This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18). 

Endogenous opiates and behavior: 2022

Background Postoperative pulmonary complications (PPCs) can significantly reduce quality of life and may be life-threatening. While predictors of PPCs have been studied in various surgeries, specific data on pancreaticoduodenectomy is limited. Methods We conducted a retrospective analysis of 338 patients who underwent pancreaticoduodenectomy for biliary, pancreatic, and duodenal tumors at our hospital from 2017 to 2023. We compared demographic, clinical, and laboratory variables between patients with and without PPCs within 30 days post-surgery. Independent risk factors were identified using multivariate logistic regression analysis, and a nomogram was developed to predict PPC risk. Model accuracy was validated with the concordance index (C-index) and calibration curves. Results Of the 338 patients, 149 (44.1%) developed PPCs. Significant variables associated with PPCs included age, smoking, alcohol consumption, type and duration of surgery, timing of nasogastric tube removal, tumor size, tumor location, and preoperative albumin levels. Multivariate logistic regression analysis identified independent risk factors: type and duration of surgery, tumor location, maximum tumor diameter, and preoperative albumin levels. The nomogram incorporating these factors had a C-index of 0.749. The ROC curve showed an AUC of 0.75, indicating satisfactory predictive performance. Calibration curves, decision curve analysis (DCA), and clinical impact curves confirmed the model's validity and reliability. Conclusion Type and duration of surgery, tumor location, maximum tumor diameter, and preoperative albumin levels are independent risk factors for PPCs after pancreaticoduodenectomy. We developed a new nomogram to predict PPCs in these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00423-025-03681-0.

pdf/risk-factors-and-predictive-model-for-postoperative-3qh3f2i58ank.pdf

Risk factors and predictive model for postoperative pulmonary complications following pancreaticoduodenectomy: a retrospective cohort study

Traumatic brain injury (TBI) in children often leads to poor developmental outcomes attributable to progressive cell loss caused by secondary injuries, including endoplasmic reticulum (ER) stress. Buprenorphine (BPN) is commonly used in children for pain management; however, the effects of BPN on ER stress in the pediatric population are still inconclusive. This study investigated the sex-specific effects of BPN on ER stress, abnormal protein accumulation, and cell loss in a mouse impact acceleration model of pediatric TBI. On post-natal day 20–21 (P20–21), male and female littermates were randomized into sham, TBI + saline and TBI + BPN groups. BPN (0.075 mg/kg) was administered to TBI + BPN mice at 30 min after injury and then every 6–12 h for 2 days. The impact of BPN was evaluated at 1, 3, and 7 days post-injury. We found that TBI induced more prominent ER stress pathway activation at 1 and 3 days post-injury in males, compared to females, whereas abnormal protein accumulation and cell loss were more severe in females at 7 days post-injury, compared with males. Although BPN partially ameliorated abnormal protein accumulation and cell loss in both males and females, BPN only decreased ER stress pathway activation in males, not in females. In conclusion, BPN exhibits sex-specific effects on ER stress, abnormal protein accumulation, and cell loss in a time-dependent manner at the acute phase after pediatric TBI, which provides the rationale to assess the potential effects of BPN on long-term outcomes after pediatric TBI in both males and females. 

Sex-Specific Effects of Buprenorphine on Endoplasmic Reticulum Stress, Abnormal Protein Accumulation, and Cell Loss After Pediatric Mild Traumatic Brain Injury in Mice

BACKGROUND Postoperative pulmonary complications (PPCs) are the most common complications following major upper abdominal surgeries, particularly hepatobiliary procedures, and significantly compromise surgical outcomes and patients’ quality of life. Although the adoption of laparoscopy has lowered their incidence, PPCs remain a frequent and serious concern after hepatobiliary surgery. Existing research on risk factors specific to hepatobiliary surgeries is limited, particularly regarding the epidemiology and risk factors of PPCs in liver and gallbladder surgeries in China. Therefore, this study aimed to investigate the risk factors for PPCs in a large hepatobiliary center. AIM To identify the incidence and risk factors for PPCs following hepatobiliary surgery based on perioperative variables. METHODS Retrospective data were collected from patients who underwent liver, gallbladder, or pancreatic surgery at a hepatobiliary center in China between May 2023 and December 2023. We retrospectively reviewed comprehensive medical records to extract demographic and hospital admission information for determining PPC incidence. Statistically significant variables were initially screened through univariate analysis, followed by binary logistic regression modeling to identify independent predictors of PPCs. Hospitalization expenditures and duration of stay were further contrasted across the study cohorts. RESULTS This study included 1941 patients who underwent liver, gallbladder, or pancreatic surgery, of whom 78 developed PPCs, resulting in an incidence rate of 4.02%. Logistic regression analysis revealed two independent predictors of PPCs in hepatobiliary surgery patients: Age ≥ 75 year (odds ratio = 8.350, 95%CI: 3.521-19.798, P < 0.001) and prolonged anesthesia (odds ratio = 1.052, 95%CI: 1.015-1.091, P = 0.006). Patients with PPCs had significantly elevated healthcare resource utilization, including higher total hospitalization costs, increased medication expenses, longer hospital stays, and extended postoperative admissions (all P < 0.001). CONCLUSION Age ≥ 75 years and prolonged anesthesia emerged as independent predictors of PPCs following hepatobiliary surgery. These complications were correlated with protracted hospitalization and increased healthcare costs.

Epidemiology and risk of pulmonary complications following hepatobiliary surgical procedures: A retrospective study

Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

/pdf/agonists-specific-for-k-opioid-receptor-induces-apoptosis-of-14g0g2p8.pdf

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Several studies have shown that propofol administration during surgery effectively attenuates remifentanil-induced hyperalgesia (RIH). Ciprofol, a novel intravenous sedative agent analogous to propofol, has not yet been proven efficacious in alleviating RIH. The present study aimed to investigate the effect of ciprofol on RIH and the possible mechanisms involved.The RIH model was established by an infusion of remifentanil (1 μg·kg-1·min-1) 60 min in rats with incisional pain. Ciprofol (0.1, 0.25, and 0.4 mg·kg-1·min-1) was simultaneously infused to evaluate its effect on RIH. The antinociception of ciprofol was verified by measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). γ-aminobutyric acid type A receptor α2 subunit (α2GABAAR), N-methyl-d-aspartate receptor NR2B subunit (NR2B), calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and phosphorylated CaMKIIα (P-CaMKIIα) in the spinal cord and hippocampus of rats were assessed by western blotting and immunohistochemistry.The results showed that ciprofol dose-dependently increased PWMT and PWTL values in RIH rats. Moreover, ciprofol upregulated α2GABAAR and downregulated NR2B and P-CaMKIIα in the rat spinal cord and hippocampus.Ciprofol alleviates RIH effectively, and the anti-hyperalgesic mechanisms may involve increasing α2GABAAR levels and decreasing NR2B and P-CaMKIIα levels in the spinal cord and hippocampus. 

Ciprofol alleviates remifentanil-induced hyperalgesia by regulating α2GABAARs, NR2B, and P-CaMKIIα levels in the spinal cord and hippocampus.

Risk factors for pulmonary complications after laparoscopic liver resection: a multicenter retrospective analysis

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Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Ciprofol alleviates remifentanil-induced hyperalgesia by regulating α2GABAARs, NR2B, and P-CaMKIIα levels in the spinal cord and hippocampus.

Risk factors for pulmonary complications after laparoscopic liver resection: a multicenter retrospective analysis