Brain research
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Cannabinoids, such as anandamide, are involved in pain transmission. We evaluated the effects of AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), an anandamide reuptake inhibitor, monitoring the expression of c-fos, a marker of activated neurons and the pain-related behaviours using formalin test. The study was carried out in an experimental model of inflammatory pain made by a single injection of formalin in rat hind paws. ⋯ We found that Fos-positive neurons in dorsal superficial and deep laminae of the lumbar spinal cord increased in formalin-injected animals and that AM404 significantly reduced Fos induction. Co-administration of cannabinoid CB(1) receptor antagonist (AM251), cannabinoid CB(2) receptor antagonist (AM630) and transient receptor potential vanilloid type 1 (TRPV-1) antagonist (capsazepine), attenuate the inhibitory effect of AM404 and this effect was higher using cannabinoid CB(2) and vanilloid TRPV-1 receptor antagonists. These results suggest that AM404 could be a useful drug to reduce inflammatory pain in our experimental model and that cannabinoid CB(2) receptor and vanilloid TRPV-1 receptor, and to a lesser extent, the cannabinoid CB(1) receptor are involved.
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Alcohols and volatile anesthetics modulate the function of cys-loop ligand-gated ion channels, binding to a putative site between transmembrane domains two and three. The extracellular linker between these two domains is important in the transduction of the gating signal from the glycine binding site to the channel gate. Although the anesthetic binding site is proposed to be in the same region throughout the cys-loop receptor family, the modulatory effects of these compounds depend on the receptor. ⋯ Mutation at this residue did not affect thiol binding to residues in TM2 or TM3 and it does not appear that residue 281 constitutes part of the alcohol binding site. The K281P receptors displayed constitutive activity in the absence of glycine, and unlike wild-type receptors, this channel opening was antagonized by application of either volatile anesthetics or another GlyR modulator, zinc. Our data suggest that the TM2-TM3 extracellular loop plays a role in the transduction of signals generated by allosteric modulators in addition to gating signals that follow glycine binding.
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Gastric electrical stimulation (GES) has been suggested as a therapy for patients with gastric motility disorders or morbid obesity. However, it is unclear whether GES also affects intestinal sensory and motor functions. Furthermore, little is known about intraspinal visceroreceptive transmission and processing for duodenal afferent information. ⋯ Resiniferatoxin (2.0 microg/kg, i.v.), an ultrapotent agonist of transient receptor potential vanilloid receptor-1 (TRPV1), abolished DD responses and GES effects on all neurons examined in vagotomized rats. Additionally, 29/33 (88%) DD-responsive neurons received inputs from somatic receptive fields on the back, flank and medial/lateral abdominal areas. It was concluded that GES mainly exerted an excitatory effect on T9-T10 spinal neurons with duodenal input transmitted by sympathetic afferent fibers expressing TRPV1; spinal neuronal responses to GES were strengthened with an increased pulse width and/or frequency of stimulation; T9-T10 spinal neurons processed input from the duodenum and might mediate effects of GES on duodenal sensation and motility.
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Conditioned taste aversions (CTAs) may be acquired when an animal consumes a novel taste (conditioned stimulus; CS) and then experiences the symptoms of poisoning (unconditioned stimulus; US). Animals will later avoid the taste that was previously associated with malaise. Extinction of a CTA is observed following repeated, non-reinforced exposures to the CS and represents itself as a resumption of eating/drinking the once-avoided tastant. ⋯ Low levels of c-Fos expression in the central nucleus of the amygdala (CE) were observed throughout EXT with little change in expression detectable following SR. These measurements reflect the dynamic nature of brain activity during acquisition and extinction of a CTA and highlight an important role for cortical neurons in the brain reorganization that occurs during SR of a CTA. The data also suggest that certain sub-nuclei of the AMY may play a relatively minor role in SR of this defensive reaction to a learned fear.
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The role of the cellular prion protein (PrP(c)) in neuronal functioning includes neuronal excitability, cellular adhesion, neurite outgrowth and maintenance. Here we investigated the putative involvement of the PrP(c) function on the nociceptive response using PrP(c) null (Prnp(0/0)) and wild-type (Prnp(+/+)) mice submitted to thermal and chemical models of nociception. PrP(c) null mice were more resistant than wild-type mice to thermal nociception of the tail-flick test. ⋯ In contrast, the same pre-treatment did not alter the formalin response in PrP(c) null mice. These results indicate a role of PrP(c) in the nociceptive transmission, including the thermal tail-flick test and visceral inflammatory nociception (acetic acid-induced abdominal constriction). Our findings show that PrP(c) is involved with a response mediated by inflammation (paw edema) and by visceral conditioning stimuli.