Injection Of Morphine Research Articles

Differential Effects of Intrahippocampal Administration of Ceftriaxone on Morphine Dependence and Withdrawal Syndrome in Rats.

Glutamate is a key factor in opiate addiction. Glial glutamate transporter-1 (GLT-1) plays a prominent role in glutamate homeostasis. Therefore, different regimens of ceftriaxone as a GLT-1 activator were prescribed to determine whether modulating GLT-1 prevents morphine dependence or withdrawal syndrome. Rats received 10 mg/kg morphine subcutaneously for ten consecutive days. Intrahippocampal ceftriaxone (0.5 μL of 0.5 mM solution) was injected 30 min before morphine administration to assess its effect on dependence process. In the next experiment, after the animals became dependent, ceftriaxone was injected before or after the last morphine administration, and its effect on withdrawal symptoms was evaluated. The reversibility of developed dependence was evaluated in the conditions when morphine and ceftriaxone were administered simultaneously. Two hours after the last morphine injection, naloxone hydrochloride (1.5 mg/kg) was administered, and morphine withdrawal syndrome was recorded for 25 min. Ceftriaxone administration before each morphine injection caused a decrease in the occurrence of withdrawal symptoms. Single dose of ceftriaxone after or before the last dose of morphine did not change the withdrawal symptoms significantly. Ceftriaxone injection for 5 days after becoming dependent could decrease the occurrence of some withdrawal symptoms. Modulation of glutamate with ceftriaxone during morphine injection may be able to prevent dependence. However, a single dose of ceftriaxone after becoming dependent could not decrease withdrawal syndrome. More prolonged administration of ceftriaxone could alleviate the induced dependence.

Targeting exosomal double-stranded RNA-TLR3 signaling pathway attenuates morphine tolerance and hyperalgesia

Long-term morphine use leads to tolerance and hyperalgesia in patients with chronic pain, with neuroinflammation playing a key role, but its underlying mechanisms remain elusive. This study determines that repeated intrathecal morphine injections increase double-stranded RNA (dsRNA) production in spinal neurons, due to downregulated adenosine deaminase RNA specific 1 (ADAR1) expression. Lentivirus-induced ADAR1 elevation decreases the high levels of intracellular dsRNA and attenuates morphine tolerance and hyperalgesia. dsRNA is released into cerebrospinal fluid via exosomes (Exos) after repeated morphine injections and is taken up by microglia for TLR3-TRIF-IL-6 signaling activation. Blocking Exos release with GW4869 or inhibition of TLR3 signaling mitigates neuroinflammation, preventing the development of morphine tolerance and hyperalgesia. Intrathecal injection of TLR3 inhibitor alone shows analgesic effects in neuropathic pain, and co-administration with morphine amplifies the analgesic efficacy of morphine. These findings demonstrate that targeting dsRNA-TLR3 signaling to mitigate neuroinflammation could be a promising treatment for morphine tolerance.

Anti-nociceptive effects of non-antibiotic derivatives of demeclocycline and doxycycline against formalin-induced pain stimulation

In previous studies, some tetracycline (TC) antibiotics showed potential as analgesic. We investigated here the analgesic activity of new non-antibiotic TC derivatives using the formalin-induced nociceptive pain model in adult C57BL/6 mice. Specifically, we tested the effects of i.p. injections of DDMC (5, 10, 20 mg.kg-1) and DDOX (10, 20, 40 mg.kg-1), which are non-antibiotic derivatives of demeclocycline and doxycycline, respectively. Repeated treatments with DDMC remarkably reduced nociceptive pain in both phases of the test, at 10 mg.kg-1 its efficacy was comparable to that of 10 mg.kg-1 of morphine. DDOX was also effective in this paradigm but intrinsically less potent than DDMC, exerting analgesic effects between 20 and 40 mg.kg-1. Interestingly, a single injection of DDMC (10 mg.kg-1) was sufficient to produce a robust anti-nociceptive effect similar to that of morphine. A single injection of DDOX (40 mg.kg-1) also produced anti-nociceptive effects but only in the second phase of the test. Noticeably, male mice exhibited a better analgesic response to DDMC (10 mg.kg-1) than females. A single injection of DDMC (10 mg.kg-1) and morphine but not of DDOX (40mg.kg-1), powerfully inhibited formalin-induced spinal cord c-Fos expression whereas both TC derivatives restrained the activation of Iba-1-immunoreactive cells, indicating a potential indirect effect on inflamed microglial cells. In summary, the non-antibiotic TCs, DDMC and DDOX, demonstrated notable analgesic efficacy against formalin-induced pain, suggesting their potential as alternatives for analgesic treatment.

Long‐lasting behavioral and neurochemical effects of early‐life environmental enrichment in rats submitted to neonatal morphine administration

AbstractThe present study examined the medium‐ and long‐term effects of early environmental enrichment (EE) on neuromotor, nociceptive, cognitive, behavioral, and neurochemical parameters in newborn rats repeatedly exposed to morphine. The study employed 90 Wistar rats: 10 adult nulliparous females and 80 male pups. Litter was split into standard and EE housing. Following, half of each litter received saline (S) or morphine (M) injections, resulting in four groups: SC + S, EE + S, SC + M, and EE + M. EE was applied from PND1 to PND21, while morphine or saline was given daily (5 μg/s.c.) from PND8 to PND14. Neuromotor development was similar between groups. In the OF test, morphine reduced outer and total crossings, whereas EE increased inner crossings and rearings. Adult rats showed a decrease in outer and total crossings and grooming and an increase in rearing. EE increased the number of protected and unprotected head dipping. Adult rats showed an increase in protected head dipping. Adult rats showed a lower recognition index, and, when exposed to EE, a lower anxiety index and analgesia. EE increased brainstem and hippocampal BDNF levels. Adult rats had increased hypothalamus, spinal cord, and brainstem BDNF levels, an increase in the spinal cord, and decreased hypothalamus TNF‐α levels. This study demonstrated that early‐life EE raises BDNF levels in the brainstem and hippocampus of rats and modifies their behaviors (such as nociception, exploration, and anxiety) in a state‐dependent manner (morphine and age).

Cross-sectional study on the current status of county-level cancer prevention and treatment capabilities in the four southwestern provinces of China.

184 Background: Lung cancer (LC) stands out as the most prevalent form of cancer in China, and it is also the primary cause of cancer-related mortality. Notably, 42.3% of newly diagnosed cancer patients are identified at the grassroots level each year. In response, the Chinese government is actively promoting tiered diagnosis and treatment approaches. This study aims to evaluate the current state of county-level cancer prevention and treatment capabilities in China, offering suggestion for policy and the standardized pathway development. Methods: A cross-sectional study was conducted in 470 district and county (city) hospitals across four provinces in southwest China: Sichuan, Yunnan, Guangxi, and Guizhou, from December 2023 to March 2024. The study was initiated by 13 hospitals, and all participating physicians signed informed consent forms. All analyses were conducted by SPSS 22.0. Results: Of the 470 county-level hospitals in China, 151 have a permanent population of over 500,000. 146 counties (198 hospitals) have established cancer specialties. There are 74 medical linear accelerators and 33 cobalt-60 treatment machines. Among them, 63.6% are tertiary hospitals, and 94.9% are public hospitals. 37.4% of hospitals have linear accelerators, and 16.7% have cobalt-60 treatment machines. 89.8% perform TNM staging, 79.1% perform radical surgery, 96.4% perform chemotherapy, 83.2% perform endocrine therapy, 97.5% perform targeted therapy, 87.3% perform immunotherapy, 54.8% perform interventional therapy, and 34.0% perform radiotherapy. Additionally, 56.8% conduct multidisciplinary diagnosis and treatment (MDT), and 37.0% provide palliative care. 83% hospitals have pathology departments, and 46.0% have established cancer centers. 79% hospitals can perform routine pathological diagnosis, and 17.0% can perform genetic testing in-hospital. Imaging departments have conducted CT plain scans in 96.4% of cases, CT enhancements in 87.7%, MRI plain scans in 84.1%, and MRI enhancements in 72.3%. Fibro-bronchoscopy was carried out in 87.2% of cases, and gastrointestinal endoscopy in 84.2%. Morphine injection was accessible in 84.8% of cases, oxycodone in 64.5%, and tramadol in 86.8%. Non-steroidal analgesics were accessible in 88.3% of cases. Conclusions: In the southwestern areas of China, the penetration rate of oncology expertise is 31.1%. Most medical institutions offering oncology specialties are tertiary public hospitals. The average number of radiotherapy machines per county or district is 0.16. The development of surgery, oncology, and the imaging is well. Radiotherapy is still in developing, and the genetic testing capacity in-hospital is insufficient. The application of TNM staging is satisfactory. Accessibility to analgesic and anti-inflammatory drugs is well, but the construction of county cancer centers still needs improvement.

Diurnal sex differences in morphine withdrawal revealed by continuous assessment of voluntary home cage wheel running in the rat

Animal studies modeling recreational opioid use show more severe withdrawal symptoms in male compared to female rats, whereas our study modeling opioid use for pain showed a greater withdrawal-induced decrease in wheel running in female rats. The objective of this experiment was to determine whether sex differences in spontaneous morphine withdrawal are caused by differences in assessment method (i.e., wheel running vs. somatic symptoms). Twice daily injections of morphine (5 – 20 mg/kg, s.c.) for 5 days produced a dose and time dependent decrease in wheel running that was greater in male compared to female rats. Termination of morphine administration resulted in an overall decrease in running and a decrease in the amount of running during the dark phase of the light cycle from 95 % to approximately 75 %. In male rats, this decrease in the percent of dark running was caused by a large decrease in dark phase running, whereas female rats had a slightly higher increase in light phase running. Withdrawal also reduced maximal running speed and caused a decrease in body weight that was larger in male than female rats. Withdrawal symptoms were greatest on the day following the last morphine injection, but persisted for all 3 days of assessment. Morphine withdrawal produced a greater decrease in dark phase wheel running and body weight in male rats and a greater increase in light phase running in female rats. Voluntary home cage wheel running provides a continuous measure of opioid withdrawal that is consistent with other measures of opioid withdrawal.

The Effects of Eating a Traditional High Fat/High Carbohydrate or a Ketogenic Diet on Sensitivity of Female Rats to Morphine.

Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n = 8/diet) ate either a standard (low fat) laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, i.p.) injections. Morphine was administered acutely and chronically (involving 18 days of twice-daily injections, increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, i.p., to induce dependence and assess tolerance). The adverse effects of morphine (i.e., tolerance, withdrawal, and changes in body temperature) were assessed throughout the study. Acute morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Observable withdrawal signs and body temperature were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss in ways that could be relevant for patients.

Protracted opioid withdrawal behaviors are reduced by nitric oxide inhibition in mice

Following opioid cessation, patients with opioid use disorder experience physical and psychological withdrawal symptoms. Prolonged negative affect, including anxiety and heightened stress reactivity, continues after physical withdrawal symptoms subside, contributing to the high relapse rates. The nitric oxide system plays a role in synaptic plasticity downstream of the mu opioid receptor pathway, and nitric oxide synthase inhibitors attenuate physical opioid withdrawal signs. We hypothesized that N(gamma)-nitro-l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, would reduce negative affect after protracted opioid withdrawal. Therefore, we first modeled withdrawal in male and female mice using 5 days of morphine injections followed by behavioral tests after one week of forced abstinence from morphine. One week of morphine withdrawal caused altered responses to tests of affective behavior in both male and female mice. There were, however, both subtle and significant sex differences among many of the behavioral measures of negative affect. Males and females had differences in immobility during the tail suspension test during morphine withdrawal, while only females had altered grooming in the sucrose splash test. Forced l-NAME in the animals’ drinking water during withdrawal attenuated all physical and affective measures of withdrawal in males and females but there were subtle differences. Together, these results suggest that the nitric oxide system may be a target to ameliorate the different behavioral manifestations of negative affect in males and females.

Evaluation of Postoperative Pain in Posterior Segment Surgery of the Eye at the CHU-IOTA

Postoperative pain is predictable and therefore preventable; its management should be a priority. Posterior segment surgery is an underestimated source of pain. The objective of this work is to highlight the intensity of postoperative pain in this type of surgery. This was a 6-month prospective descriptive longitudinal study. Involving 67 patients operated for a pathology of the posterior segment. The simple verbal scale was used to assess pain in the postoperative period at HO, H8, H16 and H24. During the period, posterior segment surgery accounted for 1.88% of the institute's surgical activities. Male predominates with 88%; The mean age was 45.7 years with extremes of 7 and 75 years, vitrectomy accounted for 71.6% and scleral cryoindentation 28.4%. Peribulbar anaesthesia combining bupivacaine and xylocaine was the most commonly used with 80.6%. Intravenous injection of morphine intraoperatively was associated with peribulbar anesthesia in 19.4% of cases of scleral cryoindentation. In the immediate postoperative period (H0), pain was intense in 37%, moderate in 52% and low in 11% of patients after cryoindentation while it was absent in 52% and low in 48% of patients after vitrectomy. At H8 and H16, severe pain was reported in 47% of cryoindentations; It was reported as weak to moderate after vitrectomy in 91.66%. At H24, after treatment, patients had moderate pain in 69%, and low pain in 31% after cryoindentation; It was low in 85.71% after vitrectomy. This work allowed us to highlight the feelings of patients operated on in the posterior segment and to propose a postoperative management protocol. Keywords: Pain, Posterior segment, Locoregional anesthesia, Verbal scale.

Reinforcing systems of the brain and quantification of their work

BACKGROUND: The reinforcing systems of the brain are represented by the ventral forbrain dopaminergic bundle, which innervates the emotiogenic structures of the limbic system. Their study shows the reproduction of unconditioned (self-stimulation, self-administration) and conditioned reflex (preference for place, temperature, color) reactions. The quantitative assessment of the brain’s reinforcing systems remains unclear. For self-stimulation of brain structures, the change of the pedal presses in the Skinner chamber and some calculated coefficients are used, for example, the “mismatch coefficient”, which characterizes the temporal characteristics of the pedal pressings. AIM: To develop, test, and substantiate an additional objective quantitative method for assessing the reinforcing systems of the brain, called the “addiction coefficient”, based on an analysis of the effect of three psychoactive compounds (amphetamine, morphine and ethanol) in different doses on self-stimulation of the lateral hypothalamus in rats. MATERIALS AND METHODS: The main method for studying the reinforcing systems of the brain was the reaction of self-stimulation of the lateral hypothalamus in Wistar rats, which was modulated by the administration of psychoactive substances. The psychomotor stimulant amphetamine (phenamine) hydrochloride (0.5, 1, 2, and 4 mg/kg), narcotic analgesic morphine hydrochloride (1, 2, 4, and 8 mg/kg), and ethanol (0.5, 1, 2, and 4 g/kg) administered intraperitoneally were used as inductors of reinforcing. The control was the administration of of 0.9% NaCl solution (0.1, 0.2, 0.4, and 0.8 ml/rat). RESULTS: The use of different controls, characterized by an increase or decrease in the self-stimulation reaction in response to the introduction of 0.9% NaCl solution, showed that calculated coefficients, including the “mismatch coefficient”, can change in different directions and do not objectively reflect the reinforcing effects of pharmacological substances. The proposed “addiction coefficient”, which reflected the component of psychic dependence, changed unidirectionally toward an increase. The degree of this increase can be tens and hundreds of percent of the control and is significantly independent of the initial values of self-stimulation. As expected, the “addiction coefficient” increased most clearly after amphetamine administration and less significantly after morphine and ethanol injections. CONCLUSIONS: The “addiction coefficient” of a psychoactive substance, calculated as the ratio of the increase in pedal presses to the value of the “mismatch coefficient”, is a clear quantitative indicator when assessing the reinforcing properties of psychoactive substances in the self-stimulation reaction of the lateral hypothalamus. The “addiction coefficient” does not significantly depend on the initial level of self-stimulation and is recommended for a comparative assessment of the reinforcing properties of primarily related psychoactive compounds.

Mu-opioid receptor knockout on Foxp2-expressing neurons reduces aversion-resistant alcohol drinking.

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1fl/fl). Male and female Foxp2-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and homozygous Cre- (control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on Foxp2-expressing neurons renders mice more sensitive to quinine-adulterated ethanol (EtOH). Mice with the deletion (vs. Cre- controls) also consumed less alcohol during the final sessions of the IA task, responded less for sucrose under an FR3 schedule, and were less active at baseline and following morphine injection. Foxp2-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that Foxp2-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking.

Effects of Acetic Acid and Morphine in Shore Crabs, Carcinus maenas: Implications for the Possibility of Pain in Decapods.

Noxious chemicals, coupled with morphine treatment, are often used in studies on pain in vertebrates. Here we show that injection of morphine caused several behavioural changes in the crab, Carcinus maenas, including reduced pressing against the sides of the enclosure and more rubbing and picking at the mouth parts and, at least for a short time, more defensive displays. Subsequent injection of acetic acid into one rear leg caused rubbing of the injected leg and the injected leg was held vertically off the ground. These activities directed at or involving the specific leg are consistent with previous observations of directed behaviour following noxious stimuli and are consistent with the idea that decapods experience pain. Further, acetic acid but not injection of water induced autotomy of the injected leg in these animals. Because autotomy is temporally associated with directed behaviour, it is possible that the autotomy is a pain-related response. Acetic acid is clearly a noxious substance when applied to decapods. However, morphine had no effect on the activities associated with acetic acid injection and thus there is no evidence for an analgesic effect. Further, the injection of acetic acid did not interfere with behavioural effects of morphine. The activities directed towards the site of injection are like those observed with injection, or with external application, of various noxious substances and the present study adds to a growing body of knowledge about possible pain in decapods.

Characterization and validation of a spontaneous acute and protracted oxycodone withdrawal model in male and female mice

Opioid use disorder (OUD) is a serious health problem that may lead to physical dependence, in addition to affective disorders. Preclinical models are essential for studying the neurobiology of and developing pharmacotherapies to treat these problems. Historically, chronic morphine injections have most often been used to produce opioid-dependent animals, and withdrawal signs indicative of dependence were precipitated by administering an opioid antagonist. In the present studies, we have developed and validated a model of dependence on oxycodone (a widely prescribed opioid) during spontaneous withdrawal in male and female C57BL/6J mice. Dependence was induced by chronically administering oxycodone through osmotic minipumps at different doses for 7 days. Somatic withdrawal signs were measured after 3, 6, 24, and 48 h following minipump removal. Additionally, sensitivity to mechanical, thermal, and cold stimuli, along with anxiety-like behavior, were also measured. Our results indicated that spontaneous withdrawal following discontinuation of oxycodone produced an increase in total withdrawal signs after 60 and 120 mg/kg/day regimens of oxycodone administration. These signs were reversed by the administration of clinically approved medications for OUD. In general, both female and male mice showed similar profiles of somatic signs of spontaneous withdrawal. Spontaneous withdrawal also resulted in mechanical and cold hypersensitivity lasting for 24 and 14 days, respectively, and produced anxiety-like behaviors after 2 and 3 weeks following oxycodone removal. These results help validate a new model of oxycodone dependence, including the temporally distinct emergence of somatic, hyperalgesic, and anxiety-like behaviors, potentially useful for mechanistic and translational studies of opioid dependence.

Incidental dural tears during pediatric posterior spinal fusions

PurposeTo characterize the frequency of incidental dural tears in pediatric spine surgery, their treatment, complications, and results of long-term follow-up.MethodsA retrospective review of all pediatric patients who underwent a posterior spinal fusion (PSF) between 2004–2019 at a tertiary children’s hospital was conducted. Electronic medical records were reviewed for patient demographics, intra-operative data, presence of an incidental dural tear, repair method, and patient outcomes.Results3043 PSFs were reviewed, with 99 dural tears identified in 94 patients (3.3% overall incidence). Mean follow-up was 35.7 months (range 0.1–142.5). When the cause of the dural tear was specified, 69% occurred during exposure, 5% during pedicle screw placement, 4% during osteotomy, 2% during removal of implants, and 2% during intra-thecal injection of morphine. The rate of dural tears during primary PSF was significantly lower than during revision PSF procedures (2.6% vs. 6.2%, p < 0.05). 86.9% of dural tears were repaired and/or sealed intraoperatively, while 13.1% had spontaneous resolution. Postoperative headaches developed in 13.1% of patients and resolved at a mean of 7.6 days. There was no difference in the incidence of headaches in patients that were ordered bedrest vs. no bedrest (p > 0.99). Postoperative infections occurred in 9.5% of patients and 24.1% patients were identified to have undergone a revision surgery.ConclusionsIncidence of intra-operative dural tears in pediatric spine surgery is 3.3%. Although complications associated with the dural tear occur, most resolve over time and there were no long-term sequelae in patients with 2 years of follow up.Level of evidenceLevel IV.

Morphine timing-dependent modulation of TRPV1 phosphorylation correlates with differential morphine effects on myocardial ischemia/reperfusion injury

Opioids are used for pain relief in patients suffering from acute myocardial ischemia or infarction. Clinical and laboratory studies demonstrate that morphine treated patients or the experimental animal model suffering acute myocardial ischemia and reperfusion, may worsen myocardial viability. As transient receptor potential vanilloid 1 (TRPV1) plays important roles in pain sensation and cardio-protection, we query whether opioids may exacerbate myocardial viability via interaction with TRPV1 activity in the pain relief. We found the co-expressions of TRPV1 and opioid μ, δ and κ receptors in adult rat cardiomyocytes. Intravenous injection of morphine (0.3 mg/kg) at 20 min after induction of myocardial ischemia, in the rat model of acute myocardial ischemia and reperfusion, induced significant reduction of phosphorylated TRPV1 (p-TRPV1) in the ventricular myocardium and increase in serum cardiac troponin I (cTnI), compared with the ischemia/reperfusion controls (all P < 0.05). The effects of morphine were completely reversed by selective opioid μ, δ and κ receptor antagonists. While significant upregulation of p-TRPV1 (P < 0.05) and improvement of ±dP/dt max (all P < 0.05) were detected in the animals giving the same dose of morphine before induction of myocardial ischemia. The changes in p-TRPV1 correlate with the alterations of cTnI (r = −0.5840, P = 0.0283) and ±dP/dt max (r = 0.8084, P = 0.0005 and r = −0.8133, P = 0.0004, respectively). The findings of this study may indicate that potentiation and attenuation of TRPV1 sensitivity correlate with the improvement of the cardiac performance and the aggravation of myocardial viability, respectively, by giving morphine before and during myocardial ischemia and reperfusion.

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

Current Status of Cognition and Clinical Practice of Refractory Cancer Pain in Shanghai: A Questionnaire Survey.

This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai. From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China. A total of 238 responses participated in the survey. This survey reports physicians' understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors' knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff's understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training. Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.

Preconception opioids interact with mouse strain to alter morphine withdrawal in the next generation.

Transgenerational effects of preconception morphine exposure in female rats have been reported which suggest that epigenetic modifications triggered by female opioid exposure, even when that exposure ends several weeks prior to pregnancy, has significant ramifications for their future offspring. The current study compares two mouse strains with well-established genetic variation in their response to mu opioid receptor agonists, C57BL/6J (BL6) and 129S1/svlmJ (129) to determine whether genetic background modifies the impact of preconception opioid exposure. Adolescent females from both strains were injected daily with morphine for a total of 10 days using an increasing dosing regimen with controls receiving saline. Several weeks after their final injection, aged-matched BL6 and 129 morphine (Mor-F0) or saline (Sal-F0) females were mated with drug naïve males to generate Mor-F1 and Sal-F1 offspring, respectively. As adults, F1 mice were made morphine dependent using thrice daily morphine injections for 4 days. On day 5, mice were administered either saline or morphine followed 3 h later by naloxone. Behavioral and physiological signs of withdrawal were then measured. Regardless of strain or sex, morphine-dependent Mor-F1 mice had significantly lower levels of withdrawal-induced corticosterone but significantly higher glucose levels when compared to Sal-F1 controls. In contrast, both strain- and preconception opioid exposure effects on physical signs of morphine dependence were observed.

The Inflammation/NF-κB and BDNF/TrkB/CREB Pathways in the Cerebellum Are Implicated in the Changes in Spatial Working Memory After Both Morphine Dependence and Withdrawal in Rat.

We aimed to explore the impact of the cerebellum on the decline in spatial working memory following morphine dependence and withdrawal. Two groups of male Wistar rats received intraperitoneal injections of either saline (1ml/kg) or morphine (10mg/kg) twice daily for 10days, serving as the control and dependent groups. Additionally, a withdrawal group underwent a 30-day withdrawal period after the dependence phase. Spatial working memory was assessed using a Y maze test. ELISA and western blot were used to assess protein levels in the cerebellum. On day 1, morphine impaired spatial working memory, deteriorated further after 10days of morphine use, and nearly returned to its initial level following a 30-day withdrawal period. On day 10, significant increases in TNF-α, IL-1β, and CXCL12 and a notable decrease in IL-10 levels were detected in the morphine-dependent group, which did not completely restore in the withdrawal group. The protein levels of CXCR4, TLR4, P2X7R, and NF-κB sharply increased in the morphine-dependent group. However, these levels almost returned to normal after withdrawal. In the morphine-dependent group, BDNF decreased, while TrkB and CREB1 increased noticeably. Nevertheless, after withdrawal, TrkB and CREB1 but not BDNF levels returned to normal. In the morphine-dependent group, both CACNA1 and KCNMA1 decreased significantly and after withdrawal, only KCNMA1 showed partial restoration, while CACNA1 did not. It can be concluded that inflammation/NF-κB and BDNF/TrkB/CREB pathways play key roles in neural adaptation within the cerebellum, contributing to the decline in spatial working memory after both morphine dependence and withdrawal.

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations.

The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse), are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, we show that bath perfusion of morphine (10 µM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability in PVT neurons that project to the NAcSh. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath-perfused morphine (10 µM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1 and D2 receptor-expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP.