Articles: neuropathic-pain.
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Proc. Natl. Acad. Sci. U.S.A. · Mar 2014
Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury.
Neuronal calcium (Ca(2+))-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca(2+)-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. ⋯ Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca(2+)-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.
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Neuroscience letters · Mar 2014
Intrathecal carbenoxolone inhibits neuropathic pain and spinal wide-dynamic range neuronal activity in rats after an L5 spinal nerve injury.
Spinal glial gap junctions may play an important role in dorsal horn neuronal sensitization and neuropathic pain. In rats after an L5 spinal nerve ligation (SNL), we examined the effects of intrathecal injection of carbenoxolone (CBX), a gap junction decoupler, on neuropathic pain manifestations and on wide-dynamic range (WDR) neuronal activity in vivo. Intrathecal injection of CBX dose-dependently (0.1-50 μg, 10 μl) inhibited mechanical hypersensitivity in rats at 2-3 weeks post-SNL. ⋯ Further, rats did not develop tachyphylaxis to CBX-induced inhibition of mechanical hypersensitivity after repetitive drug treatments (25 μg/day) during days 14-16 post-SNL. Electrophysiological study in SNL rats showed that spinal topical application of CBX (100 μg, 50 μl), which mimics intrathecal drug administration, attenuated WDR neuronal responses to mechanical stimuli and to repetitive intracutaneous electrical stimuli (0.5 Hz) that induce windup, a short-form of activity-dependent neuronal sensitization. The current findings suggest that the inhibition of neuropathic pain manifestations by intrathecal injection of CBX in SNL rats may involve an inhibition of glial gap junctions and an attenuation of WDR neuronal activity in the dorsal horn.
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J. Neurosci. Methods · Mar 2014
Rotterdam Advanced Multiple Plate: a novel method to measure cold hyperalgesia and allodynia in freely behaving rodents.
To investigate the pathophysiology of temperature hypersensitivity in neuropathic pain rodent models, it is essential to be able to quantify the phenotype as objective as possible. Current temperature sensitivity measuring paradigms are performed during exposure to external factors, i.e. light, sound and smell, which modulate behavior significantly. In addition the present outcome measure for temperature hypersensitivity in rodents is the examination of the hind paw lift upon exposure to a certain temperature, which reflects more a reflex-flexion than an experience of pain. ⋯ The results indicate that the RAMP is able to quantify cold hyperalgesia and allodynia in neuropathic pain rats while resolves some of the problems of conventional temperature sensitivity measuring paradigms in rodents.
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Neuropathic pain is a serious physical disabling condition resulting from lesion or dysfunction of the peripheral sensory nervous system. Despite the fact that the mechanisms underlying neuropathic pain are poorly understood, the involvement of voltage-gated calcium (Ca(V)) channels in its pathophysiology has justified the use of drugs that bind the Ca(V) channel α₂δ auxiliary subunit, such as gabapentin (GBP), to attain analgesic and anti-allodynic effects in models involving neuronal sensitization and nerve injury. GBP binding to α₂δ inhibits nerve injury-induced trafficking of the α₁ pore forming subunits of Ca(V) channels, particularly of the N-type, from the cytoplasm to the plasma membrane of pre-synaptic terminals in dorsal root ganglion neurons and dorsal horn spinal neurons. ⋯ In addition, using the patch clamp technique we show that GZ4 treatment significantly decreased whole-cell currents through N-type Ca(V) channels heterologously expressed in HEK-293 cells. Interestingly, the behavioral and electrophysiological time course of GZ4 actions reflects that its mechanism of action is similar but not identical to that of GBP. While GBP actions require at least 24 h and imply uptake of the drug, which suggests that the drug acts mainly intracellularly affecting channels trafficking to the plasma membrane, the faster time course (1-3 h) of GZ4 effects suggests also a direct inhibition of Ca(2+) currents acting on cell surface channels.
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Mas-related G-protein-coupled receptor subtype C (MrgC) may play an important role in pain sensation. However, the distribution of MrgC receptors in different subpopulations of rodent dorsal root ganglion (DRG) neurons has not been clearly demonstrated owing to a lack of MrgC-selective antibody. It is also unclear whether peripheral nerve injury induces different time-dependent changes in MrgC expression in injured and uninjured DRG neurons. ⋯ In animal behavior tests, chronic constriction injury of the sciatic nerve induced mechanical pain hypersensitivity in wild-type mice and Mrg-clusterΔ(-/-) mice (Mrg KO). However, the duration of mechanical hypersensitivity was longer in the Mrg KO mice than in their wild-type littermates, indicating that activation of Mrgs may constitute an endogenous mechanism that inhibits the maintenance of neuropathic pain in mice. These findings extend our knowledge about the distribution of MrgC in rodent DRG neurons and the regulation of its expression by nerve injury.