Journal of neurophysiology
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Primary hyperalgesia after tissue injury is suggested to result from sensitization of primary afferent fibers, but sensitization to mechanical stimuli has been difficult to demonstrate. In the companion study, sensitization of mechano-responsive Adelta- and C-fibers did not explain pain behaviors 45 min after an incision in the rat hindpaw. In the present study, we examined mechanical response properties of Adelta- and C-fibers innervating the glabrous skin of the plantar hindpaw in rats 1 day after an incision or sham procedure. ⋯ The results indicate that sensitization of Adelta- and C-fibers is apparent 1 day after incision. Because sensitization of afferent fibers to mechanical stimuli correlated with behavioral results, sensitization may contribute to the reduced withdrawal threshold after incision. Spontaneous activity in Adelta- and C-fibers may account for nonevoked pain behavior and may also contribute to mechanical hyperalgesia by amplifying responses centrally.
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The purpose of this study was to examine which primary afferent fibers are sensitized to mechanical stimuli after an experimental surgical incision to the glabrous skin of the rat hindpaw. Afferent fibers teased from the L(5) dorsal root or the tibial nerve were recorded in anesthetized rats. The mechanical response properties of each fiber were characterized before and 45 min after an incision (or sham procedure) within the mechanical receptive field. ⋯ In a group of MIA Adelta- and C-fibers, a greater percentage of 17 fibers studied (41%) were sensitized after incision. In this model, the principal effect of an incision, when examined 45 min after the insult, is an increase in receptive field size of the afferents, particularly those characterized as MIAs. To the extent that the mechanical hyperalgesia characterized in the same model is initiated in the periphery, it would appear that spatial summation of modestly increased response magnitude is important to the development of hyperalgesia.
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Recent studies indicate that descending pain modulatory pathways undergo time-dependent changes in excitability following inflammation involving both facilitation and inhibition. The cellular and molecular mechanisms of these phenomena are unclear. In the present study, we examined N-methyl-D-aspartate (NMDA) receptor gene expression and neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in pain modulatory circuitry, after complete Freund's adjuvant (CFA)-induced hindpaw inflammation. ⋯ A population study (n = 165) confirmed an increase in on- and off-like cells and a decrease in neutral-like cells at 24 h after inflammation as compared with naïve rats (P < 0.001). These results suggest that enhanced NMDA receptor activation mediates time-dependent changes in excitability of RVM pain modulatory circuitry. The functional phenotypic switch of RVM neurons provides a novel mechanism underlying activity-dependent plasticity and enhanced net descending inhibition after inflammation.
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The perforant path constitutes the primary projection system relaying information from the neocortex to the hippocampal formation. Long-term synaptic potentiation (LTP) in the perforant path projections to the dentate gyrus is well characterized. However, surprisingly few studies have addressed the mechanisms underlying LTP induction in the direct perforant path projections to the hippocampus. ⋯ The selective sensitivity of lateral perforant path-CA3 LTP to mu-opioid receptor antagonists corresponds with the distribution of mu-opioid receptors within the stratum lacunosum-moleculare of area CA3 where perforant path projections to CA3 terminate. These data indicate that both lateral and medial perforant path projections to the CA3 region display LTP, and that LTP induction in medial and lateral perforant path-CA3 synapses are differentially sensitive to NMDA receptor and mu-opioid receptor antagonists. This suggests a role for opioid, but not NMDA receptors in the induction of LTP at lateral perforant path projections to the hippocampal formation.
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Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-D-aspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. ⋯ Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.