwide. Conventional medications employed in the treatment of chronic pain typically demonstrate limited analgesic effectiveness and frequently give rise to debilitating side effects, such as tolerance and addiction, thereby diminishing patient compliance with medication. Consequently, there is an urgent need for the development of efficacious novel analgesics and innovative methodologies to address chronic pain. Recently, a growing body of evidence has suggested that multireceptor ligands targeting opioid receptors (ORs) are favorable for improving analgesic efficacy, decreasing the risk of adverse effects, and occasionally yielding additional advantages. In this study, the intrathecal injection of a recently developed peptide (VYWEMEDKN) at nanomolar concentrations decreased pain sensitivity in naïve mice and effectively reduced pain-related behaviors in nociceptive pain model mice with minimal opioid-related side effects. Importantly, the compound exerted significant rapid-acting antidepressant effects in both the forced swim test and tail suspension test. It is possible that the rapid antihyperalgesic and antidepressant effects of the peptide are mediated through the OR pathway. Overall, this peptide could both effectively provide pain relief and alleviate depression with fewer side effects, suggesting that it is a potential agent for chronic pain and depression comorbidities from the perspective of pharmaceutical development.

Analgesia and blood sugar control are considered as two main unmet clinical needs for diabetes related neuropathic pain patients. Transient receptor potential vanilloid type-1 (TRPV1) channel is a highly validated target for pain perception, while no TRPV1 antagonists have been approved due to hyperthermia side effects. Herein, two series of new TRPV1 antagonists with flavonoid skeleton were designed by the structure-based drug design (SBDD) strategy. After comprehensive evaluation, compound CX-3 was identified as a promising TRPV1 antagonist. CX-3 exhibited equivalent TRPV1 antagonistic activity with classical TRPV1 antagonist BCTC in vitro, and exerted better analgesic activity in vivo than that of BCTC in the formalin induced inflammatory pain model without hyperthermia risk. Moreover, CX-3 exhibited robust glucose-lowering effects and showed high selectivity over other ion channels. Overall, these findings identified a first-in-class highly selective TRPV1 antagonist CX-3, which is a promising candidate to target the pathogenesis of diabetes related neuropathic pain.

BACKGROUND: Adenosine A3 receptor (A3R) exerts analgesic, anti-inflammatory, and anti-nociceptive effects. In this study, we determined the analgesic mechanism of manual acupuncture (MA) in rats with complete Freund\'s adjuvant (CFA)-induced arthritis and explored whether MA ameliorates inflammation in these rats by upregulating A3R.
METHODS: Sixty Sprague Dawley (SD) rats were randomly divided into the following groups: Control, CFA, CFA + MA, CFA + sham MA, CFA + MA + DMSO, CFA + MA + IB-MECA, and CFA + MA + Reversine groups. The arthritis rat model was induced by injecting CFA into the left ankle joints. Thereafter, the rats were subjected to MA (ST36 acupoint) for 3 days. The clinical indicators paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and open field test (OFT) were used to determine the analgesic effect of MA. In addition, to explore the effect of A3R on inflammation after subjecting arthritis rats to MA, IB-MECA (A3R agonist) and Reversine (A3R antagonist) were injected into ST36 before MA.
RESULTS: MA ameliorated the pathological symptoms of CFA-induced arthritis, including the pain indicators PWL and PWT, number of rearing, total ambulatory distance, and activity trajectory. Furthermore, after MA, the mRNA and protein expression of A3R was upregulated in CFA-induced arthritis rats. In contrast, the protein levels of TNF-α, IL-1β, Rap1, and p-p65 were downregulated after MA. Interestingly, the A3R agonist and antagonist further downregulated and upregulated inflammatory cytokine expression, respectively, after MA. Furthermore, the A3R antagonist increased the degree of ankle swelling after MA.
CONCLUSIONS: MA can alleviate inflammatory pain by inhibiting the NF-κB signaling pathway via upregulating A3R expression of the superficial fascia of the ST36 acupoint site in CFA-induced arthritis rats.

Ottonia anisum (O. anisum), belonging to the family Piperaceae, is renowned for its medicinal properties. The plant is rich in alkaloids, terpenoids and flavonoids with recorded bioactivities. The stems, roots, and leaves, of the O. anisum have been extensively used in the folk medicine. Therefore, the present study was conducted to examine the pharmacological activities of O. anisum root extract. Methanolic root extract of O. anisum was assessed for local anesthetic, analgesic, anti-inflammatory and HCl-induced acute lung injury activities in animal models. Local anesthetic activity assessed in frog and guinea pigs through foot withdrawal reflex and intradermal wheal method, respectively, revealed the dose-dependent onset time of anesthesia response. In the case of HCl-induced ALI, the mice group orally administered with O. anisum extract were assessed for bronchoalveolar lavage fluid (BLF) contents, oxidative stress, and proinflammatory molecules. The analysis revealed the reduction in inflammatory molecules, neutrophils, and oxidative stress in the extract treated mice group. In addition, the redox homeostasis, reduced GSH and the catalase activity was found to be restored in the treated groups. Intriguingly, the genes associated with the NFkB expression was found to be downregulated in O. anisum extract treated groups. Moreover, the extract unveiled the significant analgesic and anti-inflammatory activities. Overall, the findings emphasize the clinical applicability of O. anisum extract in the treatment of ALI as well as the potential usage in local anesthetic, analgesic, and anti-inflammatory agents during the treatments.

UNASSIGNED: To compare the early analgesic effects and the impact on knee joint function recovery after unicompartmental knee arthroplasty (UKA) between single adductor canal block (SACB) and continuous adductor canal block (CACB) combined with local infiltration anesthesia (LIA) using a prospective study.
UNASSIGNED: The patients with knee osteoarthritis admitted between April 2022 and December 2023 were enrolled as a subject. Among them, 60 patients met the selection criteria and were enrolled in the study. They were randomly assigned to the SACB group or CACB group in a ratio of 1:1 using a random number table method. There was no significant difference between the two groups ( P>0.05) in terms of age, gender, height, body mass, body mass index, affected side, and preoperative resting visual analogue scale (VAS) score and active VAS score, Oxford knee score (OKS), and American Hospital of Special Surgery (HSS) score. All patients received multimodal analgesia management using LIA combined with SACB or CACB. The operation time, pain related indicators (resting and activity VAS scores, number and timing of breakthrough pain, opioid consumption), joint function related indicators (quadriceps muscle strength, knee range of motion, OKS score, and HSS score), as well as postoperative block complications and adverse events were recorded and compared between the two groups.
UNASSIGNED: There was no significant difference in the operation time between the two groups ( P<0.05). All patients in the two groups were followed up with a follow-up time of (9.70±4.93) months in the SACB group and (12.23±5.05) months in the CACB group, and the difference was not significant ( P>0.05). The CACB group had a significant lower resting VAS score at 24 hours after operation compared to the SACB group ( P<0.05). There was no significant difference in resting and active VAS scores between the two groups at other time points ( P>0.05). The CACB group had a significantly lower incidence of breakthrough pain compared to the SACB group [9 cases (30.00%) vs. 17 cases (56.67%); P<0.05). However, there was no significant difference in the timing of breakthrough pain occurrence and opioid consumption between the two groups ( P>0.05). Four cases in the SACB group and 7 cases in the CACB group experienced adverse events, with no significant difference in the incidence of adverse events between the two groups ( P>0.05). The CACB group had significantly better knee joint mobility than the SACB group at 1 and 2 days after operation ( P<0.05). There was no significant difference between the two groups in knee joint mobility on 0 day after operation and quadriceps muscle strength and OKS and HSS scores at different time points ( P>0.05).
UNASSIGNED: In UKA, the analgesic effects and knee joint function recovery are similar when compared between LIA combined with SACB and LIA combined with CACB. However, SACB is simpler to perform and can avoid adverse events such as catheter displacement and dislocation. Therefore, SACB may be a better choice.
UNASSIGNED: 采用前瞻性对比研究，比较分析膝关节单髁置换术（unicompartmental knee arthroplasty，UKA）术中采用局部浸润麻醉（local infiltration anesthesia，LIA）联合单次收肌管阻滞（single adductor canal block，SACB）或连续收肌管阻滞（continuous adductor canal block，CACB）的早期镇痛效果及对膝关节功能恢复的影响。.
UNASSIGNED: 以2022年4月—2023年12月收治的膝关节骨关节炎患者作为研究对象，其中60例符合选择标准纳入研究，按照随机数字表法以1∶1比例分配至SACB组或CACB组。两组患者年龄、性别、身高、体质量、身体质量指数、手术侧别以及术前静息疼痛视觉模拟评分（VAS）、活动VAS评分、牛津大学膝关节评分（OKS）和美国特种外科医院（HSS）评分等基线资料比较，差异均无统计学意义（ P>0.05）。两组患者接受LIA联合SACB或CACB多模式镇痛管理。记录并比较两组手术时间、疼痛相关指标（静息以及活动VAS评分，发生突破性疼痛例数及时间，阿片类药物消耗量）、关节功能相关指标（股四头肌肌力、膝关节活动度、OKS评分和HSS评分）以及术后阻滞并发症、不良事件。.
UNASSIGNED: 两组手术时间差异无统计学意义（ P<0.05）。两组患者术后均获随访，SACB组随访时间为（9.70±4.93）个月、CACB组为（12.23±5.05）个月，差异无统计学意义（ P>0.05）。除CACB组术后24 h静息VAS评分低于SACB组，差异有统计学意义（ P<0.05）外，其余各时间点两组静息和活动VAS评分比较差异均无统计学意义（ P>0.05）。 CACB组9例（30.00%）发生突破性疼痛，较SACB组17例（56.67%）减少，发生率差异有统计学意义（ P<0.05）；但两组突破性疼痛发生时间和阿片类药物消耗量比较，差异均无统计学意义（ P>0.05）。SACB组4例、CACB组7例发生不良事件，发生率差异无统计学意义（ P>0.05）。CACB组术后1、2 d膝关节活动度优于SACB组（ P<0.05）；两组术后0 d膝关节活动度以及各时间点股四头肌肌力、OKS评分、HSS评分比较，差异均无统计学意义（ P>0.05）。.
UNASSIGNED: UKA术中LIA联合SACB或CACB镇痛效果以及患者膝关节功能恢复程度相似，但SACB具有操作简便，能避免导管移位、脱位等不良事件发生，可能是一种更好选择。.

Diterpenes represent one of the most diverse and structurally complex families of natural products. Among the myriad of diterpenoids, grayanane diterpenes are particularly notable. These terpenes are characterized by their unique 5/7/6/5 tetracyclic system and are exclusive to the Ericaceae family of plants. Renowned for their complex structures and broad spectrum of bioactivities, grayanane diterpenes have become a primary focus in extensive phytochemical and pharmacological research. Recent studies, spanning from 2018 to January 2024, have reported a series of new grayanane diterpenes with unprecedented carbon skeletons. These compounds exhibit various biological properties, including analgesic, antifeedant, anti-inflammatory, and inhibition of protein tyrosine phosphatase 1B (PTP1B). This paper delves into the discovery of 193 newly identified grayanoids, representing 15 distinct carbon skeletons within the Ericaceae family. The study of grayanane diterpenes is not only a deep dive into the complexities of natural product chemistry but also an investigation into potential therapeutic applications. Their unique structures and diverse biological actions make them promising candidates for drug discovery and medicinal applications. The review encompasses their occurrence, distribution, structural features, and biological activities, providing invaluable insights for future pharmacological explorations and research.