Benzofuran Iboga-analogs Modulate Nociception and Inflammation in an Acute Mouse Pain Model.

Pain management following acute injury or post-operative procedures is highly necessary for proper recovery and quality of life. Opioids and non-steroidal anti-inflammatory drugs (NSAIDS) have been used for this purpose, but opioids cause addiction and withdrawal symptoms whereas NSAIDS have several systemic toxicities. Derivatives of the naturally occurring iboga alkaloids have previously shown promising behavior in anti-addiction of morphine by virtue of their interaction with opioid receptors. On this frontier, four benzofuran analogs of the iboga family have been synthesized and their analgesic effects have been studied in formalin induced acute pain model in Swiss albino mice at 30 mg/kg of body weight dose administered intraperitoneally. The antioxidant, anti-inflammatory and neuro-modulatory effects of the analogs were analyzed. Reversal of tail flick latency, restricted locomotion and anxiogenic behavior were observed in iboga alcohol, primary amide and secondary amide. Local neuroinflammatory mediators' substance P, calcitonin gene related peptide, cyclooxygenase-2 and p65 were significantly decreased whereas the depletion of brain derived neurotrophic factor and glia derived neurotrophic factor was overturned on iboga analog treatment. Behavioral patterns after oral administration of the best analog were also analyzed. Taken together, these results show that the iboga family of alkaloid has huge potential in pain management.

Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.

Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling in spinal cord; Hsp90 inhibition in spinal cord enhances opioid anti-nociception. Building on these findings, we injected the non-selective Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.9-3.5-fold in acute and chronic pain models. At the same time, tolerance was reduced from 21-fold to 2.9 fold and established tolerance was rescued, while the potency of constipation and reward was unchanged. These results demonstrate that spinal Hsp90 inhibition can improve the therapeutic index of morphine. However, we also found that systemic non-selective Hsp90 inhibition blocked opioid pain relief. To avoid this effect, we used selective small molecule inhibitors and CRISPR gene editing to identify 3 Hsp90 isoforms active in spinal cord (Hsp90α, Hsp90ß, and Grp94) while only Hsp90α was active in brain. We thus hypothesized that a systemically delivered selective inhibitor to Hsp90ß or Grp94 could selectively inhibit spinal cord Hsp90 activity, resulting in enhanced opioid therapy. We tested this hypothesis using intravenous delivery of KUNB106 (Hsp90ß) and KUNG65 (Grp94), showing that both drugs enhanced morphine anti-nociceptive potency while rescuing tolerance. Together, these results suggest that selective inhibition of spinal cord Hsp90 isoforms is a novel, translationally feasible strategy to improve the therapeutic index of opioids.

Synergistic Antinociceptive Effect of ß-Caryophyllene Oxide in Combination with Paracetamol, and the Corresponding Gastroprotective Activity.

Pain is the most frequent symptom of disease. In treating pain, a lower incidence of adverse effects is found for paracetamol versus other non-steroidal anti-inflammatory drugs. Nevertheless, paracetamol can trigger side effects when taken regularly. Combined therapy is a common way of lowering the dose of a drug and thus of reducing adverse reactions. Since ß-caryophyllene oxide (a natural bicyclic sesquiterpene) is known to produce an analgesic effect, this study aimed to determine the anti-nociceptive and gastroprotective activity of administering the combination of paracetamol plus ß-caryophyllene oxide to CD1 mice. Anti-nociception was evaluated with the formalin model and gastroprotection with the model of ethanol-induced gastric lesions. According to the isobolographic analysis, the anti-nociceptive interaction of paracetamol and ß-caryophyllene oxide was synergistic. Various pain-related pathways were explored for their possible participation in the mechanism of action of the anti-nociceptive effect of ß-caryophyllene oxide, finding that NO, opioid receptors, serotonin receptors, and K+ATP channels are not involved. The combined treatment showed gastroprotective activity against ethanol-induced gastric damage. Hence, the synergistic anti-nociceptive effect of combining paracetamol with ß-caryophyllene oxide could be advantageous for the management of inflammatory pain, and the gastroprotective activity should help to protect against the adverse effects of chronic use.

Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice.

Low efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1hr. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. Significance Statement This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.

Antinociceptive and Cardiorespiratory Effects of a Single Dose of Dexmedetomidine in Laboratory Mice Subjected to Craniotomy under General Anaesthesia with Isoflurane and Carprofen or Meloxicam.

Pain refinement represents an important aspect of animal welfare in laboratory animals. Refining analgesia regimens in mice undergoing craniotomy has been sparsely investigated. Here, we sought to investigate the effect of dexmedetomidine in combination with other analgesic drugs on intraoperative anti-nociceptive effects and cardiorespiratory stability. All mice were anaesthetised with isoflurane and received local lidocaine infiltration at the surgical site. Mice were randomised into treatment groups consisting of either carprofen 5 mg kg-1 or meloxicam 5 mg kg-1 with or without dexmedetomidine 0.1 mg kg-1 administered subcutaneously. Intra-anaesthetic heart rates, breathing rates, isoflurane requirements, and arterial oxygen saturations were continuously monitored. We found that administration of dexmedetomidine significantly improved heart and breathing rate stability during two of four noxious stimuli (skin incision and whisker stimulation) compared to non-dexmedetomidine-treated mice and lowered isoflurane requirements throughout anaesthesia by 5-6%. No significant differences were found between carprofen and meloxicam. These results demonstrate that dexmedetomidine reduces nociception and provides intra-anaesthetic haemodynamic and respiratory stability in mice. In conclusion, the addition of dexmedetomidine to anaesthetic regimes for craniotomy offers a refinement over current practice for laboratory mice.

Possibility of Using Surgical Pleth Index in Predicting Postoperative Pain in Patients after Vitrectomy Performed under General Anesthesia.

Adequacy of anesthesia concept (AoA) in the guidance of general anesthesia (GA) is based on entropy, and it also reflects the actual depth of anesthesia and the surgical pleth index (SPI). Therefore, this study aimed to analyze the potential existence of relationships between SPI values at certain stages of the AoA-guided GA for vitreoretinal surgeries (VRS) and the incidence of intolerable postoperative pain perception (IPPP). A total of 175 patients were each assigned to one of five groups. In the first, the VRS procedure was performed under GA without premedication; in the second group, patients received metamizole before GA; in the third, patients received acetaminophen before GA; in the fourth group, patients received Alcaine before GA; and, in the peribulbar block group, the patients received a peribulbar block with a mix of the solutions of lignocaine and bupivacaine. Between the patients declaring mild and statistically significant differences in the IPPP in terms of SPI values before induction (52.3 ± 18.8 vs. 63.9 ± 18.1, p < 0.05) and after emergence from GA (51.1 ± 13 vs. 68.1 ± 8.8; p < 0.001), it was observed that the patients postoperatively correlated with heart rate variations despite the group allocation. The current study proves the feasibility that preoperative SPI values help with predicting IPPP immediately after VRS under AoA guidance and discrimination (between mild diagnoses and IPPP when based on postoperative SPI values) as they correlate with heart rate variations. Specifically, this applies when the countermeasures of IPPP and hemodynamic fluctuations are understood to be of importance in reducing unwelcome adverse events.

Revolutionizing orofacial pain management: the promising potential of stem cell therapy.

Orofacial pain remains a significant health issue in the United States. Pain originating from the orofacial region can be composed of a complex array of unique target tissue that contributes to the varying success of pain management. Long-term use of analgesic drugs includes adverse effects such as physical dependence, gastrointestinal bleeding, and incomplete efficacy. The use of mesenchymal stem cells for their pain relieving properties has garnered increased attention. In addition to the preclinical and clinical results showing stem cell analgesia in non-orofacial pain, studies have also shown promising results for orofacial pain treatment. Here we discuss the outcomes of mesenchymal stem cell treatment for pain and compare the properties of stem cells from different tissues of origin. We also discuss the mechanism underlying these analgesic/anti-nociceptive properties, including the role of immune cells and the endogenous opioid system. Lastly, advancements in the methods and procedures to treat patients experiencing orofacial pain with mesenchymal stem cells are also discussed.

Evaluation of the Anti-Inflammatory Pain Effect of Ginsenoside-Conjugated O-Carboxymethyl Chitosan Particles.

Nanoparticle delivery of functional molecules or vaccines is an effective method for the treatment of many diseases. This study aims to design ginsenoside Rh2-conjugated O-carboxymethyl chitosan (O-CMC/Rh2) as a drug delivery system and explore its anti-nociceptive effects. O-CMC/Rh2 was synthesized with an esterification reaction, and its chemical composition and morphology were evaluated using proton nuclear magnetic resonance (1H NMR), the attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, and scanning electron microscopy (SEM). In addition, the in vitro cumulative release of Rh2 from the O-CMC/Rh2 was also evaluated under different pH conditions. The results showed that the ginsenoside Rh2 was successfully conjugated to the O-CMC matrix and exhibited a highly porous structure after conjugation, facilitating the release of Rh2 from O-CMC. Complete Freund's adjuvant (CFA) and burn injury-induced pain models were used to evaluate the anti-nociceptive effects of O-CMC/Rh2 on inflammatory pain. O-CMC/Rh2 reduced CFA-induced pain hypersensitivity in a dose-dependent manner and had a longer analgesic effect than Rh2. In addition, O-CMC/Rh2 also relieved the chronic pain induced by bury injury. These results indicated that O-CMC/Rh2 could be useful in reducing inflammatory pain, thus possessing a potential medicinal application in pain therapy.

Anti-nociceptive and Anti-inflammatory Activities of Visnagin in Different Nociceptive and Inflammatory Mice Models.

Pain management has been a severe public health issue throughout the world. Acute pain if not treated at the appropriate time can lead to chronic pain that can cause psychological and social distress. Nothing can be more rewarding than treating pain successfully for a physician. However, the use of chemical NSAIDs and opiate drugs has taken a toll on the patients with their unavoidable side effects. This study intends to explore the potential to treat pain by inhibiting nociception and inflammation with a safer, non-addictive, effective, and low-cost alternative agent from a natural source, visnagin. In vivo studies have been conducted using male Swiss albino mice as models for this research. Nociception was induced using different chemical and thermal stimuli such as acetic acid, glutamate, capsaicin, and formalin. To check for the anti-inflammatory properties, carrageenan was used to induce inflammation and the activity was assayed using peritoneal cavity leukocyte infiltration analysis and pro-inflammatory cytokine level comparison with the supplementation of visnagin at three different dosages. The findings of this study revealed that the visnagin treatment effectively attenuated the acetic acid-induced writhing response, glutamate-induced paw licking numbers, capsaicin-induced pain response, and formalin-induced biphasic licking incidences in the experimental mice models. Furthermore, the visnagin treatment remarkably suppressed the carrageenan-induced inflammation in mice, which is evident from the decreased leukocytes, mononuclear, and polymorphonuclear cell numbers in the mice. The levels of cytokines such as TNF-α, IL-1ß, and IL-6 were effectively reduced by the visnagin treatment in the experimental mice. The results of open field test proved that the visnagin showed a better locomotor movement in the experimental mice. These results provided evidence for the potential activity of the visnagin against inflammatory and nociceptive responses in the mice.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

BACKGROUND AND PURPOSE: Opioid-induced respiratory depression limits the use of µ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. EXPERIMENTAL APPROACH: Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. KEY RESULTS: Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. CONCLUSION AND IMPLICATIONS: In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats.

OBJECTIVE: Acute pain is the most common type of pain. The aim of the present work was carried out to study the antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide (Thm) in rats exposed to thermal pain stimulus. MATERIALS AND METHODS: The anti-nociceptive effect of the newly synthesized compound, Thm was studied in comparison to that of paracetamol (Para), dexamethasone (Dex), and morphine (Morph) at different doses using a hot plate test at a constant temperature of 48.0 ± 0.5°C. During this test, the latency time (LT) was measured when rats express pain behavior. Then, the pharmacological mechanisms were determined using receptor-antagonist drugs. RESULTS: Firstly, the obtained result showed pain modulation of the pretreated rats with Thm at 10 mg/kg dose proved by the delay of latency time during the thermal test. This significant antinociceptive activity of the thiocyanoacetamide was more effective than that of paracetamol or dexamethasone and less than that of morphine. Second, the pretreatment with acebutolol or risperidone antagonist drugs of, respectively, adrenergic and serotonin receptors demonstrated the elimination of pain modulation with Thm 10 mg/kg dose proved by a short latency time of rat's response in hot plate test. In this case, the pharmacological mechanism of Thm was characterized by the involvement of adrenergic and serotoninergic systems. CONCLUSIONS: It may be concluded that Thm constitutes a promising antinociceptive drug including beta-adrenergic and serotoninergic targets. The present study warrants further investigation to determine the side effects of this compound.

Epidural lidocaine, butorphanol, and butorphanol - lidocaine combination in dromedary camels.

BACKGROUND: The use of general anesthesia in dromedary camels is constrained by risks related to decubitus. Caudal epidural analgesia is an alternative convenient technique providing loco-regional analgesia for numerous invasive and noninvasive painful conditions. Lidocaine is probably the most commonly used local anesthetic in clinical practice, but has a relatively short duration and may not provide significant long term analgesic benefits. Epidural administration of an opioid-local anesthetic mixture would improve the quality and length of analgesia and minimizes the adverse motor effects provoked by local anesthetics. Butorphanol (potent agonist-antagonist opioid) has been used to improve the duration of epidural analgesia in some animal species, but not in camels. Therefore, our purpose was to investigate the onset and duration of analgesia as well as the clinical and hemato-biochemical effects produced by the epidural administration of butorphanol (0.04 mg/kg), lidocaine (0.22 mg/ kg), and butorphanol-lidocaine (0.04 mg/kg-0.22 mg/ kg) mixture in nine adult dromedary camels in a crossover experimental study. RESULTS: The onset of analgesia was not statistically different between lidocaine (6.5 ± 2.3 min) and butorphanol-lidocaine (7.3 ± 1.5 min) combination. Delayed onset of analgesia was reported after butorphanol administration (14.7 ± 3.5 min). Butorphanol-lidocaine combination produced marked longer duration (175 ± 8.7 min) than lidocaine (55 ± 6.8 min) and butorphanol (158 ± 5.3 min). Mild ataxia was observed in the butorphanol-lidocaine and lidocaine treated animals and slight sedation was reported after butorphanol and butorphanol-lidocaine administration. A transient significant increase in the glucose levels was recorded after all treatments. CONCLUSIONS: Epidural administration of butorphanol augments the analgesic effects and duration of lidocaine with minimal adverse effects.

Comparing the anti-nociceptive, sedative and clinicophysiological effects of epidural detomidine, detomidine-lidocaine and lidocaine in donkeys.

BACKGROUND: Epidural analgesia using the alpha-2 agonist detomidine (DE), alone or in combination with lidocaine (LD), is frequently employed for standing surgical procedures in horses, but its use has not been evaluated in donkeys. METHODS: In a randomised controlled prospective trial, 24 healthy adult donkeys were assigned to four groups (n = 6), each receiving 40 µg/kg of DE, 0.22 mg/kg of LD, combined DE and LD (DELD) or 0.9% sterile normal saline epidurally. After epidural injection of each treatment, the onset, degree and duration of sedation and anatomical extension of anti-nociception were observed. RESULTS: DE and DELD treatments resulted in complete bilateral analgesia with loss of sensation in the tail, perineum, inguinal area, chest and the caudal aspect of the upper pelvic limb, and extended distally to the dorsal metatarsal area. DE and DELD resulted in a significantly (p < 0.05) longer duration of anti-nociception (110 ± 15.4 min and 141.6 ± 14.7 min, respectively) than LD (75.8 ± 4.9 min). The DELD duration of sedation was significantly (p < 0.05) longer than the DE duration (118.3 ± 19.4 min and 108.3 ± 7.5 min, respectively). LIMITATION: The current study's main limitation is using only one dose of DE. CONCLUSION: DE and DELD produced a very effective, safe and acceptable sedative and analgesic effect in the perineal and inguinal regions of donkeys.

Effects of Lidocaine Injection at Acupuncture Points on Perioperative Analgesia in Cats Undergoing Ovariohysterectomy.

Background: Pharmacopuncture is an acupuncture-related technique that has been used to amplify the therapeutic effects of different medications. Objectives: To investigate the analgesic efficacy of a lidocaine injection at acupoints in cats undergoing ovariohysterectomy. Methods: Thirty cats were randomly distributed into two groups (n = 15, per group). The experimental group received a bilateral administration of lidocaine at the following acupoints: Stomach 36 (ST-36) and Spleen 6 (SP-6) (Lido group). The control group did not receive lidocaine (Control group). All cats were sedated with dexmedetomidine and anesthesia was induced with propofol and maintained with isoflurane. Intraoperatively, fentanyl was given to control cardiovascular responses to surgical stimulation. Postoperative pain was assessed at various time points, up to 24 hours after extubation, using the UNESP-Botucatu multidimensional composite pain scale (MCPS) and Glasgow feline composite measure pain scale (CMPS-Feline). Sedation scores were measured at the same time points. Morphine/meloxicam was administered as rescue analgesia. Data were analyzed using t-tests, Fisher´s exact test, the Mann-Whitney test, and the Friedman test (p < 0.05). Results: Intraoperatively, more cats in the Control group required analgesic supplementation than those in the Lido group, but the difference was not significant (p = 0.65). Postoperative pain, sedation scores, and analgesic requirements did not differ between groups. Rescue analgesia was given to 67% (10/15) of the cats in each group. Conclusion: The administration of lidocaine at ST-36 and SP-6 acupuncture points did not provide significant perioperative analgesic benefits in healthy cats undergoing ovariohysterectomy.

Comparative evaluation of sedative and anti-nociceptive effects of epidural romifidine, romifidine-lidocaine, and lidocaine in donkeys (Equus asinus).

Background: Local and regional anesthetic procedures are valuable tools in veterinary practice. Caudal epidural administration of local anesthetic agents is widely reported for surgical interventions of the tail, anus, rectum, vulva, vagina, urethra, and bladder in the standing horse. Epidural analgesia is also obtained using various drugs such as alpha-2 adrenoceptor agonists, dissociative anesthetics, and opioids. The present study evaluates the anti-nociceptive and sedative effects of epidural administration of romifidine, a romifidine-lidocaine combination, and lidocaine alone in donkeys. Materials and methods: In a randomized prospective study, twenty-four healthy adult donkeys were assigned to four groups (three experimental and one control; n = 6) received either 50 µg/kg of romifidine, 0.30 mg/kg of lidocaine, combined romifidine (50 µg/kg) and lidocaine (0.30 mg/kg) diluted in 0.9% sterile normal saline solution to a total injection volume of 12 ml, or an equivalent volume of sterile saline epidurally. After epidural injection of each treatment, the onset, degree, and duration of sedation and anatomical extension of anti-nociception were documented. Observations began immediately (time 0) pre-administration and at 5, 15, 30, 45, 60, and 30-min intervals subsequently until 210 min after drug injection. Time to onset of perineal analgesia was documented every minute after the epidural injection by evaluating the animal's response to pinpricks. Results: Only romifidine and romifidine-lidocaine induced mild to moderate sedation. Romifidine, romifidine-lidocaine, and lidocaine induced complete bilateral caudal epidural analgesia with loss of sensation in the perineum, tail, inguinal region, caudal aspect of the upper hind limb, chest areas, and extended distally to the dorsal metatarsal area. Sedation lasted longer (p < 0.05) with romifidine (160 ± 15.4 min) than with romifidine-lidocaine (141.6 ± 13.2 min). Longer-lasting analgesia (p < 0.05) was obtained with romifidine (158.3 ± 9.8 min) and romifidine-lidocaine (165 ± 9.4 min) than with lidocaine (75.8 ± 8 min). Conclusions: Epidural administration of a single dose of romifidine or a combination of romifidine-lidocaine produced mild to moderate sedation and complete anti-nociception in the perineal and inguinal regions of donkeys. The clinical usefulness of epidural romifidine or romifidine-lidocaine combinations to perform obstetric procedures in donkeys needs to be assessed.

Comparative Study of the Sedative and Anti-nociceptive Effects of Sacrococcygeal Epidural Administration of Romifidine, Lidocaine, and Romifidine/Lidocaine in the Dromedary Camel.

In a randomized prospective study, comparative sedative and anti-nociceptive effects of epidural administration of romifidine (RO), lidocaine (LD), and a combination of romifidine-lidocaine (ROLD) in camel were evaluated. Eighteen healthy adult dromedary camels were assigned randomly to three treatment groups (n = 6), each receiving 50 µg/kg of RO, 0.30 mg/kg of LD, or a combination of both RO and LD. All treatments were expanded in 0.9% sterile normal saline solution to a final dose volume of 20 ml and administered directly into the sacrococcygeal space. After epidural injection of each treatment, the onset time, duration, anatomical extension of anti-nociception, and sedation were documented. Anti-nociception was tested at different areas using a pinprick test and artery forceps pinching at the perineum and inguinal area. RO and ROLD treatments resulted in mild to severe sedation and complete bilateral analgesia with loss of sensation in the tail, perineum, scrotum in males, vulva in females, the caudal aspect skin of the upper hind limb, and inguinal region (udder in females and the prepuce in males). The anatomic extent of anti-nociception reached the chest cranially and the footpad distally. Camels who received LD showed the shortest duration (P < 0.001) to the onset of perineal anti-nociception (3.67 ± 0.33 min) followed by those who received RO LD (4.00 ± 0.37 min) and RO (6.67 ± 0.33 min), respectively. RO and ROLD resulted in significantly (P < 0.001) longer periods of analgesia (158.33 ± 4.01 min and 165 ± 3.87 min, respectively) than LD (75.83 ± 3.27). An epidural RO and ROLD would appear to produce a very effective and acceptable anti-nociceptive effect in the perineal and inguinal regions of camels.

Agmatine prevents development of tolerance to anti-nociceptive effect of ethanol in mice.

Drug tolerance is directly correlated with drug abuse and physical dependence. The development of tolerance is manifested as the decline in pharmacological responses of drugs following repeated administration of the constant dose. The present study evaluated the effect of agmatine in ethanol-induced anti-nociception and tolerance in the tail-flick assay in mice. In an acute protocol, ethanol (1 and 2 g/kg, i.p. [intraperitoneally]) and agmatine (20 and 40 µg/mouse, i.c.v. [intracerebroventricularly]) produced significant analgesic effects in mice, as was evident from the increased baseline tail-flick latency when tested 20 minutes after their administration. Agmatine in a per se non-effective dose (5 µg/mouse, i.c.v.), L-arginine (40 µg/mouse, i.c.v.), and arcaine (25 µg/mouse, i.c.v.) significantly potentiated the anti-nociceptive effect of ethanol. Blood ethanol analysis showed no significant differences in blood ethanol concentration between ethanol/saline- and ethanol/agmatine-treated mice, suggesting that the effects of agmatine were not due to any possible effects on the pharmacokinetics of ethanol. In a separate study, mice were injected with ethanol (2 g/kg, i.p., 12%) or saline (1 mL/kg, i.p.) once daily for 9 days. On days 1, 3, 5, 7, and 9 of the experiment, they were subjected to the tail-flick test. Agmatine (5-20 µg/mouse, i.c.v.), L-arginine (40 µg/mouse, i.c.v.), arcaine (25 µg/mouse, i.c.v.), aCSF (2 µL/mouse, i.c.v.), or saline (1 mL/kg, i.p.) was administered daily prior to the first daily ethanol or saline injections, and reaction latencies were determined in the tail-flick assay. Injections of agmatine, L-arginine, and arcaine prevented the development of tolerance to ethanol-induced analgesia. Given that agmatine and its endogenous modulation can prevent tolerance to the anti-nociceptive effects of ethanol, these data suggest it as a possible new therapeutic strategy for the treatment of alcohol use disorder and associated complications.

Synthesis, characterization and in vitro, in vivo, in silico biological evaluations of substituted benzimidazole derivatives.

A series of substituted benzimidazole derivatives were synthesized by reacting O-phenylenediamine with various aromatic aldehydes or glycolic acid using various inexpensive reagents in aqueous media. Synthesized compounds were characterized and elucidated by IR, 1H NMR, ESI-MS spectra. Resultant compounds were screened for in vitro antimicrobial, cytotoxic, antioxidant, lipid peroxidation and cholinesterase inhibitory activities, in vivo analgesic and anti-inflammatory, and in silico anti-acetylcholinesterase and anti-butyrylcholinesterase activities. Among the synthesized compounds, compound 3b showed most promising central analgesic effect (46.15%) compared to morphine (48.08%), whereas compounds 6, 3c and 3a showed significant peripheral analgesic activity at two different dose levels (25 mg/kg and 50 mg/kg). Compounds 3b and 3a at the dose of 100 mg/kg showed significant anti-inflammatory effects from the first hour and onward, whereas compounds 6 and 3b showed moderate cytotoxic activities. In addition, compound 3a showed significant antioxidant activity having IC50 value of 16.73 µg/ml compared to 14.44 µg/ml for the standard BHT. Compound 6, 3a and 3b exhibited mild to moderate cholinesterase inhibitory activity. In silico studies revealed that compound 3a and 3b might be suitable for cholinesterase inhibitory activity. A comprehensive computational and experimental data suggested compounds 3b and 3a as the best possible candidates for pharmacological activity. All the experimental data were statistically significant (p < 0.01 level).

Dieckol attenuates the nociception and inflammatory responses in different nociceptive and inflammatory induced mice model.

Pain is the common indicator of inflammatory ailments and traumatic tissue injuries. The dieckol is an important therapeutic compound, which present in many seaweeds. The present research work was planned to assess the anti-inflammatory and anti-nociceptive actions of dieckol by using animal model. The anti-nociceptive action of dieckol was investigated by acetic acid triggered writhing, formalin provoked nociception, tail immersion test, hot-plate methods and the anti-inflammatory effects was explored by carrageenan triggered paw edema method. In the present investigation the administration of dieckol was remarkably suppressed and inhibited the acetic acid-provoked writhing, formalin-triggered nociception, tail immersion test, hot plate-provoked nociception in the experimental animals. The dieckol was significantly (p < 0.05) inhibited the carrageenan-triggered inflammation, leukocyte infiltration and diminished the formation of pro-inflammatory regulators in the experimental animals. Altogether, the dieckol was showed a potent anti-nociceptive and anti-inflammatory activity.

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways.

The diversity offered by natural products has timelessly positioned them as a good source for novel therapeutics for the management of diverse medical conditions, including pain. This study evaluated hydro-ethanolic root bark extract of Ziziphus abyssinica (ZAE) as well as ß-amyrin and polpunonic acid isolated from the plant for analgesic property. The study also investigated the mechanism responsible for this action in the extract. The antinociceptive potential of ZAE (30, 100, and 300 mg/kg, p. o.) was assessed using the tail-immersion test (TIT), acetic acid-induced writhing test (AAT), and formalin test (FT). The extract's effect on acute and chronic musculoskeletal pain was also assessed by administering carrageenan unilaterally into the rat gastrocnemius muscles and measuring pain at 12 h and 10 days for acute and chronic pain respectively. The involvement of pro-inflammatory mediators (prostaglandin E2, bradykinin, TNF-α, and IL-1ß) was assessed. The possible pathways mediating the observed analgesic effect of ZAE were further assessed using the antagonists: naloxone, glibenclamide, NG-L-nitro-arginine methyl ester (L-NAME), atropine, nifedipine, and yohimbine in the FT. Also the analgesic effect of two triterpenoid compounds, ß-amyrin and polpunonic acid, previously isolated from the plant was assessed using the TIT. The anti-nociceptive activity of ZAE was demonstrated in the TIT by the significant (p < 0.05) increase in tail withdrawal threshold in ZAE-treated mice. ZAE also markedly reduced writhing and paw licking responses in both AAT and FT and significantly (p < 0.05) attenuated both acute and chronic musculoskeletal pain. ZAE also significantly reversed hyperalgesia induced by intraplantar injection of PGE2, bradykinin, TNF-α, and IL-1ß. Furthermore, data revealed the involvement of opioidergic, ATP-sensitive K+ channels and NO-cGMP pathways in the analgesic effect of ZAE. Both ß-amyrin and polpunonic acid exhibited analgesic activity in the tail suspension test. Our study demonstrates ZAE as an important source of new therapeutic agents for pain management.