The Journal of neuroscience : the official journal of the Society for Neuroscience
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Previous studies have shown that long-term potentiation (LTP) can be induced in the lateral nucleus of the amygdala (LA) after stimulation of central auditory pathways and that auditory fear conditioning modifies neural activity in the LA in a manner similar to LTP. The present experiments examined whether intra-LA administration of inhibitors of protein synthesis or protein kinase A (PKA) activity, treatments that block LTP in hippocampus, interfere with memory consolidation of fear conditioning. ⋯ Additional experiments showed that anisomycin and Rp-cAMPS interfered with long-term memory (LTM), but not short-term memory (STM), of fear and that the effect on LTM was specific to memory consolidation processes rather than to deficits in sensory or performance processes. Findings suggest that the LA is essential for memory consolidation of auditory fear conditioning and that this process is PKA and protein-synthesis dependent.
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The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. ⋯ Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
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A group of neurons with the characteristics of dentate gyrus granule cells was found at the hilar/CA3 border several weeks after pilocarpine- or kainic acid-induced status epilepticus. Intracellular recordings from pilocarpine-treated rats showed that these "granule-like" neurons were similar to normal granule cells (i. e., those in the granule cell layer) in membrane properties, firing behavior, morphology, and their mossy fiber axon. However, in contrast to normal granule cells, they were synchronized with spontaneous, rhythmic bursts of area CA3 pyramidal cells that survived status epilepticus. ⋯ Many BrdU-labeled cells at the hilar/CA3 border also were double-labeled with a neuronal marker (NeuN). Taken together with the recent evidence that granule cells that are born after seizures can migrate into the hilus, the results suggest that some newly born granule cells migrate as far as the CA3 cell layer, where they become integrated abnormally into the CA3 network, yet they retain granule cell intrinsic properties. The results provide insight into the physiological properties of newly born granule cells in the adult brain and suggest that relatively rigid developmental programs set the membrane properties of newly born cells, but substantial plasticity is present to influence their place in pre-existing circuitry.
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Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heat-evoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32 degrees C. ⋯ This suggests a constitutive expression of signaling receptors for TNF and IL-1 beta and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.
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Extracellular ATP has been known to activate sensory neurons via the ATP-gated ion channels P2X receptors, indicating that the P2X receptors may play a role in signal transduction of pain from the periphery to the spinal cord in vivo. Here, we found a novel nociceptive response induced by ATP, mechanical allodynia (hypersensitivity to innocuous mechanical stimulus). Injection of alpha,beta-methylene ATP (alpha(beta)meATP), an agonist to P2X receptor, into plantar surface in rats produced the mechanical allodynia along with previously described nocifensive behavior and thermal hyperalgesia. ⋯ ATP has been shown to produce two distinguishable electrophysiological responses (inward currents with rapid and slow desensitization) in dorsal root ganglion (DRG) neurons. In the present electrophysiological experiment, the percentage of DRG neurons that responded to alpha(beta)meATP with slow desensitizing inward current remained constant in capsaicin-treated rats, whereas the percentage that responded with rapid desensitizing current dramatically decreased. Taken together with our previous finding that the alpha(beta)meATP-activated slow desensitizing current in DRG neurons is mediated by heteromeric P2X2/3 (P2X2 and P2X3) receptors, it is hypothesized that activation of heteromeric P2X2/3 receptors in peripheral terminals of capsaicin-insensitive primary afferent fibers leads to the induction of mechanical allodynia.