Ketamine: More than Just NMDA Blocker

Ketamine has been extensively used in the medical field for more than 50 years, but its exact mechanism of action remains unknown. It\'s used to induce dissociative anesthesia (a state of profound analgesia, amnesia with light sleep, immobility, and a sense of disassociation from one\'s own body and surroundings). Clinical studies on ketamine as a dissociative anesthetic, a model for psychosis, and as a rapidly acting antidepressant have sparked great interest in understanding its effects at the molecular and cellular level. It exerts uncompetitive inhibitory effects on NMDARs (N-Methyl-D-asperate) and may preferentially affect the function of NMDARs in interneurons. The hypnotic effects of this drug are attributed to its blocking action on NMDA and HCN1 receptors; however, both positive and negative modulation of choline, amine, and opioid systems appears to occur. It is likely that ketamine\'s effect on chronic pain and depression far outlasts its actual levels. This could be due to the hyperglutamatergic state induced by ketamine causing a secondary increase in structural synaptic connectivity. The authors of this review have attempted to highlight the action of ketamine not only on NMDA receptors but also on a variety of biochemical processes and functions found in intercellular environments, which may explain its diverse role in many diseases.

Developmental pharmacology of opioids

Recognition of the need for alternative analgesic regimens for managing neonatal and childhood pain has led to a rich literature concerning the ways in which early life pain differs from that at older ages. As in adults, opiates are often considered the gold-standard analgesic class of drugs, of which morphine is the prototypical agent. There is a wealth of data detailing clinical observations, measurements, and interventions with regard to the use of opioids in treating pain in children. Studies in the early part of this century have highlighted that, in humans, age is an important factor that influences the morphine requirement of neonates following surgery, and dose requirements are influenced by both pharmacokinetic and pharmacodynamic factors. Laboratory studies have extended our understanding of changes within the peripheral and central nervous systems that underlie alterations in nociception in early life. This chapter will review what is currently known about the actions of opioids upon nociceptive and nociresponsive elements of the nervous system in early life, how they differ from adult responses, and ask whether manipulating endogenous opioid systems in early life may have consequences on neurodevelopment.

Pain

This chapter is dedicated to pain and analgesia, the area where most of the knowledge about the mechanisms of the placebo effect comes from. Expectation of pain reduction plays a crucial role in placebo analgesia. The placebo analgesic effect is mediated by the endogenous opioid systems and antagonized by cholecystokinin (CCK) in some circumstances. In other conditions, the endocannabinoid system is involved. Many brain imaging studies indicate that several areas are involved in placebo analgesia, including the dorsolateral prefrontal cortex and those regions involved in dopaminergic reward mechanisms. The prefrontal lobes are fundamental for a placebo response to occur: if there is no prefrontal control, there is no placebo response. The nocebo hyperalgesic effect is mediated by anxiety, which activates a CCK system that, in turn, facilitates pain transmission. The endogenous pain modulatory descending circuits represent the biological substrate for the action of placebos on pain.

Genesis of the Heroin-Induced Addictive Process: Articulation Between Psychodynamic and Neurobiological Theories

Psychotherapeutic consultations of drug addict's patients in a Care, Support and Prevention Center in Addictology led us to propose several hypotheses on the genesis of addiction and its articulation with currently available neurobiological data. This care center dispenses both pharmacological maintenance medications for heroin dependence, such as methadone or buprenorphine, and psychological support. Our first hypothesis posits that the addictive process is driven by the narcissistic vulnerability of these patients, its neurobiological foundations being mainly mediated by the activation of endogenous opioid systems. Drug use/abuse could be a way to make arise the “True Self,” therefore overcoming the defensive system's set up to protect oneself from early traumas. The neurobiological impact of traumas is also developed and articulated with psychodynamic concepts, particularly those of Winnicott. Additionally, functions of addiction such as defensive, anti-depressant roles and emotional regulation are discussed in relationship with their currently known neuroscientific bases. Although the experience in the psychodynamic clinic is at a level of complexity much higher than what is currently accessible to the neurosciences, most of the research in this domain stays in line with our psychological understanding of the addictive process. Finally, we outline some critically sensitive points regarding the therapeutic support.

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.