Morphine Analgesia Research Articles

Abstract 5589: The effect of morphine-based perioperative analgesia on circulating tumor cells dissemination in colorectal cancer patients

Abstract Purpose: Circulating tumor cells (CTCs) are primary or metastatic tumor cells shed into the bloodstream and are considered precursors of distant metastatic spread and can act as an independent prognostic and predictive biomarker. Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide and metastasis is the major cause of death. Previous studies showed poorer survival in CRC patients treated perioperatively with morphine in comparison to piritramide. Patients and Methods: In total, 150 CRC stage I-III patients undergoing either radical or laparoscopic surgery were enrolled in this prospective multicentric randomized study (NCT03700411). Patients were randomized into three arms using different perioperative analgesia - morphine, piritramide, and epidural analgesia. Three peripheral blood samples were collected preoperatively, one day and one month after surgery respectively. To preserve the cellular content of specimens, Cell-Free DNA BCT® (Streck, Inc.) blood collection tubes were used. The CTCs were identified using CytoTrack CT11TM (2/C, Denmark), a semi-automated immunofluorescence microscopy detecting the pan-cytokeratin and EpCAM signals. The method recovery rate was analyzed using SW-480 cancer cell line by flow cytometry. Results: The CTCs recovery rate of the method was 72% and the method was certified by ISO 15189. The analyses of CTC presence revealed the highest positivity rate in the samples collected from patients treated with morphine on the first day after surgery (51.4 %). Also, a significant increase in positivity (from 23.5 % for the perioperatively collected samples) compared to samples from patients treated with epidural analgesia (31.1 % to 33.3 %) and piritramide (44.2% to 41.0%) was observed. The CTC presence was lower in control samples collected after one month irrespective of the analgesia type. The highest positivity among the control samples was in those associated with morphine analgesia (32.1 % versus 25.7% for epidural and 25.0% for piritramide analgesia). Conclusion: A significant increase in CTC levels was found in postoperative blood samples of CRC patients treated with morphine compared to piritramide and epidural analgesia. Enrollment in the study is ongoing. Acknowledgments: This study was supported by the Ministry of Health of the Czech Republic (NV18-03-00470), Palacky University Olomouc (LF 2022_012), European Union - Next Generation EU (LX22NPO5102) and European Regional Development Fund (ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868). Citation Format: Pavel Stejskal, Josef Srovnal, Emil Berta, Alona Rehulkova, Lubomír Večeřa, Tomas Gabrhelik, Filip Haiduk, Jan Maca, Jan Bruthans, Pavel Michalek, Pavla Kourilova, Marian Hajduch. The effect of morphine-based perioperative analgesia on circulating tumor cells dissemination in colorectal cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5589.

Abstract 2201: Effect of opioid and cannabinoid receptors gene expression on survival of patients with colorectal cancer

Abstract Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer death in the world. CRC patients are often treated with opioid (e.g., morphine, or synthetic opioid piritramide) analgesia for pain, nausea, and side effects of chemotherapy. These analgesics act through opioid and cannabinoid receptors, which pathways are involved in tumor progression and metastases and thus can negatively affect the survival of patients. In our previous studies, we analyzed the presence of circulating tumor cells (CTCs) in two groups of CRC patients. One group received morphine analgesia (MA) and second piritramide analgesia (PA). We found that MA associated with increased CTCs levels and significantly shorter cancer-specific survival (CSS). These findings lead to further analysis of the opioid and cannabinoid receptors tumor gene expressions. We expected that the different expression of specific receptors in tumor tissue makes a difference between the effects of MA and PA on patients´ survival. Methods: Gene expression of opioid receptors µ (OPRM), κ (OPRK), δ (OPRD), nociceptin (OPRL) and cannabinoid receptors 1 and 2 (CB1, CB2) was analyzed in RNA purified from tumor tissues in 131 patients with CRC. Expression of markers was detected using real-time RT-PCR on LightCycler 1536 from Roche. Β-actin gene expression was used for gene expression normalization. Specific cut-off values were calculated for each marker using maxstat R software, ver. 3.3.1. Relationship between expression of receptors in tumor tissue and patients’ survival was analyzed using COX regression, Kruskal-Wallis/ANOVA test, and Kaplan-Meier method. Results: In total, 118 patients (45 females and 73 males, average age 68 years), of clinical stage-III were analyzed. It was found that MA in CRC patients was associated with significantly shorter cancer-specific survival (CSS; p=0,027). The univariate survival analysis revealed that CRC patients with high OPRM tumor tissue gene expression had significantly longer overall survival (OS; p=0.017) and patients with CB2 gene expression had significantly longer disease-free survival (DFS; p=0,029). All other tested opioid receptors expressions had no statistically significant effect on patients’ survival. Conclusion: The diverse opioid receptors’ expressions on tumor and immune cells can affect the survival of cancer patients treated with opioid analgesia. Morphine perioperative analgesia seems to shorten the CCS in CRC patients in our study. However, further research is required to elucidate the effect of opioids on different cell populations. Acknowledgement: This study was supported by Ministry of Health of the Czech Republic [NV18-03-00470]; Palacky University Olomouc [LF 2022_012]; European Regional Development Fund [ENOCHCZ.02.1.01/0.0/0.0/16_019/0000868) and European Union - Next Generation EU (EXCELES LX22NPO5102). Citation Format: Monika Vidlarova, Josef Srovnal, Emil Berta, Sona Gurska, Alona Rehulkova, Pavla Kourilova, Marian Hajduch. Effect of opioid and cannabinoid receptors gene expression on survival of patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2201.

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

EFFECT OF THİAMİNE ON MORPHİNE ANALGESİA AND TOLERANCE İN RATS

Absract: The latest research have demonstrated that inflammation, oxidative stress and apoptosis plays a majör role in morphine analgesia and tolerance development. This search goals to examine the possible role of thiamine use on oxidative stress, inflammation and apoptosis in the development of morphine analgesia and morphine tolerance in rats. 
 Methods: Thirty-six male Wistar rats were used in this study. The rats were severed into six groups: saline, 100 mg/kg thiamine, 5 mg/kg morphine, thiamine + morphine, morphine tolerance and thiamine + morphine tolerance. The resulting analgesic effect was measured by hot plate and tail movement analgesia tests. TAS and TOS, inflammation parameters, and apoptosis protein levels of the dorsal root ganglion tissues sample were measured using an ELISA kit. 
 Results: When thiamine was given alone, it did not show anti-nociceptive effect (p>0.05). In addition, thiamine enhanced the analgesic effect of morphine (p < 0.05) and also significantly reduced tolerance to morphine (p < 0.05). However, it reduced TOS when administered with a single dose of morphine and tolerance induction (p < 0.05). In addition, thiamine reduced apoptosis protein levels after tolerance development (p < 0.05). 
 Conclusion: Consequently, these results may attain by reducing TOS, inflammation, and apoptosis.

A small molecule ligand for the novel pain target, GPR171, produces minimal reward in mice

ProSAAS is one of the most abundant proteins in the brain and is processed into several smaller peptides. One of which, BigLEN, is an endogenous ligand for the G protein-coupled receptor, GPR171. Recent work in rodent models has shown that a small-molecule ligand for GPR171, MS15203, increases morphine antinociception and is effective in lessening chronic pain. While these studies provide evidence for GPR171 as a possible pain target, its abuse liability has not yet been assessed and was evaluated in the current study. We first mapped the distribution of GPR171 and ProSAAS throughout the reward circuit of the brain using immunohistochemistry and showed that GPR171 and ProSAAS are localized in the hippocampus, basolateral amygdala, nucleus accumbens, prefrontal cortex. In the major dopaminergic structure, the ventral tegmental area (VTA), GPR171 appeared to be primarily localized in dopamine neurons while ProSAAS is outside of dopamine neurons. Next, MS15203 was administered to mice with or without morphine, and VTA slices were stained for the immediate early gene c-Fos as a marker of neuronal activation. Quantification of c-Fos-positive cells revealed no statistical difference between MS15203 and saline, suggesting that MS15203 does not increase VTA activation and dopamine release. The results of a conditioned place preference experiment showed that treatment with MS15203 produced no place preference indicating a lack of reward-related behavior. Taken together this data provides evidence that the novel pain therapeutic, MS15203, has minimal reward liability. Therefore, GPR171 deserves further exploration as a pain target. Significance statementMS15203, a drug that activates the receptor GPR171, was previously shown to increase morphine analgesia. The authors use in vivo and histological techniques to show that it fails to activate the rodent reward circuitry, providing support for the continued exploration of MS15203 as a novel pain drug, and GPR171 a novel pain target.

Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats

AimsChronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (KATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, KATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence. Main methodsIntraperitoneal injection (i.p.) of carbon tetrachloride (CCl4) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed. Key findingsMorphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats. SignificanceThe data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly coexpressed with Oprm1 (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.SIGNIFICANCE STATEMENT The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new Oprm1-Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

Addition of preoperative transversus abdominis plane block to multimodal analgesia in open gynecological surgery: a randomized controlled trial

BackgroundTransversus abdominis plane (TAP) block can provide effective analgesia for abdominal surgery. However, it was questionable whether TAP had additional effect in the context of multimodal analgesia (MMA). Therefore, this study aimed to assess the additional analgesic effect of preoperative TAP block when added to MMA protocol in open gynecological surgery.MethodsIn this prospective, randomized-controlled trial, 64 patients scheduled for open gynecological surgery were randomized to receive preoperative TAP block (Study group, n = 32) or placebo (Control group, n = 32) in addition to MMA protocol comprising dexamethasone, acetaminophen, flurbiprofen and celecoxib, and rescued morphine analgesia. The primary outcome was rescued morphine within 24 h after surgery. Secondary outcomes included pain scores, adverse effects, quality of recovery measured by 40-item quality of recovery questionnaire score (QoR-40) at 24 h, and quality of life measured with short-form health survey (SF − 36) on postoperative day (POD) 30.ResultsThe Study group had less rescued morphine than the control group within 24 h [5 (2–9) vs. 8.5 (5–12.8) mg, P = 0.013]. The Study group had lower pain scores at 1 h [3 (2–4) vs. 4 (3–5), P = 0.007], 2 h [3 (2–4) vs. 3.5 (3–5), P = 0.010] and 6 h [3 (2–3) vs. 3 (2.3–4), P = 0.028], lower incidence of nausea at 48 h (25.8% vs. 50%, P = 0.039), and higher satisfaction score [10 (10–10) vs. 10 (8–10), P = 0.041]. The SF-36 bodily pain score on POD 30 was higher in the Study group (59 ± 13 vs. 49 ± 16, P = 0.023).ConclusionsPreoperative TAP block had additional analgesic effect for open gynecological surgery when used as part of multimodal analgesia. Rescued morphine within 24 h was significantly reduced and the SF-36 bodily pain dimension at 30 days after surgery was significantly improved.Trial registrationwww.chictr.org.cn (ChiCTR2000040343, on Nov 28 2020).

Comparison between pericapsular nerve group block and morphine infusion in reducing pain of proximal femur fracture in the emergency department: A randomized controlled study

ABSTRACT Background This study aimed to assess the safety and efficacy of analgesia with pericapsular nerve group (PENG) block as an adjuvant to morphine infusion for the management of preoperative pain in patients with proximal femur fractures. Methods This single-blinded, parallel-group, randomized trial enrolled 36 adult patients with proximal femur fractures who were prepared for surgery. The patients were randomly allocated to two groups. In the PENG group, 18 patients received a US-guided PENG block as an adjuvant to patient-controlled morphine analgesia (PCA), while in the PCA group, 18 patients received PCA only. The primary outcome was the total morphine consumption in 24 hours before the surgery. The secondary outcomes included the visual analogue scale (VAS), need for rescue analgesia, total sleep hours, incidence of respiratory depression, hemodynamic stability, and incidence of nausea and vomiting during the first 24 hours post-procedure. Results The PENG block significantly decreased the total dose of morphine, VAS score at one-hour post-procedure, need for rescue analgesia, incidence of respiratory depression and nausea but increased the sleeping hours. Vomiting was comparable in the two groups (p = 0.121). Significantly higher mean arterial pressures from 8 to 20 hours after the block as well as heart rates immediately after the block were observed in the PENG group compared to the PCA group. Conclusion In patients with proximal femur fractures, preoperative PENG block can be used as an adjuvant to morphine infusion for controlling the pain and the total dose of morphine usage.

Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance.

The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein-coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor-mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.

αN-Acetyl β-Endorphin Is an Endogenous Ligand of σ1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for σ2Rs in σ1R Oligomers.

The opioid peptide β-endorphin coexists in the pituitary and brain in its αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (σ1R) displayed positive effects. Thus, αN-acetyl β-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, αN-acetyl β-Endorphin reduced the analgesia of morphine, β-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by β-Endorphin and absent in σ1R-/- mice. We observed that σ1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, β-Endorphin promoted the exchange of σ2Rs by G proteins at σ1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the αN-acetyl derivative, as σ1R oligomerization decreased and σ2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological β-Endorphin-specific epsilon receptor is a σ1R-regulated MOR and that β-Endorphin and αN-acetyl β-Endorphin are endogenous ligands of σ1R.

The Effect of Epidural Analgesia on Quality of Recovery (QoR) after Radical Prostatectomy.

No studies are currently regarding the quality of recovery (QoR) after open radical prostatectomy (ORP) and epidural morphine analgesia. This was a randomized, prospective, and controlled study that explored QoR on the first postoperative day after ORP. Sixty-one men were randomized into two groups. The first (epidural) group received general anesthesia combined with epidural anesthesia and postoperative epidural analgesia with morphine and ropivacaine. The second (control) group received general anesthesia and continuous postoperative intravenous analgesia with tramadol. Both groups received multimodal analgesia with metamizole. The primary outcome measure was the total QoR-40 score. Secondary outcome measures were: QoR-15, QoR-VAS and the visual analogue scale (VAS) for pain, anxiety and nausea. The median difference in the total QoR-40 score after 24 postoperative hours between the two groups of patients was 2 (95% CI: -3 to 8), p = 0.35. The global multivariate inference test for secondary outcomes between groups was not significant p > 0.05). QoR-VAS was correlated with QoR-40 (r = 0.69, p ≤ 0.001) and with QoR-15 (r = 0.65, p ≤ 0.001). The total QoR-40 and QoR-15 alpha coefficient with 95% CI was 0.88 (0.83-0.92) and 0.83 (0.77-0.89), respectively. There was no difference in the QoR between the epidural and the control group after ORP. The QoR-40 and QoR-15 showed good convergent validity and adequate reliability.

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies.

Recent studies have indicated the involvement of chemokine-C-motif ligand 1 (XCL1) in nociceptive transmission; however, the participation of its two receptors, canonical chemokine-C-motif receptor 1 (XCR1) and integrin alpha-9 (ITGA9), recently recognized as a second receptor, has not been clarified to date. The aim was to explore by which of these receptors XCL1 reveals its pronociceptive properties and how the XCL1-XCR1 and XCL1-ITGA9 axes blockade/neutralization influence on pain-related behavior and opioid analgesia in the model of neuropathic pain. In our studies we used Albino Swiss mice which were exposed to the unilateral sciatic nerve chronic constriction injury (CCI) as a neuropathic pain model. Animals received single intrathecal (i.t.) injection of XCL1, XCL1 neutralizing antibodies, antagonist of XCR1 (vMIP-II) and neutralizing antibodies of ITGA9 (YA4), using lumbar puncture technique. Additionally we performed i.t. co-administration of abovementioned neutralizing antibodies and antagonists with single dose of morphine/buprenorphine. To assess pain-related behavior the von Frey and cold plate tests were used. To measure mRNA and protein level the RT-qPCR and Western Blot/Elisa/immunofluorescence techniques were performed, respectively. Statistical analysis was conducted using ANOVA with a Bonferroni correction. Presented studies have shown time-dependent upregulation of the mRNA and/or protein expression of XCL1 in the spinal cord after nerve injury as measured on day 1, 4, 7, 14, and 35. Our immunofluorescence study showed that XCL1 is released by astroglial cells located in the spinal cord, despite the neural localization of its receptors. Our results also provided the first evidence that the blockade/neutralization of both receptors, XCR1 and ITGA9, reversed hypersensitivity after intrathecal XCL1 administration in naive mice; however, neutralization of ITGA9 was more effective. In addition, the results proved that the XCL1 neutralizing antibody and, similarly, the blockade of XCR1 and neutralization of ITGA9 diminished thermal and mechanical hypersensitivity in nerve injury-exposed mice after 7 days. Additionally, neutralization of XCL1 improves morphine analgesia. Moreover, blockade of XCR1 positively influences buprenorphine effectiveness, and neutralization of ITGA9 enhances not only buprenorphine but also morphine analgesia. Therefore, blockade of the XCL1-ITGA9 interaction may serve as an innovative strategy for the polypharmacotherapy of neuropathic pain in combination with opioids.

Intra-incisional injection of magnesium sulfate for post cesarean pain management

Background and objectives: cesarean section is estimated for about 30% of child births worldwide and it is one of the most common surgical procedures. Pain relief after cesarean delivery is especially important as the consequences of inadequate pain relief are expressed not only by the mother but by the newborn as well. Magnesium has been reported to produce important analgesic effects including the potentiation of morphine analgesia, attenuation of morphine tolerance and the suppression of neuropathic pain. The objectives of this study were to determine the efficacy of intra-incisional injection of magnesium sulfate for post cesarean pain management as in patient underwent elective cesarean section and the reduced need for extra analgesic use postoperatively. Methods: a randomized, placebo controlled, single-blinded study with a total of 200 pregnant participants scheduled for cesarean section in Sulaimani maternity teaching hospital, from 1st of May 2016 to 15th of August 2016. Patients were randomly allocated to two groups, those with odd numbers were assigned to case group (100) received 750mg of magnesium sulfate and patients with even numbers assigned to the placebo group (100) received 20mg of normal saline. Results: The mean Visual Analogue Score after 4 hours, 8 hours, 12 hours and 24hours was significantly less for the intervention (Magnesium sulfate) group when compared with the control (Normal Saline). Conclusions: Subcutaneous administration of magnesium sulfate in post cesarean section pain management can be used as a successful modality or method for pain management.

Blockade of orexin receptor type-1 by SB-334867 and activation of orexin receptor type-2 attenuate morphine tolerance in rats.

The interaction of orexinergic neurons with the opioidergic system and their effects on morphine analgesia and tolerance have not been fully elucidated. The purpose of the study was to evaluate the effects of the orexin-1 and orexin-2 receptor (OX1R and OX2R) agonist and antagonist on morphine analgesia and tolerance in rats. A total of 90 Wistar albino male rats weighing 180-220 g wereused in the experiments. To induce morphine tolerance, rats were injected with a single dose of morphine (50 mg kg-1, s.c.) for 3 days. Morphine tolerance was assessed on day 4 in randomly selected rats by analgesia tests. In order to evaluate morphine tolerance situation, orexin-A, SB-334867, orexin-B andTCSOX2 29 were administered together with morphine for 3 days. The analgesic effects of orexin-A (10 μg kg-1), OXR1 antagonist SB-334867 (10 mg kg-1), OXR2 agonist orexin-B (15 μg kg-1), OXR2 antagonist TCS OX2 29 (0.5 mg kg-1) and morphine (5 mg kg-1) were measured at 15 or 30-min intervals by tail-flick and hot-plate antinociceptive tests. The results suggested that the combination of orexin-1 receptor antagonist SB-334867 and orexin-B with morphine significantly increased the analgesic effect compared to morphine-tolerant rats. In addition, administration of orexin-A and -B alone showed significant analgesic effects compared to the saline group. However, co-administration of orexin-A and -B with morphine didnot increase the analgesic efficacy of morphine. The results of this study demonstrated that co-administration of SB-334867 and orexin-B with morphine attenuated morphine tolerance. Further studies are needed to elucidate the details of the interaction between orexin receptors and the opioidergic system.

Morphine suppresses the immune function of lung cancer by up-regulating MAEL expression

BackgroundPatients with cancer rely on morphine for analgesia, while studies have indicated morphine can induce immunosuppression in cancer. Therefore, investigating the immunosuppressive roles and molecular mechanism of morphine on lung cancer progression is imperative.MethodsLactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of morphine to lung cancer cells. The percentage of CD4+ and CD8+ T cells was detected by flow cytometry. In addition, Maelstrom (MAEL), Nrf2, and PTEN were determined by western blot and RT-qPCR. Immune factors programmed death-ligand 1 (PD-L1), transforming growth factor (TGF-β), interleukin (IL)-10, and IL-2 were determined by western blot and ELISA assay.ResultsMorphine increased the levels of PD-L1, TGF-β, and IL-10, while decreased IL-2 level. Morphine enhanced MAEL expression in A549 cells and H460 cells. Morphine up-regulated Nrf2 and down-regulated PTEN, and morphine-induced MAEL up-regulation was reversed by PTEN. However, MAEL silencing inhibited the enhanced effects of morphine on cell viability and proliferation of A549 cells. Furthermore, morphine treatment reduced the LDH release and the percentage of CD8+ T cells, and increased the ratio of CD4+/CD8+ T cells and tumor weight. Meanwhile, MAEL silencing reversed the effects of morphine on immune factors (PD-L1, TGF-β, IL-10, and IL-2), the percentage of CD8+ T cells, and the ratio of CD4+/CD8+ T cells.ConclusionMorphine activated MAEL in lung cancer cells by Nrf2/PTEN pathway and regulated the immune factors, thereby promoting tumor immune escape.

ROBOTIC ASSISTED MINIMALLY INVASIVE CARDIAC SURGERY DA VINCI ROBOTIC SYSTEM. ANALYSIS OF PERIOPERATIVE CONSIDERATIONS

<h3>Introduction</h3> Robotic assisted minimally invasive cardiac surgery is a complex procedure where the anesthesiologist works in situations that require management skills. <h3>Method</h3> The study design is a retrospective observational model, which was performed with chart review. Data were collected from 104 patients who underwent minimally invasive cardiac surgery and were repaired using the Da Vinci robot-assisted minimally invasive approach from November 2019 to March 2022. The variables collected were assigned into three groups: preoperative variables, intraoperative variables and postoperative variables. The preparatory variables were age, sex, personal history of interest, Anesthetic Risk Scale (ASA), European System for Cardiac Operation Risk Evaluation II (EUROESCORE II), preoperative echocardiography, preoperative laboratory tests and diagnosis. Intraoperative variables were type of anesthesia, airway device used, invasive monitor, intraoperative transesophageal echocardiography data, complications, vasoactive drug use, blood product transfusion, extracorporeal circulation times and aortic clamping times, analgesic technique, extubation and surgical outcome. Finally, the postoperative variables were length of stay in the intensive care unit, length of hospital stay and postoperative complications. <h3>Results</h3> On the ASA 101 patients (97.1%) were in the ASA IV group and only 3 patients were in the ASA V group (2.9%). In the Euroescore II 103 patients scored less than 3 (99.03 %) and only one patient scored above 3 (0.9 %). Regarding anesthesia, 71 patients received total intravenous general anesthesia (68,3%) and 32 patients received balanced general anesthesia (30,7%) and in 1 patient this information could not be collected (0,9%)).. For airway management, a left double-lumen tube was used in 21 patients (20.8%), a Vivasight-type camera tube in 47 patients (46.6%) and a bronchial blocker through a conventional tube under fibrobronchoscopic vision in 33 patients (32.6%). In 3 patients this information could not be collected. Only 1 patient suffered serious complications during surgery (0.96 %). Vasoactive drugs were used in 81 patients (78%). Blood products were transfused in 7 patients (6.7%). The analgesic technique used consisted of locoregional blocks in 59 patients (56%), Locoregional block + patient-controlled morphine analgesia (PCA) in 14 patients (13,4%), PCA only in 29 patients (27,8%) and in 4 patients we do not know this information (3,8%). With regard to postoperative complications, 26 patients (25 %) were recorded. One patient died (0.96%). <h3>Conclusions</h3> In minimally invasive robotic-assisted cardiac surgery there are fundamental details to consider before, during and post-intervention such as the selection of the right patient, preoperative assessment, anesthetic technique, airway management, performing a good transesophageal echocardiographic study, hemodynamic behavior of the patient during the intervention, measures to take in case of complications and postoperative management, among others. Little literature exists so far and more studies are needed. ANALYSIS OF ANAESTHETIC CONSIDERATIONS

Ефективність та безпечність пролонгованої внутрішньовенної інфузії лідокаїну для післяопераційного знеболювання та відновлення після оперативних втручань у дітей віком 8-17 років

Postoperative pain control in pediatric practice is an important issue not only for patients but also for the health care system overall. The results of meta-analyses and a large number of studies have shown that intravenous infusions of lidocaine significantly improve the quality of postoperative analgesia and help reduce the consumption of narcotic analgesics after various surgical procedures in adult patients. This technique is rarely reported in the pediatric population due to insufficient data on its efficacy and safety. The purpose - to evaluate the efficacy and safety of perioperative continuous intravenous infusion of lidocaine as a component of multimodal analgesia in children aged 8 years and older to improve pain control and quick recovery after surgery. Materials and methods. The prospective controlled study included 74 (50 boys, 24 girls) children who underwent surgical procedures under general anesthesia. The age of the patients was from eight to 18 years. Patients were divided into two groups: the (study) Group 1 (n=28) included children who received intravenous lidocaine as a component of multimodal analgesia in the perioperative period, and the second (control) group (n=46) included children who were not administered lidocaine. Pain intensity, duration of the postoperative narcotic analgesics administration and their dosage, the time for recovery of intestinal motility, the transition period to full enteral nutrition, the length of hospital stay, and the nature of postoperative complications were evaluated. Data analysis was performed using the statistical package “SPSS 20” (SPSS Inc.) version 21.0.0 for Windows. Results. The results of our study demonstrated that pain intensity, as well as total postoperative morphine requirement, were significantly lower in the lidocaine group compared to the control group during the 48-hour follow-up period (p&lt;0.05). Additional morphine analgesia on postoperative day 1 was documented in 5 (17.9%) patients in the lidocaine group and 19 (41.3%) patients in the control group. Intestinal motility was restored within 3.79±1.81 hours postoperatively in the study group and was significantly shorter compared to the control group. In the postoperative period, there was a significantly lower frequency of postoperative nausea in patients in the study group. Side effects of lidocaine infusion were not registered. Conclusions. Prolonged perioperative infusion of lidocaine as a component of multimodal analgesia helps to reduce the consumption of narcotic analgesics and significantly improves the quality of pain syndrome treatment in the postoperative period in children. Due to the earlier restoration of bowel motility, lidocaine infusion may be useful for rapid postoperative rehabilitation programs. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Overexpression of GDNF in Spinal Cord Attenuates Morphine Analgesic Tolerance in Rats with Bone Cancer Pain

Bone cancer pain (BCP) is one of the typical and distressing symptoms in cancer patients. Morphine is a widely used analgesic drug for BCP; however, long-term morphine administration will lead to analgesic tolerance. Our previous study indicated that spinal glial cell line-derived neurotrophic factor (GDNF) exerts analgesic effects in rats with BCP. In this study, BCP was established by inoculated Walker 256 carcinoma cells into rat tibias, while morphine tolerance (MT) was induced by intrathecally injecting morphine twice daily from the 9th to 15th postoperative day (POD) in BCP rats. The BCP rats developed mechanical and thermal hyperalgesia on POD 5 and it lasted to POD 15. The analgesic effect of morphine was decreased after repeat administration. Western blots and immunochemistry tests showed that GDNF was gradually decreased in the spinal cord after the development of MT in rats with BCP, and GDNF was colocalized with the μ opioid receptor (MOR) in the superficial laminate of the spinal cords. The overexpression of GDNF by lentivirus significantly attenuated MT, and restored the expression of MOR in the spinal cord. In summary, our results suggest that the reduction of GDNF expression participated in the development of MT in rats with BCP and could be a promising therapeutic option for BCP.

Effect of Narcotic Analgesia on Decision to Operate in Acute Appendicitis

Aim: To study that narcotic analgesia administration in patients of acute appendicitis does not delay the diagnosis and does not interfere with the decision to operate in these patients. Study design: A randomized cross-over study. Setting and duration of study: Study was done at surgery department of Combined military hospital Lahore over a period of two years from March 2019-2021. Methodology: It was a double-blind randomized crossover study. A total of 100 patients, who were confirmed as acute appendicitis by clinical examination, were included. All the male and female patients of age 16 years and above were included in the study. The patients were divided in two groups each having 50 patients. The drugs were labelled as drug A and drug B. Drug A was morphine and drug B was placebo. Each drug was given to both the groups by crossover with an interval of 30 minutes and the components of physical examination were analyzed for both groups. The pain score was calculated by the visual analogue scale (VAS) for both the groups at both intervals. The p-value was calculated by using student’s t-test. The frequency and percentages of the decision to operate were calculated. The data was tabulated and then analyzed on SPSS version 23. Results: The pain score was calculated for both groups of male and females. The pain score difference was calculated in both groups and then p-value was calculated which came out to be significant. The frequencies of the decision to be operated were also calculated in both the groups and the results showed that there was no effect of narcotic analgesia on the decision to operate in patients with clinically diagnosed acute appendicitis Conclusion: The use of morphine analgesia in the patients of acute appendicitis does not alter the diagnostic efficacy of the patients of acute appendicitis. Keywords: Acute abdominal pain, acute appendicitis, Narcotic analgesia, Visual analog scale (VAS)