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Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.International Journal of Biological... 2024Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the...
Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.
Topics: Humans; Morphine; Apelin Receptors; Cancer Pain; Lipoylation; Neuralgia; Neoplasms
PubMed: 38164190
DOI: 10.7150/ijbs.86888 -
Molecules (Basel, Switzerland) Jun 2023Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of... (Review)
Review
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to -methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.
Topics: Humans; Analgesics, Opioid; Morphinans; Pain; Analgesics; Morphine; Receptors, Opioid, mu
PubMed: 37375318
DOI: 10.3390/molecules28124761 -
Cleveland Clinic Journal of Medicine Sep 2023Buprenorphine is a safe and effective treatment for opioid use disorder but remains underutilized because a major challenge of conventional buprenorphine initiation... (Review)
Review
Buprenorphine is a safe and effective treatment for opioid use disorder but remains underutilized because a major challenge of conventional buprenorphine initiation (termed ) is that the patient must already be in opioid withdrawal. Previous legal barriers and clinician lack of familiarity with the unique pharmacology of buprenorphine have also limited its use. In this review, we outline changes regarding buprenorphine prescribing laws and physician perceptions of buprenorphine. We also review buprenorphine pharmacology and novel low-dose buprenorphine induction procedures that can be adopted in primary care settings to improve treatment acceptability, retention, and outcomes.
Topics: Humans; Buprenorphine; Opioid-Related Disorders; Physicians; Substance Withdrawal Syndrome; Primary Health Care
PubMed: 37657832
DOI: 10.3949/ccjm.90a.23022 -
Frontiers in Public Health 2022Impulsivity, affective instability, and neglect of oneself and other people's safety as symptoms of personality dysfunction are associated with risky behaviors regarding...
BACKGROUND
Impulsivity, affective instability, and neglect of oneself and other people's safety as symptoms of personality dysfunction are associated with risky behaviors regarding the transmission of infectious diseases either sexually or by intravenous drug abuse.
OBJECTIVE
The aim of this study was to analyze the association between hepatitis C virus (HCV) infection and personality dysfunction in opiate addicts on opioid substitution treatment.
METHODS
This was a cross-sectional, observational investigation of patients over 18 years of age who were actively participating in opioid substitution treatment at five centers in Bosnia and Herzegovina. The occurrence of HCV infection was the primary study outcome, and personality functioning, the main independent variable, was assessed using the Severity Indices of Personality Problems (SIPP-118) questionnaire. The association between scores of personality functioning domains items and HCV infection status was determined by binary logistic regression analysis.
RESULTS
Patients on opioid substitution therapy with HCV infection more frequently had personality disorders (OR 2.168, 95% CI 1.161-4.05) and were treated longer than patients without HCV infection (OR 1.076, 95% CI 1.015-1.14). HCV infection was associated with lower self-respect (OR 0.946, 95% CI 0.906-0.988), decreased capacity to have enduring relationships with other people (OR 0.878, 95% CI 0.797-0.966), and lower capability to cooperate with others (OR 0.933, 95%CI 0.888-0.98). On the other hand, except for self-respect, other elements of the Identity Integration domain (enjoyment, purposefulness, stable self-image, and self-reflexive functioning), when more functional, increased the risk of HCV infection.
CONCLUSIONS
Our study demonstrates that opiate addicts on opioid substitution treatment have a higher risk of HCV infection if their personality is dysfunctional, especially in the aspects of self-respect, enduring relationships, and cooperativity. The risk is even higher in addicts who have an established diagnosis of any kind of personality disorder.
Topics: Adolescent; Adult; Cross-Sectional Studies; Hepacivirus; Hepatitis C; Humans; Opiate Alkaloids; Opiate Substitution Treatment; Opioid-Related Disorders; Personality; Personality Disorders
PubMed: 36159261
DOI: 10.3389/fpubh.2022.1009413 -
Basic & Clinical Pharmacology &... Jul 2022Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess...
Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol.
Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Denmark; Humans; Morphine; Oxycodone; Tramadol
PubMed: 35538919
DOI: 10.1111/bcpt.13741 -
The Primary Care Companion For CNS... Feb 2022
Topics: Buprenorphine; Humans; Male; Middle Aged; Naloxone
PubMed: 35213940
DOI: 10.4088/PCC.21cr03007 -
Harm Reduction Journal Sep 2021Heroin and cocaine are among the most dangerous illicit drugs available and their presence on the market is increasing. These facts have led to the investigation of the...
BACKGROUND
Heroin and cocaine are among the most dangerous illicit drugs available and their presence on the market is increasing. These facts have led to the investigation of the quality of heroin and cocaine samples seized in Luxembourg by police and customs but also collected at the national supervised drug consumption facilities.
METHODS
Samples obtained from 2019 to 2020 were analyzed to determine their composition and content using GC-MS, HPLC-UV and LC-Q-ToF. The statistical evaluation of concentration changes depending on the source of collection is based on an ANOVA single factor test and a two-tailed t test.
RESULTS
Results showed important differences between seizure and collection sources. For both drugs, customs samples had significantly higher concentrations than police samples and the latter had significantly higher concentrations than samples from drug consumption facilities, whereas for heroin two cutting steps were identified, for cocaine samples only one appears to occur on the local market. Indeed, cocaine samples seized by police consisted of a mixture of low and high concentration samples.
CONCLUSION
The results show that extensive adulteration with pharmacological active and inactive compounds takes place at local levels, which, however, are different for heroin and cocaine. This knowledge on variability of quality of drugs should be considered in the elaboration of drug and harm prevention strategies.
Topics: Cocaine; Drug Contamination; Heroin; Humans; Illicit Drugs; Luxembourg
PubMed: 34530816
DOI: 10.1186/s12954-021-00544-x -
Veterinaria Italiana Dec 2022This study describes the selected pharmacodynamics and pharmacokinetics of nalbuphine (NAL) in xylazine (XYL)‑sedated horses. Five adult healthy horses were randomly...
This study describes the selected pharmacodynamics and pharmacokinetics of nalbuphine (NAL) in xylazine (XYL)‑sedated horses. Five adult healthy horses were randomly received 2 treatments at a 1‑week interval; XYL treatment (0.55 mg/kg IV) and XYL/NAL treatment (XYL, 0.55 mg/kg IV; NAL, 0.3 mg/kg IV). The measured pharmacodynamic variables were sedative and analgesic effects and the effect on ataxia and some physiological parameters. for the pharmacokinetics of NAL, its plasma concentrations were measured using HPLC and a 2‑compartment analysis was performed. Greater and prolonged sedation was evident after XYL/NAL treatment compared with XYL treatment. Slightly improved and prolonged analgesia was demonstrated after XYL/NAL treatment. Significant changes in blood pressure and respiratory rate lasted for a shorter duration with XYL/NAL treatment than with XYL treatment. After XYL treatment, rectal temperature was significantly different from baseline and XYL/NAL treatment. Elimination half‑life of NAL was 3.47 ± 1.39 hours and total body clearance was 2.88 ± 0.73 L/kg/hour. In conclusion, addition of NAL to XYL resulted in remarkable advantages on the measured parameters. The obtained pharmacokinetics of NAL could be useful in determining the effective NAL infusion rate, which could be further evaluated as an adjunctive agent to XYL for prolonged sedation in horses.
Topics: Animals; Horses; Xylazine; Nalbuphine
PubMed: 37219832
DOI: 10.12834/VetIt.2408.16506.1 -
Neuron Sep 2020Opioids are commonly used as analgesics for severe pain, but their addictive potential has sparked a misuse epidemic. In this issue of Neuron, Keyes et al. (2020)...
Opioids are commonly used as analgesics for severe pain, but their addictive potential has sparked a misuse epidemic. In this issue of Neuron, Keyes et al. (2020) examine the contributions of distinct paraventricular thalamus (PVT) outputs to contextual opioid memories. They identify a PVT→NAc→LH circuit essential for recall of opioid experiences.
Topics: Analgesics, Opioid; Neural Pathways; Neurons; Opiate Alkaloids; Thalamus
PubMed: 32971000
DOI: 10.1016/j.neuron.2020.09.006 -
Journal of Trace Elements in Medicine... Jul 2020Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical... (Review)
Review
Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
Topics: Animals; Humans; Morphine; Morphine Dependence; Neural Pathways; Transition Elements
PubMed: 32179426
DOI: 10.1016/j.jtemb.2020.126495