Mol Pain
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There are substantial disagreements about the expression of gastrin-releasing peptide (GRP) in sensory neurons and whether GRP antibody cross-reacts with substance P (SP). These concerns necessitate a critical revaluation of GRP expression using additional approaches. Here, we show that a widely used GRP antibody specifically recognizes GRP but not SP. ⋯ Our comprehensive study demonstrates that a majority of GRPergic fibers are of primary afferent origin. A number of factors such as low copy number ofGrptranscripts, small percentage of cells expressingGrp, and the use of an eGFP GENSAT transgenic as a surrogate for GRP protein have contributed to the controversy. Optimization of experimental procedures facilitates the specific detection of GRP expression in dorsal root ganglia neurons.
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Small fiber neuropathy is a painful sensory nervous system disorder characterized by damage to unmyelinated C- and thinly myelinated Aδ- nerve fibers, clinically manifested by burning pain in the distal extremities and dysautonomia. The clinical onset in adulthood suggests a time-dependent process. ⋯ In the present study, we report time-dependent degeneration of neurites from dorsal root ganglia neurons in culture expressing small fiber neuropathy-associated G856D mutant Nav1.7 channels and demonstrate a time-dependent increase in intracellular calcium levels [Ca2+]i and reactive oxygen species, together with a decrease in ATP levels. Together with a previous clinical report of burning pain in the feet and hands associated with reduced levels of Na+/K+-ATPase in humans with high altitude sickness, the present results link energetic stress and reactive oxygen species production with the development of a painful neuropathy that preferentially affects small-diameter axons.
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Optogenetic tools enable cell selective and temporally precise control of neuronal activity; yet, difficulties in delivering sufficient light to the spinal cord of freely behaving animals have hampered the use of spinal optogenetic approaches to produce analgesia. We describe an epidural optic fiber designed for chronic spinal optogenetics that enables the precise delivery of light at multiple wavelengths to the spinal cord dorsal horn and sensory afferents. ⋯ Epidural optogenetics provides a robust and powerful solution for activation of both excitatory and inhibitory opsins in sensory processing pathways. Our results demonstrate the potential of spinal optogenetics to modulate sensory behavior and produce analgesia in freely behaving animals.
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Anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 are important ubiquitin-ligases in proliferating cells and terminally differentiated neurons. In recent years, APC/C-Cdh1 has been reported as an important complex contributing to synaptic development and transmission. Interestingly, cortical APC/C-Cdh1 is found to play a critical role in the maintenance of neuropathic pain, but it is not clear whether APC/C-Cdh1 in spinal dorsal cord is involved in molecular mechanisms of neuropathic pain conditions. ⋯ This study indicates that a downregulation of Cdh1 expression in spinal dorsal horn is involved in molecular mechanisms underlying the maintenance of neuropathic pain. Upregulation of spinal Cdh1 may be a promising approach to treat neuropathic pain.
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The N-methyl-D-aspartate subtype of glutamate receptor plays a critical role in morphine tolerance. D-serine, a co-agonist of N-methyl-D-aspartate receptor, participates in many physiological and pathophysiological processes via regulating N-methyl-D-aspartate receptor activation. The purinergic P2X7 receptor activation can induce the D-serine release in the central nervous system. This study aimed to investigate the role of the ventrolateral midbrain periaqueductal gray D-serine in the mechanism of morphine tolerance in rats. The development of morphine tolerance was induced in normal adult male Sprague-Dawley rats through subcutaneous injection of morphine (10 mg/kg). The analgesic effect of morphine (5 mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds in rats with an electronic von Frey anesthesiometer. The D-serine concentration and serine racemase expression levels in the ventrolateral midbrain periaqueductal gray were evaluated through enzyme-linked immunosorbent assay and Western blot analysis, respectively. The effects of intra-ventrolateral midbrain periaqueductal gray injections of the D-serine degrading enzyme D-amino acid oxidase and antisense oligodeoxynucleotide targeting the P2X7 receptor on chronic morphine-treated rats were also explored. ⋯ Our data indicate that the development of antinociceptive tolerance to morphine is partially mediated by ventrolateral midbrain periaqueductal gray D-serine content, and the activation of the ventrolateral midbrain periaqueductal gray P2X7 receptor is an essential prelude to D-serine release. These results suggest that a cascade involving P2X7 receptor-D-serine-N-methyl-D-aspartate receptor mediated signaling pathway in the supraspinal mechanism of morphine tolerance.