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Journal of Neurosurgery. Case Lessons Mar 2022The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder...
BACKGROUND
The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder (SUD) becomes a chronic, lifelong condition. Health system-level data in recent years indicate a significant increase in patients with coexisting SUD and degenerative disc disease, representing an emerging population. A retrospective electronic medical record review identified seven patients with SUD who underwent elective spine surgery by orthopedic or neurosurgical staff from 2012 to 2021. The authors present two of these illustrative cases and a framework that can be used in the treatment of similar patients.
OBSERVATIONS
Substances used included opioids, benzodiazepines, barbiturates, cocaine, methamphetamines, hallucinogens, lysergic acid diethylamide, phencyclidine, and cannabis. All were abstaining from drug use preoperatively, with four patients in a formal treatment program. Five patients were discharged with an opioid prescription, and two patients deferred opioids. Three experienced a relapse of substance use within 1 year. All patients presented for follow-up, although two required additional contact for follow-up compliance.
LESSONS
Perioperative protocols focusing on patient-led care plans, pain control, communication with medication for opioid use disorder providers, family and social support, and specific indicators of possible poor results can contribute to better outcomes for care challenges associated with these diagnoses.
PubMed: 36273856
DOI: 10.3171/CASE21656 -
British Journal of Pharmacology Jan 2023Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an...
BACKGROUND AND PURPOSE
Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis.
KEY RESULTS
Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway.
CONCLUSION AND IMPLICATIONS
This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
Topics: Animals; Rats; Male; Phencyclidine; Schizophrenia; Fingolimod Hydrochloride; Brain-Derived Neurotrophic Factor; Rats, Sprague-Dawley; Cognitive Dysfunction; Cytokines; Disease Models, Animal
PubMed: 36106568
DOI: 10.1111/bph.15954 -
International Journal of Molecular... Aug 2022NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of...
NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions.
Topics: Animals; Central Nervous System; Excitatory Postsynaptic Potentials; Mice; Peptides; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission
PubMed: 36012124
DOI: 10.3390/ijms23168867 -
Cureus Jul 2022Ketamine is a phencyclidine derivative that acts as a noncompetitive N-methyl-D-aspartate as well as a glutamate receptor antagonist. It also has other minor mechanisms... (Review)
Review
Ketamine is a phencyclidine derivative that acts as a noncompetitive N-methyl-D-aspartate as well as a glutamate receptor antagonist. It also has other minor mechanisms that contribute to its extensive drug profile. Ketamine is a bronchodilator and maintains normal airway reflexes and, thus, permits spontaneous respiration. This, coupled with the fact that it produces potent analgesia, makes it highly suitable for children. Despite its many merits, the drug's side effects, along with its cultural image of being a drug of abuse, a drug used in veterinary medicine, or a "date-rape drug" have sullied its reputation within the armamentarium of medicine. Even though it is widely used in developing countries, its use in Western nations has diminished. We have strived to explore the various clinical uses of ketamine in children through this article. In addition, the article also highlights how some of the fears associated with using the drug are unfounded and provides ways by which the drug's side effects can be prevented and managed.
PubMed: 35989801
DOI: 10.7759/cureus.27065 -
Addiction (Abingdon, England) Dec 2022Hallucinogen use is potentially harmful. Information on whether such use has increased in recent decades is lacking. This study assessed overall and age-specific time...
BACKGROUND AND AIMS
Hallucinogen use is potentially harmful. Information on whether such use has increased in recent decades is lacking. This study assessed overall and age-specific time trends in the prevalence of 12-month hallucinogen use in the US general population.
DESIGN
Cross-sectional.
SETTING
Data from the US National Survey on Drug Use and Health, 2002-19.
PARTICIPANTS
Respondents aged ≥ 12 years (n = 1 006 051).
MEASUREMENTS
Predictors were continuous years. Outcome variables included any hallucinogen use and use of lysergic acid diethylamide (LSD), ecstasy and phencyclidine (PCP) in the past year. Socio-demographic variables (gender, age, race/ethnicity, educational level and family income) were covariates.
FINDINGS
Overall, hallucinogen use increased between 2015 and 2019 [prevalence difference (PD) = +0.44, P < 0.05]. Since 2002, hallucinogen use has increased in adults aged ≥ 26 years (PD, 2002-14 = +0.24, P < 0.05; PD, 2015-19 = +0.45, P < 0.001) and decreased in adolescents aged 12-17 years (PD, 2002-14 = -1.60, P < 0.0001; PD, 2015-19 = -0.73, P < 0.001). Ecstasy use has decreased in adolescents (PD, 2002-14 = -0.56, P < 0.001), adults aged 18-25 years (PD, 2015-19 = -0.96, P < 0.01) and ≥ 26 years (PD, 2015-19 = -0.13, P < 0.05). LSD use between 2002 and 2019 increased overall (PD = +0.71, P < 0.0001) and in all age groups (12-17: PD = +0.67, P < 0.001; 18-25: PD = +3.12, P < 0.0001; ≥ 26: PD = +0.36, P < 0.0001). Conversely, PCP use between 2002 and 2019 decreased overall (PD = -0.06, P < 0.001), in adolescents (PD = -0.24, P < 0.001) and young adults (PD = -0.32, P < 0.0001).
CONCLUSIONS
Since 2002, hallucinogen use in the United States has decreased among adolescents but increased in adults and is now estimated to affect more than 3 million adults aged 26+ years and more than 5.5 million adults aged 18+ years.
Topics: Young Adult; Adolescent; Humans; United States; Adult; Lysergic Acid Diethylamide; Hallucinogens; Cross-Sectional Studies; N-Methyl-3,4-methylenedioxyamphetamine; Substance-Related Disorders
PubMed: 35978453
DOI: 10.1111/add.15987 -
The International Journal of... Sep 2022Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal...
BACKGROUND
Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.
METHODS
We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.
RESULTS
Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.
CONCLUSIONS
ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.
Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Guanidines; Isoquinolines; Male; Memory Disorders; Methamphetamine; Mice; Mice, Knockout; Phencyclidine; Rats; Rats, Transgenic; Receptors, Serotonin; Scopolamine; Serotonin; Serotonin Antagonists
PubMed: 35882205
DOI: 10.1093/ijnp/pyac041 -
The International Journal of... Dec 2022The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative...
BACKGROUND
The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity.
METHODS
NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models.
RESULTS
Following a single oral dose, zelquistinel (0.1-100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance.
CONCLUSIONS
Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.
Topics: Animals; Rats; Mice; Receptors, N-Methyl-D-Aspartate; Depressive Disorder, Major; Rats, Sprague-Dawley; Antidepressive Agents; Long-Term Potentiation; Phencyclidine
PubMed: 35882204
DOI: 10.1093/ijnp/pyac043 -
Frontiers in Neural Circuits 2022Abnormally high-amplitude hippocampal gamma activity (30-100 Hz) in behaving animals is seen after a hippocampal seizure, following injection of phencyclidine (PCP) or... (Review)
Review
Abnormally high-amplitude hippocampal gamma activity (30-100 Hz) in behaving animals is seen after a hippocampal seizure, following injection of phencyclidine (PCP) or ketamine, and transiently in a delirium stage during induction of general anesthesia. High-amplitude hippocampal gamma activity in behaving rats is associated with hyperactive behavior and impairment in sensorimotor gating and sensory gating. The medial septum is necessary for the high-amplitude gamma activity and abnormal behaviors observed following a hippocampal seizure or injection of PCP/ketamine. Glutamatergic projection of the hippocampus to the nucleus accumbens (NAC) and dopaminergic transmission in NAC is necessary for abnormal behaviors. Large hippocampal gamma waves are suggested to contribute to seizure-induced automatism following temporal lobe seizures, and the schizophrenia-like symptoms induced by PCP/ketamine. Low-amplitude gamma activity is found during general anesthesia, associated with loss of consciousness in humans and loss of righting reflex in animals. Local inactivation or lesion of the medial septum, NAC, and brain areas connected to the septohippocampal-NAC system attenuates the increase in hippocampal gamma and associated behavioral disruptions induced by hippocampal seizure or PCP/ketamine. Inactivation or lesion of the septohippocampal-NAC system decreases the dose of anesthetic necessary for gamma decrease and loss of consciousness in animals. Thus, it is proposed that the septohippocampal-NAC system serves to control consciousness and the behavioral hyperactivity and neural dysfunctions during psychosis.
Topics: Animals; Consciousness; Electroencephalography; Gamma Rays; Hippocampus; Humans; Ketamine; Psychotic Disorders; Rats; Rats, Long-Evans; Seizures; Unconsciousness
PubMed: 35874429
DOI: 10.3389/fncir.2022.895000 -
Nature Communications Jul 2022N-methyl-D-aspartate receptors (NMDARs) are transmembrane proteins that are activated by the neurotransmitter glutamate and are found at most excitatory vertebrate...
N-methyl-D-aspartate receptors (NMDARs) are transmembrane proteins that are activated by the neurotransmitter glutamate and are found at most excitatory vertebrate synapses. NMDAR channel blockers, an antagonist class of broad pharmacological and clinical significance, inhibit by occluding the NMDAR ion channel. A vast literature demonstrates that NMDAR channel blockers, including MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. Here we use electrophysiological recordings from transfected tsA201 cells and cultured neurons, NMDAR structural modeling, and custom-synthesized compounds to show that NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration ("membrane-to-channel inhibition" (MCI)). Our demonstration that ligand-gated channels are subject to MCI, as are voltage-gated channels, highlights the broad expression of this inhibitory mechanism.
Topics: Dizocilpine Maleate; Ion Channels; Ketamine; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 35840593
DOI: 10.1038/s41467-022-31817-z -
Frontiers in Pain Research (Lausanne,... 2022The phencyclidine-derivative ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one] was added to the World Health Organization's Model List of Essential Medicines... (Review)
Review
The phencyclidine-derivative ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one] was added to the World Health Organization's Model List of Essential Medicines in 1985 and is also on the Model List of Essential Medicines for Children due to its efficacy and safety as an intravenous anesthetic. In sub-anesthetic doses, ketamine is an effective analgesic for the treatment of acute pain (such as may occur in the perioperative setting). Additionally, ketamine may have efficacy in relieving some forms of chronic pain. In 2019, Janssen Pharmaceuticals received regulatory-approval in both the United States and Europe for use of the S-enantiomer of ketamine in adults living with treatment-resistant major depressive disorder. Pre-existing anxiety/depression and the severity of postoperative pain are risk factors for development of chronic postsurgical pain. An important question is whether short-term administration of ketamine can prevent the conversion of acute postsurgical pain to chronic postsurgical pain. Here, we have reviewed ketamine's effects on the biopsychological processes underlying pain perception and affective mood disorders, focusing on non-NMDA receptor-mediated effects, with an emphasis on results from human trials where available.
PubMed: 35832728
DOI: 10.3389/fpain.2022.872696