Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical compo-nent of descending nociceptive facil...Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical compo-nent of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotro-phic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and ?uorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate me-chanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.展开更多
The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 rece...The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus (NRM) and nucleus gigantocellularis pars α (NGCα)]. Fluorescence immunohistochemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryptophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.展开更多
Objective: To study the characteristics of the postsynaptic potentials in thoracic sympatheticpreganglionic neurons (SPNs) evoked by electrical stimulation of the rostral ventrolateral medulla (RVLM ) incats. Methods:...Objective: To study the characteristics of the postsynaptic potentials in thoracic sympatheticpreganglionic neurons (SPNs) evoked by electrical stimulation of the rostral ventrolateral medulla (RVLM ) incats. Methods: In 11 α--chloralose/urethane anesthetized, artificially ventilated cats, intracellular recordings weremade from T, spinal cord with microelectrodes filled with 3 mol/L KCl. SPNs were identified by antidromicstimulation of the T3 white ramus. Results: Twenty--four SPNs were recorded, the resting membrane potentials ofwhich ranged between -- 45 -- -- 90 mV. The onset latency and threshold of the antidromic action potentialsaveraged (6. 48 + 0. 89) ms and (2. 86 + 0. 37) V respectively. Single pulse (0. 2 ms. 50-- 300 PA) electricalstimulation of RVLM evoked fast excitatory postsynaptic potentials (eEPSPs) with short latencies (4--47 ms) inall the 24 SPNs. In 11 of the SPNs, EPSPs with longer latencies (IEPSPs, 70-- 140 ms) were also recorded. Mostof the eEPSPs and some of the IEPSPs were typical monosynaptic EPSPs as they were of constant onset latency.Conclusion: The results provided direct physiological evidence for that some RVLM sympathoexcitatory neuronsproject monosynaptically to thoracic SPNs. The descending pathways from RVLM may consist of two distinctgroups of fibers, the conduction velocities were calculated to be 5--25 m/s and 0. 78-- 1. 6 m/s respectively.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.30901396,No.81070890,No.30872441and No.81171259)
文摘Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical compo-nent of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotro-phic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and ?uorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate me-chanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.
基金supported by grants from National Natural Science Foundation of China(No.81071307,No.81271766,and No.81673964)Special Fund of Fundamental Scientific Research Business Expense for Higher School of Central Government(No.2012TS060)
文摘The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus (NRM) and nucleus gigantocellularis pars α (NGCα)]. Fluorescence immunohistochemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryptophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.
文摘Objective: To study the characteristics of the postsynaptic potentials in thoracic sympatheticpreganglionic neurons (SPNs) evoked by electrical stimulation of the rostral ventrolateral medulla (RVLM ) incats. Methods: In 11 α--chloralose/urethane anesthetized, artificially ventilated cats, intracellular recordings weremade from T, spinal cord with microelectrodes filled with 3 mol/L KCl. SPNs were identified by antidromicstimulation of the T3 white ramus. Results: Twenty--four SPNs were recorded, the resting membrane potentials ofwhich ranged between -- 45 -- -- 90 mV. The onset latency and threshold of the antidromic action potentialsaveraged (6. 48 + 0. 89) ms and (2. 86 + 0. 37) V respectively. Single pulse (0. 2 ms. 50-- 300 PA) electricalstimulation of RVLM evoked fast excitatory postsynaptic potentials (eEPSPs) with short latencies (4--47 ms) inall the 24 SPNs. In 11 of the SPNs, EPSPs with longer latencies (IEPSPs, 70-- 140 ms) were also recorded. Mostof the eEPSPs and some of the IEPSPs were typical monosynaptic EPSPs as they were of constant onset latency.Conclusion: The results provided direct physiological evidence for that some RVLM sympathoexcitatory neuronsproject monosynaptically to thoracic SPNs. The descending pathways from RVLM may consist of two distinctgroups of fibers, the conduction velocities were calculated to be 5--25 m/s and 0. 78-- 1. 6 m/s respectively.
