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Cortical layers have classically been identified by their distinctive and prevailing cell types and sizes, as well as the packing densities of cell bodies or myelinated fibers. The densities of multiple receptors for classical neurotransmitters also vary across the depth of the cortical ribbon, and thus determine the neurochemical properties of cyto- and myeloarchitectonic layers. However, a systematic comparison of the correlations between these histologically definable layers and the laminar distribution of transmitter receptors is currently lacking. We here analyze the densities of 17 different receptors of various transmitter systems in the layers of eight cytoarchitectonically identified, functionally (motor, sensory, multimodal) and hierarchically (primary and secondary sensory, association) distinct areas of the human cerebral cortex. Maxima of receptor densities are found in different layers when comparing different cortical regions, i.e. laminar receptor densities demonstrate differences in receptorarchitecture between isocortical areas, notably between motor and primary sensory cortices, specifically the primary visual and somatosensory cortices, as well as between allocortical and isocortical areas. Moreover, considerable differences are found between cytoarchitectonical and receptor architectonical laminar patterns. Whereas the borders of cyto- and myeloarchitectonic layers are well comparable, the laminar profiles of receptor densities rarely coincide with the histologically defined borders of layers. Instead, highest densities of most receptors are found where the synaptic density is maximal, i.e. in the supragranular layers, particularly in layers II–III. The entorhinal cortex as an example of the allocortex shows a peculiar laminar organization, which largely deviates from that of all the other cortical areas analyzed here. •Borders of cyto- and myeloarchitectonic layers are comparable.•Receptor density profiles reveal specific laminar patterns for each receptor type.•Laminar patterns of receptors differ from those of cyto-and myeloarchitecture.•Layers of the entorhinal area distinctly differ from those of all isocortical areas.•GABA and glutamate receptor distributions are similar to synaptic laminar densities.

The intraparietal sulcus (IPS) is structurally and functionally heterogeneous. We performed a quantitative cyto-/myelo- and receptor architectonical analysis to provide a multimodal map of the macaque IPS. We identified 17 cortical areas, including novel areas PEipe, PEipi (external and internal subdivisions of PEip), and MIPd. Multivariate analyses of receptor densities resulted in a grouping of areas based on the degree of (dis)similarity of their receptor architecture: a cluster encompassing areas located in the posterior portion of the IPS and associated mainly with the processing of visual information, a cluster including areas found in the anterior portion of the IPS and involved in sensorimotor processing, and an ‘intermediate’ cluster of multimodal association areas. Thus, differences in cyto-/myelo- and receptor architecture segregate the cortical ribbon within the IPS, and receptor fingerprints provide novel insights into the relationship between the structural and functional segregation of this brain region in the macaque monkey.

Recently, two extrastriate visual areas on the posterior fusiform gyrus, areas FG1 and FG2, were identified based on cytoarchitectonical criteria (Caspers et al. in Brain Struct Funct 218:511–526, 2013a ). They are located within the object-related ventral visual stream at the transition between early and higher-order (category-specific) visual areas. FG2 has a topographical position which is best comparable to the face or visual word-form recognition area. However, the precise function of FG2 is presently unknown. Since transmitter receptors are key molecules of neurotransmission, we analysed the regional and laminar distribution of 15 different receptor binding sites by means of quantitative in vitro receptor autoradiography. Significant differences between receptor densities of both areas were found for NMDA, GABA B , M 3 , nicotinic α 4 /β 2 and 5-HT 1A receptors as well as for GABA A associated benzodiazepine binding sites. These results support the cytoarchitectonic segregation of FG1 and FG2 into two distinct cortical areas. In addition, principal component and hierarchical cluster analyses of the multireceptor data of both fusiform areas and 24 visual, auditory, somatosensory and multimodal association areas not only revealed the typical receptor architectonic characteristics of visual areas for FG1 and FG2, but also suggest their putative function as object recognition regions due to the similarity of their receptor fingerprints with those of areas of the ventral visual stream. Furthermore, FG1 and FG2 build a cluster with the multimodal association areas of the inferior parietal lobule. This underlines their hierarchically high position in the visual system of the human cerebral cortex.

Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB1/CB2 agonists, CB2 selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Δ9-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Δ9-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research.

The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson's disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson's disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.

Brodmann's area (BA) 5 of the human superior parietal cortex occupies a central anatomical position between the primary motor (BA 4), somatosensory (area 3b and BA 2), cingulate (area 23c), and superior parietal association cortex (BA 7). We studied the regional and laminar distributions of the binding sites of 12 different neurotransmitter receptors (glutamatergic: AMPA, kainate, NMDA; GABAergic: GABA A, GABA B; cholinergic: muscarinic M2, nicotinic; adrenergic: α 1, α 2; serotoninergic: 5-HT 1A, 5-HT 2; dopaminergic: D1) in human postmortem brains by means of quantitative receptor autoradiography, since the structural and functional aspects of human BA 5 are widely unknown, and previous observations have demonstrated characteristic differences in receptor distribution between motor and somatosensory areas. Binding site densities were measured in the cytoarchitectonically defined BA 5 and surrounding regions. Similarities and differences of receptor distribution between cortical areas were studied by cluster analysis of mean binding site densities averaged over all cortical layers, univariate and multivariate statistics, and by density profiles representing laminar receptor distribution patterns. Based on regional heterogeneities of binding site densities and of the cytoarchitecture within BA 5, we suggest a subdivision into three subareas: medial area 5M, lateral area 5L, and area 5Ci in the region around the cingulate sulcus. BA 5 is therefore a heterogeneous cortical region, comprising three subareas showing receptor expression patterns similar to the adjoining higher order somatosensory, multimodal parietal, or cingulate regions. These findings suggest that human BA 5 constitutes a higher order cortical area, clearly distinct from the primary somatosensory and motor cortex.

Neuropathic pain is generally defined as a chronic pain state resulting from peripheral or central nerve injury, or both. An effective treatment for neuropathic pain is still lacking. The NMDA receptor, one type of the ionotropic glutamate receptors, is known to be important for triggering long-lasting changes in synapses. NMDA receptor-dependent synaptic plasticity plays roles not only in physiological functions such as learning and memory, but also in unwanted pathological conditions such as chronic pain. This review addresses recent progress on NMDA receptors in neuropathic pain, with particular emphasis on the NR2B-subunit-containing receptors. The expression and function of NMDA receptors in synaptic plasticity in the pain transmission pathway from dorsal root ganglia to the anterior cingulate cortex is reviewed, and preclinical and clinical investigations of selective NMDA receptor in neuropathic pain are discussed. The NMDA receptors, in particular NR2B-containing NMDA receptors, serve as promising targets for treatment of neuropathic pain.

Various cyto- and myeloarchitectonic maps of the human parietal cortex have been published since the beginning of the past century. However, the parietal lobe remains an uncharted region, since these anatomical findings fail to explain the much greater areal differentiation, especially in the posterior parietal cortex, which has recently been revealed by functional imaging studies. This lack of congruence does not imply a total lack of correspondence between anatomical and functional data, since several practically forgotten architectonic studies published during the first 5 decades of the past century demonstrate a much more differentiated map of the parietal cortex than the popular map of Brodmann and others. Moreover, recent receptor-architectonic studies also demonstrate a detailed architectonic pattern the functional aspects of which will be explored in the near future.

The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent α2-adrenoceptor-mediated inhibitory system and 5-HT3 (and likely also 5-HT2) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.

GABAergic inhibitory transmission is very abundant within the insect brain. We, therefore, studied the functional properties of the ionotropic GABA receptor of honeybee mushroom body Kenyon cells in vitro. GABA applications elicit rapidly activating and desensitizing currents, which are concentration-dependent between 10 and 500 μM. The mean peak amplitude induced by 500 μM GABA at a holding potential of -110 mV is -1.55 ± 0.23 nA (SEM, n = 29). The GABA-induced current is mediated by Cl⁻ ions because (1) the reversal potential of the GABA-induced current of -40.6 mV is very close to the calculated Nernst potential of chloride (-44.8 mV). (2) With equimolar chloride concentrations the reversal potential shifted to about 0 mV. GABA or muscimol are equally efficient channel agonists, whereas CACA is a partial agonist. Picrotoxin or philanthotoxin (100 μM) completely and reversibly block the GABA-induced current, bicuculline (100 μM) has no effect. Elevating the intracellular Ca²⁺ concentration increases the GABA current amplitude. This modualtory effect is blocked by the kinase blocker K 252a, but not by blockers of CaMkinaseII (KN-93), PKC (bisindolylmaleimide) or PKA (KT 5720). We conclude that Kenyon cells express functional GABA receptors whose properties support an inhibitory role of GABAergic transmission.