The Journal of neuroscience : the official journal of the Society for Neuroscience
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Transgenic overexpression of NMDA NR2B receptors in forebrain regions increased behavioral responses to persistent inflammatory pain. However, it is not known whether inflammation leads to the upregulation of NR2B receptors in these regions. ⋯ Inhibition of NR2B receptors in the ACC selectively reduced behavioral sensitization related to inflammation. Our results demonstrate that the upregulation of NR2B receptors in the ACC contributes to behavioral sensitization caused by inflammation.
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Spinal NMDA receptor (NMDAR), protein kinase C (PKC), and glucocorticoid receptor (GR) have all been implicated in the mechanisms of morphine tolerance; however, how these cellular elements interact after chronic morphine exposure remains unclear. Here we show that the expression of spinal NMDAR and PKCgamma after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 microg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKCgamma within the rat's spinal cord dorsal horn. ⋯ Moreover, the expression of phosphorylated CREB was upregulated within the spinal cord dorsal horn after chronic morphine, and a CREB antisense oligodeoxynucleotide coadministered intrathecally with morphine prevented the upregulation of GR, NR1, and PKCgamma. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKCgamma expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKCgamma may be an important mechanism that contributes to the development of morphine tolerance.
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The development of abnormal primary sensory neuron excitability and neuropathic pain symptoms after peripheral nerve injury is associated with altered expression of voltage-gated sodium channels (VGSCs) and a modification of sodium currents. To investigate whether the beta2 subunit of VGSCs participates in the generation of neuropathic pain, we used the spared nerve injury (SNI) model in rats to examine beta2 subunit expression in selectively injured (tibial and common peroneal nerves) and uninjured (sural nerve) afferents. Three days after SNI, immunohistochemistry and Western blot analysis reveal an increase in the beta2 subunit in both the cell body and peripheral axons of injured neurons. ⋯ Although injured neurons show the most marked upregulation,beta2 subunit expression is also increased in neighboring non-injured neurons and a similar pattern of changes appears in the spinal nerve ligation model of neuropathic pain. That increased beta2 subunit expression in sensory neurons after nerve injury is functionally significant, as demonstrated by our finding that the development of mechanical allodynia-like behavior in the SNI model is attenuated in beta2 subunit null mutant mice. Through its role in regulating the density of mature VGSC complexes in the plasma membrane and modulating channel gating, the beta2 subunit may play a key role in the development of ectopic activity in injured and non-injured sensory afferents and, thereby, neuropathic pain.
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Mechanical hypersensitivity of the colon underlies in part the chronic abdominal pain experienced by patients with irritable bowel syndrome, yet the molecules that confer mechanosensitivity to colon sensory neurons and their contribution to visceral pain are unknown. We tested the hypothesis that transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3 (ASIC3) are peripheral mechanosensors in colon afferent neuronal fibers that mediate visceral nociceptive behavior in mice. Visceral nociception, modeled by the visceromotor response to colorectal distension, and colon afferent fiber mechanosensitivity were assessed in control (C57BL/6) mice and two congenic knock-out mouse strains with deletions of either TRPV1 or ASIC3. ⋯ The behavioral deficits observed in both strains of knock-out mice were associated with a significant and selective reduction in afferent fiber sensitivity to circumferential stretch of the colon, an effect that was mimicked in control preparations by pretreatment with capsazepine, a TRPV1 antagonist, but not amiloride, a nonselective ASIC antagonist (both 500 microM). In addition, whereas stretch-evoked afferent fiber responses were enhanced by chemical inflammatory mediators in control mice, this effect was differentially impaired in both knock-out mouse strains. These results demonstrate a peripheral mechanosensory role for TRPV1 and ASIC3 in the mouse colon that contributes to nociceptive behavior and possibly peripheral sensitization during tissue insult.
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Comparative Study
Effect of domain interaction on apolipoprotein E levels in mouse brain.
Apolipoprotein (apo) E4 is a risk factor for heart disease, Alzheimer's disease, and other forms of neurodegeneration, but the underlying mechanisms are unknown. Domain interaction, a structural property that distinguishes apoE4 from apoE2 and apoE3, results in more rapid turnover and lower plasma levels of apoE4. To determine whether domain interaction affects brain apoE levels, we analyzed brain homogenates from human apoE3 and apoE4 knock-in mice, wild-type mice, and Arg-61 apoE mice, in which domain interaction was introduced by gene targeting. ⋯ These results demonstrate that domain interaction is responsible for the lower levels of both human apoE4 and mouse Arg-61 apoE in mouse brain. Cells may recognize apoE4 and Arg-61 apoE as misfolded proteins and target them for degradation or accumulation. Thus, degradation/accumulation or lower levels of apoE4 may contribute to the association of apoE4 with Alzheimer's disease.