Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species‐related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA‐injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX‐related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked

Benzodiazepines and z-drugs - between treatment effectiveness and the risk of addiction

Benzodiazepines (BZDs) and Z-drugs are commonly prescribed medications for anxiety and sleep disorders. This review examines their efficacy, associated risks, and alternative treatment options. BZDs enhance the activity of gamma-aminobutyric acid (GABA), reducing anxiety, while Z-drugs selectively target GABA-A receptors' alpha-1 subunits for sedative effects. Despite their effectiveness, both drug classes carry the risk of addiction, physical and psychological dependence, and withdrawal symptoms. Side effects, such as drowsiness, dizziness, and cognitive impairment, are also associated with their use. Recent studies indicate that chronic use of BZDs and Z-drugs may lead to cognitive impairment and an increased risk of dementia in older adults. Furthermore, individual factors, dosage, duration of use, and drug interactions can affect their efficacy. Prescribing trends show a decline in benzodiazepine prescriptions and an increase in Z-drug use due to perceived safety advantages. However, evidence suggests that Z-drugs carry similar risks of adverse effects and addiction potential as benzodiazepines. Healthcare professionals should carefully assess patients before prescribing these drugs and monitor their use to prevent dependence and addiction. Brief interventions, patient education, drug withdrawal support, and cognitive behavioral therapy have shown effectiveness in reducing long-term benzodiazepine and Z-drug use. Alternative treatments, including cognitive behavioral therapy and relaxation techniques, should be considered, particularly for patients with a history of addiction or those at high risk of addiction. In conclusion, the risk of addiction, withdrawal symptoms, and adverse effects associated with benzodiazepines and Z-drugs necessitates cautious prescribing and the exploration of alternative treatment options.&nbsp

Clinical Implications of Kratom (Mitragyna speciosa) Use: a Literature Review

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY), http://creativecommons.org/licenses/by/4.0/Purpose of Review: This work aims to provide an up-to-date review of the preclinical and clinical scientific literature on the therapeutic value of kratom to better understand the underlying mechanisms related to its use and inform future therapeutic applications. Recent Findings: A growing number of studies, mainly of cross-sectional nature, describe the widespread use of kratom by individuals to self-treat pain, psychiatric symptoms, and substance use disorders (SUD) outside a controlled clinical setting. Preclinical evidence suggests kratom is effective as an analgesic agent and might decrease the self-administration of other drugs. A randomized controlled trial has further supported kratom’s therapeutic value as an analgesic. Investigations in nonclinical samples of long-term kratom users also indicate its therapeutic benefit in managing SUD symptoms (e.g., craving) and long-term or acute symptoms (e.g., withdrawal) for alcohol, opioids, and other illicit drugs. However, episodes of kratom-related intoxications have also been reported, often due to the adulteration and the contamination of kratom products mainly sold online or mixed toxicities when consumed outside clinical and traditional settings. Summary: Evidence on the clinical implications of kratom use is still limited and uncertain, with kratom research constantly evolving. Therefore, further randomized trials are needed.Peer reviewe

Exploring the use of Kratom (Mitragyna speciosa) via the YouTube Data Tool: a Novel Netnographic Analysis

© 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for the Study of Emerging Drugs. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ )Kratom (Mitragyna speciosa) is a tree native to Southeast Asia with long history of traditional medicinal use. The aim of this study was to investigate the nature of self-reported exported experiences as shared on YouTube™ videos. A total of 500 videos with 19,478,180 views and 134, 863 comments emerged from the data scrape extracted via the YouTube Data Tool. 12 out of the 16 most viewed videos emerged from our searches were manually processed and selected for inductive thematic analysis. Kratom use for the self-medication of a number of health conditions was described in the videos, including for opioid dependence/addiction (83.4%), pain (75%), anxiety (67%) and depression (42%), substance use problems (42%) as well as for energy boosting (50%), mood elevation (25%) and nootropic effects (25%). Although most of the described experiences were positive (58%), side-effects such as dependence and withdrawal (50%), nausea (42%), loss of appetite (25%), sedation (25%), loss of motivation (16.7%), headache (16.7%), drowsiness (16.7%), dry mouth and frequent urination (16.7%) were also reported and associated in 25% of the cases to chronic ingestions. Overall, our findings would show that Kratom is used more frequently for self-medication, than as a recreational drug. It also supports the need for more controlled clinical studies to better assess the safety and the efficacy of its use in a therapeutic context.Peer reviewe

MR-guided focused ultrasound thalamotomy for lithium-induced tremor: a case report and literature review

Drug-induced tremor is a common side effect of lithium with an occurrence of approximately 25% of patients. Cessation of the offending drug can be difficult, and many medical treatments for drug-induced tremor are ineffective. Deep brain stimulation (DBS) has been shown in a limited number of case reports to effectively reduce drug-induced tremor, however, which remains an invasive therapeutic option. MR-guided focused ultrasound (MRgFUS) thalamotomy is an FDA-approved non-invasive treatment for essential tremor (ET). To the best of our knowledge, MRgFUS thalamotomy has never been reported to treat drug-induced tremor. Here, we present a case of a left-handed 55-year-old man with a progressive, medically refractory lithium-induced tremor of the bilateral upper extremities. The patient underwent MRgFUS thalamotomy targeting the right ventral intermediate nucleus (VIM) of the thalamus to treat the left hand. There was almost complete resolution of his left-hand tremor immediately following MRgFUS. There were no side effects. The patient continues to show excellent tremor control at 90-day follow-up and remains free from side effects. This case demonstrates MRgFUS thalamotomy as a possible novel treatment option to treat drug-induced tremor

Prenatal Cocaine Exposure and Mother–Infant Interaction: Implications for Occupational Therapy Intervention

The literature from multiple disciplines on in utero cocaine exposure and mother–infant interaction and attachment was examined for possible relationships and implications for occupational therapists. Maternal cocaine use and neurobehavioral deficits in neonates prenatally exposed to cocaine may result in interactional difficulties between mother and infant. Knowledge of child development, sensory regulation, and infant cues will enable therapists to assist the mother in creating positive interactive experiences between herself and her child

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is ∆9-tetrahydrocannabinol (∆9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems

Characterization of Manganese-Induced Neurodegenration in C. elegans Treated with Winterberry Leaf Extract

Neurodegeneration is a condition present in Alzheimer’s disease (AD) and Parkinson’s disease (PD) in which the cells of the nervous system experience loss of function and death. Around the world, each year PD and AD affect 6.2 million and 29.8 million people, respectively, with the exact causes remaining unknown. Manganese (Mn) is a transition metal which is essential for human survival in trace concentrations. However, overexposure to Mn can induce neurodegeneration through the accumulation of reactive oxygen species and the eventual onset of oxidative stress. An extract produced from winterberry leaves (Ilex verticillata) exhibits antioxidant properties as it has been shown to protect against Mn-induced oxidative stress in the nematode worm, Caenorhabditis elegans. Due to this observed response in C. elegans, it was hypothesized that the winterberry leaf extract (WLE) could offer protection against neurodegeneration of dopaminergic neurons. To evaluate dopaminergic integrity and its effect on nematode behavior, a wild-type C. elegans strain was treated with several concentrations of WLE and manganese chloride (MnCl2). A motility assay with the wild-type N2 worm strain was anticipated to produce a dose-dependent increase in movement upon treatment with WLE. Mn-exposed worms pre-treated with WLE were expected to also have an increase in movement. In a 1-nonanol dopamine-dependent repulsion assay, worms pre-treated with WLE were predicted to repulse faster from 1-nonanol exposure compared to Mn-treated worms. The expected results of a progeny assay would show that pre-treatment of worms with WLE would increase the percentage of hatched progeny compared to the Mn control. Overall, our hypothesis is that pre-treatment with WLE may offer C. elegans protection against Mn-induced dopaminergic neurodegeneration and merits further exploration as a potential alternative medicine which could be used to treat people affected by neurodegenerative disorders

The Effect of Magnification Loupes on Posture During Instrumentation by Dental Hygienists

Purpose: The purpose of this study was to determine the effects of dental magnification loupes on posture during instrumentation. Methods: A convenience sample of twenty-seven righthanded dental hygienists with no history of injuries or disabilities of the head, neck, and trunk regions was enrolled. Baseline posture calibration was taken. Accelerometers were placed on four locations of the head and trunk (occipital pole of head, cervical vertebrae: C5, thoracic vertebrae: T5, lumbar vertebrae: L1) to measure changes in posture. Accelerations in three axes were recorded (anterior/posterior (AP), medial/lateral (ML), vertical (VT)). Mean accelerations of the three axes were used to compute average forward tilt (APangle) and sideways tilt (MLangle) of each sensor. For each axis, root mean square (rms) was also calculated to determine the magnitude of tremor fluctuations (i.e., APrms, MLrms and VTrms). Chair mounted typodonts with artificial calculus represented a simulated oral environment. Subjects were randomly assigned to wear loupes during the first or second half of the experiment and instructed to instrument all areas of the mouth with an ODU 11/12 explorer. An end user opinion survey was completed by participants. Results: Twenty seven participants (26 female and 1 male) completed the study. Results revealed no statistically significant differences between loupes and no loupes in the tilt angle of each sensor location in the AP or ML planes. In contrast, a statistically significant difference in mean fluctuations while wearing loupes (M=.215152, SD=.0741530) (rms) in AP at C5; t(24)=2.63, p=.015, compared to not wearing loupes (M=.261028, SD=.1379292) indicated posture fluctuations decreased while wearing loupes. APrms was only significant at C5; for ML and VT axes and sensor positions (head, C5, T5, L1) there were no statistically significant differences in mean fluctuations (rms) between wearing loupes and not. Overall, 74% of the participants strongly agreed that magnification loupes made exploring easier and 67% of participants strongly agreed that magnification loupes improved their posture. Conclusion: While participants perceived that magnification loupes enhanced their posture, the study provided little evidence that wearing loupes leads to changes in body orientation; only to reduced postural tremors at C5 in the AP axis

The role of stress, sex and early-life environment in shaping alcohol vulnerability

Background: Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats represent a unique animal model of excessive alcohol drinking and anxiety disorder. They show innate upregulation of the corticotropin-releasing factor receptor 1 (CRF1) which correlates with heightened ethanol consumption and stress sensitivity. Stress, dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational alcohol use to dependence and GR is considered to play an essential role in modulating stress-associated behaviors Here, we investigated the effect of pharmacological blockade of GR on alcohol self-administration (SA) using male and female msP and Wistar rats. Furthermore, we evaluated if GR antagonism might decrease innate symptoms of anxiety in msPs. Methods: Animals were trained to self-administer 10% (v/v) alcohol. Once stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Finally, we evaluated the effect of mifepristone injection (0.0 and 60 mg/kg) on novelty-induced hypophagia (NIH) assay, comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Results: Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Additionally, we found that male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Importantly, the enhanced anxiety-like behavior and startle responses were not ameliorated by mifepristone administration. Conclusions: Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Results also suggest sex differences in the ability of alcohol to regulate GR transmission. Moreover, the increased expression of stress- related behaviors in msPs are not mediated by activation of GR system