SUMMARY1. In the cat anaesthetized with sodium pentobarbitone, electrical activity was recorded from single unmyelinated sensory fibres innervating the cornea.2. Based on their response to mechanical (calibrated aesthesiometer), chemical (10 mm acetic acid or 616 mm NaCl) and thermal (cooling from 35 to 5°C; heating to 51°C) stimuli, corneal unmyelinated fibres were classified as polymodal (71 %) or 'cold' nociceptors (29 %).3. Polymodal units responded to mechanical indentation of the cornea and developed fatigue after repeated stimulation. They were excited by temperatures over 37°C and exhibited sensitization to repeated heating.4. Corneal polymodal units were also activated by topical application of 10 mM acetic acid and hypertonic NaCl (616 mM). Capsaicin (0 33 mM) elicited a discharge of impulses that was followed by inactivation to mechanical, chemical and thermal stimuli.5. 'Cold' nociceptors had small receptive fields, preferentially located at the periphery of the cornea. They were excited by small temperature decreases of the corneal surface in a range between 30 and 8°C, but were not responsive to noxious heat.6. 'Cold' nociceptors encoded temperature changes between 35 and 23 'C. The discharge was proportional to the velocity of the temperature drop; sustained temperatures were not signalled by changes in static frequency values. 'Cold' nociceptive fibres responded to hypertonic NaCl (616 mM) and weakly to 10 mM acetic acid. Capsaicin (0 33 mM) first excited and then inactivated 'cold' nociceptors.7. Thermoreceptive fibres were found in the episclera. They fired in bursts and responded to small temperature decreases, but were insensitive to irritant chemicals and capsaicin.

SUMMARY1. Single-unit electrical activity was recorded from thin myelinated sensory nerve fibres innervating the cornea of deeply anaesthetized cats.2. Based on their responses to mechanical (calibrated von Frey hairs), chemical (10 mM-acetic acid and/or 616 mM-NaCl) and thermal (ice-cold or heat up to 51°C) stimuli, corneal Ad fibres were classified as polymodal nociceptors (63%), highthreshold mechanoceptors (22%) and mechano-heat nociceptors (15%). Thin myelinated fibres responding only to cold were found in the limbus of the eye.3. Application of 10 mM-acetic acid on the corneal surface for 30 s evoked in polymodal fibres a brisk discharge of impulses often followed by a low-frequency impulse activity. NaCl (616 mM) produced a more gradual and sustained firing response.4. The responses of polymodal fibres to acid were proportional to extracellular pH values (pH range: 4 5-6 0). After sensitization to repeated heating, most mechanoheat units developed a sensitivity to acidic stimulation.5. Topical 0 33 mM-capsaicin excited polymodal nociceptors of the cornea; 5 min after capsaicin about 15 % of these fibres were inactivated to all subsequent stimuli. In the rest of the fibres, chemical and thermal sensitivity disappeared after 0 33-3 3 mM-capsaicin, but mechanosensitivity was preserved.6. Corneal mechanoceptors and limbal cold receptors were not affected by capsaicin (up to 33 mM).7. These experiments demonstrate that the cornea of the cat is innervated by polymodal as well as mechanoceptive Ad nociceptors. In polymodal nociceptive fibres, mechanical and chemical sensitivities appear to be subserved by separate transduction mechanisms.

In the present work, several experimental approaches were used to determine the presence of the glucagon-like peptide-1 receptor (GLP-1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP-1 receptor mRNA in several brain areas. In addition, GLP-1R, glucose transporter isoform (GLUT-2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP-1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross-linking assays. Specific binding of amide to the GLP-1R was detected in several brain areas and was inhibited by unlabelled GLP-1(7-36) amide, exendin-4 and exendin (9-39). A further aim of this work was to evaluate cerebral-glucose metabolism in control subjects by positron emission tomography (PET), using 2-[F-18] deoxy-D-glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP-1(7-36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG-6-phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT-2-and GK-containing cells. The existence of specific subpopulations of neurones involved in energy homeostasis, and located in the so-called 'satiety and hunger centres' of the hypothalamus, is well established. These neuronal pathways, containing both orexigenic and anorexigenic peptides, generate integrated responses to afferent stimuli that are related to modifications in metabolites or in the storage of fuels. Feeding behaviour is controlled by the antagonist effects of both classes of molecules, glucagon-like peptide-1 (GLP-1) being one of the components of the numerous groups of anorexigenic peptides. GLP-1(7-36) amide is a member of the glucagon-related peptide family. It is produced by posttranslational modification of GLP-1, which is encoded by the

BackgroundAlzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.MethodsWe have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET).ResultsNovel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.ConclusionsIn summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Recent research suggests that the allocation of attentional resources to emotional content during word processing might be sensitive to task requirements. This question was investigated in two tasks with similar instructions. The stimuli were positive, negative, and neutral nouns. Participants had to identify meaningful words embedded in a stream of non-recognizable stimuli (task 1) or pseudowords (task 2). Task 1 could be successfully performed on the basis of the perceptual features whereas a lexico-semantic analysis was required in task 2. Effects were found only in task 2. Positive nouns were identified faster, with fewer errors and elicited larger amplitude in an early negativity. Also, the amplitude of a late positivity was larger for both positive and negative nouns than for neutral nouns. It is concluded that some degree of linguistic processing is needed to direct attention to the affective content during word processing.