Agmatine requires GluN2B-containing NMDA receptors to inhibit the development of neuropathic pain

A decarboxylated form of L-arginine, agmatine, preferentially antagonizes NMDArs containing Glun2B subunits within the spinal cord and lacks motor side effects commonly associated with non-subunit-selective NMDAr antagonism, namely sedation and motor impairment. Spinally delivered agmatine has been previously shown to reduce the development of tactile hypersensitivity arising from spinal nerve ligation. The present study interrogated the dependence of agmatine’s alleviation of neuropathic pain (spared nerve injury (SNI) model) on GluN2B-containing NMDArs. SNI-induced hypersensitivity was induced in mice with significant reduction of levels of spinal GluN2B subunit of the NMDAr and their floxed controls. Agmatine reduced development of SNI-induced tactile hypersensitivity in controls but had no effect in subjects with reduced levels of GluN2B subunits. Ifenprodil, a known GluN2B-subunit-selective antagonist, similarly reduced tactile hypersensitivity in controls but not in the GluN2B-deficient mice. In contrast, MK-801, an NMDA receptor channel blocker, reduced hypersensitivity in both control and GluN2B-deficient mice, consistent with a pharmacological pattern expected from a NMDAr antagonist that does not have preference for GluN2B subtypes. Additionally, we observed that spinally delivered agmatine, ifenprodil and MK-801 inhibited nociceptive behaviors following intrathecal delivery of NMDA in control mice. By contrast, in GluN2B-deficient mice, MK-801 reduced NMDA-evoked nociceptive behaviors, but agmatine had a blunted effect and ifenprodil had no effect. These results demonstrate that agmatine requires the GluN2B subunit of the NMDA receptor for inhibitory pharmacological actions in pre-clinical models of NMDA receptor-dependent hypersensitivity.

Investigation of NMDA Receptor Channel Blockers in a Series of Methylene Blue Conjugates Using QSAR and Molecular Modeling

29 conjugates of methylene blue and four chemical structures, including derivatives of carbazole, tetrahydrocarbazole, substituted indoles and γ-carboline, combined with a 1-oxopropylene spacer have been studied as channel blockers of the NMDA receptor (binding site of MK-801) by using four QSAR methods (multiple linear regression, random forest, support vector machine, Gaussian process) and molecular docking. QSAR models have satisfactory characteristics. The analysis of regression models at the statistical level revealed an important role of the hydrogen bond in the complex formation. This was also confirmed by the study of modeled by docking complexes. It was found that the increase in the inhibitory activity of the part of compounds could be attributed to appearance of additional H bonds between the ligands and the receptor.

Substance Use Disorders

There is a consistent body of evidence showing that substance abuse and dependence can worsen preexisting medical conditions, can temporarily mimic medical and psychiatric disorders, and can themselves cause medical problems, including life-threatening overdose. Substance use disorders are common in young and middle-aged persons: the lifetime prevalence of these syndromes, including alcoholism, is over 20% for men and about 15% for women. This chapter discusses dependence, abuse, substance use disorder, and substance-induced disorders involving depressants, stimulants, opioids, cannabinoids, hallucinogens, N-methyl-D-aspartate (NMDA) receptor channel blockers, and inhalants. Epidemiology, etiology, pathophysiology, diagnosis (including clinical assessment and laboratory tests), and treatment are reviewed. Treatment of intoxication, overdose, withdrawal, and rehabilitation is discussed. A figure illustrates the neurocircuitry of addiction. Tables describe the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic criteria for abuse and dependence; frequently misused drugs; neural effects of commonly abused drugs; the natural history of drug dependence; conditions affecting the outcome of urinary drug tests; and pharmacologic options for treatment of drug overdose. This chapter contains 1 figure , 6 tables and 112 references

Substance Use Disorders

There is a consistent body of evidence showing that substance abuse and dependence can worsen preexisting medical conditions, can temporarily mimic medical and psychiatric disorders, and can themselves cause medical problems, including life-threatening overdose. Substance use disorders are common in young and middle-aged persons: the lifetime prevalence of these syndromes, including alcoholism, is over 20% for men and about 15% for women. This chapter discusses dependence, abuse, substance use disorder, and substance-induced disorders involving depressants, stimulants, opioids, cannabinoids, hallucinogens, N-methyl-D-aspartate (NMDA) receptor channel blockers, and inhalants. Epidemiology, etiology, pathophysiology, diagnosis (including clinical assessment and laboratory tests), and treatment are reviewed. Treatment of intoxication, overdose, withdrawal, and rehabilitation is discussed. A figure illustrates the neurocircuitry of addiction. Tables describe the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic criteria for abuse and dependence; frequently misused drugs; neural effects of commonly abused drugs; the natural history of drug dependence; conditions affecting the outcome of urinary drug tests; and pharmacologic options for treatment of drug overdose. This chapter contains 112 references.

Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.