Neuroscience
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The hypothesis that prostaglandins contribute to hyperalgesia resulting from nerve injury was tested in rats in which the sciatic nerve was partially transected on one side. Subcutaneous injection of indomethacin (a classic inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical hyperalgesia for up to 10 days after injection. Subcutaneous injection of meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time-course. ⋯ Comparable injections into the contralateral paw or abdomen had no effect on mechanical or thermal hyperalgesia, suggesting that the effects we observed were local rather than systemic. We conclude that prostaglandins, probably prostaglandin E1 or E2, contribute to the peripheral mechanisms underlying hyperalgesia following nerve injury. These data provide further evidence that inflammatory mediators contribute to neuropathic pain, and may warrant further study of peripherally administered non-steroidal anti-inflammatory drugs as a possible treatment for such pain in patients.
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The present investigation details the modulation of medullary dorsal horn neuron responses to excitatory amino acids and peripheral cutaneous stimuli by orphanin FQ (nociceptin), an endogenous ligand for the opioid receptor-like, receptor. Effects of orphanin FQ, administered microiontophoretically or given intracerebroventricularly, were tested on the responses of nociceptive-specific, wide dynamic range and low threshold neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (urethane or pentobarbital) male rats. Microiontophoretic application of orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 86% (71/82) of neurons, and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses in 86% (30/35) of neurons. ⋯ Orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 85% (11/13) of neurons whereas the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses were facilitated in 69% (9/13) of neurons. We suggest that orphanin FQ produces a predominantly inhibitory effect on, (i) noxious stimuli evoked responses, (ii) excitatory amino acid receptor-mediated transmission and, (iii) the substance P-induced facilitation of the N-methyl-D-aspartate-evoked responses. We conclude that orphanin FQ primarily produced an antinociceptive action at the level of the dorsal horn of the medulla.
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Neuronal activity was recorded from the anterior cingulate cortex of behaving rats during discrimination and learning of conditioned stimuli associated with or without reinforcements. The rats were trained to lick a protruding spout just after a conditioned stimulus to obtain reward (intracranial self-stimulation or sucrose solution) or to avoid aversion. The conditioned stimuli included both elemental (auditory or visual stimuli) and configural (simultaneous presentation of auditory and visual stimuli predicting reward outcome opposite to that predicted by each stimulus presented alone) stimuli. ⋯ Analysis by the multidimensional scaling of responses of 38 differential conditioned stimulus-related neurons indicated that the anterior cingulate cortex categorized the conditioned stimuli into three groups based on reward contingency, regardless of the physical characteristics of the stimuli, in a two-dimensional space; the three conditioned (two elemental and one configural) stimuli predicting sucrose solution, the three conditioned (two elemental and one configural) stimuli predicting no reward, and the lone conditioned stimulus predicting intracranial self-stimulation. The results suggest that the anterior cingulate cortex is organized topographically; stimulus attributes predicting reward or no reward are represented in the rostral and ventral parts of the anterior cingulate cortex, while the caudal and dorsal parts of the anterior cingulate cortex are related to execution of learned instrumental behaviors. These results are in line with recent neuropsychological studies suggesting that the rostral part of the anterior cingulate cortex plays a crucial role in socio-emotional behaviors by assigning a positive or negative value to future outcomes.
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The classic opioid peptide, enkephalin, and the novel member of the opioid family, nociceptin/orphanin FQ, inhibit the spontaneous electrical activity of neurons recorded from the rostral ventrolateral medulla, presumably cardiovascular neurons. In this study, the putative effects of endomorphin-1 and endomorphin-2, the newly discovered endogenous ligands for the micro-opioid receptor, on the electrical activity of rostral ventrolateral medulla neurons were investigated in rat brain slices in vitro. Like enkephalin and nociceptin, perfusion of endomorphin-1 or endomorphin-2 profoundly inhibited spontaneous discharges of 43% and 38% of the medullary neurons, respectively. ⋯ The selective mu antagonist, beta-funaltrexamine, prevented the neuronal inhibition induced by endomorphins, but not by enkephalin and nociceptin. Neither naloxone nor beta-funaltrexamine alone had a significant effect on the firing rate of the neurons. These results demonstrate that endomorphin-1 and, to a lesser extent, endomorphin-2 exert an inhibitory modulation of the electrical activity of rostral ventrolateral medulla neurons, which is mediated through the stimulation of mu-opioid receptors.
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Synaptic plasticity has been implicated in the mechanisms contributing to the shaping of the cortical circuits responsible for the transmission of the visual input in the rat primary visual cortex. However, the degree of plasticity of the thalamocortical synapse may change during development, perhaps reflecting the degree of stabilization of the circuitry subserving it. We have chosen the ability of this synapse to be first depressed and then potentiated as a specific indicator of its plasticity. ⋯ The decrease in this form of cortical synaptic plasticity closely matches the stabilization of the cortical circuitry towards an adult pattern of connectivity and function. Depressed cortical synapses cannot be potentiated in normal rats at postnatal 23, but they can be potentiated in rats reared in the dark from postnatal days 17 to 29. Moreover, application of brain-derived neurotrophic factor, known to be expressed in an activity-dependent manner, was able to restore the ability of synapses to be potentiated after long-term depression, thus indicating its important modulatory role in brain development.