Journal of neurophysiology
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To learn about the sequence of brain activation patterns during heat pain, we acquired positron emission tomographic (PET) brain scans at different times during repetitive heat stimulation (40 or 50 degrees C; 5-s contact) of each subject's left forearm. Early scans began at the onset of 60 s of stimulation; late scans began after 40 s of stimulation, which continued throughout the 60-s scan period (total stimulus duration 100 s). Each subject (14 normal, right-handed subjects; 10 male, 4 female; ages 18-42) used a visual analog scale to rate the perceived stimulus intensity (0 = no heat, 7 = pain threshold, 10 = barely tolerable pain) after each scan. ⋯ Structures that are equally active throughout stimulation (contralateral mid-anterior cingulate and premotor cortex) are less likely to mediate these psychophysical changes. Some cortical, but not subcortical, structures showed significant or borderline activation only during the early scans (ipsilateral premotor cortex, contralateral perigenual anterior cingulate, lateral prefrontal, and anterior insular cortex); they may mediate pain-related attentive or anticipatory functions. Overall, the results reveal that 1) the pattern of brain activation and the perception of heat pain both change during repetitive noxious heat stimulation, 2) cortical activity can be detected before subcortical responses appear, and 3) timing the stimulation with respect to the scan period can, together with psychophysical measurements, identify brain structures that are likely to participate in the perception of pain.
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It is now well established that the analgesic actions of opioids can be modified by "anti-analgesic" or "antiopioid" peptides, among them cholecystokinin (CCK). Although the focus of much recent work concerned with CCK-opioid interactions has been at the level of the spinal cord, CCK also acts within the brain to modify opioid analgesia. The aim of the present study was to characterize the actions of CCK in a brain region in which the circuitry mediating the analgesic actions of opioids is relatively well understood, the rostral ventromedial medulla (RVM). ⋯ Opioid suppression of ON-cell firing was not significantly altered by CCK. Thus CCK acting within the RVM attenuates the analgesic effect of systemically administered morphine by preventing activation of the putative pain inhibiting output neurons of the RVM, the OFF cells. CCK thus differs from another antiopioid peptide, orphanin FQ/nociceptin, which interferes with opioid analgesia by potently suppressing all OFF-cell firing.
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Focal ischemia evokes a sudden loss of membrane potential in neurons and glia of the ischemic core termed the anoxic depolarization (AD). In metabolically compromised regions with partial blood flow, peri-infarct depolarizations (PIDs) further drain energy reserves, promoting acute and delayed neuronal damage. Visualizing and quantifying the AD and PIDs and their acute deleterious effects are difficult in the intact animal. ⋯ This study shows that anoxic depolarization evoked by global ischemia-like conditions is a spreading process that is focally initiated at multiple sites in cortical and subcortical gray. The combined energy demands of O(2)/glucose deprivation and the AD greatly exacerbate neuronal damage. Glutamate receptor antagonists neither block the AD in the ischemic core nor, we propose, block recurrent PID arising close to the core.
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The heterogeneous family of G-protein-coupled metabotropic glutamate receptors (mGluRs) provides excitatory and inhibitory controls of synaptic transmission and neuronal excitability in the nervous system. Eight mGluR subtypes have been cloned and are classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the ability to inhibit cAMP formation. ⋯ When given as posttreatment, the group II agonists LCCG1 (100 microM, n = 5) and LY379268 (100 microM, n = 6) and the group III agonist LAP4 (100 microM, n = 6) reversed the capsaicin-induced sensitization. After washout of the agonists, the central sensitization resumed. Our data suggest that, while activation of both group II and group III mGluRs can reverse capsaicin-induced central sensitization, it is the actions of group II mGluRs in particular that undergo significant functional changes during central sensitization because they modulate responses of sensitized STT cells but have no effect under control conditions.
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Comparative Study
Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons.
In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subunit composition of subsynaptic GABA(A) receptors (GABA(A)Rs) at differing developmental stages as well as other factors. These include changes in the driving force for chloride-mediated conductances as well as the quantity and/or cleft lifetime of released neurotransmitter. ⋯ These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In the first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kinetically but retain distinct responses to modulatory drugs, possibly reflecting continued immaturity in synaptic structure and function persisting through adolescence.