Effects Of Morphine Research Articles

μ opioid receptor carboxyl terminal-derived peptide alleviates morphine tolerance by inhibiting β-arrestin2.

The interaction between the μ opioid receptor (MOR) and β-arrestin2 serves as a model for addressing morphine tolerance. A peptide was designed to alleviate morphine tolerance through interfering with the interaction of MOR and β-arrestin2. We developed a peptide derived from MOR. The MOR-TAT-pep peptide was expressed in E. coli Bl21(DE3) and purified. The effects of MOR-TAT-pep in alleviating morphine tolerance was examined through behavior tests. The potential mechanism was detected by Western blotting, Mammalian Two-Hybrid and other techniques. The pretreatment with MOR-TAT-pep prior to morphine usage led to an enhanced analgesic effectiveness of morphine and a significant reduction in the development of morphine tolerance. The peptide directly interacted with β-arrestin2 during morphine treatment and deceased the membrane recruitment of β-arrestin2. MOR-TAT-pep effectively suppressed the increase of β-arrestin2 induced by morphine. The MOR-TAT-pep could alleviate morphine tolerance through inhibition of β-arrestin2.

Zingerone Alleviates Morphine Tolerance and Dependence in Mice by Reducing Oxidative Stress-Mediated NLRP3 Inflammasome Activation.

Morphine (MPH) is widely used for pain management; however, long-term MPH therapy results in antinociceptive tolerance and physical dependence, limiting its clinical use. Zingerone (ZIN) is a natural phenolic compound with neuroprotective effects. We investigated the effects of single and repeated doses of ZIN on MPH-induced tolerance, dependence, and underlying biochemical mechanisms. After a dose-response experiment, tolerance was developed to MPH (10mg/kg, i.p.) for seven days. In the single-dose study, ZIN was administered on day seven. In the repeated-dose study, ZIN was administered for seven days. Naloxone (5mg/kg, i.p., 120min after MPH) was injected to assess withdrawal signs on day seven. The levels of thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), total thiol (TT), and glutathione peroxidase (GPx) were measured in the prefrontal cortex. The protein levels of interleukin-1 beta (IL-1β) and NLRP3-ASC-Caspase-1 axis were assessed by ELISA and Western blotting, respectively. Results showed that ZIN (100mg/kg) had no antinociceptive activity, and subsequent experiments were performed at this dose. Repeated ZIN reversed MPH antinociceptive tolerance, whereas single ZIN did not. Single and repeated ZIN attenuated naloxone-induced jumping. In addition, repeated ZIN significantly inhibited weight loss. Repeated ZIN suppressed the MPH-induced increase in TBARS, NO, IL-1β, NLRP3, ASC, and Caspase-1. It also inhibited MPH-induced TT and GPx reduction. In contrast, single ZIN had no effect. Findings suggest that ZIN reduces MPH-induced tolerance and dependence by suppressing oxidative stress and NLRP3 inflammasome activation. This study provides a novel therapeutic approach to reduce the side effects of MPH.

Regulation of the Endogenous Opiate Signaling Pathway against Oxidative Stress and Inflammation: A Considerable Approach for Exploring Preclinical Treatment of Parkinson’s Disease

Introduction: Oxidative stress and inflammation are major factors contributing to the progressive death of dopaminergic neurons in Parkinson’s disease (PD). Recent studies have demonstrated that morphine’s biosynthetic pathway, coupled with nitric oxide (NO) release, is evolutionarily conserved throughout animals and humans. Moreover, dopamine is a key precursor for morphine biosynthesis. Method: The present study evaluated a series of preclinical experiments to evaluate the effects of low-level morphine treatment upon neuro-immune tissues exposed to rotenone and 6-OHDA as models of PD, followed by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay and cell/tissue computer-assisted imaging analyses to assess cell/neuronal viability. Results: Morphine at normal physiological concentrations (i.e., 10−6 M and 10−7 M) provided neuroprotection, as it significantly inhibited rotenone and 6-OHDA dopaminergic insults; thereby, reducing and/or forestalling cell death in invertebrate ganglia and human nerve cells. To ensure that morphine caused this neuroprotective effect, naloxone, a potent opiate receptor antagonist, was employed and the results showed that it blocked morphine’s neuroprotective effects. Additionally, co-incubation of NO synthase inhibitor L-NAME also blocked morphine’s neuroprotective effects against rotenone and 6-OHDA insults. Conclusions: Taken together, the present preclinical study showed that while morphine can attenuate lipopolysaccharide-induced inflammation and cell death, both naloxone and L-NAME can abolish this effect. Preincubation of morphine precursors (i.e., L-3,4-dihydroxyphenylalanine, reticuline, and trihexyphenidyl [THP] at physiological concentrations) mimics the observed morphine effect. However, high concentrations of THP, a precursor of the morphine biosynthetic pathway, induced cell death, indicating the physiological importance of morphine biosynthesis in neural tissues. Thus, understanding the morphine biosynthetic pathway coupled with a NO signaling mechanism as a molecular target for neuroprotection against oxidative stress and inflammation in other preclinical models of PD is warranted.

Doxycycline diminishes the rewarding and psychomotor effects induced by morphine and cocaine

Few pharmacological treatments are available for substance use disorders (SUDs). Neuroplastic changes induced by increased activity of metalloproteinase (MMP) enzymes in the brain are among the several molecular processes that may play a role in drug addiction. Doxycycline, a widely used tetracycline that crosses the blood-brain barrier, inhibits MMPs and has been investigated as a potential treatment for brain disorders. However, the effects of doxycycline on rewarding properties of drugs of abuse remain not investigated. Here, we tested the effects of low doses of doxycycline on the rewarding effects of morphine and cocaine in conditioned place preference (CPP) and locomotor sensitization in mice. Acute doxycycline (10 mg/kg) attenuated the cocaine-induced CPP and hyperlocomotion. Repeated doxycycline (10 mg/kg) blocked hyperlocomotion and attenuated the locomotor sensitization induced by cocaine. It also decreased the rewarding effects in the CPP induced by morphine and cocaine. Our results suggest that doxycycline could be repurposed for treating SUDs.

The Effect of Caudal Ropivacaine and Morphine on Postoperative Analgesia in Total Laparoscopic Hysterectomy: A Prospective, Double-Blind, Randomized Controlled Trial.

Multiple regional nerve blocks proved no additional benefit in total laparoscopic hysterectomy in multimodal analgesia, as postoperative pain may mainly originate from the vaginal cuff. Theoretically, caudal block can relieve pain from the vaginal cuff by a sacral spinal nerve block. We aimed to verify whether a caudal block with ropivacaine and morphine can achieve an analgesic effect without additional adverse effects after a total laparoscopic hysterectomy. Forty-eight patients undergoing total laparoscopic hysterectomy were randomly allocated to receive preoperative caudal block with 20 mL of mixture including 0.25% ropivacaine and 2 mg morphine (caudal block group) or sham block (sham group). The primary outcome was the postoperative 24 h cumulative sufentanil consumption. Median (IQR) sufentanil consumption in the first 24 postoperative hours of the caudal block group and the sham group was 0.00 (0.00 to 0.05) μg/kg vs 0.13 (0.04 to 0.21) μg/kg, respectively, p < 0.001. The majority of patients felt that visceral pain was more intense than incisional pain at 1, 6, 12, and 24 h post-surgery in the sham group (95.8% at 1 h, 95.8% at 6 h, 95.8% at 12 h, and 75% at 24 h post-surgery). Compared to the sham group, the caudal block reduced visceral pain scores at rest and during movement at 1 h (p < 0.001), 6 h (p < 0.001), 12 h (p < 0.001), and 24 h (p < 0.001) post-surgery. Intraoperative remifentanil consumption was significantly lower in the caudal block group than in the sham group (p = 0.004). There were no significant differences in other secondary outcomes between the two groups. A caudal block with ropivacaine and morphine could provide a satisfactory analgesic effect for 24 h postoperatively without additional adverse effects after total laparoscopic hysterectomy.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve painbut provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of theskin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation wassignificantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

Abstract PO-089: Opioid-mediated suppression of anti-tumor immunity via peripheral OPRM1 signaling in head and neck squamous cell carcinoma

Abstract Head and Neck squamous cell carcinoma (HNSCC) causes severe pain, beyond what is reported in other cancer types. Opioids are the current backbone of HNSCC pain treatment but may have an immunomodulatory effect in the presence of cancer; T cells express opioid receptors. We recently demonstrated that opioids may affect the efficacy of anti-PD1 monoclonal antibody (mAb) treatment in recurrent/metastastic HNSCC patients; opioid usage was associated with significantly lower progression free survival and overall survival as well as decreased CD8 T cells in the tumor microenvironment. We hypothesized that cancer immunosurveillance is impaired by the immunosuppressive actions of exogenous opioids via peripheral mu-opioid receptor (OPRM1) signaling. A syngeneic mouse oral cancer model was used to determine if analgesic morphine impacted the tumor-associated immune response during tumor progression and in response to anti-PD1 mAb; mouse oral cancer cell line 1 (MOC1) tumor-bearing mice were treated with vehicle or morphine (10mg/kg i.p., 2x daily for 4.5 days) and the tumor-associated immune infiltrate was assessed between groups using flow cytometry. Anti-PD1 mAb (250µg/mouse, 3 × 2 day interval) was initiated directly following morphine treatment. Co-administration of methylnaltrexone (MNTX), a peripheral OPRM1 antagonist used to confirm specificity and site of action of the morphine-induced effects. Finally, any direct effects of morphine on tumor cells were investigated in oral cancer cell lines using quantitative PCR and colorimetric proliferation assays. Morphine induced a 75±5% reduction in CD8+ T cells and a 90±3% reduction in CD19+ B cells in MOC1 compared to sham mice (n=6/group); morphine-induced immunosuppression was completely blocked with co-treatment of MNTX. Studies involving morphine administration prior to anti-PD1 treatment are currently underway but given the substantial suppression in infiltrating lymphocyte populations, efficacy is expected to be lessened. Lastly, Oprm1 expression was not detected at the mRNA level in mouse oral cancer cell lines. In vitro, 10µM morphine did not induce cell proliferation (proliferation relative to vehicle after 48hr; vehicle=100±8.3%, morphine=115.7±9.6%) or improve wound healing (wound closure after 24hr; vehicle=76.2±11.6%, morphine=78.5±11.4%). Taken together, our data suggest that morphine suppresses anti-tumor immunity via peripheral OPRM1 signaling in immune cells but not tumor cells. Further investigation is warranted to determine whether peripheral opioid blockade (i.e. MNTX) can slow tumor progression and improve response to cancer treatments while preserving centrally-mediated analgesia. Citation Format: Lisa A. McIlvried, Mona Yuan, Nicole L. Horan, Megan A. Atherton, Marci L. Nilsen, Dan P. Zandberg, Nicole N. Scheff. Opioid-mediated suppression of anti-tumor immunity via peripheral OPRM1 signaling in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-089.

Effects of MIdazolam versus MOrphine in acute cardiogenic pulmonary edema and chronic obstructive pulmonary disease: An analysis of MIMO trial

AimsChronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure. The MIMO trial showed that patients with acute cardiogenic pulmonary edema (ACPE) treated with midazolam had fewer serious adverse events than those treated with morphine. In this post hoc analysis, we examined whether the presence/ absence of COPD modifies the reduced risk of midazolam over morphine. MethodsPatients >18 years old clinically diagnosed with ACPE and with dyspnea and anxiety were randomized (1:1) at emergency department arrival to receive either intravenous midazolam or morphine. In this post hoc analysis, we calculated the relative risk (RR) of serious adverse events in patients with and without COPD. Calculating the CochranMantel-Haenszel interaction test, we evaluated if COPD modified the reduced risk of serious adverse events in the midazolam arm compared to morphine. ResultsOverall, 25 (22.5%) of the 111 patients randomized had a history of COPD. Patients with COPD were more commonly men with a history of previous episodes of heart failure, than participants without COPD. In the COPD group, the RR for the incidence of serious adverse events in the midazolam versus morphine arm was 0.36 (95%CI, 0.1–1.46). In the group without COPD, the RR was 0.44 (95%CI, 0.22–0.91). The presence of COPD did not modify the reduced risk of serious adverse events in the midazolam arm compared to morphine (p for interaction =0.79). ConclusionsThe reduced risk of serious adverse events in the midazolam group compared with morphine is similar in patients with and without COPD.

Pain and anxiety in patients with breast cancer treated with morphine versus tramal with virtual reality

The treatment of pain and anxiety in cancer patients includes both pharmaceutical and non-pharmacological approaches. The researchers of this study aimed to compare the effectiveness of morphine versus Tramal with virtual reality therapy (VR) in reducing pain and anxiety in female patients with breast cancer. The sample was composed of 80 women with breast cancer who where treated at a specialized cancer center in Jordan. A quasi-experimental design was used in the study intervention. When used with VR, the tramal analgesics did not differe significactly from the effect of morphine in reducing the pain and anxiety. However, both groups had a significant drop in the level of pain and anxiety. When combined with VR, the use of weak opioids such as Tramal will have nearly the same effect as strong opioids such as Morphine in reducing pain and anxiety in breast cancer patients.

Opioid-Sparing Effect of Intrathecal Morphine for Postoperative Pain Control.

Opioid-Sparing Effect of Intrathecal Morphine for Postoperative Pain Control.

Omission of perioperative morphine reduces postoperative pain in proctological interventions: a single-center analysis

There is an increase in outpatient procedures and this trend will continue in the future. For hemorrhoidectomy, it is the standard of treatment in many health care systems. Perioperative management including adequate pain control is of paramount importance to ensure successful ambulatory surgery. This study investigates the role and effect of morphine compared to short-acting opiates applied before, during, or after proctological interventions and with focus on hemorrhoidectomy. A retrospective analysis of a prospective database was conducted comparing two populations. The control cohort received morphine (Yes-Mô) intra- and postoperatively, while the intervention group did not receive morphine (No-Mô) between January 2018 and January 2020. Both cohorts were balanced by propensity score matching. The outcomes were postoperative pain measured by numeric ratings scale (NRS) one hour postoperatively, pain 24 h postoperatively, success rate of outpatient management, and complication rate including postoperative nausea and vomiting as well as urinary retention. The intervention population comprised 54 patients and the control group contained 79 patients. One hour after surgery, patients in No-Mô reported lower NRS (1.44 ± 1.41) compared to Yes-Mô (2.48 ± 2.30) (p = 0.029). However, there was no difference in NRS 24 h postoperatively (No-Mô: 1.61 ± 1.41 vs Yes-Mô: 1.63 ± 1.72; p = 0.738). 100% of No-Mô was managed as outpatients while only 50% of Yes-Mô was dismissed on the day of the operation (p = < 0.001). There was no difference in postoperative complications (including postoperative nausea and vomiting (PONV) and urinary retention) between the two groups (PONV No-Mô 7.4% vs Yes-Mô 5.6%, p = 1.0 and urinary retention No-Mô 3.7% vs Yes-Mô 7.4%, p = 0.679). No-Mô received an oral morphine equivalent of 227.25 ± 140.35 mg intraoperatively and 11.02 ± 18.02 mg postoperatively. Yes-Mô received 263.17 ± 153.60 mg intraoperatively and 15.97 ± 14.17 mg postoperatively. The difference in received morphine equivalent between the groups was not significant after matching for the intraoperative (p = 0.212) and postoperative (p = 0.119) received equivalent. Omission of perioperative morphine is a viable but yet not understood method for reducing postoperative pain. Omission of morphine leads to a lower use of total morphine equivalent to attain satisfactory analgesia. The reduction of the overall opiate load and using opiates with a very short half-life potentially leads to a reduction of side effects like sedation. This in turn promotes discharge of the patient on the day of surgery. Omission of morphine is safe and does not increase postoperative complications.

Comparison of the analgesic effect of intrathecal morphine between laparoscopic and open living donor hepatectomy: Propensity score matching analysis.

Laparoscopic donor hepatectomy is being increasingly adopted in transplant programs due to its numerous advantages. However, the role of intrathecal morphine (ITM) in laparoscopic donor hepatectomy has not been thoroughly investigated. This study aimed to compare the analgesic effects and safety of ITM between laparoscopic and open donor hepatectomy. This retrospective study included 742 donors who underwent hepatectomy with ITM between April 2007 and June 2019. Among them, 168 and 574 donors underwent laparoscopic hepatectomy (LH) and open hepatectomy (OH), respectively. Propensity score matching yielded two comparable groups of 168 donors each. The primary endpoint was the incidence of moderate-to-severe pain (maximum numerical rating scale [NRS] pain score ≥ 4) within 24 postoperative hours. The LH group had a significantly lower incidence of moderate-to-severe pain within 24 postoperative hours than the OH group (16.1% vs 64.3%, P < .001). Moreover, the cumulative rescue intravenous opioids (in morphine-equivalent dose) on postoperative day (POD) 1 was lower in the LH group than in the OH group (3.3 [0-8.3] mg vs 10 [3.3-17.3] mg; P < .001). There were no significant between-group differences in the incidence of respiratory depression (2.4% vs 0.6%; P = .371) and prescriptions for pruritus (14.3% vs 15.5%; P = .878). However, the prescriptions for postoperative nausea and vomiting (PONV) was significantly higher in the LH group than in the OH group (64.9% vs 41.7%; P < .001). The predictors of antiemetic agent prescription included the use of laparoscopic procedure (adjusted odds ratio [OR], 2.05; 95% confidence interval [CI], 1.11-3.79; P = .021) and female sex (adjusted OR, 5.63; 95% CI, 3.19-9.92; P < .001). Preoperative ITM administration resulted in a significantly lower incidence of moderate-to-severe pain within 24 postoperative hours after laparoscopic donor hepatectomy than after open donor hepatectomy.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats.

Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.

Intrathecal Morphine Use Improves Postoperative Analgesia and Reduces Opioid Consumption in Patients Undergoing Total Knee Arthroplasty Under Spinal Anesthesia: A Retrospective Study.

Background Intrathecal morphine (ITM) provides effective postoperative analgesia for patients undergoing total knee arthroplasty (TKA) under spinal anesthesia (SA). The management of pain in patients undergoing TKA has remained a challenge for anesthesiologists, as no single regional anesthesia technique is adequate with regard to balancing effective analgesia with minimal side effects. Severe postoperative pain following TKA has been shown to negatively impact patient outcomes and mortality. This study is aimed to describe the effect of intrathecal morphine in patients undergoing total knee arthroplasty. Methods This was a retrospective, descriptive, and single-center study conducted on patients undergoing total knee arthroplasty from June 1, 2022, to June 1, 2023. The sample size consisted of 50 patients who were 18 years and older, American Society of Anesthesiology (ASA) class 1-3, and patients who had received either 150 mcg (experimental) or noITM dose under spinal anesthesia. Oral morphine requirement (OME) and visual analog pain scale (VAS) were used to assess pain in the first 24 hours after surgery. Results The experimental group had significantly lower OME usage in the post-anesthesia care unit (PACU) (p < 0.001) and at six hours (p = 0.040) postoperatively. At 12 hours and 24 hours postoperatively, the two groups had similar OME use (p > 0.20, for both). The experimental group had significantly less total OME use over the first 24-hour postoperative period.The experimental group had significantly lower pain scores in the PACU (p<0.001) and at six hours postop (p=0.002); there were no significant differences between groups at 12- and 24-hours postop. The ambulation distance was clinically significant and better in the ITM group but was not statistically significant (p = 0.080). There was no difference between groups in the incidence of postoperative nausea and vomiting (PONV). Conclusion The careful use of ITM with the optimal dose offers an effective addition to regional anesthesia for improved analgesia with minimal side effects. The 150 mcg ITM dose provided good analgesic effects with longer duration and was not associated with respiratory depression.

Western diet consumption does not impact the rewarding and aversive effects of morphine in male Sprague-Dawley rats

The impacts of high-fat and/or high-sugar diets on opioid-induced effects are well documented; however, little is known about the effect of such diet on the affective responses to opiates. To address this issue, in the present experiment male Sprague-Dawley rats were given ad libitum access to a western-style diet (high in saturated fat and sugar) or a standard laboratory chow diet beginning in adolescence and continuing into adulthood at which point they were trained in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure to assess the aversive and rewarding effects of morphine, respectively. On four conditioning cycles, animals were given access to a novel saccharin solution, injected with morphine (1 mg/kg or 5 mg/kg), and then placed on one side of a place preference chamber. Animals were then tested for place preference and saccharin preference. All subjects injected with morphine displayed significant avoidance of the morphine-associated solution (CTA) and preferred the side associated with the drug (CPP). Furthermore, there were no differences between the two diet groups, indicating that chronic exposure to the western diet had no impact on the affective properties of morphine (despite increasing caloric intake, body weight, body fat and lean body mass). Given previously reported increases in drug self-administration in animals with a history of western-diet consumption, this study suggests that western-diet exposure may increase drug intake via mechanisms other than changes in the rewarding or aversive effects of the drug.

Supraspinal neuroinflammation and anxio-depressive-like behaviors in young- and older- adult mice with osteoarthritis pain: the effect of morphine.

Asteoarthritis (OA) is a leading cause of chronic pain in the elderly population and is often associated with emotional comorbidities such as anxiety and depression. Despite age is a risk factor for both OA and mood disorders, preclinical studies are mainly conducted in young adult animals. Here, using young adult (11-week-old) and older adult (20-month-old) mice, we evaluate in a monosodium-iodoacetate-(MIA)-induced OA model the development of anxio-depressive-like behaviors and whether brain neuroinflammation may underlie the observed changes. We also test whether an effective pain treatment may prevent behavioral and biochemical alterations. Mechanical allodynia was monitored throughout the experimental protocol, while at the end of protocol (14days), anxio-depressive-like behaviors and cognitive dysfunction were assessed. Neuroinflammatory condition was evaluated in prefrontal cortex, hippocampus and hypothalamus. Serum IFNγ levels were also measured. Moreover, we test the efficacy of a 1-week treatment with morphine (2.5mg/kg) on pain, mood alterations and neuroinflammation. We observed that young adult and older adult controls (CTRs) mice had comparable allodynic thresholds and developed similar allodynia after MIA injection. Older adult CTRs were characterized by altered behavior in the tests used to assess the presence of depression and cognitive impairment and by elevated neuroinflammatory markers in brain areas compared to younger ones. The presence of pain induced depressive-like behavior and neuroinflammation in adult young mice, anxiety-like behavior in both age groups and worsened neuroinflammation in older adult mice. Morphine treatment counteracted pain, anxio-depressive behaviors and neuroinflammatory activation in both young adult and older adult mice. Here, we demonstrated that the presence of chronic pain in young adult mice induces mood alterations and supraspinal biochemical changes and aggravates the alterations already evident in older adult animals. A treatment with morphine, counteracting the pain, prevents the development of anxio-depressive disorders and reduces neuroinflammation.

Maladaptive plasticity induced by morphine is mediated by hippocampal astrocytic Connexin-43

AimsDrug addiction is an aberrant learning process that involves the recruitment of memory systems. We have previously demonstrated that morphine exposure causes maladaptive synaptic plasticity which involved hippocampal glial cells, especially astrocytes. Morphine addiction has been associated with astrocytic connexin 43 (Cx43), which plays a role in synaptic homeostasis. This study aimed to examine the role of hippocampal astrocytic Cx43 in morphine-induced maladaptive plasticity as a mechanism of addiction. Main methodsMale rats were injected with morphine (10 mg/kg) subcutaneously every 12 h for nine days to induce dependence. Cx43 was inhibited by TAT-Gap19 (1 μl/1 nmol) microinjection in the CA1 region of the hippocampus 30 min before each morning morphine injection. Field potential recordings were used to assess synaptic plasticity. fEPSP was recorded from the CA1 area following CA3 stimulation. Key findingsElectrophysiological results showed that morphine treatment altered baseline synaptic responses. It also appears that morphine treatment augmented long-term potentiation (LTP) compared with the control group. Hippocampal astrocytic Cx43 inhibition, with the TAT-Gap19, undermines these effects of morphine on baseline synaptic responses and LTP. Despite this, long-term depression (LTD) did not differ significantly between the groups. Additionally, in the morphine-receiving group, inhibition of Cx43 significantly reduced the paired-pulse index at an 80-millisecond inter-pulse interval when assessing short-term plasticity. SignificanceThe results of this study demonstrated that inhibiting Cx43 reduced synaptic plasticity induced by morphine. It can be concluded that hippocampal astrocytes through Cx43 are involved in morphine-induced metaplasticity.

Effect of Intrathecal Morphine on Postdural Puncture Headache in Obstetric Anaesthesia.

Intrathecal morphine is used as an effective component of multimodal analgesia in postoperative analgesia in cesarean section patients. We aimed to analyze the relationship between intrathecal morphine administration and postdural puncture headache (PDPH), pain score and analgesia consumption in the postoperative period, and maternal fetal effects. One hundred four pregnant women aged ≥18 years (American Society of Anesthesiology physical status I or II, >36 weeks gestation) who were scheduled for elective cesarean section under spinal anaesthesia were included in this study. Spinal anesthesia consisted of bupivacaine with or without morphine (Group M: 10 mg heavy marcaine + 25 mcg fentanyl + 100 mcg morphine; Group F: 10 mg heavy marcaine + 25 mcg fentanyl). The effect of intrathecal morphine on PDPH, postoperative pain score, analgesia consumption, and maternal and fetal effects were recorded for 5 days. PDPH developed in a total of 33 patients (Group M: 18 and Group F: 15, P=0.274). When we evaluated PDPH with the VAS, there was no significant difference between the groups. The postoperative visual analogue scale (VAS) was lower in the morphine group, and no statistically significant difference was found in the VAS 1st hr and VAS 2nd hr, whereas the VAS 6th hr and VAS 24th hr were found to be statistically significant. There was no difference in terms of PDPH, the first analgesic requirement and postoperative nausea-vomiting, but meperidine consumption was lower in the morphine group. Low-dose intrathecal morphine did not affect the incidence of PDPH. It is an effective method that can be used in cesarean section patients without increasing the maternal and fetal side effects from postoperative analgesia.