A piercing epistolary novel, The Antagonist explores, with wit and compassion, how the impressions of others shape, pervert, and flummox both our perceptions of ourselves and our very nature. Gordon Rankin Jr., aka “Rank,” thinks of himself as “King Midas in reverse”—and indeed misfortune seems to follow him at every turn. Against his will and his nature, he has long been considered—given his enormous size and strength—a goon and enforcer by his classmates, by his hockey coaches, and, not least, by his “tiny, angry” father. He gamely lives up to their expectations, until a vicious twist of fate forces him to flee underground. Now pushing forty, he discovers that an old, trusted friend from his college days has published a novel that borrows freely from the traumatic events of Rank’s own life. Outraged by this betrayal and feeling cruelly misrepresented, he bashes out his own version of his story in a barrage of e-mails to the novelist that range from funny to furious to heartbreaking. With The Antagonist, Lynn Coady demonstrates all of the gifts that have made her one of Canada’s most respected young writers. Here she gives us an astonishing story of sons and fathers and mothers, of the rewards and betrayals of male friendship, and a large-spirited, hilarious, and exhilarating portrait of a man tearing his life apart in order to put himself back together. This ebook edition includes a Reading Group Guide.
The Handbook of Antagonism: Conceptualizations, Assessment, Consequences, and Treatment of the Low End of Agreeableness looks at the theoretical and empirical underpinnings of antagonism, highlighting the consequences of the trait, its role in a number of problem behaviors and psychiatric disorders, and how it exerts itself on externalizing behaviors. Covering the biological and evolutionary roots of antagonism, the book provides clinical insight on assessment strategies, while also outlining a number of treatment techniques, including motivational interviewing, cognitive behavioral therapy, interpersonal psychology and psychodynamic treatment approaches. In addition, the book explores the development of antagonism across childhood and adolescence, discussing the societal consequences of the trait, as well as its role in a number of problem behaviors, such as aggression, violence, crime and substance use.
Comprehensive and authoritative, Opioid Receptors and Antagonists: From Bench to Clinic offers neuroscientists, pharmacologists and interested clinicians a unique survey of the extensive and diverse research efforts currently employed with opioid antagonists to develop novel innovative drug therapies. Summarizes the present understanding of the chemistry, pharmacology and molecular biology of opioid receptors and their subtypes Highlights differences and similarities between the opioid pharmacology of animals and human Describes current and potential therapeutic areas for opioid antagonists, including substance abuse, alcohol and ingestive behaviors, behavioral disorders and other medical indications, supported by nonclinical and clinical evidence Focuses on the development of exciting and innovative drug delivery approaches that are being used with opioid antagonists for the above medical indications
Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia.
