Int Rev Neurobiol
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Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglia (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of incomplete knowledge about the mechanisms underlying painful PDN, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs that have significant side effects or potential for abuse. ⋯ Understanding details of posttranslational regulation of nociceptive channel activity may facilitate development of novel therapies for treatment of painful PDN. We argue that pharmacological targeting of the specific pathogenic mechanism rather than of the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.
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Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. ⋯ We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders.
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During the last decade, there has been an increase in the availability and use of novel psychoactive substances (NPS), also known as "legal highs," across the world. They include a wide range of products, from natural plant-originated substances to synthetic compounds, that can be purchased both online and from high street retailers. "Legal highs" mimic psychoactive effects of illicit drugs of abuse. However, they are claimed to consist of compounds that are legal to sell, possess, and use, often labeled as "not for human consumption" to circumvent drug abuse legislation. ⋯ Although the prevalence and pattern of NPS use differ between various countries, the most popular groups are SCs and psychostimulants, described in this chapter. Currently, there is limited information available on the potential acute toxicity (harms) associated with the use of these substances. However, the number of intoxicated people presenting with emergencies is constantly increasing, providing evidence that negative health and social consequences may indeed seriously affect recreational and chronic users.
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Alzheimer's disease (AD) is a neurodegenerative condition characterized by increased accumulation of Aβ and degeneration of cholinergic signaling between basal forebrain and hippocampus. Nicotinic acetylcholine receptors (nAChRs) are important mediators of cholinergic signaling in modulation of learning and memory function. Accumulating lines of evidence indicate that a nAChR subtype, α7 receptor (α7-nAChR), plays an important role in modulations of excitatory neurotransmitter release, improvement of learning and memory ability, and enhancement of cognitive function. ⋯ However, the mechanisms underlying the role of α7-nAChRs in AD pathogenesis are very complex, and either neuroprotective effects or neurotoxic effects may occur through the α7-nAChRs. These effects depend on the levels of α7-nAChR expression and function, disease stages, or the use of α7-nAChR agonists, antagonists, or allosteric modulators. In this chapter, we summarize recent progresses in the roles of α7-nAChRs played in AD pathogenesis and therapy.
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Developmental neocortical malformations resulting from abnormal neurogenesis, disturbances in programmed cell death, or neuronal migration disorders may cause a long-term hyperexcitability. Early generated Cajal-Retzius and subplate neurons play important roles in transient cortical circuits, and structural/functional disorders in early cortical development may induce persistent network disturbances and epileptic disorders. In particular, depolarizing GABAergic responses are important for the regulation of neurodevelopmental events, like neurogenesis or migration, while pathophysiological alterations in chloride homeostasis may cause epileptic activity. ⋯ The neocortical focus may be surrounded by widespread molecular, structural, and functional disturbances, which are difficult to recognize with imaging technologies. However, modern imaging and electrophysiological techniques enable focused hypotheses of the neocortical epileptogenic zone, thus allowing more specific epilepsy surgery. Focal cortical malformation can be successfully removed with minimal rim, close to or even within eloquent cortex with a promising risk-benefit ratio.