- Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders. [Journal Article]
- NNeuropsychopharmacology 2018 Feb 05
- Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined ...
Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.
- Disulfiram attenuates morphine or methadone withdrawal syndrome in mice. [Journal Article]
- BPBehav Pharmacol 2018 Feb 16
- Taking opioids is often accompanied by the development of dependence. Unfortunately, treatment of opioid dependence is difficult, particularly because of codependence - for example, on alcohol or oth...
Taking opioids is often accompanied by the development of dependence. Unfortunately, treatment of opioid dependence is difficult, particularly because of codependence - for example, on alcohol or other drugs of abuse. In the presented study, we analyzed the potential influence of disulfiram, a drug used to aid the management of alcoholism, on opioid abstinence syndrome, which occurs as a result of opioid withdrawal. Opioid dependence in mice was induced by subcutaneous administration of either morphine or methadone at a dose of 48 mg/kg for 10 consecutive days. To trigger a withdrawal syndrome, the opioid receptor antagonist, naloxone, was administered at a dose of 1 mg/kg (subcutaneous), and the severity of withdrawal signs was assessed individually. Interruption of chronic treatment with morphine or methadone by naloxone has led to the occurrence of opioid abstinence signs such as jumping, paw tremor, wet-dog shakes, diarrhea, teeth chattering, ptosis, and piloerection. Importantly, pretreatment with disulfiram (25, 50, and 100 mg/kg) reduced the intensity of withdrawal signs induced by naloxone in morphine or methadone-treated mice. These findings show the effectiveness of disulfiram in reducing opioid abstinence signs.
- Suction electrode recording in locus coeruleus of newborn rat brain slices reveals network bursting comprising summated non-synchronous spiking. [Journal Article]
- NLNeurosci Lett 2018 Feb 12; 671:103-107
- The brainstem locus coeruleus (LC) controling behaviors like arousal, sleep, breathing, pain or opioid withdrawal is an established model for spontaneous action potential synchronization. Such synchr...
The brainstem locus coeruleus (LC) controling behaviors like arousal, sleep, breathing, pain or opioid withdrawal is an established model for spontaneous action potential synchronization. Such synchronous 'spiking' might produce an extracellular field potential (FP) which is a crucial tool for neural network analyses. We found using ≥10 μm tip diameter suction electrodes in newborn rat brainstem slices that the LC generates at ∼1 Hz a robust rhythmic FP (rFP). During distinct rFP phases, LC neurons discharge with a jitter of ±33 ms single spikes that summate to a ∼200 ms-lasting population burst. The rFP is abolished by blocking voltage-gated Na+channels with tetrodotoxin (TTX, 50 nM) or gap junctions with mefloquine (100 μM) and activating μ-opioid receptors with [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin (DAMGO, 1 μM). Raising superfusate K+from 3 to 7 mM either increases rFP rate or transforms its pattern to slower and longer multipeak bursts similar to those during early recovery from DAMGO. The results show that electrical coupling of neonatal LC neurons does not synchronize their spiking as previously proposed. They also indicate that both increased excitability (by elevated K+) and recovery from inhibition (by opioids) can enhance spike desynchronization to transform the population burst pattern. Both observations show that this gap junction-coupled neural network has a more complex connectivity than currently assumed. These new findings along with the inhibitory drug effects that are in line with previous reports based on single neuron recording point out that field potential analysis is pivotal to further the understanding of this brain circuit.
- A Commentary: Do α2-Adrenergic Agonists Decrease the Symptoms Associated With Opioid Withdrawal? [Letter]
- AEAnn Emerg Med 2018; 71(2):268
- Managing Opioid Use Disorder and Co-Occurring Posttraumatic Stress Disorder Among Veterans. [Journal Article]
- JPJ Psychosoc Nurs Ment Health Serv 2018 Feb 15; :1-7
- Support and safety measures are essential for Veterans admitted to acute psychiatric units with co-occurring posttraumatic stress disorder (PTSD) and opioid use disorder (OUD) to avoid unpleasant wit...
Support and safety measures are essential for Veterans admitted to acute psychiatric units with co-occurring posttraumatic stress disorder (PTSD) and opioid use disorder (OUD) to avoid unpleasant withdrawal symptoms. A human patient simulator was used to train clinicians to recognize opioid withdrawal symptoms. Clinicians were educated to assess for opioid withdrawal symptoms using the Clinical Opiate Withdrawal Scale. Knowledge was evaluated via pre/posttest. All participants' (N = 12) posttest scores improved. Participants self-rated their perception of clinical knowledge and practice skills as higher postintervention. Veterans indicated decreased concern about opioid withdrawal symptoms and increased perception that symptoms were adequately evaluated and treated by clinicians. Overall, the intervention appeared to enhance the provision of quality care in Veterans with OUD and co-occurring PTSD on an acute inpatient psychiatric unit. [Journal of Psychosocial Nursing and Mental Health Services, xx(x), xx-xx.].
- The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model. [Journal Article]
- JPJ Pain Res 2018; 11:281-291
- CONCLUSIONS: The LFE and HFE program reduced neuropathic pain. Our findings indicated that aerobic exercise-induced alleviated neuropathic pain through the regulation of glial cell activation, expression of BDNF in the ipsilateral spinal dorsal horn, and the endogenous opioid system.
- A Novel Rat Model of Extremity Trauma for Pre-hospital Pain Management Research. [Journal Article]
- JTJ Trauma Acute Care Surg 2018 Feb 14
- CONCLUSIONS: Our ET model includes long bone fracture and soft tissue injury, but no fixation surgery, mimicking pre-hospital extremity trauma. Our model produces acute, steady, and reproducible trauma-related pain behaviors, and is clinically relevant regarding the pain behaviors and established responses to common analgesics. This model of acute pain due to ET is ideal for pre-hospital pain management research.
- Altered signaling in the descending pain modulatory system after short-term infusion of the μ-opioid agonist remifentanil. [Journal Article]
- JNJ Neurosci 2018 Feb 12
- μ-Opioid receptor agonists are widely used within the contemporary treatment of pain but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxiou...
μ-Opioid receptor agonists are widely used within the contemporary treatment of pain but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli - a phenomenon that has been for example reported after application of the fast-acting μ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 μg/kg-bodyweight/min) compared to control in the brain, brainstem and spinal cord in drug-naïve male volunteers employing functional magnetic resonance imaging. Subsequent to remifentanil suspension we observed reduced heat pain thresholds and increased neuronal responses in pain encoding as well as in key regions of the descending pain modulatory system, such as the periaqueductal grey matter, the nucleus cuneiformis and the rostral ventromedial medulla. Moreover, the spinal pain-related multi-voxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that already subsequent to a short-term infusion of the μ-opioid receptor agonist remifentanil signaling in the descending pain modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.Significance Statement:Opioids are widely used in modern medicine but besides their known side effects it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Employing the fast-acting μ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers this study demonstrates how signaling changes occur along the entire descending pain modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly, by revealing modified responses in pain modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans.
- Necessity for interrupted time series to analyze the effects of propoxyphene withdrawal from the market and health outcome trend estimates. [Letter]
- ARArthritis Rheumatol 2018 Feb 13
- We read with great interest the study by Curtis et al.1that examines time trends of opioid use among older adults with rheumatoid arthritis (RA) in the United States. We think that certain additional...
We read with great interest the study by Curtis et al.1that examines time trends of opioid use among older adults with rheumatoid arthritis (RA) in the United States. We think that certain additional methodologic and health policy considerations are necessary. First, the authors did not specify the selection process in the methods and did not specify missing value rates before selecting patients for analysis. This article is protected by copyright. All rights reserved.
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- Reply to "Necessity for interrupted time series to analyze the effects of propoxyphene withdrawal from the market and further health outcome trend estimates". [Journal Article]
- ARArthritis Rheumatol 2018 Feb 13
- We appreciate the interest in our work and the opportunity to respond to the comments by Dr. Yoo et al. regarding our article on "Changing trends in opioid use among patients with rheumatoid arthriti...
We appreciate the interest in our work and the opportunity to respond to the comments by Dr. Yoo et al. regarding our article on "Changing trends in opioid use among patients with rheumatoid arthritis in the United States" This article is protected by copyright. All rights reserved.