Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses

Molecular Pain

Volker Neugebauer¹  Hita Adwanikar¹  Yu Fu¹  Guangchen Ji¹ 

[1] Department of Neuroscience & Cell Biology, The University of Texas Medical Branch, 301 University Blvd, Galveston, Texas, 77555-1069, USA

关键词: Vocalizations;    Synaptic transmission;    CRF;    Pain;    Amygdala;   

Others  :  862648
DOI  :  10.1186/1744-8069-9-2

 received in 2013-01-03, accepted in 2013-02-13,  发布年份 2013

【 摘 要 】

Background

Corticotropin-releasing factor (CRF) plays an important role in affective states and disorders. CRF is not only a “stress hormone” but also a neuromodulator outside the hypothalamic-pituitary-adrenocortical (HPA) axis. The amygdala, a brain center for emotions, is a major site of extrahypothalamic expression of CRF and its G-protein-coupled receptors. Our previous studies showed that endogenous activation of CRF1 receptors in an arthritis pain model contributes to amygdala hyperactivity and pain-related behaviors. Here we examined the synaptic and behavioral effects of CRF in the amygdala of normal animals in the absence of tissue injury or disease.

Results

Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in brain slices from normal rats showed that CRF (0.1-10 nM) increased excitatory postsynaptic currents (EPSCs) at the “nociceptive” parabrachio-amygdaloid (PB-CeLC) synapse and also increased neuronal output. Synaptic facilitation involved a postsynaptic action and was blocked by an antagonist for CRF1 (NBI27914, 1 μM) but not CRF2 (astressin-2B, 1 μM) and by an inhibitor of PKA (KT5720, 1 μM) but not PKC (GF109203X, 1 μM). CRF increased a latent NMDA receptor-mediated EPSC, and this effect also required CRF1 and PKA but not CRF2 and PKC. Stereotaxic administration of CRF (10 μM, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CRF were blocked by a NBI27914 (100 μM) and KT5720 (100 μM) but not GF109203x (100 μM). CRF effects persisted when HPA axis function was suppressed by pretreatment with dexamethasone (50 μg/kg, subcutaneously).

Conclusions

Non-pain-related activation of CRF1 receptors in the amygdala can trigger pain-responses in normal animals through a mechanism that involves PKA-dependent synaptic facilitation in CeLC neurons independent of HPA axis function. The results suggest that conditions of increased amygdala CRF levels can contribute to pain in the absence of tissue pathology or disease state.

【 授权许可】

   
2013 Ji et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Takahashi LK: Role of CRF(1) and CRF(2) receptors in fear and anxiety. Neurosci Biobehav Rev 2001, 25:627-636.
• [2]Bale TL, Vale WW: CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 2004, 44:525-557.
• [3]Hauger RL, Risbrough V, Brauns O, Dautzenberg FM: Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 2006, 5:453-479.
• [4]Reul JM, Holsboer F: Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2002, 2:23-33.
• [5]Koob GF, Zorrilla EP: Update on corticotropin-releasing factor pharmacotherapy for psychiatric disorders: a revisionist view. Neuropsychopharmacology 2012, 37:308-309.
• [6]Blank T, Nijholt I, Grammatopoulos DK, Randeva HS, Hillhouse EW, Spiess J: Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning. J Neurosci 2003, 23:700-707.
• [7]Arzt E, Holsboer F: CRF signaling: molecular specificity for drug targeting in the CNS. Trends Pharmacol Sci 2006, 27:531-538.
• [8]Tache Y, Bonaz B: Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest 2007, 117:33-40.
• [9]Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM: Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci 2009, 1179:120-143.
• [10]Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F: Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000, 34:171-181.
• [11]Charney DS: Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 2003, 417:38-50.
• [12]Gray TS: Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. Ann N Y Acad Sci 1993, 697:53-60.
• [13]Koob GF: The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res 2010, 1314:3-14.
• [14]Asan E, Yilmazer-Hanke DM, Eliava M, Hantsch M, Lesch KP, Schmitt A: The corticotropin-releasing factor (CRF)-system and monoaminergic afferents in the central amygdala: investigations in different mouse strains and comparison with the rat. Neuroscience 2005, 131:953-967.
• [15]Sanchez MM, Young LJ, Plotsky PM, Insel TR: Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 1999, 408:365-377.
• [16]Maren S: Synaptic mechanisms of associative memory in the amygdala. Neuron 2005, 47:783-786.
• [17]Pape HC, Pare D: Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 2010, 90:419-463.
• [18]Phelps EA, Ledoux JE: Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005, 48:175-187.
• [19]Harrigan EA, Magnuson DJ, Thunstedt GM, Gray TS: Corticotropin releasing factor neurons are innervated by calcitonin gene-related peptide terminals in the rat central amygdaloid nucleus. Brain Res Bull 1994, 33:529-534.
• [20]Schwaber JS, Sternini C, Brecha NC, Rogers WT, Card JP: Neurons containing calcitonin gene-related peptide in the parabrachial nucleus project to the central nucleus of the amygdala. J Comp Neurol 1988, 270:416-426.
• [21]Neugebauer V, Li W, Bird GC, Han JS: The amygdala and persistent pain. Neuroscientist 2004, 10:221-234.
• [22]Neugebauer V, Galhardo V, Maione S, Mackey SC: Forebrain pain mechanisms. Brain Res Rev 2009, 60:226-242.
• [23]Adedoyin MO, Vicini S, Neale JH: Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model. Mol Pain 2010, 6:60-77.
• [24]Ikeda R, Takahashi Y, Inoue K, Kato F: NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain 2007, 127:161-172.
• [25]Neugebauer V, Li W, Bird GC, Bhave G, Gereau RW: Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J Neurosci 2003, 23:52-63.
• [26]Han JS, Neugebauer V: Synaptic plasticity in the amygdala in a visceral pain model in rats. Neurosci Lett 2004, 361:254-257.
• [27]Han JS, Li W, Neugebauer V: Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. J Neurosci 2005, 25:10717-10728.
• [28]Bird GC, Lash LL, Han JS, Zou X, Willis WD, Neugebauer V: Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol 2005, 564:907-921.
• [29]Fu Y, Neugebauer V: Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J Neurosci 2008, 28:3861-3876.
• [30]Ren W, Neugebauer V: Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1. Mol Pain 2010, 6:93-106. BioMed Central Full Text
• [31]Greenwood-Van Meerveld B, Johnson AC, Schulkin J, Myers DA: Long-term expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus in response to an acute colonic inflammation. Brain Res 2006, 1071:91-96.
• [32]Ulrich-Lai YM, Xie W, Meij JTA, Dolgas CM, Yu L, Herman JP: Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav 2006, 88:67-76.
• [33]Rouwette T, Vanelderen P, Reus MD, Loohuis NO, Giele J, Egmond JV, Scheenen W, Scheffer GJ, Roubos E, Vissers K, et al.: Experimental neuropathy increases limbic forebrain CRF. Eur J Pain 2011, 16:61-71.
• [34]McNally GP, Akil H: Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal. Neuroscience 2002, 112:605-617.
• [35]Ji G, Fu Y, Ruppert KA, Neugebauer V: Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. Mol Pain 2007, 3:13-17. BioMed Central Full Text
• [36]Bourbia N, Ansah OB, Pertovaara A: Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy. J Pain 2010, 11:1461-1471.
• [37]Ji G, Neugebauer V: Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. J Neurophysiol 2007, 97:3893-3904.
• [38]Ji G, Neugebauer V: Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors. J Neurophysiol 2008, 99:1201-1212.
• [39]Rainnie DG, Fernhout BJ, Shinnick-Gallagher P: Differential actions of corticotropin releasing factor on basolateral and central amygdaloid neurones, in vitro. J Pharmacol Exp Ther 1992, 263:846-858.
• [40]Schiess MC, Callahan PM, Zheng H: Characterization of the electrophysiological and morphological properties of rat central amygdala neurons in vitro. J Neurosci Res 1999, 58:663-673.
• [41]Sah P, Faber ES, de Lopez AM, Power J: The amygdaloid complex: anatomy and physiology. Physiol Rev 2003, 83:803-834.
• [42]Ren W, Palazzo E, Maione S, Neugebauer V: Differential effects of mGluR7 and mGluR8 activation on pain-related synaptic activity in the amygdala. Neuropharmacology 2011, 61:1334-1344.
• [43]Li Z, Ji G, Neugebauer V: Mitochondrial reactive oxygen species are activated by mGluR5 through IP3 and activate ERK and PKA to increase excitability of amygdala neurons and pain behavior. J Neurosci 2011, 31:1114-1127.
• [44]Wyllie DJ, Manabe T, Nicoll RA: A rise in postsynaptic Ca2+ potentiates miniature excitatory postsynaptic currents and AMPA responses in hippocampal neurons. Neuron 1994, 12:127-138.
• [45]Fu Y, Han J, Ishola T, Scerbo M, Adwanikar H, Ramsey C, Neugebauer V: PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior. Mol Pain 2008, 4:26-46. BioMed Central Full Text
• [46]Han JS, Adwanikar H, Li Z, Ji G, Neugebauer V: Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats. Mol Pain 2010, 6:10-23. BioMed Central Full Text
• [47]Neugebauer V, Han JS, Adwanikar H, Fu Y, Ji G: Techniques for assessing knee joint pain in arthritis. Mol Pain 2007, 3:8-20. BioMed Central Full Text
• [48]Han JS, Neugebauer V: mGluR1 and mGluR5 antagonists in the amygdala inhibit different components of audible and ultrasonic vocalizations in a model of arthritic pain. Pain 2005, 113:211-222.
• [49]Lowery EG, Spanos M, Navarro M, Lyons AM, Hodge CW, Thiele TE: CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology 2010, 35:1241-1252.
• [50]Ganon-Elazar E, Akirav I: Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology 2012, 37:456-466.
• [51]Kohda K, Harada K, Kato K, Hoshino A, Motohashi J, Yamaji T, Morinobu S, Matsuoka N, Kato N: Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience 2007, 148:22-33.
• [52]Yu B, Shinnick-Gallagher P: Corticotropin-releasing factor increases dihydropyridine- and neurotoxin-resistant calcium currents in neurons of the central amygdala. J Pharmacol Exp Ther 1998, 284:170-179.
• [53]Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB, Oltersdorf T: Cloning and characterization of a functionally distinct corticotropin- releasing factor receptor subtype from rat brain. Proc Natl Acad Sci U S A 1995, 92:836-840.
• [54]Bittencourt JC, Sawchenko PE: Do centrally administered neuropeptides access cognate receptors?: an analysis in the central corticotropin-releasing factor system. J Neurosci 2000, 20:1142-1156.
• [55]Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE: Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 2000, 428:191-212.
• [56]Chalmers DT, Lovenberg TW, De Souza EB: Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci 1995, 15:6340-6350.
• [57]Ansah OB, Bourbia N, Goncalves L, Almeida A, Pertovaara A: Influence of amygdaloid glutamatergic receptors on sensory and emotional pain-related behavior in the neuropathic rat. Behav Brain Res 2010, 209:174-178.
• [58]Pedersen LH, Scheel-Kruger J, Blackburn-Munro G: Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury. Pain 2007, 127:17-26.
• [59]Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR: Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 2004, 303:1512-1514.
• [60]Bourgeais L, Gauriau C, Bernard J-F: Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a PHA-L study in the rat. Eur J Neurosci 2001, 14:229-255.
• [61]Gray TS, Magnuson DJ: Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat. Peptides 1992, 13:451-460.
• [62]Lee HS, Kim MA, Valentino RJ, Waterhouse BD: Glutamatergic afferent projections to the dorsal raphe nucleus of the rat. Brain Res 2003, 963:57-71.
• [63]Veinante P, Stoeckel ME, Freund-Mercier MJ: GABA- and peptide-immunoreactivities co-localize in the rat central extended amygdala. Neurorep 1997, 8:2985-2989.
• [64]Day HE, Curran EJ, Watson SJ Jr, Akil H: Distinct neurochemical populations in the rat central nucleus of the amygdala and bed nucleus of the stria terminalis: evidence for their selective activation by interleukin-1beta. J Comp Neurol 1999, 413:113-128.
• [65]Egli M, Koob GF, Edwards S: Alcohol dependence as a chronic pain disorder. Neurosci Biobehav Rev 2012, 36:2179-2192.
• [66]Hoare SR, Sullivan SK, Ling N, Crowe PD, Grigoriadis DE: Mechanism of corticotropin-releasing factor type I receptor regulation by nonpeptide antagonists. Mol Pharmacol 2003, 63:751-765.
• [67]Rivier J, Gulyas J, Kirby D, Low W, Perrin MH, Kunitake K, DiGruccio M, Vaughan J, Reubi JC, Waser B, et al.: Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists. J Med Chem 2002, 45:4737-4747.
• [68]Hoare SR, Sullivan SK, Fan J, Khongsaly K, Grigoriadis DE: Peptide ligand binding properties of the corticotropin-releasing factor (CRF) type 2 receptor: pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivity. Peptides 2005, 26:457-470.
• [69]Minami K, Gereau RW, Minami M, Heinemann SF, Harris RA: Effects of ethanol and anesthetics on type 1 and 5 metabotropic glutamate receptors expressed in Xenopus laevis oocytes. Mol Pharmacol 1998, 53:148-156.
• [70]Ji G, Sun H, Fu Y, Li Z, Pais-Vieira M, Galhardo V, Neugebauer V: Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation. J Neurosci 2010, 30:5451-5464.
• [71]Stiller CO, Taylor BK, Linderoth B, Gustafsson H, Warsame Afrah A, Brodin E: Microdialysis in pain research. Adv Drug Deliv Rev 2003, 55:1065-1079.
• [72]Alheid GF, De Olmos JS, Beltramino CA: Amygdala and extended amygdala. In The rat nervous system. Edited by Paxinos G. San Diego, CA: Academic; 1995:495-578.
• [73]Han JS, Bird GC, Li W, Neugebauer V: Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. J Neurosci Meth 2005, 141:261-269.
• [74]Ji G, Neugebauer V: Hemispheric lateralization of pain processing by amygdala neurons. J Neurophysiol 2009, 1102:2253-2264.
• [75]Paxinos G, Watson C: The rat brain in stereotaxic coordinates. New York: Academic Press; 1998.
• [76]Cabell L, Audesirk G: Effects of selective inhibition of protein kinase C, cyclic AMP- dependent protein kinase, and Ca(2+)-calmodulin-dependent protein kinase on neurite development in cultured rat hippocampal neurons. Int J Dev Neurosci 1993, 11:357-368.
• [77]Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-Perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F: The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 1991, 266:15771.