Analgesic Effect Research Articles

Phytochemical screening and evaluation of antibacterial, antipyretic, hypoglycemic, and anxiolytic effects of Adiantum philippense leaf extracts

Adiantum philippense (AP) is a source of various important phytochemicals and has been traditionally used to cure many diseases, including dysentery, ulcers, fevers, cooling, and elephantiasis. This study aimed to evaluate the anti-bacterial, anti-pyretic, analgesic, and anxiolytic effects of AP using a number of in vitro and in vivo test protocols. For this, dried leaves were extracted by the Soxhlet extractor using ethanol. The crude ethanol extract was then fractionated by treating with chloroform and n-hexane. A preliminary phytochemical screening was done for its crude extracts. The antibacterial activity of ethanol, chloroform, and n-hexane extracts of AP was tested against 10 pathogenic bacteria at concentrations of 500 µg/disc. The ethanol extract showed significant activity against Gram (+ve) and Gram (-ve) bacteria. In mice, the chloroform extracts showed significant (p <0.05) antipyretic and hypoglycemic effects, while the ethanol extract exerted significant anxiolytic effects on mice. The results obtained from this study indicate that AP leaf extracts contain important phytochemical groups and exert antibacterial, antipyretic, hypoglycemic, and anxiolytic effects. Further studies are required to isolate the bioactive compounds responsible for these claimed biological activities.

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABAB) receptor-coupled CaV2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABAB receptor-coupled CaV2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

Investigation of the anti-inflammatory, anti-pruritic, and analgesic effects of sophocarpine inhibiting TRP channels in a mouse model of inflammatory itch and pain

Ethnopharmacological relevanceSophocarpine is a bioactive compound extracted from the dried root of Sophorae Flavesentis Aiton, a plant that has been used for thousands of years for various conditions including skin itch and pain. Its antipruritic and analgesic effects are suggested in publications, while the molecular mechanisms underneath interacting with TRP channels are not understood. Aim of the studyWe investigated the anti-inflammatory, antipruritic, and analgesic effects of sophocarpine in a murine inflammatory itch and pain model to elucidate the underlying mechanisms. Materials and methodsWe evaluated sophocarpine's anti-pruritic and analgesic effects by monitoring mice's scratching and wiping behaviors, and the anti-inflammatory effect by measuring psoriasis area and severity index (PASI) score. The mRNA and protein expression of TRPA1/TRPV1 was analyzed by real-time quantitative polymerase chain reaction and western blotting. We further investigated the relationship between sophocarpine and TRPA1/TRPV1 in mice administered allyl-isothiocyanate (AITC) or capsaicin and by molecular docking. ResultsWe found that sophocarpine decreased scratching bouts, wipes, and the PASI score, reduced the TNF-α and IL-1β in the skin and TRPA1 and TRPV1 in the trigeminal ganglion. Pretreatment of sophocarpine decreased AITC-induced scratching bouts and wipes and capsaicin-induced wipes. We also found potential competitive bindings between sophocarpine and AITC/capsaicin to TRPA1/TRPV1. ConclusionsSophocarpine is a potential competitive inhibitor of TRPA1 and TRPV1 channels eliciting strong anti-inflammatory, anti-pruritic, and analgesic effects, suggesting its significant therapeutic potential in treating diseases with inflammatory itch and pain.

Nanoscale lipid-methylprednisolone conjugates: Effective anti-inflammatory, antioxidant, and analgesic agents

In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid, used for the potential treatment of inflammatory diseases. The LDCs 1–2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain via an ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1–2 were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization via dynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1–2 exhibited excellent stability for about a month, with good polydispersity (around 0.2) and a negative zeta potential between −20 mV and −34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1–2 surpassed 90 %, as determined by HPLC analysis. In vitro cytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1–2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1–2 effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1–2 was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1–2 were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1–2 compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1–2 exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1–2 as potential drug candidates in future pre-clinical and clinical trials.

The Mechanisms and Quality Markers of Anti-rheumatoid Arthritis of Traditional Chinese Medicine.

RA is a recurrent autoimmune disease that has significant adverse effects on the physical and mental health of patients. Traditional Chinese medicine has shown significant advantages in the prevention and treatment of RA. Numerous clinical and experimental studies have confirmed that traditional Chinese medicine components have clear therapeutic effects and minimal adverse reactions in treating RA. The research on traditional Chinese medicine for the prevention and treatment of RA has become a hot topic in the field of autoimmune diseases. The related references about the mechanisms and Q-markers of anti-RA of traditional Chinese medicine in this review were collected from Willy, SpringLink, Web of Science, Elsevier, PubMed, SciFinder, Scopus, ACS publications, Baidu Scholar, Google Scholar, and CNKI. The traditional Chinese medicine components such as terpenoids, flavonoids, and alkaloids have significant anti-RA effects, and their mechanisms are mainly to inhibit NF-κB signaling pathway, inhibit the proliferation of RA fibroblasts like synovial cells, and regulate Th1/Th2 cell balance, and so on. Predicting and studying the Q-markers of traditional Chinese medicine anti-RA by plant phylogeny and chemical componentss, traditional medicinal properties, pharmacokinetics, component measurability, correlation between composition and efficacy, and gut microbiota will provide scientific foundations for the research and further development of anti-RA traditional Chinese medicine. The active components of traditional Chinese medicine exhibited the characteristic of multiple mechanisms in the treatment of RA, such as terpenoids had anti-angiogenesis effects, flavonoids had anti-inflammatory and cartilage protective effects, and alkaloids had antiinflammatory and analgesic effects. The proposal of Q-markers for anti-RA provided new research ideas for promoting the development of new drugs for anti-RA and ensuring the safety and effectiveness of clinical medications.

Melatonin's Impact on Wound Healing.

Melatonin (5-methoxy-N-acetyltryptamine) is an indoleamine compound that plays a critical role in the regulation of circadian rhythms. While melatonin is primarily synthesized from the amino acid tryptophan in the pineal gland of the brain, it can also be produced locally in various tissues, such as the skin and intestines. Melatonin's effects in target tissues can be mediated through receptor-dependent mechanisms. Additionally, melatonin exerts various actions via receptor-independent pathways. In biological systems, melatonin and its endogenous metabolites often produce similar effects. While injuries are common in daily life, promoting optimal wound healing is essential for patient well-being and healthcare outcomes. Beyond regulating circadian rhythms as a neuroendocrine hormone, melatonin may enhance wound healing through (1) potent antioxidant properties, (2) anti-inflammatory actions, (3) infection control, (4) regulation of vascular reactivity and angiogenesis, (5) analgesic (pain-relieving) effects, and (6) anti-pruritic (anti-itch) effects. This review aims to provide a comprehensive overview of scientific studies that demonstrate melatonin's potential roles in supporting effective wound healing.

Effect of Suanzaoren on Perioperative Analgesia, Hemodynamics and Postoperative Delirium

Hip fracture is not only accompanied by severe pain, but also impair body tissue and organ functions in patients, particularly in elderly individuals who have reduced tolerance and are prone to organ damage after experiencing a hip fracture. Surgery is the primary clinical approach for treating hip fractures. However, both the fracture trauma and surgical procedure can result in significant pain during the perioperative period, leading to abnormal hemodynamic fluctuations and an increased risk of postoperative delirium. Therefore, it is crucial to select an appropriate intervention method to facilitate the postoperative rehabilitation of hip fracture patients. Traditional Chinese Medicine (TCM) acknowledges that surgery will have different degrees of impact on muscles and bones, Qi and blood. Suanzaoren Decoction contains suanzaoren, anemarrhena asphodeloides, ligusticum chuanxiong and other TCM. The effective components of these TCM, such as spinosin, sarsasapogenin, and tetramethylpyrazine, have been proved to have analgesic effects. This study demonstrates, through clinical trials, that Suanzaoren Decoction exerts a positive influence on promoting the postoperative rehabilitation of hip fracture patients by reducing postoperative pain, stabilizing hemodynamic indexes, improving inflammatory state, and shortening the duration of postoperative delirium (all P &lt;0.05). The fact that Suanzaoren Decoction can effectively promote the postoperative rehabilitation of hip fracture patients may be related to the anti-inflammatory, analgesic and neuroprotective effects of the effective ingredients in the prescription, such as spinosin, sarsasapogenin and tetramethylpyrazine. Therefore, this study believes that Suanzaoren Decoction+ERAS intervention program represents an optimal approach for hip fracture surgery patients within the perioperative period.

Adjunctive use of hypnosis for clinical pain: a systematic review and meta-analysis.

Systematic reviews suggest that stand-alone hypnotic suggestions may improve pain outcomes compared with no treatment, waitlist, or usual care. However, in clinical practice, hypnosis is often provided adjunctively with other interventions, which might have different effects than those reported in previous reviews. This systematic review aimed to summarize the analgesic effects of adjunctive hypnosis in adults with clinical pain. Seven databases (MEDLINE, Embase, PsycINFO, Emcare, SCOPUS, CENTRAL, Cochrane) were searched up to January 2024. Randomised controlled trials comparing the analgesic effects of adjunctive hypnosis (hypnosis + primary intervention) with those of the primary intervention alone were included. Meta-analyses (random-effects model) calculated mean differences (MD, [95% confidence intervals]) for pain intensity (0-100). Seventy studies were pooled in meta-analyses (n = 6078). Hypnosis adjunctive to usual care had a small additional analgesic effect (chronic pain: -8.2 [-11.8, -1.9]; medical procedures/surgical pain: -6.9 [-10.4, -3.3]; burn wound care: -8.8 [-13.8, -3.9]). Hypnosis adjunctive to education had a medium additional analgesic effect for chronic pain (-11.5 [-19.7, 3.3]) but not postsurgery pain (-2.0 [-7.8, 3.7]). When paired with psychological interventions, hypnosis slightly increased analgesia in chronic pain only at the three-month follow-up (-2 [-3.7, -0.3]). Hypnosis adjunctive to medicines had a medium additional analgesic effect for chronic pain (-13.2, [-22.5, -3.8]). The overall evidence certainty is very low; therefore, there is still uncertainty about the analgesic effects of adjunctive hypnosis. However, hypnosis adjunct to education may reduce pain intensity for chronic pain. Clarification of proposed therapeutic targets of adjunctive hypnosis to evaluate underlying mechanisms is warranted.

The analgesic effect and mechanism of the active components screening from Corydalis yanhusuo by P2X3 receptors

Ethnopharmacological relevanceCavidine (CAV) is the main bioactive ingredient of Corydalis ternata f. yanhusuo (Y.H.Chou & Chun C.Hsu) Y.C.Zhu, which is a traditional Chinese herbal containing a variety of uses such as analgesic, anticancer, and anti-inflammatory properties. Aim of the studyThe goal is to screen Corydalis yanhusuo for anti-central sensitization active components and investigate and clarify the pharmacological mechanism and therapeutic efficacy of the active ingredient CAV in the treatment of chronic pain. Material and MethodsFirst, cell membrane immobilized chromatography was used to screen the bioactive ingredients in Corydalis yanhusuo. Spare nerve injury (SNI) model and complete Freund's adjuvant (CFA) mice model were constructed to identify the analgesic effect of CAV. RNA-seq and bioinformatics analyses were used to explore the potential targets of CAV in CFA mice and SNI mice. HE staining was used to observe the infiltration of inflammatory cells in the dorsal root ganglion (DRG) and spinal cord(SC) of CFA mice and SNI mice. WB and qPCR were used to detect the level of inflammatory factors TNF-α, IL-1β, and IL-6 in DRG and SC of mice. SNI and CFA mice were used to study the effect and mechanism of CAV on microglial activation. Results9 potential active ingredients were screened out from Corydalis yanhusuo that can regulate P2X3 receptors. CAV showed good analgesic effects, increased the mechanical pain and thermal pain thresholds of CFA mice and SNI mice, inhibited the expression of DRG and SC inflammatory factors, downregulated IBA-1, and inhibited microglial activation. Further in vivo and in vitro experiments showed that CAV significantly inhibited the expression of P2X3 receptors and the activation of its downstream MAPK pathway in DRG neurons and SC. ConclusionThis study is the first to indicate that CAV exerts an analgesic effect by inhibiting microglia activation via the P2X3 signaling pathway axis, providing the clinical utility of CAV in chronic pain therapy.

Low level laser therapy alleviates mechanical allodynia in a postoperative and neuropathic pain model and alters the levels of inflammatory factors in rats.

This study aimed to investigate the analgesic and preventive effect of low-level laser therapy (LLLT) on the incisional pain model and spinal nerve ligation (SNL) model in rats and identify the possible mechanisms of action. Male Sprague-Dawley rats were used, divided into different treatment groups. The single application group received LLLT before or after skin incision or SNL. The consecutive application group received LLLT for six consecutive days post-incision, three days pre-incision, or three consecutive days pre-SNL. The control group underwent skin incision or SNL without LLLT. The von Frey test was used to quantify the pain associated with mechanical allodynia. Pro-inflammatory cytokine level and alterations in nerve growth factor (NGF) expression were measured by using ELISA and immunohistochemistry, respectively in the skin, muscle of the paw, and spinal cord dorsal horn (SCDH). In the incisional pain model, LLLT showed significant analgesic and preventive effect. LLLT ameliorated SNL-induced mechanical allodynia but LLLT had no preventive effect. LLLT decreased interleukin-1β (IL-1β) expression levels in the skin, muscle, and SCDH and reduced the optical density of skin and spinal cord NGF in the incisional pain model. LLLT alleviated incisional pain and neuropathic pain caused by SNL in rats, and reduced the levels of IL-1β and NGF in the peripheral tissue and SCDH in the incisional pain model. LLLT might be effective in patients with post-operative pain and peripheral neuropathic pain.

Impact of Dipyrone Administration on Postoperative Analgesia and Aspirin Effect in Patients Undergoing Coronary Artery Bypass Grafting: The Prospective Randomized DipASA Study

ObjectiveThe aim of the study was to investigate the impact of dipyrone administration on postoperative analgesia and acetylsalicylic acid (ASA) effect in patients undergoing coronary artery bypass grafting (CABG). DesignA prospective randomized study. SettingSingle-university hospital setting. ParticipantsNinety-eight patients who underwent CABG between April 2022 and May 2023. InterventionsASA effect were measured at six time points with impedance aggregometry (Multiplate) and thromboelastography (TEG6sPlateletMapping). Patients were randomized to one of three groups: intravenous ASA and dipyrone at the same time (group 1), intravenous ASA and dipyrone with a 2-hour delay (group 2), and intravenous ASA alone (group 3). Postoperative analgesic effects (numeric rating scale, NRS) and the prevalence of potential ASA non-response (defined as ASPI>40U and TEG-ASA-inhibition<50%) were recorded. Measurements and Main Results80 of 90 analyzed patients took ASA preoperatively. All patients received intravenous ASA 100mg from postoperative day 1. The effect of ASA did not significantly differ between the study groups at any time for either platelet function test. NRS values did not differ between the study groups at any time (p=0.469). Patients in group 3 received significantly more additional co-analgesics than patients who received dipyrone (p=0.005). ASA non-response was detected in 38.9% and 67.8% on 7th postoperative day, respectively. ConclusionsDipyrone given after CABG seems to be safe and did not show any significant effect on platelet inhibition after ASA administration. Patients taking dipyrone postoperatively need significantly less additional co-analgesics. The ASA effect on platelet function should be checked at least once after surgery.

Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.

Analysis of clinical application effects of Esketamine combining Sufentanil in labor analgesia and their impacts on postpartum depression.

To evaluate the clinical effects of Esketamine combining Sufentanil in labor analgesia and their impacts on postpartum depression. This was a retrospective study. One hundred and fifty primiparae with spontaneous labor were selected at SSL Central Hospital of Dongguan City from July 10, 2021 to May 10, 2022 as the research objects and randomly divided into two groups (each n=75). While the control group underwent epidural infusion of Sufentanil for analgesia, the study group was administered Esketamine combining Sufentanil. Compared analgesic effects, time of birth course, adverse reactions, pain intensity, scores assigned to depression and anxiety before analgesia and after delivery were made for pregnant women in both groups. The response rates of the study and control groups reached 100% and 93%, respectively, with statistically significant differences (p=0.02). The time of the first, second, and third stages of labor in the study group were all significantly lower than that of the control group; showing statistical significance (p=0.00). Regarding adverse reactions showed no statistically significant differences (p=0.44). Moreover, the study group showed noticeably lower pain intensity than those of the control group during delivery, 20 minutes and one hour after delivery; and their differences were statistically significant (p=0.00). After delivery, both the SAS and SDS of the study group were respectively lower than those of the control group, with statistically significant differences as well (p=0.00). Applying Esketamine combining Sufentanil in epidural painless delivery produces rather favorable analgesic effects, shortens the time of the birth process, and improves postpartum anxiety and depression without leading to more adverse reactions.

The Effect of Metoclopramide on the Antinociceptive, Locomotor and Neurobehavioral Effects of Metamizole in Mice

Abstract Combining analgesic medications with distinct pharmacodynamics may result in effective analgesia and reduced adverse effects by lowering dosages of one or both medications. The objective was to investigate the nature of interactions of metoclopramide and metamizole by measuring the antinociceptive and neurobehavioral effects in mice. The drugs were administered intraperitoneally (ip) in mice. The antinociceptive effect was determined by the up-and-down method. Isobolographic analysis was performed by simultaneous injection of the two drugs at ED50 ratios of 1:1 and 0.5:0.5. The treated mice were also subjected to an open-field behavioral test as well as dorsal immobility and negative geotaxis behavioral paradigms. The ED50 of metoclopramide and metamizole were 33.71 and 43 mg/kg ip, respectively. Lower ED50 was established for metoclopramide and metamizole by 48.44% and 47.49%, respectively when given at a ratio of 0.5:0.5, and by 35.81% and 29.88%, respectively at a ratio of 1:1. The combined dose of metoclopramide and metamizole (8 and 10 mg/kg, ip, respectively) significantly decreased the open field-activity test in mice. This was observed by lower number of squares crossing compared to the control. Additionally, the drug combination resulted in a substantial increase in the duration of dorsal immobility response and delayed the negative geotaxis task when compared with the control group. The results indicated that the interaction between metoclopramide and metamizole in lower dose ratio with ED50 50:50, was synergistic in producing analgesia in mice with reduced risk for adverse reaction but with decreased behavioral and motor neuronal activity.

Ketorolac Dose Ceiling Effect for Pediatric Headache in the Emergency Department

OBJECTIVE This study sought to demonstrate a non-inferiority analgesic ceiling effect previously ­demonstrated within adults for pediatric patients receiving a maximum ketorolac dose of 15 mg. METHODS We conducted a retrospective cohort study of pediatric ED patients weighing at least 60 kg treated with 30 mg (pre-intervention) or 15 mg (post-intervention) intravenous (IV) ketorolac for headache. The primary outcome included patient-reported pain scores. Additional outcomes included demographic variables, adjunct medication use and adverse effects. Categorical data were evaluated using a χ2 test, and numerical data were evaluated using an ANOVA F test and Welch 2-sample t test. RESULTS The pre- and post-intervention groups included 216 and 62 patients, respectively. Overall demographics were similar between the groups (72.3% female, 49.3% White/Caucasian, mean age 15.5 years, mean weight 79.2 kg, and mean baseline 10-point pain score 7.5). Twelve (5.6%) in the pre-intervention group required rescue analgesic compared with 2 patients (3.2%) in the post-intervention group (p = 0.416). In the pre-intervention group, 198 patients (91.7%) received nausea medication compared with 52 patients (83.9%) in the post-intervention group (p = 0.087). Mean 10-point pain scores following ketorolac administration decreased by 3.9 in the pre-intervention group compared with 5.1 in the post-intervention group (p = &amp;lt; 0.001). Common (0.9%) or rare (0.9%) side effects were infrequent and only seen in the pre-intervention group patients. CONCLUSIONS Truncating the maximum intravenous ketorolac dose in pediatric patients at least 60 kg in weight to 15 mg compared with 30 mg results in effective analgesia in pediatric patients with headache. Future research could explore differences in admission rates, treatment of other indications, or treatment with multiple-dose regimens.

Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia

Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Nav1.7 and Nav1.8. Genetic deletion of Nav1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Nav1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal.Adult deletion of Nav1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Nav1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Nav1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Nav1.7 channel. Here we show that sensory neuron sodium channels Nav1.1, Nav1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Nav1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Nav1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.

The role of mu-opioid receptors in pancreatic islet α-cells.

Diabetes is a complex disease that impacts more than 500 million people across the world. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is historically treated with exogenous opioids like morphine, oxycodone, or tramadol. Although these opioids are effective analgesics, growing evidence indicates that they may directly impact the endocrine pancreas function in patients. One common feature of these exogenous opioid ligands is their preference for the mu opioid receptor (MOPR), so we aimed to determine if endogenous MOPRs directly regulate pancreatic islet metabolism and hormone secretion. We show that pharmacological antagonism of MOPRs enhances glucagon secretion, but not insulin secretion, from human islets under high glucose conditions. This increased secretion is accompanied by increased cAMP signaling. mRNA expression of MOPRs is robust in non-diabetic human islets, but downregulated in islets from T2D donors, suggesting a link between metabolism and MOPR expression. Conditional genetic knockout of MOPRs in murine α-cells increases glucagon secretion under high glucose conditions without increasing glucagon content. Consistent with downregulation of MOPRs during metabolic disease, conditional MOPR knockout mice treated with a high fat diet show impaired glucose tolerance, increased glucagon secretion, increased insulin content, and increased islet size. Together, these results demonstrate a direct mechanism of action for endogenous opioid regulation of endocrine pancreas.

Benzylpiperidine derivatives as new dual μ-opioid and σ1 receptor ligands with potent antinociceptive effects

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ1R) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σ1R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ1R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [Ki (MOR) = 56.4 nM] and σ1R [Ki (σ1R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED50 = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED50 = 6.88 mg/kg in mice), formalin test (ED50 = 13.98 mg/kg in rats) and complete Freund’s adjuvant (CFA)-induced chronic pain model (ED50 = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.

Effect of intraperitoneal lidocaine administration versus traditional analgesics only on postoperative pain control in laparoscopic bariatric surgeries.

Effect of intraperitoneal lidocaine administration versus traditional analgesics only on postoperative pain control in laparoscopic bariatric surgeries.

A Narrative Review on the Potential of Black Seeds (Nigella Sativa) in the Management of West Nile Virus Infection

Abstract: West Nile virus (WNV) infection is a mosquito-borne illness that is endemic to Africa, Asia, the Middle East, Australia, and Europe. WNV-infected individuals can only be managed with symptomatic therapy and supportive care at this point of time. Thus, we have analyzed the possible beneficial effects of black seeds (N. sativa) in this literature review. To find relevant articles, various online databases, such as the Web of Science, Medline, PMC, PubMed, Embase, EBSCO, Google Scholar, Science Direct, and reference lists were searched. The antiviral, analgesic, anti-inflammatory, antioxidant, and immunomodulatory effects of black seeds (N. sativa) have been established by numerous clinical, animal, in vivo, in vitro, and in silico studies. It has been found that black seeds (N. sativa) have the potential to be included as adjuvant therapy in addition to symptomatic treatment and supportive care in the early stages of WNV infection once randomized controlled clinical trials (RCTs) affirm the safety and efficacy of black seeds (N. sativa) in WNV infection management as they have been considered the gold standard of treatment in clinical studies.