Neuroscience
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From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. ⋯ Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.
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Comparative Study
Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles.
In order to study the neurobiological basis of seasonal changes in hippocampal structure and function, the rate of cell proliferation was examined in male and female wild meadow voles captured during different seasons. We found that the number of [3H]thymidine-labeled cells varied across the seasons and across sex in the meadow vole. Non-breeding female meadow voles had a higher rate of cell proliferation and cell death than males captured during either season or breeding females. ⋯ Females captured during the non-breeding season had higher rates of cell proliferation in the granule cell layer than females captured during the breeding season. This seasonal fluctuation was related to hormone levels, with high levels of corticosterone and estradiol being related to lower levels of cell proliferation. These seasonal changes in cell proliferation may be related to known changes in spatial learning in the meadow vole and provide insights into changes in the hippocampus that occur in other species, including primates.
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The hippocampus has long been known to be important for memory function. However, the involvement of hippocampal dopamine systems with memory has received little attention. In the current study, dopamine D1 and D2 hippocampal receptor system involvement with memory was assessed in female Sprague-Dawley rats by local infusion of D1 and D2 agonists and antagonists into the ventral hippocampus. ⋯ This study provides clear evidence that hippocampal D2 activity is positively related to working memory performance, while evidence for D1 systems is less compelling. Dopamine D2 receptors in the ventral hippocampus were shown to have important influences on spatial working memory. In a consistent pattern of effects ventral hippocampal infusion of the D2 agonist quinpirole improved working memory performance in the radial-arm maze, while ventral hippocampal infusion of the D2 antagonist raclopride impaired performance.
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The effect of the novel GABAc receptor antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl-phosphinic acid (TPMPA) on synaptic transmission and GABA-mediated responses was investigated with electrophysiological recordings from the in vitro spinal cord preparation of the neonatal rat. Bath-applied TPMPA (10 microM) had no effect on spinal reflexes evoked by dorsal root stimulation, on ventral root polarization level or amplitude of ventral root depolarizations induced by exogenously applied GABA (0.5 mM). TPMPA significantly attenuated the depressant action of GABA on spinal reflexes without changing responses induced by the GABA(A) receptor agonist isoguvacine (50 microM) or the GABA(B) receptor agonist baclofen (0.5-2 microM). ⋯ This bursting pattern, which is generated at the level of the interneuronal network, was significantly slowed down by TPMPA, which also increased the duration of individual bursts and the number of intraburst oscillations. These results suggest that in the neonatal rat spinal cord some functional GABAc receptors exist: their role was clearly unmasked following pharmacological block of GABA(A) (and glycine) receptors. Under these conditions GABAc receptors appeared to contribute to the excitation of spinal interneurons supporting rhythmic bursting activity.
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Comparative Study
Transgenic mice over-expressing substance P exhibit allodynia and hyperalgesia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists.
A transgenic mouse has been developed which, during development, over-expresses nerve growth factor under the control of a myelin basic protein promoter. These animals display an ectopic network of substance P-containing sensory fibers in the white matter of the spinal cord. To study the functional significance of this model to nociception, these mice were studied in a test measuring the latency to tail withdrawal from a noxious radiant heat stimulus. ⋯ The neurokinin-1 receptor antagonist CP-96,345, but not the inactive stereoisomer CP-96,344, administered subcutaneously 30 min before the 450 g stimulus, blocked the stimulation-induced allodynia in transgenic mice, and revealed a transient antinociception in transgenic and control mice. Ketamine, an N-methyl-D-aspartate receptor antagonist, given intraperitoneally 10 min before 450 g stimulation, blocked the allodynia in transgenic mice. These results indicate that these transgenic mice display hyperalgesia and allodynia, and that these nociceptive responses are reversed by substance P and N-methyl-D-aspartate receptor antagonists.