Current opinion in neurobiology
-
Pain is a complex consciousness that emerges from the brain, and is commonly a result of nociception; the physiological process initiated by activation of specialised high-threshold peripheral sensory neurons. When pain is persistent, its affective aspects can dominate and cause considerable suffering. This chronic pain state is not an inevitable consequence of physical injury or disease. ⋯ The biological bases for chronic pain can now be defined and measured by brain neuroimaging at a systems level, where penetrance of genetic variation should be higher when compared to syndromal phenotypes. To date, very few neuroimaging studies have attempted to connect brain activity associated with pain to genes. We review these together with other pertinent studies here, and suggest how neuroimaging endophenotypes might prove useful for the development of treatments for chronic pain.
-
Curr. Opin. Neurobiol. · Jun 2012
ReviewFunctional regulation of GABAA receptors in nervous system pathologies.
Inhibitory neurotransmission is primarily governed by γ-aminobutyric acid (GABA) type A receptors (GABAARs). GABAARs are heteropentameric ligand-gated channels formed by the combination of 19 possible subunits. GABAAR subunits are subject to multiple types of regulation, impacting the localization, properties, and function of assembled receptors. ⋯ While the regulatory mechanisms governing synaptic receptors have begun to be defined, little is known about the regulation of extrasynaptic receptors. We examine the contributions of GABAARs to the pathogenesis of neurodevelopmental disorders, schizophrenia, depression, epilepsy, and stroke, with particular focus on extrasynaptic GABAARs. We suggest that extrasynaptic GABAARs are attractive targets for the treatment of these disorders, and that research should be focused on delineating the mechanisms that regulate extrasynaptic GABAARs, promoting new therapeutic approaches.
-
Curr. Opin. Neurobiol. · Jun 2012
ReviewRegulation of AMPA receptor trafficking and synaptic plasticity.
AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic plasticity, are thought to underlie information coding and storage in learning and memory. ⋯ The life cycle of AMPARs from their biosynthesis, membrane trafficking, and synaptic targeting to their degradation are controlled by a series of orchestrated interactions with numerous intracellular regulatory proteins. Here we review recent progress made toward the understanding the regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins.
-
Curr. Opin. Neurobiol. · Dec 2011
ReviewPain and itch: insights into the neural circuits of aversive somatosensation in health and disease.
Although pain and itch are distinct sensations, most noxious chemicals are not very specific to one sensation over the other, and recent discoveries are revealing that Trp channels function as transducers for both. A key difference between these sensations is that itch is initiated by irritation of the skin, whereas pain can be elicited from almost anywhere in the body; thus, itch may be encoded by the selective activation of specific subsets of neurons that are tuned to detect harmful stimuli at the surface and have specialized central connectivity that is specific to itch. ⋯ Importantly, just as there are inhibitory circuits in the dorsal horn that mediate cross-inhibition between modalities, it appears that there are also excitatory connections that can be unmasked upon injury or in disease, leading to abnormally elevated pain states such as allodynia. We are now beginning to understand some of this dorsal horn circuitry, and these discoveries are proving to be relevant for pathological conditions of chronic pain and itch.
-
Curr. Opin. Neurobiol. · Aug 2010
Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0.
Microglia are increasingly recognized as critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. The core signalling pathway is through P2X4 purinergic receptors on the microglia which, via the release of brain-derived neurotrophic factor, cause disinhibition of nociceptive dorsal horn neurons by raising intracellular chloride levels. ⋯ There is increased discharge output, unmasking of responses to innocuous peripheral inputs and spontaneous activity in neurons that otherwise only signal nociception. Together the changes caused by microglia-neuron signalling may account for the main symptoms of neuropathic pain in humans.