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Cited by 185Neuropeptides and Animal PhysiologyNeuroscience and Neuropharmacology ResearchPain Mechanisms and Treatments

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Differential Mechanisms of CRF1 and CRF2 Receptor Functions in the Amygdala in Pain-Related Synaptic Facilitation and Behavior

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Fu, Yu, Neugebauer, Volker·2008·The Journal of Neuroscience
DOI 10.1523/jneurosci.0227-08.2008PMC PMC2557030
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Abstract

A major site of extrahypothalamic expression of corticotropin-releasing factor (CRF) and its G-protein-coupled CRF1 and CRF2 receptors is the amygdala, a key player in emotions and affective disorders. Pain-related plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) generates emotional-affective responses and anxiety-like behavior. CRF1 receptor antagonists have anxiolytic effects. Although both CRF1 and CRF2 receptors couple positively to adenylyl cyclase, they can have opposite effects, but the underlying mechanism is unknown. This study addressed CRF1 and CRF2 receptor functions and mechanisms in the amygdala in a model of arthritic pain. Using whole-cell patch-clamp recordings of CeLC neurons, we found that a selective CRF1 receptor antagonist (NBI27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)]) amino-pyridine inhibited synaptic facilitation in brain slices from arthritic rats through a postsynaptic mechanism. Inhibition of the NMDA receptor-mediated synaptic component was occluded by a protein kinase A (PKA) inhibitor, consistent with our previous demonstration of PKA-dependent increased NMDA receptor function in arthritis pain-related plasticity. NBI27914 also decreased neuronal excitability through inhibition of highly tetraethylammonium (TEA)-sensitive ion channels that contribute to action potential repolarization and firing rate. In contrast, a CRF2 receptor antagonist (astressin-2B [cyclo(31–34) [d-Phe11,His12,CαMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8–40)]) facilitated synaptic transmission through presynaptic inhibition of GABAergic transmission (disinhibition). NBI27914 inhibited arthritis pain-related behaviors (audible and ultrasonic vocalizations and hindlimb withdrawal reflexes). Astressin-2B had no significant behavioral effect. The data suggest that endogenous CRF1 receptor activation in the amygdala contributes to pain-related synaptic facilitation, increased excitability, and pain behavior through a postsynaptic mechanism involving activation of PKA and highly TEA-sensitive K+-currents. Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance.

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Figures

Figure 1 Recording and stimulation sites in amygdala brain slices. The different nuclei of the amygdala and subdivisions of the central nucleus are easily discerned. Stimulation electrodes were positioned in the BLA and on fibers that contained afferents from the PB to stimulate the BLA-CeLC and PB-CeLC synapses, respectively (Neugebauer et al., 2003; Lopez de Armentia and Sah, 2004, 2007; Neugebauer, 2006; Ikeda et al., 2007). The patch electrode was positioned in the CeLC. CeM, CeL, CeLC, Medial, lateral, and laterocapsular divisions of the central nucleus, respectively.
Figure 1 Recording and stimulation sites in amygdala brain slices. The different nuclei of the amygdala and subdivisions of the central nucleus are easily discerned. Stimulation electrodes were positioned in the BLA and on fibers that contained afferents from the PB to stimulate the BLA-CeLC and PB-CeLC synapses, respectively (Neugebauer et al., 2003; Lopez de Armentia and Sah, 2004, 2007; Neugebauer, 2006; Ikeda et al., 2007). The patch electrode was positioned in the CeLC. CeM, CeL, CeLC, Medial, lateral, and laterocapsular divisions of the central nucleus, respectively.CC-BY-NC-SA · From the PDF
Figure 2 Increased synaptic transmission in the arthritis pain model is reduced by a CRF1 receptor antagonist but not by a CRF2 receptor antagonist. Input- output functions of the PB-CeLC synapse were obtained by measuring EPSC peak amplitude (picoamperes) as a function of afferent fiber volley stimulus intensity (microamperes) for each neuron. Monosynaptic EPSCswereevokedbyelectricalstimulation of increasing intensities. Insets show original traces of evoked EPSCs (average of 2-3 EPSCs) at different stimulus intensities. A-D , Synaptic transmission was studied in brain slices from normal rats ( A , C ) and from arthritic rats ( B , D ). Inputoutput functions were measured before and during application of antagonists for CRF1 (NBI27914, 500 nM, 15 min; A , B ) and CRF2 (astressin-2B, 500 nM, 15 min; C , D ) receptors. The antagonists had no effects under normal conditions (NBI27914, n = 10; astressin-2B, n = 5). NBI27914 significantly inhibited enhanced synaptic transmission in the arthritis pain model ( n = 10), whereas astressin-2B had facilitatory effects ( n = 5). Whole-cell voltage-clamp recordings of CeLC neurons held at -60mV.* p < 0.05, ** p < 0.01, *** p < 0.001 (repeatedmeasures two-way ANOVA followed by Bonferroni's post hoc tests).
Figure 2 Increased synaptic transmission in the arthritis pain model is reduced by a CRF1 receptor antagonist but not by a CRF2 receptor antagonist. Input- output functions of the PB-CeLC synapse were obtained by measuring EPSC peak amplitude (picoamperes) as a function of afferent fiber volley stimulus intensity (microamperes) for each neuron. Monosynaptic EPSCswereevokedbyelectricalstimulation of increasing intensities. Insets show original traces of evoked EPSCs (average of 2-3 EPSCs) at different stimulus intensities. A-D , Synaptic transmission was studied in brain slices from normal rats ( A , C ) and from arthritic rats ( B , D ). Inputoutput functions were measured before and during application of antagonists for CRF1 (NBI27914, 500 nM, 15 min; A , B ) and CRF2 (astressin-2B, 500 nM, 15 min; C , D ) receptors. The antagonists had no effects under normal conditions (NBI27914, n = 10; astressin-2B, n = 5). NBI27914 significantly inhibited enhanced synaptic transmission in the arthritis pain model ( n = 10), whereas astressin-2B had facilitatory effects ( n = 5). Whole-cell voltage-clamp recordings of CeLC neurons held at -60mV.* p < 0.05, ** p < 0.01, *** p < 0.001 (repeatedmeasures two-way ANOVA followed by Bonferroni's post hoc tests).CC-BY-NC-SA · From the PDF
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Figure 4 Evidence for postsynaptic effects of a CRF1 receptor antagonist. Analysis of mEPSC amplitude ( A ) and frequency ( B ) in the presence of TTX (1 𝛍 M) and bicuculline (30 𝛍 M) showed that NBI27914 (NBI, 500 nM) significantly reduced the cumulative amplitude distribution ( p < 0.01, Kolmogorov-Smirnov test; A ) and mean amplitude ( p < 0.05, paired t test; A , bar histogram; n = 4) but not interevent interval distribution ( p > 0.05, Kolmogorov-Smirnov test; B ) and mean frequency (events per second; p > 0.05, paired t test; B , bar histogram; n = 4). C , D , The PPR, a measure of presynaptic mechanisms, was not changed by NBI27914 (500 nM). PPR was calculated as the ratio of the second and the first of two consecutive EPSCs evoked at the BLA-CeLC synapse by two electrical stimuli of equal intensity at increasing interstimulus intervals. Peak EPSC amplitudes were measured as the difference between the current level before the stimulus artifact and the peak of the EPSC. NBI27914 had no significant effect on the PPR ratio at various stimulus intervals at the BLA-CeLC ( n = 5) and PB-CeLC synapse ( n = 5, p > 0.05, repeated-measures two-way ANOVA), further arguing against a presynaptic action. Insets show current traces (average of 8 -10 EPSCs) recorded in an individual CeLC neuron to illustrate that PPR (50 ms stimulus interval) was not affected by NBI27914. Symbols and error bars represent mean ± SE ( A-D ). Neurons were recorded in voltage clamp at -60mVinslices from arthritic rats (6 h after induction). * p < 0.05.
Figure 4 Evidence for postsynaptic effects of a CRF1 receptor antagonist. Analysis of mEPSC amplitude ( A ) and frequency ( B ) in the presence of TTX (1 𝛍 M) and bicuculline (30 𝛍 M) showed that NBI27914 (NBI, 500 nM) significantly reduced the cumulative amplitude distribution ( p < 0.01, Kolmogorov-Smirnov test; A ) and mean amplitude ( p < 0.05, paired t test; A , bar histogram; n = 4) but not interevent interval distribution ( p > 0.05, Kolmogorov-Smirnov test; B ) and mean frequency (events per second; p > 0.05, paired t test; B , bar histogram; n = 4). C , D , The PPR, a measure of presynaptic mechanisms, was not changed by NBI27914 (500 nM). PPR was calculated as the ratio of the second and the first of two consecutive EPSCs evoked at the BLA-CeLC synapse by two electrical stimuli of equal intensity at increasing interstimulus intervals. Peak EPSC amplitudes were measured as the difference between the current level before the stimulus artifact and the peak of the EPSC. NBI27914 had no significant effect on the PPR ratio at various stimulus intervals at the BLA-CeLC ( n = 5) and PB-CeLC synapse ( n = 5, p > 0.05, repeated-measures two-way ANOVA), further arguing against a presynaptic action. Insets show current traces (average of 8 -10 EPSCs) recorded in an individual CeLC neuron to illustrate that PPR (50 ms stimulus interval) was not affected by NBI27914. Symbols and error bars represent mean ± SE ( A-D ). Neurons were recorded in voltage clamp at -60mVinslices from arthritic rats (6 h after induction). * p < 0.05.CC-BY-NC-SA · From the PDF
Figure 5 Evidence for presynaptic effects of a CRF2 receptor antagonist. Analysis of mEPSC amplitude ( A ) and frequency ( B ) in the presence of TTX (1 𝛍 M) and bicuculline (30 𝛍 M). Astressin-2B (A-2B, 500 nM) significantly shifted the cumulative interevent interval distribution toward shorter intervals ( p < 0.05, Kolmogorov-Smirnov test; B ) and increased the mean frequency (events per second; p < 0.05, paired t test; B , bar histograms; n = 5). Astressin-2B had no significant effect on the cumulative amplitude distribution ( p > 0.05, KolmogorovSmirnov test; A ) and mean amplitude ( p > 0.05, paired t test; A , bar histograms; n = 5). C , D , PPR, a measure of presynaptic mechanisms, was decreased by astressin-2B (500 nM) at the BLA-CeLC synapse ( n = 5, p < 0.001, repeated-measures two-way ANOVA) and the PB-CeLC synapse ( n = 5, p < 0.05). PPR was calculated as described in Figure 4. Insets show c urrent traces (average of 8 -10 EPSCs) recorded in an individual CeLC neuron to demonstrate that there was no PPR at the 50 ms interstimulus interval in the presence of astressin-2B. A-D , CeLC neurons were recorded at -60 mV in slices from arthritic rats (6 h after induction). * p < 0.05, ** p < 0.01.
Figure 5 Evidence for presynaptic effects of a CRF2 receptor antagonist. Analysis of mEPSC amplitude ( A ) and frequency ( B ) in the presence of TTX (1 𝛍 M) and bicuculline (30 𝛍 M). Astressin-2B (A-2B, 500 nM) significantly shifted the cumulative interevent interval distribution toward shorter intervals ( p < 0.05, Kolmogorov-Smirnov test; B ) and increased the mean frequency (events per second; p < 0.05, paired t test; B , bar histograms; n = 5). Astressin-2B had no significant effect on the cumulative amplitude distribution ( p > 0.05, KolmogorovSmirnov test; A ) and mean amplitude ( p > 0.05, paired t test; A , bar histograms; n = 5). C , D , PPR, a measure of presynaptic mechanisms, was decreased by astressin-2B (500 nM) at the BLA-CeLC synapse ( n = 5, p < 0.001, repeated-measures two-way ANOVA) and the PB-CeLC synapse ( n = 5, p < 0.05). PPR was calculated as described in Figure 4. Insets show c urrent traces (average of 8 -10 EPSCs) recorded in an individual CeLC neuron to demonstrate that there was no PPR at the 50 ms interstimulus interval in the presence of astressin-2B. A-D , CeLC neurons were recorded at -60 mV in slices from arthritic rats (6 h after induction). * p < 0.05, ** p < 0.01.CC-BY-NC-SA · From the PDF
Figure 6 Inhibition of NMDA receptor-mediated synaptic facilitation by a CRF1 receptor antagonist is occluded by a PKA inhibitor. A , NBI27914 (500 nM) inhibited the pharmacologically isolated NMDA receptor-mediated synaptic component. Monosynaptic EPSCs (average of 8-10 traces) recorded in an individual CeLC neuron in a brain slice from an arthritic rat were inhibited by NBQX (20 𝛍 M) and further reduced by NBI27914 in the continued presence of NBQX. B , A selective membranepermeable PKA inhibitor (KT5720, 1 𝛍 M) also reduced the NMDA receptor-mediated EPSC and occludedtheeffectofNBI27914.MonosynapticEPSCs(averageof8-10traces)recordedinanindividual CeLC neuron in a brain slice from an arthritic rat were inhibited by NBQX and further reduced by KT5720.CoapplicationofNBI27914withKT5720hadnoadditionaleffects(inthecontinuedpresence of NBQX). C , Summary of the significant inhibition of synaptic facilitation (peak EPSC amplitude) by NBQX( n = 4)andNBI27914( n = 4).TheinhibitoryeffectsofNBI27914andKT5720( n = 4)werenot significantly different from each other. Coapplication of NBI27914 and KT5720 ( n = 4) did not produceanadditional effect. Calibration: 50 pA, 25 ms. ** p < 0.01, *** p < 0.001 (ANOVAfollowedby Newman-Keulsmultiplecomparisontest).
Figure 6 Inhibition of NMDA receptor-mediated synaptic facilitation by a CRF1 receptor antagonist is occluded by a PKA inhibitor. A , NBI27914 (500 nM) inhibited the pharmacologically isolated NMDA receptor-mediated synaptic component. Monosynaptic EPSCs (average of 8-10 traces) recorded in an individual CeLC neuron in a brain slice from an arthritic rat were inhibited by NBQX (20 𝛍 M) and further reduced by NBI27914 in the continued presence of NBQX. B , A selective membranepermeable PKA inhibitor (KT5720, 1 𝛍 M) also reduced the NMDA receptor-mediated EPSC and occludedtheeffectofNBI27914.MonosynapticEPSCs(averageof8-10traces)recordedinanindividual CeLC neuron in a brain slice from an arthritic rat were inhibited by NBQX and further reduced by KT5720.CoapplicationofNBI27914withKT5720hadnoadditionaleffects(inthecontinuedpresence of NBQX). C , Summary of the significant inhibition of synaptic facilitation (peak EPSC amplitude) by NBQX( n = 4)andNBI27914( n = 4).TheinhibitoryeffectsofNBI27914andKT5720( n = 4)werenot significantly different from each other. Coapplication of NBI27914 and KT5720 ( n = 4) did not produceanadditional effect. Calibration: 50 pA, 25 ms. ** p < 0.01, *** p < 0.001 (ANOVAfollowedby Newman-Keulsmultiplecomparisontest).CC-BY-NC-SA · From the PDF
Figure 7 A CRF2 receptor antagonist presynaptically inhibits inhibitory synaptic transmission (disinhibition). A , Astressin-2B (500 nM) inhibited pharmacologically isolated (with NBQX, 20 𝛍 M and AP-5, 50 𝛍 M) IPSCs that were evoked in CeLC neurons by electrical stimulation in the BLA ( n = 6; bar histogram, IPSC amplitude normalized to predrug control). Individual traces show the average of 8 -10 IPSCs in one CeLC neuron. The IPSC was blocked with bicuculline (30 𝛍 M). B , In contrast, NBI27914 (500 nM) had no effect on evoked IPSCs ( n = 5), but bicuculline (30 𝛍 M) blocked the IPSCs. C-E , Astressin-2B decreased the frequency but not amplitude of pharmacologically (with NBQX, 20 𝛍 M and AP-5, 50 𝛍 M) isolated mIPSCs in the presence of TTX (1 𝛍 M), suggesting a presynaptic site of action. C , Original traces of mIPSCs in an individual neuron before and during application of astressin-2B. D , Astressin-2B had no effect on mIPSC amplitude distribution ( n = 5, p > 0.05, Kolmogorov-Smirnov test) and mean mIPSC amplitude ( p > 0.05, Dunnett's multiple comparison test; bar histogram). E , Astressin-2B shifted the cumulative interevent interval distribution toward longer intervals ( n = 5, p < 0.01, Kolmogorov-Smirnov test), decreasing the mean frequency significantly ( p < 0.001, Dunnett's multiple comparison test; bar histogram). D , E , Bicuculline (30 𝛍 M) blocked the mIPSCs significantly ( n = 3, p < 0.001, Dunnett's multiple comparison test). Miniature and evoked IPSCs were recorded at -40 mV in slices from arthritic animals (6 h after induction). *** p < 0.001.
Figure 7 A CRF2 receptor antagonist presynaptically inhibits inhibitory synaptic transmission (disinhibition). A , Astressin-2B (500 nM) inhibited pharmacologically isolated (with NBQX, 20 𝛍 M and AP-5, 50 𝛍 M) IPSCs that were evoked in CeLC neurons by electrical stimulation in the BLA ( n = 6; bar histogram, IPSC amplitude normalized to predrug control). Individual traces show the average of 8 -10 IPSCs in one CeLC neuron. The IPSC was blocked with bicuculline (30 𝛍 M). B , In contrast, NBI27914 (500 nM) had no effect on evoked IPSCs ( n = 5), but bicuculline (30 𝛍 M) blocked the IPSCs. C-E , Astressin-2B decreased the frequency but not amplitude of pharmacologically (with NBQX, 20 𝛍 M and AP-5, 50 𝛍 M) isolated mIPSCs in the presence of TTX (1 𝛍 M), suggesting a presynaptic site of action. C , Original traces of mIPSCs in an individual neuron before and during application of astressin-2B. D , Astressin-2B had no effect on mIPSC amplitude distribution ( n = 5, p > 0.05, Kolmogorov-Smirnov test) and mean mIPSC amplitude ( p > 0.05, Dunnett's multiple comparison test; bar histogram). E , Astressin-2B shifted the cumulative interevent interval distribution toward longer intervals ( n = 5, p < 0.01, Kolmogorov-Smirnov test), decreasing the mean frequency significantly ( p < 0.001, Dunnett's multiple comparison test; bar histogram). D , E , Bicuculline (30 𝛍 M) blocked the mIPSCs significantly ( n = 3, p < 0.001, Dunnett's multiple comparison test). Miniature and evoked IPSCs were recorded at -40 mV in slices from arthritic animals (6 h after induction). *** p < 0.001.CC-BY-NC-SA · From the PDF
Figure 8 A-D , Contribution of GABA A and GABA B receptors to CRF2 receptor-mediated effects on excitatory and inhibitory synaptic transmission. EPSCs ( A , C ) and IPSCs ( B , D ) evoked at the BLA-CeLC synapse were recorded in slices from arthritic animals (6 h after induction). A , In the presence of bicuculline (30 𝛍 M) to block GABA A receptors, astressin-2B (500 nM) continued to facilitate EPSCs ( n = 3, p < 0.001). B , IPSCs were blocked by bicuculline administered alone or together with astressin-2B ( n = 3, p < 0.001). C , A GABA B receptor antagonist (CGP35348, 100 𝛍 M) alone or together with astressin-2B increased EPSCs significantly ( n = 3, p < 0.05). D , CGP35348 had no effect on IPSCs. In the presence of CGP35348, astressin-2B continued to depress IPSCs ( n = 3, p < 0.001). Original traces are averages of 8 -10 EPSCs or IPSCs. EPSCs were recorded at -60mV;IPSCswererecordedat -40mV.Calibration: 25 pA, 25 ms.* p < 0.05, *** p < 0.001(comparedwithpredrugcontrols;Dunnett'smultiplecomparison test).
Figure 8 A-D , Contribution of GABA A and GABA B receptors to CRF2 receptor-mediated effects on excitatory and inhibitory synaptic transmission. EPSCs ( A , C ) and IPSCs ( B , D ) evoked at the BLA-CeLC synapse were recorded in slices from arthritic animals (6 h after induction). A , In the presence of bicuculline (30 𝛍 M) to block GABA A receptors, astressin-2B (500 nM) continued to facilitate EPSCs ( n = 3, p < 0.001). B , IPSCs were blocked by bicuculline administered alone or together with astressin-2B ( n = 3, p < 0.001). C , A GABA B receptor antagonist (CGP35348, 100 𝛍 M) alone or together with astressin-2B increased EPSCs significantly ( n = 3, p < 0.05). D , CGP35348 had no effect on IPSCs. In the presence of CGP35348, astressin-2B continued to depress IPSCs ( n = 3, p < 0.001). Original traces are averages of 8 -10 EPSCs or IPSCs. EPSCs were recorded at -60mV;IPSCswererecordedat -40mV.Calibration: 25 pA, 25 ms.* p < 0.05, *** p < 0.001(comparedwithpredrugcontrols;Dunnett'smultiplecomparison test).CC-BY-NC-SA · From the PDF
Figure9 CRF1, but not CRF2, receptors modulate neuronal excitability though K + channels. Action potentials were evoked in current-clamp mode by direct intracellular current injections of increasing magnitude through the patch electrode (50 pA steps, 500 ms) at a holding potential -60 mV. Input- output functions of neuronal excitability were obtained by averaging the frequency of action potentials evoked at each current intensity (Neugebauer et al., 2003; Bird et al., 2005; Han et al., 2005b). A , NBI27914(NBI,500nM)significantlydecreasedtheinput- outputfunctionofCeLCneuronsinslicesfromarthriticrats( n = 8, p < 0.0001, F (1,56) = 174.67, repeated-measures two-way ANOVA followed by Bonferroni's post hoc tests). B , NBI27914 also increased the spike duration (spike width) and decay time ( n = 8, p < 0.05, paired t test). C , D , A very low concentration of the K + -channel blocker TEA (50 𝛍 M) decreased the input- output function of CeLC neurons from arthritic rats ( C ; p < 0.001, n = 3,
Figure9 CRF1, but not CRF2, receptors modulate neuronal excitability though K + channels. Action potentials were evoked in current-clamp mode by direct intracellular current injections of increasing magnitude through the patch electrode (50 pA steps, 500 ms) at a holding potential -60 mV. Input- output functions of neuronal excitability were obtained by averaging the frequency of action potentials evoked at each current intensity (Neugebauer et al., 2003; Bird et al., 2005; Han et al., 2005b). A , NBI27914(NBI,500nM)significantlydecreasedtheinput- outputfunctionofCeLCneuronsinslicesfromarthriticrats( n = 8, p < 0.0001, F (1,56) = 174.67, repeated-measures two-way ANOVA followed by Bonferroni's post hoc tests). B , NBI27914 also increased the spike duration (spike width) and decay time ( n = 8, p < 0.05, paired t test). C , D , A very low concentration of the K + -channel blocker TEA (50 𝛍 M) decreased the input- output function of CeLC neurons from arthritic rats ( C ; p < 0.001, n = 3,CC-BY-NC-SA · From the PDF
Figure 10 A CRF1, but not CRF2, receptor antagonist inhibits pain-related behavior in animals with arthritis but not in normal animals. Audible ( A , B ) and ultrasonic ( C , D ) vocalizations andspinal withdrawal reflexes ( E , F ) were measured in two groups of animals: normal (left side in each graph) and arthritis (right side). In the normal group, behaviors were measured before (baseline) and during (15-20 min) drug application into the CeA by microdialysis. In the arthritis group, behaviors were measured before (baseline) and 6 h after arthritis induction and during (15-20 min) and after (30 min washout) drug application into the CeLC in the arthritis state. Vocalizations were evoked by brief (15 s) noxious (2000 g/30 mm 2 ) stimulation of the kneewithacalibrated forceps. Duration of vocalizations was measured as the arithmetic sum of the duration of each individual vocalization event during a 1 min period beginning with the onset of the mechanical stimulus as described previously (Han et al., 2005a; Neugebauer et al., 2007). A , NBI27914 (NBI, 50 𝛍 M, concentration in the microdialysis fiber) had no effect on audible vocalizations in normal animals ( n = 5) but inhibited the increased vocalizations of arthritic rats significantly ( n = 11, p < 0.001, Newman-Keuls multiple comparison test). B , Astressin-2B (50 𝛍 M, concentration in the microdialysis probe) did not affect audible vocalizations in normal rats ( n = 6) and in arthritic rats ( n = 6). C , NBI27914 had no significant effect on ultrasonic vocalizations of normal rats ( n = 5) but inhibited the increased ultrasonic vocalizations of arthritic rats ( n = 11, p < 0.01, Newman-Keuls multiple comparison test). D , Astressin-2B had no significant effect on ultrasonic vocalizations of normal rats ( n = 6) and arthritic rats ( n = 6). E , NBI27914 had no significant effect on hindlimb-withdrawal reflex
Figure 10 A CRF1, but not CRF2, receptor antagonist inhibits pain-related behavior in animals with arthritis but not in normal animals. Audible ( A , B ) and ultrasonic ( C , D ) vocalizations andspinal withdrawal reflexes ( E , F ) were measured in two groups of animals: normal (left side in each graph) and arthritis (right side). In the normal group, behaviors were measured before (baseline) and during (15-20 min) drug application into the CeA by microdialysis. In the arthritis group, behaviors were measured before (baseline) and 6 h after arthritis induction and during (15-20 min) and after (30 min washout) drug application into the CeLC in the arthritis state. Vocalizations were evoked by brief (15 s) noxious (2000 g/30 mm 2 ) stimulation of the kneewithacalibrated forceps. Duration of vocalizations was measured as the arithmetic sum of the duration of each individual vocalization event during a 1 min period beginning with the onset of the mechanical stimulus as described previously (Han et al., 2005a; Neugebauer et al., 2007). A , NBI27914 (NBI, 50 𝛍 M, concentration in the microdialysis fiber) had no effect on audible vocalizations in normal animals ( n = 5) but inhibited the increased vocalizations of arthritic rats significantly ( n = 11, p < 0.001, Newman-Keuls multiple comparison test). B , Astressin-2B (50 𝛍 M, concentration in the microdialysis probe) did not affect audible vocalizations in normal rats ( n = 6) and in arthritic rats ( n = 6). C , NBI27914 had no significant effect on ultrasonic vocalizations of normal rats ( n = 5) but inhibited the increased ultrasonic vocalizations of arthritic rats ( n = 11, p < 0.01, Newman-Keuls multiple comparison test). D , Astressin-2B had no significant effect on ultrasonic vocalizations of normal rats ( n = 6) and arthritic rats ( n = 6). E , NBI27914 had no significant effect on hindlimb-withdrawal reflexCC-BY-NC-SA · From the PDF
Figure11 Placement controls. Drug administration into the striatum had no effect on painrelated behavior in animals with arthritis. Audible ( A , B ) and ultrasonic ( C , D ) vocalizations and spinal withdrawal reflexes ( E , F ) were measured before (baseline) and 6 h after arthritis induction and during (15-20 min) drug application into the striatum in the arthritis state. Vocalizations were evoked by brief (15 s) noxious (2000 g/30 mm 2 ) stimulation of the knee with a calibrated forceps. Duration of vocalizations was measured as in Figure 10. Hindlimbwithdrawalthresholdsweremeasuredbyapplyingpressureofincreasingforcetothekneejoint
Figure11 Placement controls. Drug administration into the striatum had no effect on painrelated behavior in animals with arthritis. Audible ( A , B ) and ultrasonic ( C , D ) vocalizations and spinal withdrawal reflexes ( E , F ) were measured before (baseline) and 6 h after arthritis induction and during (15-20 min) drug application into the striatum in the arthritis state. Vocalizations were evoked by brief (15 s) noxious (2000 g/30 mm 2 ) stimulation of the knee with a calibrated forceps. Duration of vocalizations was measured as in Figure 10. HindlimbwithdrawalthresholdsweremeasuredbyapplyingpressureofincreasingforcetothekneejointCC-BY-NC-SA · From the PDF
Figure 12 Histologic verification of drug application sites. A-D , Standard diagrams (adapted from Paxinos and Watson, 1998) show coronal sections through the right brain hemisphere at different levels posterior to bregma ( -2.00 to -2.80 mm). Symbols show the positions of the microdialysis membrane in the striatum ( A , placement control) and central nucleus of the amygdala ( B-D ) in the behavioral experiments. Filled circles, Application sites of NBI27914; open circles, astressin-2B. The number of lesion sites ( n ) for NBI27914 and astressin2B, respectively, is indicated above each diagram. CeM, CeL, CeLC, medial, lateral, and laterocapsular divisions of the central nucleus of the amygdala. Calibration bars: 1 mm.
Figure 12 Histologic verification of drug application sites. A-D , Standard diagrams (adapted from Paxinos and Watson, 1998) show coronal sections through the right brain hemisphere at different levels posterior to bregma ( -2.00 to -2.80 mm). Symbols show the positions of the microdialysis membrane in the striatum ( A , placement control) and central nucleus of the amygdala ( B-D ) in the behavioral experiments. Filled circles, Application sites of NBI27914; open circles, astressin-2B. The number of lesion sites ( n ) for NBI27914 and astressin2B, respectively, is indicated above each diagram. CeM, CeL, CeLC, medial, lateral, and laterocapsular divisions of the central nucleus of the amygdala. Calibration bars: 1 mm.CC-BY-NC-SA · From the PDF
Figure 13 Modulation of synaptic facilitation by CRF1 and CRF2 receptors in the arthritis pain model. CRF1 receptor activation occurs at a postsynaptic site and increases NMDA receptor function through a PKA-dependent mechanism. Pain-related increased NMDA but not nonNMDA(AMPA)receptor function involving PKA, but not PKC, was shown previously (Bird et al., 2005). Presynaptic CRF2 receptors increase GABA release to activate postsynaptic GABA A receptors on CeLC neurons and presynaptic GABA B receptors on glutamatergic terminals. The consequence is increased inhibitory transmission and decreased excitatory transmission to the CeLC. CRF2 receptors are not involved in the modulation of neuronal excitability of CeLC neurons. The consequence of CRF1, but not CRF2, receptor activation in the CeLC is increased pain behavior in the arthritis model.
Figure 13 Modulation of synaptic facilitation by CRF1 and CRF2 receptors in the arthritis pain model. CRF1 receptor activation occurs at a postsynaptic site and increases NMDA receptor function through a PKA-dependent mechanism. Pain-related increased NMDA but not nonNMDA(AMPA)receptor function involving PKA, but not PKC, was shown previously (Bird et al., 2005). Presynaptic CRF2 receptors increase GABA release to activate postsynaptic GABA A receptors on CeLC neurons and presynaptic GABA B receptors on glutamatergic terminals. The consequence is increased inhibitory transmission and decreased excitatory transmission to the CeLC. CRF2 receptors are not involved in the modulation of neuronal excitability of CeLC neurons. The consequence of CRF1, but not CRF2, receptor activation in the CeLC is increased pain behavior in the arthritis model.CC-BY-NC-SA · From the PDF

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Metadata

Authors
Fu, Y., & Neugebauer, V.
Affiliations
The University of Texas Medical Branch at Galveston (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2008-04-09
Volume
28
Issue
15
Pages
3861-3876
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0227-08.2008
PMC
PMC2557030
OpenAlex
W2050750919
Cited by
184
References
97
Citations by year
2026: 5 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 8 · 2016: 11 · 2015: 17 · 2014: 16 · 2013: 9 · 2012: 7
FWCI
6.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Northwestern University
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS-38261, NS11255, P01NS011255, R01NS038261)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Keywords
corticotropin-releasing factor, CRF1 receptor, CRF2 receptor, amygdala, central amygdala, arthritic pain, protein kinase A, NMDA receptor, neuronal excitability, presynaptic inhibition, GABAergic neurotransmission, anxiety-like behavior, ultrasonic vocalizations
MeSH terms
CRF Receptor, Type 1, Amygdala, Aniline Compounds, Animals, Arthritis, Behavior, Animal, Electrophysiology, Enzyme Activation, Hindlimb, Neurons, Pain, Peptide Fragments, Peptides, Cyclic, Pyrimidines, Reflex, Spinal Cord, Synapses, Vocalization, Animal, Potassium Channels, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Receptors, Corticotropin-Releasing Hormone, Patch-Clamp Techniques, Tetraethylammonium, Rats, In Vitro Techniques

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