Neuroscience
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Comparative Study
The contribution of autophosphorylated alpha-calcium-calmodulin kinase II to injury-induced persistent pain.
Increases in neuronal activity in response to tissue or nerve injury can lead to prolonged functional changes in the spinal cord resulting in an enhancement/sensitization of nociceptive processing. To assess the contribution of alpha-calcium-calmodulin kinase II (alpha-CaMKII) to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a point mutation in the alpha-CaMKII gene at position 286 (threonine to alanine). The mutated protein is unable to autophosphorylate and thus cannot function independently of calcium and calmodulin. ⋯ In contrast, the decreased mechanical and thermal thresholds associated with nerve injury, Complete Freund's Adjuvant-induced inflammation or formalin-evoked tissue injury were manifest equally in wild-type and mutant mice. Double-labeling immunofluorescence studies revealed that in the mouse alpha-CaMKII is expressed in the superficial dorsal horn as well as in a population of small diameter primary afferent neurons. In summary, our results suggest that alpha-CaMKII, perhaps secondary to an N-methyl-D-aspartate-mediated calcium increase in postsynaptic dorsal horn nociresponsive neurons, is a critical contributor to the spontaneous/ongoing component of tissue-injury evoked persistent pain.
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Generation of plateau potentials in spinal motoneurons depends on activation of voltage sensitive L-type Ca(2+) channels. These channels are facilitated by metabotropic receptors known to promote release of Ca(2+) from intracellular stores. The aim of this study is to determine if Ca(2+)-release receptors in the endoplasmic reticulum (ER) that are sensitive to ryanodine (RyRs) and to inositol triphosphate receptors (IP(3)Rs) contribute to the generation of plateau potentials. ⋯ Plateau-related discharge patterns, un-facilitated or facilitated by agonists for group I glutamate metabotropic receptors, muscarine-sensitive cholinergic receptors or L-type Ca(2+) channels were inhibited by blockade of RyRs. In contrast, antagonists of IP(3)Rs or PLC preferentially inhibited plateau-related discharge patterns when facilitated by activation of metabotropic receptors but in only half of the cells when promoted in the absence of metabotropic facilitators. Our findings show that RyRs and IP(3)Rs regulate the generation of plateau potentials in motoneurons and suggest that RyRs may be directly involved with activation of the plateau potential.
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Neurons of the principal nucleus of the bed nuclei of the stria terminalis (BSTp) process pheromonal and viscerosensory stimuli associated with reproduction and relay this information to preoptic and hypothalamic cell groups that regulate reproductive function. The anteroventral periventricular nucleus of the hypothalamus (AVPV), a nucleus involved in the regulation of gonadotropin secretory patterns, receives dense projections from BSTp neurons in males but not in females. ⋯ Treatment of newborn females with testosterone or neonatal orchidectomy of males reversed these sex differences, while GAD65-immunoreactivity in the AVPV was not altered in response to exogenous hormone treatments administered to peripubertal animals. Our results suggest that projections from BSTp neurons constitute a stable, sex-specific GABAergic input to the AVPV that is patterned permanently by perinatal hormone exposure.
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Activity-regulated, cytoskeletal-associated protein (Arc) is an immediate early gene induced in excitatory circuits following behavioral episodes. Arc mRNA is targeted to activated regions of the dendrite after long-term potentiation (LTP) of the dentate gyrus, a process dependent on NMDA receptor activation. We used post-embedding immunogold electron microscopy (EM) to test whether synaptic Arc expression patterns are selectively modified by plasticity. ⋯ Post-embedding EM revealed Arc immunogold labeling in three times as many spines in the middle molecular layer of the stimulated dentate gyrus than in either the ipsilateral outer molecular layer or the contralateral middle and outer molecular layers. This upregulation did not occur with low frequency stimulation of the perforant path. Therefore Arc protein localization may be a powerful tool to isolate recently activated dendritic spines.
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A selective GABA(B) receptor agonist, baclofen, is known to suppress neuropathic pain. In the present study, we investigated the effect of baclofen on the excitability of trigeminal root ganglion (TRG) neurons by using the whole cell and perforated patch-clamp recording techniques. Under voltage-clamp (V(h)=-60 mV), voltage-dependent K(+) currents were recorded in the small diameter TRG neurons (<30 microm) and isolated by blocking Na(+) and Ca(2+) currents with appropriate ion replacement. ⋯ Application of baclofen reduced action potential duration evoked by a depolarization current pulse. These results indicated that activation of GABA(B) receptors inhibits the excitability of rat small diameter TRG neurons and this inhibitory action is mediated by potentiation of voltage-dependent K(+) currents. We therefore concluded that modification of nociceptive transmission in the trigeminal system by activation of GABA(B) receptors occurs at the level of small TRG neuron cell bodies and/or their primary afferent terminals, which are potential targets of analgesia by baclofen.