The Journal of neuroscience : the official journal of the Society for Neuroscience
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B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. ⋯ Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin-induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy.
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After CNS injuries, axon growth inhibitors from the myelin and the scar tissue at the injury site are considered major impediments to axon regeneration. The presence of several classes of inhibitors with multiple members in each class suggests functional redundancy in growth inhibition. To test redundancy within the myelin inhibitory pathway, we analyzed raphe spinal serotonergic (5-HT) axon regeneration in mice deficient in two major myelin inhibitors, Nogo and MAG, and their common receptor NgR1 (or NgR). ⋯ To assess the contribution of class 3 Semaphorins that are expressed by GFAP-negative meningeal fibroblasts at the injury site, we analyzed mice deficient in PlexinA3 and PlexinA4, two key receptors for class 3 Semaphorins, with or without additional NgR1 deletion. No enhanced regeneration of 5-HT or corticospinal axons was detected in PlexinA3/PlexinA4 double mutants or PlexinA3/PlexinA4/NgR1 triple mutants through a complete transection injury. In contrast with previous reports, these data demonstrate that attenuating myelin or Semaphorin-mediated inhibition of axon growth is insufficient to promote 5-HT axon regeneration and further indicate that even attenuating both classes of inhibitory influences is insufficient to promote regeneration of injured axons through a complete transection spinal cord injury.
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To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. ⋯ Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression.
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Picking up a cup requires transporting the arm to the cup (transport component) and preshaping the hand appropriately to grasp the handle (grip component). Here, we used functional magnetic resonance imaging to examine the human neural substrates of the transport component and its relationship with the grip component. Participants were shown three-dimensional objects placed either at a near location, adjacent to the hand, or at a far location, within reach but not adjacent to the hand. ⋯ For the first time, we have identified the neural substrates of the transport component, which include the superior parieto-occipital cortex and the rostral superior parietal lobule. Consistent with past studies, we found specialization for the grip component in bilateral anterior intraparietal sulcus and left ventral premotor cortex; now, however, we also find activity for the grasp even when no transport is involved. In addition to finding areas specialized for the transport and grip components in parietal cortex, we found an integration of the two components in dorsal premotor cortex and supplementary motor areas, two regions that may be important for the coordination of reach and grasp.
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Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. ⋯ Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.