The Journal of neuroscience : the official journal of the Society for Neuroscience
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Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. ⋯ In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.
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Research has implicated the perirhinal cortex (PRh) in several aspects of object recognition memory. The specific role of the hippocampus (HPC) remains controversial, but its involvement in object recognition may pertain to processing contextual information in relation to objects rather than object representation per se. Here we investigated the roles of the PRh and HPC in object memory reconsolidation using the spontaneous object recognition task for rats. ⋯ Moreover, disrupting functional interaction between the HPC and PRh by infusing anisomycin unilaterally into each structure in opposite hemispheres also impaired reconsolidation when reactivation was done in an altered context. These results show for the first time that the PRh is critical for reconsolidation of object memory traces and provide insight into the dynamic process of object memory storage; the selective requirement for hippocampal involvement following reactivation in an altered context suggests a substantial circuit level object trace reorganization whereby an initially PRh-dependent object memory becomes reliant on both the HPC and PRh and their interaction. Such trace reorganization may play a central role in reconsolidation-mediated memory updating and could represent an important aspect of lingering consolidation processes proposed to underlie long-term memory modulation and stabilization.
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Comparative Study
Neuronal loss in the rostral ventromedial medulla in a rat model of neuropathic pain.
Cell death has been reported in the CNS in models of neuropathic pain (Sugimoto et al., 1990; Whiteside and Munglani, 2001; Scholz et al., 2005; Fuccio et al., 2009). In our present study, we examined the effects of spinal nerve ligation (SNL) on the number of neurons in the rostral ventromedial medulla (RVM), a brainstem region involved in modulation of nociception. In rats receiving SNL, we found that the number of RVM neurons decreased by 23% in the side ipsilateral to the surgery. ⋯ Interestingly, after 5,7-DHT, mechanical withdrawal thresholds increased significantly. We conclude that nerve injury induces death of antinociceptive RVM neurons that can be reduced or abolished by TUDCA. We propose that the loss of RVM neurons shifts the balance of descending control from pain inhibition to pain facilitation.
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Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the appearance of fibrillar aggregates of insoluble α-synuclein (α-syn) called Lewy bodies (LBs). Approximately 90% of α-syn deposited in LBs is phosphorylated at serine 129 (Ser129). In contrast, only 4% of total α-syn is phosphorylated in normal brain, suggesting that accumulation of Ser129-phosphorylated α-syn is involved in the pathogenesis of PD. ⋯ Coexpression of catalytically inactive K215R mutant GRK6 failed to accelerate A53T α-syn-induced degeneration. Furthermore, introducing a phosphorylation-incompetent mutation, S129A, into A53T α-syn did not alter the pace of degeneration, even when GRK6 was coexpressed. Our study demonstrates that authentically Ser129-phosphorylated α-syn accelerates A53T α-syn neurotoxicity without the formation of detergent-insoluble α-syn, and suggests that the degenerative process could be constrained by inhibiting the kinase that phosphorylates α-syn at Ser129.
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In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450 μg·kg⁻¹·h⁻¹), fentanyl (48 μg·kg⁻¹·h⁻¹), or morphine (14 mg·kg⁻¹·h⁻¹), C-fiber-evoked field potentials were depressed and paired-pulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. ⋯ Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT₃Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT₃R antagonists.