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Background and Purpose Experimental Approach Key Results Conclusions and Implications Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ‐opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1‐positive cells also express MORs in brainstem regions mediating opioid‐induced respiratory depression. We determined the role of Tac1‐positive cells in mediating the respiratory effects of opioid drugs.In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1‐positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1‐positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole‐body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1‐positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker–Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1‐positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1‐positive cells, whereas locomotor effects induced by fentanyl were preserved.Our findings suggest that Tac1‐positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the application of frontal electroencephalography (EEG) to monitor isoflurane anesthesia in dogs. By varying anesthetic levels from deep to light planes, we observed distinct changes in EEG waveforms. At deep anesthesia (2–2.5× MAC-minimum alveolar concentration), EEG patterns were predominantly isoelectric with rare intermittent bursts. The dog was unresponsive to electrical stimulation, indicating complete unconsciousness. As anesthesia lightened (1–1.5× MAC), EEG patterns transitioned to alpha and beta dominance with occasional burst suppression. Responsiveness to electrical stimulation signified the recovery of consciousness. At light anesthesia (0.75× MAC) and recovery, EEG amplitudes decreased, and the frequency increased. This study found a stronger correlation between mean arterial blood pressure and the patient state index, a processed EEG parameter, compared to heart rate. These findings suggest that EEG is a valuable tool for the real-time monitoring and management of isoflurane anesthesia levels in dogs. This study investigated the use of frontal electroencephalography (EEG) to monitor varying levels of isoflurane anesthesia in dogs. The patient state index (PSI), burst suppression ratio (SR), and waveforms, were continuously recorded while mean arterial blood pressure (MBP), heart rate, responses to electric stimuli, and subjective anesthetic "depth" were assessed every 3 min. At deep anesthesia (2.5× MAC − 3.2%), the PSI (6.5 ± 10.8) and MBP (45.6 ± 16.4 mmHg) were the lowest, and SR was the highest (78.3 ± 24.0%). At 1× MAC (1.3%), the PSI and MBP increased significantly to 47.8 ± 12.6 and 99.8 ± 13.2, respectively, and SR decreased to 0.5 ± 2.5%. The EEG was predominantly isoelectric at 2×–2.5× MAC, indicating unconsciousness and unresponsiveness. As anesthesia lightened, waveforms transitioned to flatter and faster activity patterns with a response to noxious stimuli, suggesting regained consciousness. The PSI and MBP exhibited a stronger correlation (ρ = 0.8098, p = 0.001) than the relationship of PSI with heart rate (ρ = −0.2089, p = 0.249). Five of the six dogs experienced rough recovery, possibly due to high SR and low MBP. These findings suggest that EEG monitoring in dogs can be a valuable tool for the real-time tracking of brain states and can be used to guide the management of isoflurane anesthesia. [ABSTRACT FROM AUTHOR]

Purpose of this work is to propose an approach to the assessment of allostatic load based on the antinociceptive effect, which appears, obviously, due to changes in the activity of the endogenous opioid system (EOS); to compare the estimates obtained by measuring the pain threshold and calculating the index of respiratory effects on heart rate variability (HRV). The method of measuring the pain threshold is based on fixing the latent time of the thermonociceptive reaction (LTTR). The respiratory effect is measured by graphically determining the minimum normalized power of the fast HRV component in the range of 0.16...0.67 Hz, corresponding to the frequency of the respiratory pattern. Results. Based on small-volume experimental data (4 athletes and 4 episodes of physical activity), a quadratic two-factor regression equation was calculated for LTTR, respiratory effects factor and stress. A high correlation was demonstrated between the respiratory effect on HRV and the LTTR for one studied athlete. Conclusion. Using the example of sports, it is shown that it is possible to track the physiological cost of activities through LTTR. The inconveniences and subjectivity of the LTTR measurement procedure can be circumvented by replacing it with a normalized numerical index that considers the effect of breathing on HRV and the stress index. The proposed approach demonstrates the presence of reference values in the studied group, but requires further specially planned clinical studies.

Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil (Iridaceae) is a popularly known species with primarily ornamental economic interest. It has traditional uses as purgative, in conditions related to the menstrual cycle, for blood purification, as wound healing, and as anti-inflammatory. The anti-inflammatory and antinociceptive activities of the decoction from its aerial stems, corms, and stamens are described here with dereplication studies on LC-MS/MS supported by the GNPS platform, where phenolic compounds were annotated and correlated with its biological activity. The decoction was evaluated in chemical (formalin and capsaicin) and thermal (hot plate) induced nociception or carrageenan-induced inflammation in mice. Decoction (at 10, 30, or 100 mg/kg doses) significantly reduced formalin- or capsaicin-induced nociception. All doses also demonstrated an antinociceptive effect in the hot plate model increasing the time the animal spent in responding to thermal signal. Naloxone partially reversed the antinociceptive effect. An anti-inflammatory effect was observed since a reduction in cell migration, protein extravasation interleukin-1, and tumor necrosis factor production induced by carrageenan in the subcutaneous air pouch was quantified. Metabolomic analyses showed a predominance of phenolic substances, mainly flavonoids and chlorogenic acids. The literature showed that these two groups have significant anti-inflammatory and analgesic activity, and chemical data corroborate the pharmacological results observed. [ABSTRACT FROM AUTHOR]

Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn. [ABSTRACT FROM AUTHOR]

Aims: Bone cancer produces severe pain that is treated with opioids, but serious side effects limit opioid utilization. There is therefore a need to develop effective and safe non‐opioid alternatives. The lipid mediator, Resolvin D1 (RvD1), could be a prospective candidate for cancer pain treatment. To assess RvD1 and other potential candidates, appropriate animal models that recapitulate clinical features must be used. Although several preclinical models of cancer pain have been developed, the influence of sex on the development of cancer pain and the effectiveness of RvD1 have not been studied. Results: Using a mouse model of fibrosarcoma growth in and around the calcaneus bone, we demonstrated that the mechanical hyperalgesia in the tumor‐bearing hind paw develops independently of sex, except that it developed a little sooner in female mice. A single intravenous injection of RvD1 (0.001–10 μg/kg) decreased hyperalgesia in both sexes with similar potency (ED50 = 0.0015 μg/kg) and efficacy. Repeated daily administration of 10 μg/kg RvD1 prolonged the analgesic effect and completely abolished hyperalgesia. This was also independent of sex. Conclusion: In this preclinical mouse model of bone cancer pain, the development of pain and the analgesic effectiveness of RvD1 are not influenced by sex. [ABSTRACT FROM AUTHOR]

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration.

Various plant species from the Litsea genus have been claimed to be beneficial for pain relief. The PRISMA approach was adopted to identify studies that reported analgesic properties of plants from the Litsea genus. Out of 450 records returned, 19 primary studies revealed the analgesic potential of nine Litsea species including (1) Litsea cubeba, (2) Litsea elliptibacea, (3) Litsea japonica, (4) Litsea glutinosa, (5) Litsea glaucescens, (6) Litsea guatemalensis, (7) Litsea lancifolia, (8) Litsea liyuyingi and (9) Litsea monopetala. Six of the species, 1, 3, 4, 7, 8 and 9, demonstrated peripheral antinociceptive properties as they inhibited acetic-acid-induced writhing in animal models. Species 1, 3, 4, 8 and 9 further showed effects via the central analgesic route at the spinal level by increasing the latencies of heat stimulated-nocifensive responses in the tail flick assay. The hot plate assay also revealed the efficacies of 4 and 9 at the supraspinal level. Species 6 was reported to ameliorate hyperalgesia induced via partial sciatic nerve ligation (PSNL). The antinociceptive effects of 1 and 3 were attributed to the regulatory effects of their bioactive compounds on inflammatory mediators. As for 2 and 5, their analgesic effect may be a result of their activity with the 5-hydroxytryptamine 1A receptor (5-HT1AR) which disrupted the pain-stimulating actions of 5-HT. Antinociceptive activities were documented for various major compounds of the Litsea plants. Overall, the findings suggested Litsea species as good sources of antinociceptive compounds that can be further developed to complement or substitute prescription drugs for pain management. [ABSTRACT FROM AUTHOR]

Introduction: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1β, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. Methods: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. Results: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-β, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-β injection; (3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-β; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. Conclusion: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-β. [ABSTRACT FROM AUTHOR]

Background and Purpose: Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR‐1 and CEMR‐2 behaved as potent μ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR‐1 and CEMR‐2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid‐like side effects were also determined. Experimental Approach: The spinal antinociceptive effects of CEMR‐1 and CEMR‐2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury‐induced neuropathic pain, complete Freund's adjuvant‐induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. Key Results: Spinal administration of CEMR‐1 and CEMR‐2 produced potent and prolonged antinociceptive effects in acute pain. CEMR‐1 and CEMR‐2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR‐1 showed non‐tolerance‐forming analgesic properties, while CEMR‐2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. Conclusions and Implications: The present investigation demonstrated that CEMR‐1 and CEMR‐2 displayed potent and long‐lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR‐1 and CEMR‐2 might serve as promising analgesic compounds with minimal opioid‐like side effects. [ABSTRACT FROM AUTHOR]

In the last decade, a considerable number of studies have broadened our knowledge of the nociceptive mechanisms of pain, a global health problem in both humans and animals. The use of herbal compounds such as eugenol, menthol, thymol, and carvacrol as analgesic agents has accompanied the growing interest in this area, offering a possible solution for this complex problem. Here, we aimed to explore how these natural substances—at three different concentrations (2, 5 and 10 mg/L)—affect the pain responses in zebrafish (Danio rerio) larvae exposed to 0.05% acetic acid (AA) for 1 min. By analysing the activity of acetylcholinesterase (AChE), 5′-ectonucleotidase and NTPDases, as well as aversion and exploratory behaviours, it was observed that that although all substances were effective in counteracting the pain stimulus, the concentration range within which they do so might be very limited. Eugenol, despite its acknowledged properties in fish anaesthesia, failed to alleviate the pain stimulus at low concentrations. Contrastingly, menthol exhibited the most promising results at the lowest concentrations tested. Overall, it is concluded that menthol might be a good analgesic for this species, qualifying it as a substance of interest for prospective studies. [ABSTRACT FROM AUTHOR]

Habenaria aitchisonii Reichb was analyzed in this research, including its chemical composition and its in vitro antioxidant, anti-inflammatory, acute oral toxicity, and antinociceptive activity. The chloroform and ethyl acetate fractions were found to be the most powerful based on in vitro antioxidant, anti-inflammatory, and analgesic assays. The acute oral toxicity of the crude methanolic extract was determined before in vivo studies. The acetic acid and formalin tests were used to measure the antinociceptive effect, and the potential mechanisms involved in antinociception were explored. The carrageenan-induced paw edema test was used to examine the immediate anti-inflammatory effect, and many phlogistic agents were used to determine the specific mechanism. Furthermore, for ex vivo activities, the mice were sacrificed, the forebrain was isolated, and the antioxidant levels of glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS) and catalase (CAT) were estimated using a UV spectrophotometer. No toxicity was seen at oral dosages up to 3,000 mg/kg. The antinociceptive impact was much higher than the standard drug. Both the inflammatory and neurogenic phases of the formalin experiment revealed an analgesic effect in the chloroform and ethyl acetate fractions. In carrageenan anti-inflammatory assays, the chloroform fraction (Ha.Chf) was the most potent fraction. We further studied the GC-MS of crude plant extract and found a total of 18 compounds. In the anti-inflammatory mechanism, it was observed that the Ha.Chf inhibits the COX-2 as well as 5-LOX pathways. The results exhibited that this species is a good source of phytocomponents like germacrone, which can be employed as a sustainable and natural therapeutic agent, supporting its traditional use in folk medicine for inflammatory conditions and pain. [ABSTRACT FROM AUTHOR]

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use. [ABSTRACT FROM AUTHOR]

Background: Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice. Methods: Tat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxietylike behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex. Results: Tat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression. Conclusion: Findings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the efficacy and safety of SC methadone in four-toed hedgehogs. ANIMALS 9 to 12 healthy adult four-toed hedgehogs (7 to 9 males and 3 females). METHODS Hedgehogs underwent 3 randomized, blinded, placebo-controlled, complete crossover studies. Hind limb withdrawal latencies in response to an acute thermal noxious stimulus were measured to evaluate the antinociceptive efficacy of methadone. Single doses of SC methadone were evaluated at 0.5 and 1 mg/kg for dose-dependent effects. Additionally, methadone (1.5 mg/kg) was administered at different concentrations to assess the effect of injection volume on antinociceptive efficacy. Finally, the safety of multiple doses of methadone (1.5 mg/kg, SC, q 2 h, for 3 doses) was also evaluated. In addition to monitoring behavior during latency measurements, animals were assessed for overt sedation. Food intake, body weight, and running wheel activity were assessed daily for 6 days following methadone administration to evaluate for adverse effects. RESULTS Methadone at 1 and 1.5 mg/kg provided antinociception lasting < 2 hours, and injection volume had no significant effect on efficacy. Methadone at 0.5 mg/kg did not induce antinociception. Methadone produced transient abnormal behaviors in all hedgehogs, with more animals affected at the 1.5-mg/kg dose. Behaviors included periods of standing motionless, vocalization, chewing motions, and paw raising. Single- or multiple-dose administration of methadone had no significant effect on total food intake, body weight, or running wheel activity. CLINICAL RELEVANCE The results of this study provide additional information on providing analgesia to hedgehogs. Subcutaneous methadone (1 to 1.5 mg/kg) can be used for short-term antinociception in hedgehogs. [ABSTRACT FROM AUTHOR]

Rationale: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. Objectives: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. Results: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. Conclusions: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control. [ABSTRACT FROM AUTHOR]

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration. [ABSTRACT FROM AUTHOR]

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Abstract Aims Bone cancer produces severe pain that is treated with opioids, but serious side effects limit opioid utilization. There is therefore a need to develop effective and safe non‐opioid alternatives. The lipid mediator, Resolvin D1 (RvD1), could be a prospective candidate for cancer pain treatment. To assess RvD1 and other potential candidates, appropriate animal models that recapitulate clinical features must be used. Although several preclinical models of cancer pain have been developed, the influence of sex on the development of cancer pain and the effectiveness of RvD1 have not been studied. Results Using a mouse model of fibrosarcoma growth in and around the calcaneus bone, we demonstrated that the mechanical hyperalgesia in the tumor‐bearing hind paw develops independently of sex, except that it developed a little sooner in female mice. A single intravenous injection of RvD1 (0.001–10 μg/kg) decreased hyperalgesia in both sexes with similar potency (ED50 = 0.0015 μg/kg) and efficacy. Repeated daily administration of 10 μg/kg RvD1 prolonged the analgesic effect and completely abolished hyperalgesia. This was also independent of sex. Conclusion In this preclinical mouse model of bone cancer pain, the development of pain and the analgesic effectiveness of RvD1 are not influenced by sex.

Pekka Talke,1 Isabel Talke2 1Department of Anesthesia and Perioperative Medicine, University of California San Francisco, San Francisco, CA, USA; 2California Polytechnic State University, San Luis Obispo, CA, USACorrespondence: Pekka Talke, Email talkep@gmail.comBackground: Tetanic stimuli are used as standardized noxious inputs to investigate nociception. Previous studies have applied tetanic stimuli to various anatomical locations without validating that the resulting physiological responses were independent of the location where tetanic stimuli were applied. Our aim was to investigate the effects of three anatomical tetanic stimulus application sites on physiological variables reflecting autonomic nervous system responses as measured by photoplethysmography (PPG).Methods: Under general anesthesia, a five second, 100 hertz, 70 milliamp tetanic stimulus was applied to the ulnar nerve, medial side of the tibia, and thorax (T5 dermatome) (N=12). The effect of tetanic stimuli on PPG-derived variables (AC, DC, and ACDC) and pulse rate at each stimulus location was determined using repeated-measures analysis of variance (ANOVA) followed by Dunnett’s post hoc test. Maximum tetanic stimulus-induced changes in PPG-derived variables and pulse rates were compared among the three stimulus locations using ANOVA.Results: AC and ACDC values of PPG decreased, and the DC values of PPG increased in response to tetanic stimuli-induced vasoconstriction at each location (p< 0.001 for all). The maximum changes in the AC, ACDC, and DC values did not differ between locations (p=NS). There were no significant changes in pulse rate (p=NS).Conclusion: The results showed that tetanic stimulation at either of these three locations provides the same autonomic nervous system responses, as measured by PPG.Clinical Trial Registration: ClinicalTrials.gov; NCT03648853.Plain Language Summary: We studied how pain medications and anesthetics reduce pain in humans. The amount of pain experienced by a person can be assessed by administering a slightly uncomfortable test, such as a small electric shock to the skin. These tests are often performed before and after administering a person’s pain medication or anesthesia. It is not known if the test results change when an electric shock is applied to different areas of the body (eg, hand, leg, or chest). In this study, we applied small electric shocks to three areas of skin. We measured the participants’ responses to this test using a special medical equipment (pulse oximeter), which tells us how the body reacts to an uncomfortable stimulus. We found that the test results were the same regardless of the area where the electric shock was applied. This information will be useful for investigators studying pain and pain management.Keywords: tetanic stimulus, antinociception, pain, anatomical location, photoplethysmography

B-vitamins have been evaluated as a useful adjuvant therapy to treat pain. In spite of clinical and experimental evidence indicating the analgesic effect of B-vitamins, few studies have investigated their effect on aspects of the inflammatory pain response. In the present study, we investigated the analgesic effect of chronic application of B-complex vitamins (Neurobion) using an inflammatory experimental pain model in rats. Nociceptive behavioral responses were evaluated in male Wistar rats after plantar injection of formalin, comparing the treatment group (TG) with Neurobion pretreatment to the control group (CG) without the pretreatment. In addition, neuronal activity in the central pain pathway was evaluated using c-Fos immunohistochemical reactivity and NADPH-d histochemistry. A highly significant reduction of painful behaviors such as licking and flinching were observed in TG, especially during the secondary phase of the formalin test compared to CG. Results suggest that long-term pre-treatment using Neurobion can have a beneficial effect in reducing the chronic phase of pain. In addition, we observed a downregulation of c-Fos and NADPH-d in dorsal spinal neurons, suggesting that the antinociceptive effect induced by Neurobion could be due to a suppression of nociceptive transmission at the spinal level, particularly in the afferent regions of the dorsal spinal horn, which these neurons utilizing nitric oxide at least as one of their pain neurotransmitters.

This study investigated the use of frontal electroencephalography (EEG) to monitor varying levels of isoflurane anesthesia in dogs. The patient state index (PSI), burst suppression ratio (SR), and waveforms, were continuously recorded while mean arterial blood pressure (MBP), heart rate, responses to electric stimuli, and subjective anesthetic “depth” were assessed every 3 min. At deep anesthesia (2.5× MAC − 3.2%), the PSI (6.5 ± 10.8) and MBP (45.6 ± 16.4 mmHg) were the lowest, and SR was the highest (78.3 ± 24.0%). At 1× MAC (1.3%), the PSI and MBP increased significantly to 47.8 ± 12.6 and 99.8 ± 13.2, respectively, and SR decreased to 0.5 ± 2.5%. The EEG was predominantly isoelectric at 2×–2.5× MAC, indicating unconsciousness and unresponsiveness. As anesthesia lightened, waveforms transitioned to flatter and faster activity patterns with a response to noxious stimuli, suggesting regained consciousness. The PSI and MBP exhibited a stronger correlation (ρ = 0.8098, p = 0.001) than the relationship of PSI with heart rate (ρ = −0.2089, p = 0.249). Five of the six dogs experienced rough recovery, possibly due to high SR and low MBP. These findings suggest that EEG monitoring in dogs can be a valuable tool for the real-time tracking of brain states and can be used to guide the management of isoflurane anesthesia.

The strong ethnopharmacological utilization of Isodon rugosus Wall. Ex. Benth is evident in the treatment of several types of pain and inflammation, including toothache, earache, abdominal pain, gastric pain, and generalized body pain and inflammation. Based on this background, the antinociceptive effects of the crude extract, various fractions, and essential oil have been reported previously. In this research work, we isolate and characterize pure bioactive compounds from I. rugosus and evaluate possible mechanisms using various in vivo and in vitro models. The pure compounds were analyzed for analgesic and anti-inflammatory activities through various assays. The column chromatography of the chloroform fraction of I. rugosus led to the identification of two pure compounds, i.e., 1 and 2. Compound 1 demonstrated notable inhibition (62% writhing inhibition, 72.77% COX-2 inhibition, and 76.97% 5-LOX inhibition) and anti-inflammatory potential (>50% paw edema inhibition at various intervals). The possible mechanism involved in antinociception was considered primarily, a concept that has already been elucidated through the application of naloxone (an antagonist of opioid receptors). The involvement of adrenergic receptors was investigated using a hot plate model (an adrenergic receptor antagonist). The strong ethnomedicinal analgesic background of I. rugosus, supported by previous reports and current observations, leads to the conclusion that I. rugosus is a potential source of antinociceptive and anti-inflammatory bioactive compounds. It may be concluded from the results that the isolated analgesic compounds of I. rugosus may be a possible alternative remedy for pain and inflammation management with admirable efficacy and safety profiles. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance: In the past, Ethiopian traditional medicine employed the leaves of the native Commelina latifolia Hochst. ex C.B. Clarke plant to treat wounds, pain, and malaria. Aim of the study: The crude extract and solvent fractions of C. latifolia Hochst. ex C.B. Clarke leaves were examined in the present investigation to determine their ability to have an antiinflammatory effect and provide an antinociceptive effect in animal models. Materials and methods: The leaves of C. latifolia were extracted with 80% methanol, and the CL crude extract was further fractionated with chloroform, pure methanol, and distilled water. The carrageenan-induced paw edema model was used to test the extracts' ability to reduce inflammation. The hotplate model and the acetic acid-induced writhing test on rodents were used to test the extracts' potential antinociceptive effect to reduce pain. Results: Inflammation was decreased by 64.59% with CL crude extract (400 mg/kg); 56.34% (400 mg/kg) of methanol fraction, 64.59% of aqueous fraction (400 mg/kg), and 38.27% of chloroform fraction in the carrageenaninduced inflammatory model. All extracts demonstrated a considerable lengthening of the nociception reaction time in the hot plate test, with a maximum antinociceptive effect of 78.98% (crude extract) and 71.65% (solvent fractions). At a dosage of 400 mg/kg, the natural C. latifolia crude extract and aqueous fraction demonstrated considerable antinociceptive effects against acetylsalicylic acid (ASA) during the writhing test (48.83% and 45.37than%, respectively). The current findings support Ethiopia's traditional user's assertions that the herb can alleviate inflammation and pain. [ABSTRACT FROM AUTHOR]

Habenaria aitchisonii Reichb was analyzed in this research, including its chemical composition and its in vitro antioxidant, anti-inflammatory, acute oral toxicity, and antinociceptive activity. The chloroform and ethyl acetate fractions were found to be the most powerful based on in vitro antioxidant, anti-inflammatory, and analgesic assays. The acute oral toxicity of the crude methanolic extract was determined before in vivo studies. The acetic acid and formalin tests were used to measure the antinociceptive effect, and the potential mechanisms involved in antinociception were explored. The carrageenan-induced paw edema test was used to examine the immediate anti-inflammatory effect, and many phlogistic agents were used to determine the specific mechanism. Furthermore, for ex vivo activities, the mice were sacrificed, the forebrain was isolated, and the antioxidant levels of glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS) and catalase (CAT) were estimated using a UV spectrophotometer. No toxicity was seen at oral dosages up to 3,000 mg/kg. The antinociceptive impact was much higher than the standard drug. Both the inflammatory and neurogenic phases of the formalin experiment revealed an analgesic effect in the chloroform and ethyl acetate fractions. In carrageenan anti-inflammatory assays, the chloroform fraction (Ha.Chf) was the most potent fraction. We further studied the GC-MS of crude plant extract and found a total of 18 compounds. In the anti-inflammatory mechanism, it was observed that the Ha.Chf inhibits the COX-2 as well as 5-LOX pathways. The results exhibited that this species is a good source of phytocomponents like germacrone, which can be employed as a sustainable and natural therapeutic agent, supporting its traditional use in folk medicine for inflammatory conditions and pain.

Bromelain, the main protease enzyme found in the pineapple plant (Ananas comosus), has had its antinociceptive effect previously demonstrated. This investigation aimed to appraise the role of TRP (Transient Receptor Potential) channels in the nociception-relieving effects of bromelain in the orofacial region of adult zebrafish. The animals were pretreated with bromelain (3.0, 10.0 or 30.0 mg/mL; gavage) and submitted to open field and acute orofacial (capsaicin - TRPV1 agonist, cinnamaldehyde - TRPA1 agonist or menthol - TRPM8 agonist) nociception tests. The investigation also explored the contribution of central afferent C-fibers. Naive groups were included for comparison. Bromelain did not independently affect the zebrafish movement patterns. However, bromelain decreased the nociceptive responses elicited by all three TRP channel activators. Capsazepine (TRPV1 inhibitor) and AMTB (TRPM8 inhibitor), but not HC-030031 (TRPA1 inhibitor), prevented the antinociceptive effect of bromelain. Moreover, capsaicin-induced desensitization effectively nullified the antinociceptive effect of bromelain. Collectively, these findings corroborate the therapeutic relevance of bromelain as a suppressor of orofacial nociception, which seems to be intricately connected to the modulation of TRP channels.

The rewarding effect of opiates is mediated through dissociable neural systems in drug naïve and drug-dependent states. Neuroadaptations associated with chronic drug use are similar to those produced by chronic pain, suggesting that opiate reward could also involve distinct mechanisms in chronic pain and pain-naïve states. We tested this hypothesis by examining the effect of dopamine (DA) antagonism on morphine reward in a rat model of neuropathic pain.Neuropathic pain was induced in male Sprague-Dawley rats through chronic constriction (CCI) of the sciatic nerve; reward was assessed in the conditioned place preference (CPP) paradigm in separate groups at early (4-8 days post-surgery) and late (11-15 days post-surgery) phases of neuropathic pain. Minimal effective doses of morphine that produced a CPP in early and late phases of neuropathic pain were 6 mg/kg and 2 mg/kg respectively. The DA D1 receptor antagonist, SCH23390, blocked a morphine CPP in sham, but not CCI, rats at a higher dose (0.5 mg/kg), but had no effect at a lower dose (0.1 mg/kg). The DA D2 receptor antagonist, eticlopride (0.1 and 0.5 mg/kg), had no effect on a morphine CPP in sham or CCI rats, either in early or late phases of neuropathic pain. In the CPP paradigm, morphine reward involves DA D1 mechanisms in pain-naïve but not chronic pain states. This could reflect increased sensitivity to drug effects in pain versus no pain conditions and/or differential mediation of opiate reward in these two states.

Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil (Iridaceae) is a popularly known species with primarily ornamental economic interest. It has traditional uses as purgative, in conditions related to the menstrual cycle, for blood purification, as wound healing, and as anti-inflammatory. The anti-inflammatory and antinociceptive activities of the decoction from its aerial stems, corms, and stamens are described here with dereplication studies on LC-MS/MS supported by the GNPS platform, where phenolic compounds were annotated and correlated with its biological activity. The decoction was evaluated in chemical (formalin and capsaicin) and thermal (hot plate) induced nociception or carrageenan-induced inflammation in mice. Decoction (at 10, 30, or 100 mg/kg doses) significantly reduced formalin- or capsaicin-induced nociception. All doses also demonstrated an antinociceptive effect in the hot plate model increasing the time the animal spent in responding to thermal signal. Naloxone partially reversed the antinociceptive effect. An anti-inflammatory effect was observed since a reduction in cell migration, protein extravasation interleukin-1, and tumor necrosis factor production induced by carrageenan in the subcutaneous air pouch was quantified. Metabolomic analyses showed a predominance of phenolic substances, mainly flavonoids and chlorogenic acids. The literature showed that these two groups have significant anti-inflammatory and analgesic activity, and chemical data corroborate the pharmacological results observed.

The opioid epidemic was triggered by an overprescription of opioid analgesics. In the treatment of chronic pain, repeated opioid administrations are required which ultimately lead to tolerance, physical dependence, and addiction. A possible way to overcome this conundrum consists of a co-medication that maintains the analgesic benefits of opioids while preventing their adverse liabilities. YHS, the extract of the plant Corydalis yanhusuo, has been used as analgesic in traditional Chinese medicine for centuries. More recently, it has been shown to promote analgesia in animal models of acute, inflammatory, and neuropathic pain. It acts, at least in part, by inhibiting the dopamine D2 receptor, suggesting that it may be advantageous to manage addiction. We first show that, in animals, YHS can increase the efficacy of morphine antinociceptive and, as such, decrease the need of the opioid. We then show that YHS, when coadministered with morphine, inhibits morphine tolerance, dependence, and addiction. Finally, we show that, in animals treated for several days with morphine, YHS can reverse morphine dependence and addiction. Together, these data indicate that YHS may be useful as a co-medication in morphine therapies to limit adverse morphine effects. Because YHS is readily available and safe, it may have an immediate positive impact to curb the opioid epidemic.

The strong ethnopharmacological utilization of Isodon rugosus Wall. Ex. Benth is evident in the treatment of several types of pain and inflammation, including toothache, earache, abdominal pain, gastric pain, and generalized body pain and inflammation. Based on this background, the antinociceptive effects of the crude extract, various fractions, and essential oil have been reported previously. In this research work, we isolate and characterize pure bioactive compounds from I. rugosus and evaluate possible mechanisms using various in vivo and in vitro models. The pure compounds were analyzed for analgesic and anti-inflammatory activities through various assays. The column chromatography of the chloroform fraction of I. rugosus led to the identification of two pure compounds, i.e., 1 and 2. Compound 1 demonstrated notable inhibition (62% writhing inhibition, 72.77% COX-2 inhibition, and 76.97% 5-LOX inhibition) and anti-inflammatory potential (>50% paw edema inhibition at various intervals). The possible mechanism involved in antinociception was considered primarily, a concept that has already been elucidated through the application of naloxone (an antagonist of opioid receptors). The involvement of adrenergic receptors was investigated using a hot plate model (an adrenergic receptor antagonist). The strong ethnomedicinal analgesic background of I. rugosus, supported by previous reports and current observations, leads to the conclusion that I. rugosus is a potential source of antinociceptive and anti-inflammatory bioactive compounds. It may be concluded from the results that the isolated analgesic compounds of I. rugosus may be a possible alternative remedy for pain and inflammation management with admirable efficacy and safety profiles.

Ethnopharmacological relevance: In the past, Ethiopian traditional medicine employed the leaves of the native Commelina latifolia Hochst. ex C.B. Clarke plant to treat wounds, pain, and malaria.Aim of the study: The crude extract and solvent fractions of C. latifolia Hochst. ex C.B. Clarke leaves were examined in the present investigation to determine their ability to have an antiinflammatory effect and provide an antinociceptive effect in animal models.Materials and methods: The leaves of C. latifolia were extracted with 80% methanol, and the CL crude extract was further fractionated with chloroform, pure methanol, and distilled water. The carrageenan-induced paw edema model was used to test the extracts’ ability to reduce inflammation. The hotplate model and the acetic acid-induced writhing test on rodents were used to test the extracts’ potential antinociceptive effect to reduce pain.Results: Inflammation was decreased by 64.59% with CL crude extract (400 mg/kg); 56.34% (400 mg/kg) of methanol fraction, 64.59% of aqueous fraction (400 mg/kg), and 38.27% of chloroform fraction in the carrageenan-induced inflammatory model. All extracts demonstrated a considerable lengthening of the nociception reaction time in the hot plate test, with a maximum antinociceptive effect of 78.98% (crude extract) and 71.65% (solvent fractions). At a dosage of 400 mg/kg, the natural C. latifolia crude extract and aqueous fraction demonstrated considerable antinociceptive effects against acetylsalicylic acid (ASA) during the writhing test (48.83% and 45.37than%, respectively). The current findings support Ethiopia’s traditional user’s assertions that the herb can alleviate inflammation and pain.

Osteoarthritis (OA) is a pathology that is characterized by progressive erosion of articular cartilage. In this context, medicinal plants have become relevant tools regarding their potential role in the prevention and treatment of OA, being safe and effective. The aim of this work was investigate the therapeutic efficacy of the ethyl acetate fraction of Bixa orellana leaves (BoEA) and ellagic acid (ElAc) for the therapeutic treatment of OA induced by monosodium iodoacetate (MIA) in rats. The plant material was extracted via maceration with 70 % hydroalcoholic solvent (BoHE). The ethyl acetate (BoEA) fraction was by solvents in increasing order of polarity. The ElAc was identified and isolated in BoEA using high performance liquid chromatography (HPLC-DAD) and analytical curve. The OA was induced using MIA in the right knee at the knee joint. Doses of BoEA and ElAc were administered daily (every 24 h, orally) at concentrations of 50, 100 and 50 mg/kg, respectively, for 28 days after induced OA. We evaluated the animals through clinical and radiological examinations every 7 days and, on the 29th day, the animals were euthanized, the joints being removed for histopathological analysis and the serum for cytokine analysis. BoEA and ElAc compounds reduced inflammation and nociception in OA and were as effective as indomethacin in clinical parameters of joint discomfort and allodynia in rats, in addition to showing improvements in radiological and histopathological images, acting on the progress of cartilage deterioration, proving properties related to anti-inflammatory and analgesic processes, being important allies for new therapeutic interventions for the treatment of OA.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics. [ABSTRACT FROM AUTHOR]

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves. [ABSTRACT FROM AUTHOR]

Introduction: Nephelium lappaceum L. (Sapindaceae) is a plant known as rambutan. It is used for various purposes in traditional medicine. Objective: We aimed to evaluate the antinociceptive effects of the ethanol extract of the fruit peel of N. lappaceum (EENL), the mechanisms involved in these effects, and the acute toxicity in zebrafish. Methods: We performed chromatography coupled to mass spectrometry, acute toxicity assay in zebrafish, and evaluation in mice submitted to models of nociception and locomotor activity. Results: We identified (epi)-catechin, procyanidin B, and ellagic acid and its derivatives in EENL. We did not find any toxicity in zebrafish embryos incubated with EENL. The locomotor activity of mice submitted to oral pretreatment with EENL was not changed, but it reduced the abdominal constrictions induced by acetic acid, the licking/biting time in both the first and second phase of formalin testing and capsaicin testing, and carrageenan-induced paw mechanical allodynia. Oral pretreatment with EENL increased latency time in the hot plate test. This antinociceptive effect was significantly reversed by naloxone, L-arginine, and glibenclamide respectively showing the participation of opioid receptors, nitric oxide, and KATP channels as mediators of EENL-induced antinociception. Conclusion: EENL causes antinociception with the participation of opioid receptors, nitric oxide, and KATP channels, and is not toxic to zebrafish. [ABSTRACT FROM AUTHOR]

Aqueous and ethanolic extracts of red pitaya (Hylocereus polyrhizus) peel, pulp, and seeds were evaluated for their chemical composition by UPLC-Q-TOF-MSE, antioxidant capacity (DPPH and ABTS assays), cytotoxicity and in vitro antiproliferative effect (MTT assay), antinociceptive activity and in vivo toxicity (Zebrafish model). A total of 25 compounds were identified in the extracts, mostly betacyanins, phenolic acids, flavonoids, and organic acids. The seeds extracts displayed both the highest radical scavenging activity and total phenol content. The pulp aqueous extract and ethanolic extracts exhibited some cytotoxicity against Vero cells, depending on the concentration and exposure time. These extracts were also able to inhibit S-180 cells proliferation, however only the peel ethanolic extract showed moderate to high selective indexes (SI: 4.06, 18.63), suggesting that its antiproliferative effect is not associated with the cytotoxic effect towards non-cancer cells, such as Vero cells. Regarding the antinociceptive activity, after adjusting the dose to exclude the sedation effect, the seeds ethanolic extract displayed antinociceptive activity at the inflammatory phase, similar to morphine. The extracts (1.0, 2.5 or 5.0 mg/mL) showed to be safe for zebrafish. In summary, these findings highlight the red pitaya as a promising natural source of bioactive, both in its edible and inedible parts, which can be better probed, for instance as anticancer and antinociceptive agents. In addition, the regular consumption of red pitaya can contribute to the health promotion, and the prevention of chronic diseases. [Display omitted] • Twenty-five compounds were identified in aqueous and ethanolic extracts from red pitaya (Hylocereus polyrhizus) using UPLC-Q-TOF/MS system. • The peel ethanolic extract showed moderate to high selectivity for cancer cells (S-180), while the pulp, and seeds ethanolic extracts possibly acted as cytotoxic or cytostatic, or even both, as they showed low selectivity over the Vero cells and S-180 cells. • The seeds ethanolic extract attenuated the inflammatory response in zebrafish, which correspond the second phase of formalin-induced nociceptive behavior. • Red pitaya pulp, peel, and seeds showed no toxicity against zebrafish. [ABSTRACT FROM AUTHOR]

Cleomin, a 1,3-oxazolidine-2-thione, was recently isolated from Neocalyptrocalyx longifolium, a species traditionally used for treating painful conditions. Reports about the pharmacological activities of cleomin are lacking. Here, the antinociceptive effects of cleomin were investigated using mice models of pain, namely the formalin, the cold plate, and the tail flick tests. Motor integrity was assessed in the rota-rod test. Antagonism assays and in silico docking analyses were performed to investigate the putative mechanisms of action. Cleomin (12.5–25 mg/kg), at doses that did not induce motor impairment, induced dose-dependent antinociception in both early and late phases of the formalin test and reduced nociceptive behaviors in both the cold plate and tail flick tests. Pretreatments with phaclofen and atropine attenuated the antinociceptive effects of cleomin, implicating the involvement of GABAB and muscarinic receptors. In silico docking studies suggested satisfactory coupling between cleomin and GABAB and M2 receptors, hence corroborating their role in cleomin's activity. Pretreatments with naloxone, yohimbine, bicuculline, and methysergide did not affect the antinociception of cleomin. In silico pharmacokinetics prediction showed a good drug ability profile of cleomin. In conclusion, cleomin promoted antinociception mediated by GABAB and muscarinic receptors. These findings support further investigation of the analgesic potential of cleomin. [ABSTRACT FROM AUTHOR]

Simple Summary: The coadministration of ketamine and propofol (ketofol) via constant rate infusion (CRI) was studied as a total intravenous anesthetic in dogs. The study found that ketofol induced a biphasic EEG pattern. Subanesthetic doses during induction and recovery led to high beta EEG activity, reflecting increased brain activity. During maintenance with anesthetic doses, the EEG shifted to low beta activity, merging ketamine and propofol EEG characteristics. Ketofol CRI provided robust antinociception activity and maintained a stable heart rate and blood pressure. Subanesthetic ketofol doses caused behavioral excitement, including nystagmus, tongue flicking, salivation and muscle activity. However, these effects were temporary and not a major concern. Such excitement was absent during high-dose general anesthesia. In summary, ketofol CRI showed promise as a safe and effective total intravenous anesthetic combination for dogs. It featured distinct biphasic EEG patterns, stable cardiovascular function and potent antinociception. The effects of concurrent ketamine and propofol (ketofol) constant rate infusion (CRI) were examined in six dogs. The K:P ratio was 1:2, with an initial CRI of 0.25/0.5 mg/kg/min over ten minutes, followed by a 0.5 mg/kg ketamine bolus for induction. During induction, a comprehensive EEG frequency spectrum from delta to gamma was observed, accompanied by subanesthetic-dose ketofol-induced behavioral excitation, including nystagmus, tongue flicking, salivation and active muscle activity. The dogs were maintained on three 15 min decremental doses of ketofol CRI (0.8/1.6, 0.4/0.8 and 0.2/0.4 mg/kg/min). This phase featured a significant decrease in the Patient State Index, electromyographic activity and a shift to low beta waves (SEF95: 13–18 Hz). Additionally, profound antinociception to electric stimulation and a stable heart rate and blood pressure (MBP 81.5–110 mmHg) were observed, as well as a merging of ketamine and propofol EEG characteristics during maintenance. In the recovery phase, a return to beta and gamma EEG patterns and excitement behavior occurred, accompanied by a significant reduction in antinociception, highlighting features of low doses of ketofol. This study reveals biphasic EEG dynamic changes, associated behaviors and robust antinociception and cardiovascular function, suggesting the utility of ketofol as a total intravenous anesthetic combination in dogs. [ABSTRACT FROM AUTHOR]

Background: Morphine is the prototypical μ‐opioid receptor agonist used to provide analgesia in veterinary species. Its effects are well‐described in horses but not donkeys. Objectives: To determine the antinociceptive effects of two doses of morphine in donkeys. To describe preliminary pharmacokinetic parameters of morphine in donkeys. Study design: In vivo experiment. Methods: Eight adult castrated male donkeys were given intravenous (IV) 0.9% saline, morphine 0.1 mg/kg bwt (LDM), or morphine 0.5 mg/kg bwt (HDM) in a randomised order with a minimum 1‐week washout period. Mechanical nociceptive thresholds (MNTs) were determined by a blinded investigator pre‐injection and 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min post‐injection. Venous blood samples were collected pre‐injection and 2, 5, 10, 15, 30, 45, 60, 90, and 120 min post‐injection. Data were analysed using Friedman's test with Dunn's post hoc test for multiple comparisons. Pharmacokinetic parameters were calculated for the HDM treatment. Results: Baseline MNT was [median (interquartile range)] 8.9 (7.1–10.3) N and did not differ between treatments. Peak MNTs occurred at 60 min for both LDM (16.2 N) and HDM (25.0 N) treatments. MNTs after HDM treatment were higher than saline (p < 0.04) at 15, 60, 90, 120, 150, 180, 240, and 300 min post‐injection. MNTs after LDM treatment were higher than baseline (p < 0.05) at 45 and 60 min post‐injection. Terminal half‐life for HDM was (mean ± SD) 51.0 ± 10.7 min, the volume of distribution at steady‐state 2.07 ± 0.33 L/min and clearance 49.2 ± 4.16 ml * min/kg using noncompartmental analysis. The concentration of morphine‐3‐glucuronide (M3G) was higher than morphine‐6‐glucuronide (M6G) at all sampled time points. Main limitations: Short duration of plasma sampling for pharmacokinetic analysis; lack of objective measure of gastrointestinal function. Conclusions: The HDM treatment provided mechanical antinociception in donkeys with no significant adverse effects. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate antinociceptive efficacy of SC administration of hydromorphone hydrochloride and buprenorphine hydrochloride in ferrets (Mustela putorius furo). ANIMALS: 14 healthy adult ferrets (6 neutered males, 8 spayed females). METHODS: In a randomized, blind, controlled, complete crossover design, all 14 ferrets received a single, SC injection of hydromorphone low dose (0.1 mg/kg), hydromorphone high dose (0.2 mg/kg), buprenorphine low dose (0.02 mg/kg), buprenorphine high dose (0.04 mg/kg), or saline solution (0.2 mL/kg). Sedation and forelimb withdrawal latency from a noxious thermal stimulation were evaluated, and behavior was recorded for a total of 8 hours postinjection. RESULTS: Compared to saline, administration of hydromorphone at 0.2 mg/kg resulted in an estimated increase of withdrawal latencies of 7.4 seconds (95% CI, 3.2 to 11.6) at 60 minutes, of 6.6 seconds (2.4 to 10.8) at 90 minutes, of 6.0 seconds (1.8 to 10.2) at 120 minutes, of 7.0 seconds (2.9 to 11.1) at 180 minutes, and of 4.5 seconds (0.5 to 8.6) at 240 minutes. These differences were statistically significant. Hydromorphone administered at a lower dose and buprenorphine at either dose did not increase withdrawal latencies compared to saline. Based on the sedation score used in this study, signs of sedation increased over time in a similar fashion with all treatments, including saline. Erratic dysphoric-like behaviors occurred in all groups except for saline. CLINICAL RELEVANCE: SC administration of hydromorphone at a dose of 0.2 mg/kg provided antinociception from 1 to 4 hours postinjection. Further validation of sedation scores in ferrets is warranted. [ABSTRACT FROM AUTHOR]

Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study aimed to reveal a detailed picture of the antinociceptive mechanisms and behavioral effects of V1 and its recently synthesized phosphopeptide analog V2p in rodents using a range of methods. The studied peptides significantly reduced acute (mean V1–9.0, V2p–5.8 vs. controls–54.1 s) and inflammatory (mean V1–57.9 and V2p–53.3 vs. controls–107.6 s) nociceptive pain in the formalin test, as well as carrageenan-induced hyperalgesia (mean V1–184.7 and V2p–107.3 vs. controls–61.8 g) in the paw pressure test. These effects are mediated by activation of opioid receptors with a predominance of kappa in V1 antinociception and by delta, kappa, and mu receptors in V2p-induced antinociception. Both peptides did not change the levels of TNF-alpha and IL-1-beta in blood serum. V1 induces depression-like behavior, and V2p shows a tendency toward anxiolysis and short-term impairment of motor coordination without affecting exploratory behavior. The results characterize valorphin and its derivative as promising analgesics that exert their effects both centrally and peripherally, without causing severe behavioral changes in experimental animals. These encouraging data are a foundation for future studies focusing on the effects of hemorphins after long-term treatment. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain is one of the complications that affect a wide variety of the diabetic population and is often difficult to treat. Only a small number of patients experience pain relief, which usually comes with onerous side effects and low levels of satisfaction. The search for new analgesic drugs is necessary, given the limitations that current drugs present. Combining drugs to treat neuropathic pain has been attracting interest to improve their efficacy compared to single-drug monotherapies while also reducing dose sizes to minimize side effects. The aim of our study was to verify the antinociceptive effect of a synthetic peptide, PnPP-15, alone and combined with pregabalin, in male Swiss diabetic mice using the von Frey method. PnPP-15 is a synthetic peptide derived from PnPP19, a peptide representing a discontinuous epitope of the primary structure of the toxin PnTx2-6 from the venom of the spider Phoneutria nigriventer. The antinociceptive activity of both compounds was dose-dependent and showed synergism, which was verified by isobolographic analysis. Treatment with PnPP-15 did not cause spontaneous or forced motor changes and did not cause any damage or signs of toxicity in the analyzed organs (pancreas, lung, heart, kidney, brain, or liver). In conclusion, PnPP-15 is a great candidate for an analgesic drug against neuropathic pain caused by diabetes and exerts a synergistic effect when combined with pregabalin, allowing for even more efficient treatment. [ABSTRACT FROM AUTHOR]

Objective: The antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR), as well as gabapentin (GBP), was investigated to obtain synergistic antinociception at doses where side effects were minimal. In addition, the possible antinociceptive mechanism of PEA + MOR or PEA + GBP combinations was explored. Methods: Individual dose-response curves (DRCs) of PEA, MOR and GBP were evaluated in female mice in which intraplantar nociception was induced with 2% formalin. Isobolographic method was used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP. Key findings: The ED50 was calculated from the DRC; the order of potency was MOR > PEA > GBP. The isobolographic analysis was obtained at a 1:1 ratio to determine the pharmacological interaction. The experimental values of flinching (PEA + MOR, Zexp = 2.72 ± 0.2 μg/paw and PEA + GBP Zexp = 2.77 ± 0.19 μg/paw) were significantly lower than those calculated theoretically (PEA + MOR Zadd = 7.78 ± 1.07 and PEA + GBP Zadd = 24.05 ± 1.91 μg/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions. Conclusions: These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPARα and opioid receptor mechanisms. Furthermore, the results suggest that combinations containing PEA with MOR or GBP could be of interest in aiding the treatment of inflammatory pain. [ABSTRACT FROM AUTHOR]

Purpose: Inflammation of various degrees is common among humans. There are associated side effects with orthodox delivery systems and anti-inflammatory agents; hence, the study investigated the characteristics of herbal lipospheres and the anti-inflammatory potency of the lipospheres formulated from Pentaclethra macrophylla with the view to having a drug with a better delivery system and lesser side effects. Methods: Herbal lipospheres were formulated using solidified reverse micellar solutions (SRMS) of P90H and goat fat and characterized for particle size and morphology, pH time dependent analysis, encapsulation efficiency (EE%), and Fourier Transform infrared spectroscopy. The in vitro antinociceptive and anti-inflammatory studies were carried out using membrane stabilization by hypotonicity-induced hemolysis and the determination of anti-platelet aggregatory activity models. The in vivo antinociceptive and anti-inflammatory studies on egg albumin- and formaldehyde-induced arthritis models were conducted. A total white blood cell count and differential blood count were carried out on the rats. Results: The results showed that there was no change in pH for the PM-unloaded lipospheres and 2.5 g of PM-loaded lipospheres from day 1 to day 7, but there was a mild variation in the rest of the formulations. The EE ranged from 35.2% to 94%, increasing according to the drug concentration. The photomicrographs of the lipospheres showed that the particles were spherical in shape. The particle sizes were within the acceptable range for lipospheres. FTIR showed no interaction. In the arthritis study, PM-loaded lipospheres inhibited edema consistently throughout the duration of observation. Inhibition of the membrane increased steadily with an increase in concentration of PM in the lipospheres and the standard drug. The platelet aggregatory inhibition decreased steadily with an increase in concentration of the PM in the lipospheres as well as the standard. The T50 dose of PM had the highest percentage of WBC, and it decreased as the treatment doses increased from T100 to T200. There were no significant differences among the Neutrophil counts of the different groups. Conclusions: The study, therefore, showed that the methanol extract of Pentaclethra macrophylla formed efficient herbal lipospheres with antinociceptive and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Pain is complex and is a unique experience for individuals in that no two people will have exactly the same physiological and emotional response to the same noxious stimulus or injury. Pain is composed of two essential processes: a sensory component that allows for discrimination of the intensity and location of a painful stimulus and an emotional component that underlies the affective, motivational, unpleasant, and aversive response to a painful stimulus. Kappa opioid receptor (KOR) activation in the periphery and throughout the neuroaxis modulates both of these components of the pain experience. In this chapter we focus on recent findings that KORs contribute to the emotional, aversive nature of chronic pain, including how expression in the limbic circuitry contributes to anhedonic states and components of opioid misuse disorder. While the primary focus is on preclinical pain models, we also highlight clinical or human research where there is strong evidence for KOR involvement in negative affective states associated with chronic pain and opioid misuse.

Various plant species from the Litsea genus have been claimed to be beneficial for pain relief. The PRISMA approach was adopted to identify studies that reported analgesic properties of plants from the Litsea genus. Out of 450 records returned, 19 primary studies revealed the analgesic potential of nine Litsea species including (1) Litsea cubeba, (2) Litsea elliptibacea, (3) Litsea japonica, (4) Litsea glutinosa, (5) Litsea glaucescens, (6) Litsea guatemalensis, (7) Litsea lancifolia, (8) Litsea liyuyingi and (9) Litsea monopetala. Six of the species, 1, 3, 4, 7, 8 and 9, demonstrated peripheral antinociceptive properties as they inhibited acetic-acid-induced writhing in animal models. Species 1, 3, 4, 8 and 9 further showed effects via the central analgesic route at the spinal level by increasing the latencies of heat stimulated-nocifensive responses in the tail flick assay. The hot plate assay also revealed the efficacies of 4 and 9 at the supraspinal level. Species 6 was reported to ameliorate hyperalgesia induced via partial sciatic nerve ligation (PSNL). The antinociceptive effects of 1 and 3 were attributed to the regulatory effects of their bioactive compounds on inflammatory mediators. As for 2 and 5, their analgesic effect may be a result of their activity with the 5-hydroxytryptamine 1A receptor (5-HT1AR) which disrupted the pain-stimulating actions of 5-HT. Antinociceptive activities were documented for various major compounds of the Litsea plants. Overall, the findings suggested Litsea species as good sources of antinociceptive compounds that can be further developed to complement or substitute prescription drugs for pain management.

In the last decade, a considerable number of studies have broadened our knowledge of the nociceptive mechanisms of pain, a global health problem in both humans and animals. The use of herbal compounds such as eugenol, menthol, thymol, and carvacrol as analgesic agents has accompanied the growing interest in this area, offering a possible solution for this complex problem. Here, we aimed to explore how these natural substances—at three different concentrations (2, 5 and 10 mg/L)—affect the pain responses in zebrafish (Danio rerio) larvae exposed to 0.05% acetic acid (AA) for 1 min. By analysing the activity of acetylcholinesterase (AChE), 5′-ectonucleotidase and NTPDases, as well as aversion and exploratory behaviours, it was observed that that although all substances were effective in counteracting the pain stimulus, the concentration range within which they do so might be very limited. Eugenol, despite its acknowledged properties in fish anaesthesia, failed to alleviate the pain stimulus at low concentrations. Contrastingly, menthol exhibited the most promising results at the lowest concentrations tested. Overall, it is concluded that menthol might be a good analgesic for this species, qualifying it as a substance of interest for prospective studies.