Effects Of Morphine Research Articles

Can erector spinae plane block replace intrathecal morphine in cesarean section? A prospective randomized controlled study on opioid consumption.

After cesarean, optimal analgesia is important for early mobilization, mitigating thromboembolic risks, and mother-infant communication. Our study aims to compare the postoperative analgesic effects of intrathecal morphine (ITM) and Erector Spinae Plane Block (ESPB) in elective cesarean section under spinal anesthesia. 82 patients were randomized into ESPB and ITM groups. Both groups received spinal anesthesia with 10mg of heavy bupivacaine. In the ITM group, intrathecal morphine (100mcg) was added. The ESPB group received bilateral T10 level ESPB with 20ml 0.25% bupivacaine postoperatively. Postoperative pain control included intravenous paracetamol 4x1gr, intravenous patient-controlled analgesia with tramadol, and diclofenac 75mg for rescue analgesia when NRS > 4. NRS, tramadol consumption, and side effects were recorded 24 hours postoperatively. The primary outcome of this study is to compare 24-hour postoperative opioid consumption after cesarean sections. Secondary outcomes include postoperative pain scores, rescue analgesia needs, and potential side effects. NRS scores ≤ 4 at all time intervals and were comparable among groups. The total 24-hour tramadol consumption was significantly higher in ESPB group (median: 75; Q1,Q3[40,140]) compared to ITM (50 [27.5,60], P = 0.008). Tramadol consumption was similar among groups during 0-6 and 6-12 hours. In the 12-24 hours, it was significantly higher in ESPB group (22.5 [15,57.5]) compared to ITM (15 [12.5,25],P = 0.005). In ITM group, nausea and vomiting were observed in 3 patients, itching in 1 patient; no adverse effects were observed in ESPB group. Patients undergoing cesarean section under spinal anesthesia, intrathecal morphine reduced opioid consumption more effectively than ESPB. ESPB is not recommended as a primary analgesic option for cesarean sections.

The dual modulating effects of neuropeptide FF on morphine-induced analgesia at the spinal level.

Increasing evidence indicates that neuropeptide FF (NPFF) produces analgesic effects and augments opioid-induced analgesia at the spinal level. However, our recent research demonstrated that NPFF exerted complex opioid-modulating effects in an inflammatory pain model after intrathecal (i.t.) injection. Consistent with previous findings, we found that i.t. NPFF dose-dependently attenuated complete Freund's adjuvant-induced pain hypersensitivity. Interestingly, pharmacological results illustrated that NPFF exhibited opposite opioid-modulating effects at the spinal level depending on its administration dosage, wherein i.t. NPFF potentiated morphine-induced anti-allodynia at the dose of 10nmol, while attenuated morphine analgesia at an ultra-low-dose of 10pmol. Behavioral results obtained from neuropeptide FF receptor 2 (NPFFR2) knockout animals suggested that both pro- and anti-opioid effects of NPFF were mediated by NPFFR2. Moreover, these modulating effects of spinal NPFFR2 were selectively targeting mu-opioid receptor, had no effect on delta- and kappa-opioid receptor agonist-induced analgesia. Finally, the opioid-modulating effects of NPFF were further verified using in vitro calcium imaging assay, demonstrating that pretreated with NPFF in primary-cultured spinal neurons significantly attenuated the inhibitory effects of morphine on high-K+-induced neuronal excitability. Taken together, our results suggested that NPFF exhibited dual modulating effects on morphine-induced analgesia after i.t. administration, which provides a possible mechanism to explain the complex opioid-modulating effects of endogenous NPFF systems.

C3/C3aR Bridges Spinal Astrocyte‐Microglia Crosstalk and Accelerates Neuroinflammation in Morphine‐Tolerant Rats

ABSTRACTAimsCommunication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of glial cells and neuroinflammation in morphine tolerance (MT). This study investigated the influence of crosstalk between astrocyte and microglia on the evolution of morphine tolerance.MethodsSprague‐Dawley rats were intrathecally treated with morphine twice daily for 9 days to establish morphine‐tolerant rat model. Tail‐flick latency test was performed to identify the analgesic effect of morphine. The role of microglia, astrocyte and C3‐C3aR axis in morphine tolerance were elucidated by real‐time quantitative polymerase chain reaction, Western blot, and immunofluorescence.ResultsChronic morphine treatment notably promoted the activation of microglia, upregulated the production of proinflammatory mediators (interleukin‐1 alpha (IL‐1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q)). Simultaneously, it programed astrocytes to a pro‐inflammatory phenotype (A1), which mainly expresses complement 3 (C3) and serping1. PLX3397 (a colony‐stimulating factor 1 receptor (CSF1R) inhibitor), Compstain (a C3 inhibitor) and SB290157(a C3aR antagonist) could reverse the above pathological process and alleviate morphine tolerance to different extents.ConclusionOur findings identify C3‐C3aR axis as an amplifier of microglia‐astrocyte crosstalk, neuroinflammation and a node for therapeutic intervention in morphine tolerance.

The effects of low-dose morphine on sleep and breathlessness in COPD: A randomized trial.

Low-dose morphine may be prescribed to reduce chronic breathlessness in chronic obstructive pulmonary disease (COPD). Recent subjective findings suggest morphine may influence breathlessness through sleep-related mechanisms. However, concerns exist regarding opioid safety in COPD. The effects of morphine during sleep in COPD have not been objectively investigated. This study aimed to objectively determine the effects of low-dose morphine on sleep. What are the effects of low-dose morphine on sleep efficiency and other sleep parameters in COPD? Randomized, double-blind, crossover trial of 20mg/day sustained-release morphine for three days (steady-state) versus placebo in nineteen breathless people with COPD (n=7 female). The primary outcome was sleep efficiency during in-laboratory overnight polysomnography (PSG). Secondary and exploratory outcome measures included sleep-disordered breathing frequency/hr, oxygenation, transcutaneous carbon dioxide (TcCO2) levels, blood and physiology biomarkers, the relationship between sleep and breathlessness, external resistive load responses, and driving simulator performance. Physiology outcomes and pharmacokinetics were measured before and after each PSG. Sleep efficiency was similar between placebo and morphine (66±17 vs. 67±19%, p=0.89). Morphine did not change the frequency of sleep-disordered breathing events but reduced breathing frequency. Morphine reduced mean and nadir overnight oxygen saturation by [95%CI] 2 [-2.8 to -1.2] and 5 [-8 to -1]%, respectively. Mean TcCO2 was 3.3 [1.6 to 5.1]mmHg higher during sleep with morphine versus placebo. Eight participants (42%) met American Academy of Sleep Medicine criteria for nocturnal hypoventilation with morphine versus four (21%) on placebo, p=0.02. Morphine did not systematically reduce breathlessness or impair next day driving simulator performance. Adverse events (most frequently nausea) were increased with morphine. Steady-state, low-dose morphine does not change sleep efficiency, sleep-disordered breathing frequency, or next day alertness but may cause hypoventilation during sleep, a potentially harmful effect.

The Comparative Effect of Morphine on Proliferation of Cancer Cell Lines Originating from Different Organs: An In Vitro Study.

Background/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, pancreas, and pharynx. This poses the question of a potential pro-cancer effect of pharmaceutical opioid analgesics. In vitro studies employing a variety of experimental conditions suggest that opioid alkaloids have proliferative or antiproliferative effects. We set out to reconcile this discrepancy and explore the hypothesis that opioids promote cancer cell proliferation in an organ-dependent fashion. Methods: Using strictly controlled conditions, we tested the effect of morphine on the proliferation of a series of human cancer cell lines isolated from organs where cancer risk was linked causally to opium consumption in human studies (i.e., lung, bladder, and larynx), or control organs where no link between cancer risk and opium consumption has been reported in human studies (i.e., breast, colon, prostate). Results: Our results showed a minimal effect on proliferation on any cell line and no trend supporting an organ-specific effect of morphine. Conclusions: This argues against a direct effect of opioids on tumour cell proliferation to support their organ-specific effect.

Brain region-specific neural activation by low-dose opioid promotes social behavior.

The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region-specific neural activation induced by low-dose opioids for social behavior deficits in ASD.

The Influence of Pharmacogenetic Factors on the Pharmacokinetics of Morphine and Its Metabolites in Pediatric Patients: A Systematic Review.

Morphine is a potent analgesic used for treating surgical and cancer pain. Despite being the drug of choice for the management of severe pain in children, the high interindividual variability in morphine pharmacokinetics limits its clinical utility to effectively relieve pain without adverse effects. This review was conducted to identify and describe all studies that have assessed the effect of genetic factors on the pharmacokinetics of morphine and its main metabolites in children. Embase and Medline databases were used to conduct the literature search, and the systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Of the 188 articles screened and after the application of specific inclusion and exclusion criteria, the review identified 8 studies. These studies suggest that genetic variants of selected metabolic enzymes and transporters may play a role in the observed interindividual variability in morphine plasma concentrations. Variants of the genes SLC22A1 and ABCC3 had the most supporting evidence for genetic variants that influence morphine and morphine metabolites pharmacokinetics. Although the available evidence suggests a potential genetic contribution to the variability in morphine concentration, the heterogeneity of the included studies in terms of experimental design and small sample sizes in some studies makes it challenging to propose the use of genetic biomarkers to personalize morphine dosing. This underscores the need to conduct more comprehensive and large-scale pharmacokinetic-pharmacogenetic studies to determine how or if genetic testing can optimize morphine safety and effectiveness in children.

Comparison of awake respiratory control versus sleep obstructive sleep apnea endotypes.

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies, yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomized, crossover trial that investigated the effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing before overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study [pharyngeal critical closure pressure (Pcrit), muscle responsiveness via genioglossus intramuscular electromyography, and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions]. Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r = 0.726, P = 0.001), 2) arousal threshold correlated with awake CO2 ventilatory response threshold (r = -0.467, P = 0.047) and basal ventilation (r = -0.500, P = 0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (P < 0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine (r = -0.535, P = 0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes, such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.NEW & NOTEWORTHY Both awake ventilatory control measures and OSA endotypes measured during sleep have reported potentials in endotyping/phenotyping OSA, although no randomized, controlled trial has compared/linked between the two techniques. From a double-blind, randomized placebo-controlled crossover trial, we found that awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.

Hippocampal nicotinic acetylcholine receptor signaling mediates the anti-allodynic effect of ketamine and morphine on neuropathic pain

The present study investigated the involvement of hippocampal nicotinic acetylcholine receptors (nAChRs) in the anti-allodynic effect of ketamine/morphine on neuropathic pain in adult male Wistar rats. Morphine or ketamine administration decreased the percentage of maximum possible effect (MPE%), indicating an analgesic effect. The most significant decrease occurred with a 5 mg/kg dose of morphine (average MPE% = 98), while a 0.5 mg/kg dose of ketamine resulted in a high response (average MPE% = 91), using decision trees as a machine learning tool. Combining morphine and ketamine improved neuropathic pain (average MPE% = 91). Intra-CA1 microinjection of mecamylamine (2 μg/rat) with morphine (3 mg/kg) reduced neuropathic pain (average MPE% = 94). Co-administration of lower doses of ketamine (0.1 mg/kg, i.p.) and mecamylamine (0.5 or 1 μg/rat) with morphine (3 mg/kg) led to a considerable reduction in pain (average MPE% = 91). Utilizing the generalized least squares (GLS) model enabled the establishment of a continuous relation between drug dose and MPE% as the outcome of interest. There was a 19.60 higher average MPE% for each mg/kg increase in morphine dose. In contrast, there was a 17.05 higher average MPE% for every 0.1 mg/kg increase in ketamine dose. Each 0.1 mg/kg increase in ketamine dose, when combined with morphine (3 mg/kg), led to a 30.85 higher average MPE%. A tenfold impact of increasing mecamylamine dosage on MPE% was observed when paired with morphine. Thus, hippocampal nAChRs play a significant role in mediating the anti-allodynic effect of ketamine and morphine in neuropathic pain.

The interaction effects between opioidergic and D1-like dopamine receptors in the nucleus accumbens on pain-related behaviors in the animal model of acute pain

The opioidergic and dopaminergic systems play an essential role in processing pain information in the nucleus accumbens (NAc). The present work examined the hypothesis that interaction between opioidergic and D1-like dopamine receptors in the NAc area may influence acute pain-related behaviors. One hundred sixty adult male Wistar rats unilaterally received different doses of the drug solution or vehicle. First, separate groups of animals received different doses of morphine (5, 10, and 25 mmol/0.5 μL) and various doses of SKF38393 (1.5, 3, 6, and 12 mmol/0.5 μL) as opioid and D1-like receptor agonists in the NAc region, respectively. In the second set of experiments, animals got different amounts (1.5, 3, 6, and 12 mmol/0.5 μL) of SCH23390, a D1-like receptor antagonist, before an effective dose of morphine (10 mmol/0.5 μL). In the last experiment, the animals were given naloxone (1.5, 5, and 15 mmol/0.5 μL) before they were given an effective dose of SKF38393 (3 mmol/0.5 μL). The tail-flick test was then used to measure their acute pain threshold. The main findings showed that intra-NAc injection of morphine and SKF38393 alone causes antinociceptive responses. However, the intra-accumbal injection of SCH23390 significantly reduced the antinociceptive responses elicited by intra-NAc morphine. Additionally, intra-NAc naloxone significantly reduced the antinociceptive effects elicited by intra-NAc SKF38393. Interestingly, SCH23390 was more effective in reversing the analgesic effects of morphine (η2 = 0.61) than naloxone in reversing the analgesic effects of SKF38393 (η2 = 0.49). The findings suggest that the opioidergic and dopamine systems in the NAc collaborate to produce pain-relieving effects. This insight could potentially enhance the effectiveness of lower doses of opioids for pain management, ultimately reducing their usage in clinical settings in the future.

Effect of Raha syrup on the motivational effects of morphine and CSF serotonin levels in rats

Opiates may influence motivational processes by a dysregulation of brain reward pathways that play a role in context-induced reinstatement of drug seeking. Raha syrup as herbal bioactive compounds with anti-anxiety/depressant effects may be prevented morphine-induced reward and motivation effects. Therefore, the aim of this study was to investigate the effect of Raha syrup on the rewarding effects of morphine and motivational aspects of morphine-seeking behavior in morphine-induced conditioned place preference (CPP) model and also the cerebrospinal fluid (CSF) serotonin levels following the extinction and reinstatement in rats. In this study, adult male Wistar rats received Raha syrup via oral gavage to assess of the acquisition, extinction and reinstatement of the morphine-induced CPP and as well as measurement of the CSF serotonin levels. Administration of Raha syrup during the conditioning period significantly attenuated the acquisition of morphine-induced CPP, and increased the CSF serotonin level, 6 days after cessation of treatment during extinction, while did not affect the duration of the extinction period. Also, Raha syrup during the extinction period did not affect the reinstatement of morphine-induced CPP and the CSF serotonin levels in rats. We conclude that Raha syrup attenuated the acquisition of morphine reward probably through an increase in CSF serotonin, while could not maintain the extinguished CPP and had no effect on the reinstatement. Therefore, Raha syrup as a useful adjunctive therapeutic strategy may exert a protective effect against opiate-related rewards, while it may be ineffective to prevention of motivation or drug-seeking reinstatement (relapse).

New insights in the mechanisms of opioid analgesia and tolerance: Ultramicronized palmitoylethanolamide down-modulates vascular endothelial growth factor-A in the nervous system

Growing evidence suggests that opioid analgesics modulate angiogenesis during pathophysiological processes. Vascular endothelial growth factor-A (VEGF-A) was recently proposed to be involved in pain development. To date, no anti-angiogenic drug is used for pain management. When administered in a bioavailable formulation, (i.e., ultramicronized) N-palmitoylethanolamine (PEA) delays the onset of morphine tolerance, improves morphine analgesic activity and reduces angiogenesis in in vivo models. This study aimed at investigating whether VEGF-A is involved in PEA-induced delay of morphine tolerance. The anti-VEGF-A monoclonal antibody bevacizumab was used as a reference drug. Preemptive and concomitant treatment with ultramicronized PEA delayed morphine tolerance and potentiated the analgesic effect of morphine, while counteracting morphine-induced increase of VEGF-A in the nervous system. Similar results were obtained when bevacizumab was administered together with morphine. Of note, bevacizumab showed an analgesic effect per se. In equianalgesic treatment regimens (obtained through increasing morphine doses and associating PEA), PEA resulted in lower expression of VEGF-A in dorsal root ganglia (DRG) and spinal cord compared to morphine alone. Similar results were observed for plasma levels of the soluble VEGF receptor 1 (sFLT-1). Moreover, in morphine-treated animals, two pain-related genes (i.e., Serpina3n and Eaat2) showed a more than 3-fold increase in their expression at spinal cord and DRG level, with the increase being significantly counteracted by PEA treatment. This study supports the hypothesis that the effects of PEA on morphine analgesia and tolerance may be mediated by the down-modulation of VEGF-A and sFLT-1 in the nervous system and plasma, respectively.

Bidirectional effects of morphine on pancreatic cancer progression via the p38/JNK pathway

Cancer patients commonly use morphine to alleviate advanced pain. Studies have shown that morphine may influence and intervene in the malignancy of various cancers, but its role and effects on pancreatic cancer are less studied. This study aims to examine how morphine affects pancreatic cancer and its possible mechanisms. In vitro experiments were conducted using the CCK-8 experiment, colony formation experiment, EdU test, wound healing experiment, and transwell migration and invasion experiment. Tumor xenograft tests were employed to investigate the in vivo impact of morphine on pancreatic cancer. The Western blot (WB) assay was used to detect possible changes in key proteins of the related signaling pathway. Our experimental results showed that low concentrations of morphine (25 µM) promoted the progression of pancreatic cancer, while high concentrations of morphine (100 µM) inhibited its progression. Further, we demonstrated that morphine may interfere with the progression of pancreatic cancer by acting on the p38/JNK signaling pathway. Morphine may affect pancreatic cancer progression through the p38/JNK pathway in a bidirectional manner at different concentrations.

Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid-Free Analgesics.

The opioid crisis has highlighted the urgent need to develop non-opioid alternatives for managing pain, with an effective, safe, and non-addictive pharmacotherapeutic profile. Using an extensive structure-activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid-independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile12 residue of NT(7-12) was substituted by cyclopentylalanine, Pro7 and Pro10 were replaced by allyl-glycine followed by side-chain to side-chain cyclization is the most selective analog targeting NTS2 identified to date (Ki 2.9 nM), showing 30,000-fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose- and time-dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2-selective macrocycles can therefore be exploited as opioid-free analgesics or as opioid-sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.

Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid‐Free Analgesics

AbstractThe opioid crisis has highlighted the urgent need to develop non‐opioid alternatives for managing pain, with an effective, safe, and non‐addictive pharmacotherapeutic profile. Using an extensive structure–activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid‐independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile12 residue of NT(7–12) was substituted by cyclopentylalanine, Pro7 and Pro10 were replaced by allyl‐glycine followed by side‐chain to side‐chain cyclization is the most selective analog targeting NTS2 identified to date (Ki 2.9 nM), showing 30,000‐fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose‐ and time‐dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2‐selective macrocycles can therefore be exploited as opioid‐free analgesics or as opioid‐sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.

Redesigning a Stopped Clinical Trial as an Emulated Trial Using Real-World Data to Explore the Effectiveness of Slow-Release Oral Morphine as a Treatment for Opioid Use Disorder.

Canada is currently experiencing a problematic opioid crisis with increasing mortality rates. Traditional randomized controlled trials (RCTs) that examine the effectiveness of pharmacological treatment options for people with opioid use disorder (OUD) are challenging to conduct. An increasingly popular methodology is through the implementation of emulated clinical trials, a methodology in which key elements of a "target" RCT are replicated using previously collected healthcare-based data. They can possibly address some of the common challenges found in the conduct of RCTs, such as prolonged timelines, high cost, and poor participant recruitment. In effect, emulated trials accelerate knowledge generation by producing real-world evidence that can be akin to phase 3 effectiveness trials, without any need to recruit live participants or administer investigational products. During the COVID-19 pandemic, several trials were stopped due to increased pandemic-related research restrictions, leaving important questions about OUD treatment unanswered. In this commentary, we describe the transition of a traditional RCT to an emulated trial spurred by challenges posed by the COVID-19 pandemic. We describe our transition using a notable published framework with regards to the population sample, interventions, outcomes, and proposed analyses. This commentary aims to help other researchers and trialists apply emulated trials in substance use research and beyond, emphasizing the role of this methodology in clinical research and advancing scientific knowledge that could be otherwise lost or unattainable.

Analgesic activity of a new cannabinoid CB1 receptor modulator

Aim. To study the analgesic activity, the effect on motor functions, and the potential ulcerogenic effect of a new 2H-chromene derivative, a cannabinoid CB1 receptor modulator (code name – CHR).Materials and methods. The analgesic activity of the CHR compound was studied when injected intragastrically at an effective dose of 5 mg / kg in mouse models of acute chemogenic pain (formalin test), acute visceral pain (the acetic acid-induced writhing test), and thermal nociception (hot plate test and tail-flick test). It was compared to the effect of tramadol and morphine or diclofenac sodium at doses of 20, 4 or 10 mg / kg, respectively. The effect of a single intragastric injection of the CHR compound at a dose of 5 mg / kg on motor activity was evaluated in the open field test. The potential ulcerogenic effect of the CHR compound at a dose of 5 mg / kg with repeated intragastric administration was compared with the effect of diclofenac sodium at a dose of 10 mg / kg.Results. With subplantar administration of formalin to mice, the 2H-chromene derivative reduced the number of pain reactions by 43–63% (p &lt; 0.05). With intraperitoneal administration of acetic acid to mice, it reduced the number of writhing responses by 50% and had the same analgesic effect as diclofenac sodium and tramadol. In the hot plate test, the CHR compound increased the latency time to painful stimuli by 34% (p &lt; 0.05). In the tailflick test, it increased the latency time to painful thermal sensations by 32% (p &lt; 0.05). The CHR compound at an effective dose of 5 mg / kg did not change the motor activity of mice in the open field test and did not cause the formation of erosions and ulcers in the gastric mucosa when administered repeatedly to rats.Conclusion. The 2H-chromene derivative CHR at an effective dose of 5 mg / kg has a pronounced analgesic effect in mouse models of chemogenic, visceral, and thermal pain, which is as strong as that of tramadol, morphine, and diclofenac sodium used at effective doses. The CHR compound at an effective dose does not inhibit motor functions and does not have an ulcerogenic effect.

Comparison between Pectoral Plane Block (PECS 1 and 2) and Patient Controlled Intravenous Analgesia after Breast Surgeries

Abstract Background Breast cancer has continued to be the most common cancer among women, accounting for 31% of all new cancer cases in the female population. Every/ year, thousands of patients undergo surgery in the region of the breast and axilla. Surgery is one of the mainstays of treatment, and a procedure called modified radical mastectomy (MRM) is now a standard surgical treatment for early-stage breast cancers. Aim of the Work The primary aim of this study is to compare the efficacy of PECS 1,2 block versus PCA with iv morphine to provide prolonged post-operative analgesia. The secondary objective is to identify the side effects of both techniques as post-operative analgesic techniques, as well as intra-operative analgesia. Patients and Methods A randomized controlled Clinical trial in Ain Shams University Hospitals, Cairo, Egypt (EL Demrdash hospital and Combined operations) for 6 months carried out on women who undergo breast surgeries. Results The Results shows that the VAS score in the PECS group was highly significant lower at the 1st, 2nd and 4th hours postoperative, the time interval for the 1st dose of rescue analgesia was higher in PECS group, there was significant difference regarding heart rate and blood pressure between both groups at 1st, 2nd, 4th and 8th hours postoperative in favor for PECS group, regarding o2 saturation it was significant only after 1 hour postoperative, regarding nausea and vomiting there was significant difference in nausea in favor for PECS block while regarding vomiting it was non- significant, regarding sedation it didn’t occur in neither group so it was not applicable. Conclusion In modified radical mastectomy, PECS block is more effective than intravenous PCA in pain management postoperative, better effect on vital data like heart rate, blood pressure and o2 saturation, it also lowers the analgesic drugs consumption postoperative. Moreover, PECS block is more preferable method because it avoids the systemic side effect of morphine used for PCA like nausea and vomiting. PCA analgesic effect needs time to start its action.

Pharmacokinetics and thermal anti-nociceptive effects of oral morphine in horses.

Morphine is an effective analgesic in horses, however, IV administration at therapeutic doses has been shown to produce dose-dependent neuroexcitation and unwanted gastrointestinal effects. The analgesic effects of morphine have, at least in part, been attributed to the morphine-6-glucuronide (M6G) metabolite. Oral administration to horses results in comparable M6G concentrations to that achieved following IV administration of a therapeutic dose without the adverse effects. The anti-nociceptive effects have not yet been reported. In the current study the thermal anti-nociceptive effects of single and multiple oral doses of morphine were assessed. Six horses received a single 0.2 mg/kg IV dose of morphine and multiple oral doses of 0.8 mg/kg morphine every 12 h for 4.5 days. Blood samples were collected throughout administration, morphine, and metabolite concentrations determined and pharmacokinetic analysis performed. Drug related behavior and physiologic responses were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency in response to the application of heat. The maximum concentrations of M6G were higher following oral administration compared to IV and the combined morphine and M6G concentrations exceeded that of IV administration starting at 2 h. Oral administration of 0.8 mg/kg morphine provided and maintained comparable anti-nociception effects to IV morphine with less adverse effects, following single and multiple doses. Morphine was well tolerated following oral administration with less excitation and minimal effects on gastrointestinal borborygmi scores compared to IV administration. Results of the current study warrant further investigation of the anti-nociceptive effects of oral morphine administration to horses.

Morphine promotes non-small cell lung cancer progression by downregulating E-cadherin via the PI3K/AKT/mTOR pathway

Morphine has been suggested to affect cancer cell dynamics and decrease survival rates in lung cancer patients at specific doses, but the precise mechanisms poorly understood. In this study, we aimed to investigate the molecular mechanisms by which morphine modulates the malignant characteristics of non-small cell lung cancer. Cell proliferation was assessed via the Cell Counting Kit-8 assay, and cell migration and invasion were examined via wound healing and Transwell assays. We employed immunofluorescence staining to evaluate E-cadherin expression in A549 and Lewis lung cancer (LLC) cell lines and immunohistochemistry to evaluate E-cadherin expression in nude mice tumours. Additionally, the in vivo effects of morphine on lung cancer progression were explored in a xenograft tumour experiments, in which naloxone was used as a morphine antagonist. Western blot analysis was performed to detect E-cadherin, phosphorylated mTOR (p-mTOR), mTOR, phosphorylated AKT (p-AKT), AKT, phosphorylated PI3K (p-PI3K), and PI3K protein levels in A549 and LLC cells as well as in tumour samples. Morphine (10 µM) significantly increased the proliferation of A549 and LLC cells in vitro (p < 0.05). It also enhanced the migratory and invasive capacities of these cell lines (p < 0.01). Mechanistically, morphine treatment (10 µM) led to a reduction in the expression of E-cadherin, and an increase in the phosphorylation of PI3K, AKT, and mTOR in A549 and LLC cells (p < 0.01). Morphine treatment (1.5 mg/kg) also reduced E-cadherin expression in xenograft tumours and promoted tumour growth in vivo (p < 0.05). This effect was reversed by naloxone (0.1 mg/kg). The results demonstrated that morphine stimulates the malignant proliferation of A549 and LLC cell lines and promotes xenograft tumour growth. Perhaps by specifically targeting MOR, morphine triggers a signalling cascade that activates the PI3K/AKT/mTOR pathway while inhibiting the EMT marker E-cadherin, which may consequently promote the progression of lung cancer.