Pain Control pp 261-284 | Cite as

Amygdala Pain Mechanisms

  • Volker NeugebauerEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)


A limbic brain area, the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety, and depression. The amygdala has also emerged as an important brain center for the emotional–affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the “nociceptive amygdala”) accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral–basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.


Amygdala Pain Plasticity Neurotransmitter mGluR CGRP CRF NPS 



Basolateral amygdala


Cannabinoid receptor 1


Central nucleus of the amygdala


Laterocapsular division of the central nucleus of the amygdala


Intercalated cell mass


Lateral amygdala


Metabotropic glutamate receptor


Medial prefrontal cortex


Neuropeptide S


Parabrachial area



Work in the author’s lab is supported by National Institute of Neurological Disorders and Stroke Grants NS-081121, NS-38261, and NS-11255.


  1. Adedoyin MO, Vicini S, Neale JH (2010) Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model. Mol Pain 6:60–77PubMedCentralPubMedGoogle Scholar
  2. Amir A, Amano T, Pare D (2011) Physiological identification and infralimbic responsiveness of rat intercalated amygdala neurons. J Neurophysiol 105:3054–3066PubMedCentralPubMedGoogle Scholar
  3. Ansah OB, Bourbia N, Goncalves L, Almeida A, Pertovaara A (2010) Influence of amygdaloid glutamatergic receptors on sensory and emotional pain-related behavior in the neuropathic rat. Behav Brain Res 209:174–178PubMedGoogle Scholar
  4. Apkarian AV, Neugebauer V, Koob G, Edwards S, Levine JD, Ferrari L, Egli M, Regunathan S (2013) Neural mechanisms of pain and alcohol dependence. Pharmacol Biochem Behav 112C:34–41Google Scholar
  5. Asan E, Yilmazer-Hanke DM, Eliava M, Hantsch M, Lesch KP, Schmitt A (2005) The corticotropin-releasing factor (CRF)-system and monoaminergic afferents in the central amygdala: investigations in different mouse strains and comparison with the rat. Neuroscience 131:953–967PubMedGoogle Scholar
  6. Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557PubMedGoogle Scholar
  7. Baliki MN, Geha PY, Jabakhanji R, Harden N, Schnitzer TJ, Apkarian AV (2008) A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis. Mol Pain 4:47PubMedCentralPubMedGoogle Scholar
  8. Bie B, Zhu W, Pan ZZ (2009) Rewarding morphine-induced synaptic function of delta-opioid receptors on central glutamate synapses. J Pharmacol Exp Ther 329:290–296PubMedCentralPubMedGoogle Scholar
  9. Bie B, Wang Y, Cai YQ, Zhang Z, Hou YY, Pan ZZ (2012) Upregulation of nerve growth factor in central amygdala increases sensitivity to opioid reward. Neuropsychopharmacology 37:2780–2788PubMedCentralPubMedGoogle Scholar
  10. Bird GC, Lash LL, Han JS, Zou X, Willis WD, Neugebauer V (2005) Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol 564:907–921PubMedCentralPubMedGoogle Scholar
  11. Blank T, Nijholt I, Grammatopoulos DK, Randeva HS, Hillhouse EW, Spiess J (2003) 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 23:700–707PubMedGoogle Scholar
  12. Bourbia N, Ansah OB, Pertovaara A (2010) Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy. J Pain 11:1461–1471PubMedGoogle Scholar
  13. Bourgeais L, Gauriau C, Bernard J-F (2001) 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 14:229–255PubMedGoogle Scholar
  14. Busti D, Geracitano R, Whittle N, Dalezios Y, Manko M, Kaufmann W, Satzler K, Singewald N, Capogna M, Ferraguti F (2011) Different fear states engage distinct networks within the intercalated cell clusters of the amygdala. J Neurosci 31:5131–5144PubMedGoogle Scholar
  15. Cai YQ, Wang W, Hou YY, Zhang Z, Xie J, Pan ZZ (2013) Central amygdala GluA1 facilitates associative learning of opioid reward. J Neurosci 33:1577–1588PubMedCentralPubMedGoogle Scholar
  16. Carrasquillo Y, Gereau RW (2007) Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception. J Neurosci 27:1543–1551PubMedGoogle Scholar
  17. Carrasquillo Y, Gereau RW (2008) Hemispheric lateralization of a molecular signal for pain modulation in the amygdala. Mol Pain 4:24PubMedCentralPubMedGoogle Scholar
  18. Charney DS (2003) Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl (417):38–50Google Scholar
  19. Commons KG, Connolley KR, Valentino RJ (2003) A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders. Neuropsychopharmacology 28:206–215PubMedGoogle Scholar
  20. Crock LW, Kolber BJ, Morgan CD, Sadler KE, Vogt SK, Bruchas MR, Gereau RW (2012) Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci 32:14217–14226PubMedCentralPubMedGoogle Scholar
  21. Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694PubMedGoogle Scholar
  22. de Lacalle S, Saper CB (2000) Calcitonin gene-related peptide-like immunoreactivity marks putative visceral sensory pathways in human brain. Neuroscience 100:115–130PubMedGoogle Scholar
  23. Dobolyi A, Irwin S, Makara G, Usdin TB, Palkovits M (2005) Calcitonin gene-related peptide-containing pathways in the rat forebrain. J Comp Neurol 489:92–119PubMedGoogle Scholar
  24. Ferraguti F, Crepaldi L, Nicoletti F (2008) Metabotropic glutamate 1 receptor: current concepts and perspectives. Pharmacol Rev 60:536–581PubMedGoogle Scholar
  25. Fields HL (2000) Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 122:245–253PubMedGoogle Scholar
  26. Fu Y, Neugebauer V (2008) Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J Neurosci 28:3861–3876PubMedCentralPubMedGoogle Scholar
  27. Fu Y, Han J, Ishola T, Scerbo M, Adwanikar H, Ramsey C, Neugebauer V (2008) PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior. Mol Pain 4:26–46PubMedCentralPubMedGoogle Scholar
  28. Gauriau C, Bernard J-F (2002) Pain pathways and parabrachial circuits in the rat. Exp Physiol 87(2):251–258PubMedGoogle Scholar
  29. Goncalves L, Dickenson AH (2012) Asymmetric time-dependent activation of right central amygdala neurones in rats with peripheral neuropathy and pregabalin modulation. Eur J Neurosci 36:3204–3213PubMedGoogle Scholar
  30. Gray TS (1993) Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. Ann N Y Acad Sci 697:53–60PubMedGoogle Scholar
  31. Greenwood-Van Meerveld B, Johnson AC, Schulkin J, Myers DA (2006) Long-term expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus in response to an acute colonic inflammation. Brain Res 1071:91–96PubMedGoogle Scholar
  32. Guerrini R, Salvadori S, Rizzi A, Regoli D, Calo’ G (2010) Neurobiology, pharmacology, and medicinal chemistry of neuropeptide S and its receptor. Med Res Rev 30:751–777PubMedGoogle Scholar
  33. Han JS, Neugebauer V (2004) Synaptic plasticity in the amygdala in a visceral pain model in rats. Neurosci Lett 361:254–257PubMedGoogle Scholar
  34. Han JS, Neugebauer V (2005) mGluR1 and mGluR5 antagonists in the amygdala inhibit different components of audible and ultrasonic vocalizations in a model of arthritic pain. Pain 113:211–222PubMedGoogle Scholar
  35. Han JS, Bird GC, Neugebauer V (2004) Enhanced group III mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala. Neuropharmacology 46:918–926PubMedGoogle Scholar
  36. Han JS, Li W, Neugebauer V (2005) Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. J Neurosci 25:10717–10728PubMedGoogle Scholar
  37. Han JS, Fu Y, Bird GC, Neugebauer V (2006) Enhanced group II mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala. Mol Pain 2:18–29PubMedCentralPubMedGoogle Scholar
  38. Han JS, Adwanikar H, Li Z, Ji G, Neugebauer V (2010) Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats. Mol Pain 6:10–23PubMedCentralPubMedGoogle Scholar
  39. Harrigan EA, Magnuson DJ, Thunstedt GM, Gray TS (1994) Corticotropin releasing factor neurons are innervated by calcitonin gene-related peptide terminals in the rat central amygdaloid nucleus. Brain Res Bull 33:529–534PubMedGoogle Scholar
  40. Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM (2009) Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci 1179:120–143PubMedCentralPubMedGoogle Scholar
  41. Hay DL (2007) What makes a CGRP2 receptor? Clin Exp Pharmacol Physiol 34:963–971PubMedGoogle Scholar
  42. Hebert MA, Ardid D, Henrie JA, Tamashiro K, Blanchard DC, Blanchard RJ (1999) Amygdala lesions produce analgesia in a novel, ethologically relevant acute pain test. Physiol Behav 67(1):99–105PubMedGoogle Scholar
  43. Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Luthi A (2010) Neuronal circuits of fear extinction. Eur J Neurosci 31:599–612PubMedGoogle Scholar
  44. Holland PC, Gallagher M (2004) Amygdala-frontal interactions and reward expectancy. Curr Opin Neurobiol 14:148–155PubMedGoogle Scholar
  45. Ikeda R, Takahashi Y, Inoue K, Kato F (2007) NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain 127:161–172PubMedGoogle Scholar
  46. Ji G, Neugebauer V (2007) Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. J Neurophysiol 97:3893–3904PubMedGoogle Scholar
  47. Ji G, Neugebauer V (2008) Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors. J Neurophysiol 99:1201–1212PubMedGoogle Scholar
  48. Ji G, Neugebauer V (2009) Hemispheric lateralization of pain processing by amygdala neurons. J Neurophysiol 1102:2253–2264Google Scholar
  49. Ji G, Neugebauer V (2010) Reactive oxygen species are involved in group I mGluR-mediated facilitation of nociceptive processing in amygdala neurons. J Neurophysiol 104:218–229PubMedCentralPubMedGoogle Scholar
  50. Ji G, Neugebauer V (2011) Pain-related deactivation of medial prefrontal cortical neurons involves mGluR1 and GABAA receptors. J Neurophysiol 106:2642–2652PubMedCentralPubMedGoogle Scholar
  51. Ji G, Fu Y, Ruppert KA, Neugebauer V (2007) Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. Mol Pain 3:13–17PubMedCentralPubMedGoogle Scholar
  52. Ji G, Horvath C, Neugebauer V (2009) NR2B receptor blockade inhibits pain-related sensitization of amygdala neurons. Mol Pain 5:21–26PubMedCentralPubMedGoogle Scholar
  53. Ji G, Sun H, Fu Y, Li Z, Pais-Vieira M, Galhardo V, Neugebauer V (2010) Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation. J Neurosci 30:5451–5464PubMedCentralPubMedGoogle Scholar
  54. Ji G, Fu Y, Adwanikar H, Neugebauer V (2013) Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses. Mol Pain 9:2PubMedCentralPubMedGoogle Scholar
  55. Jongen-Relo AL, Amaral DG (1998) Evidence for a GABAergic projection from the central nucleus of the amygdala to the brainstem of the macaque monkey: a combined retrograde tracing and in situ hybridization study. Eur J Neurosci 10:2924–2933PubMedGoogle Scholar
  56. Jungling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK, Pape HC (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron 59:298–310PubMedCentralPubMedGoogle Scholar
  57. Kolber BJ, Montana MC, Carrasquillo Y, Xu J, Heinemann SF, Muglia LJ, Gereau RW (2010) Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior. J Neurosci 30:8203–8213PubMedCentralPubMedGoogle Scholar
  58. Koob GF (2010) The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res 1314:3–14PubMedGoogle Scholar
  59. Kruger L, Sternini C, Brecha NC, Mantyh PW (1988) Distribution of calcitonin gene-related peptide immunoreactivity in relation to the rat central somatosensory projection. J Comp Neurol 273:149–162PubMedGoogle Scholar
  60. Kulkarni B, Bentley DE, Elliott R, Julyan PJ, Boger E, Watson A, Boyle Y, El-Deredy W, Jones AK (2007) Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum 56:1345–1354PubMedGoogle Scholar
  61. Laviolette SR, Grace AA (2006) Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs. J Neurosci 26:6458–6468PubMedGoogle Scholar
  62. Leonard SK, Ring RH (2011) Immunohistochemical localization of the neuropeptide S receptor in the rat central nervous system. Neuroscience 172:153–163PubMedGoogle Scholar
  63. Li W, Neugebauer V (2004a) Block of NMDA and non-NMDA receptor activation results in reduced background and evoked activity of central amygdala neurons in a model of arthritic pain. Pain 110:112–122PubMedGoogle Scholar
  64. Li W, Neugebauer V (2004b) Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in central amygdala neurons. J Neurophysiol 91:13–24PubMedGoogle Scholar
  65. Li W, Neugebauer V (2006) Differential changes of group II and group III mGluR function in central amygdala neurons in a model of arthritic pain. J Neurophysiol 96:1803–1815PubMedGoogle Scholar
  66. Li N, Liang J, Fang CY, Han HR, Ma MS, Zhang GX (2008) Involvement of CGRP and CGRPl receptor in nociception in the basolateral nucleus of amygdala of rats. Neurosci Lett 443:184–187PubMedGoogle Scholar
  67. Li W, Chang M, Peng YL, Gao YH, Zhang JN, Han RW, Wang R (2009) Neuropeptide S produces antinociceptive effects at the supraspinal level in mice. Regul Pept 156:90–95PubMedGoogle Scholar
  68. Li Z, Ji G, Neugebauer V (2011) 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 31:1114–1127PubMedCentralPubMedGoogle Scholar
  69. Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Pare D (2008) Amygdala intercalated neurons are required for expression of fear extinction. Nature 454:642–645PubMedCentralPubMedGoogle Scholar
  70. Liu CC, Ohara S, Franaszczuk P, Zagzoog N, Gallagher M, Lenz FA (2010) Painful stimuli evoke potentials recorded from the medial temporal lobe in humans. Neuroscience 165:1402–1411PubMedCentralPubMedGoogle Scholar
  71. Ma W, Chabot J-G, Powell KJ, Jhamandas K, Dickerson IM, Quirion R (2003) Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience 120:677–694PubMedGoogle Scholar
  72. Manning BH (1998) A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J Neurosci 18:9453–9470PubMedGoogle Scholar
  73. Manning BH, Mayer DJ (1995a) The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test. Pain 63:141–152PubMedGoogle Scholar
  74. Manning BH, Mayer DJ (1995b) The central nucleus of the amygdala contributes to the production of morphine antinociception in the rat tail-flick test. J Neurosci 15(12):8199–8213PubMedGoogle Scholar
  75. Marek R, Strobel C, Bredy TW, Sah P (2013) The amygdala and medial prefrontal cortex: partners in the fear circuit. J Physiol 591:2381–2391PubMedCentralPubMedGoogle Scholar
  76. Mason P (2005) Deconstructing endogenous pain modulations. J Neurophysiol 94:1659–1663PubMedGoogle Scholar
  77. McDonald AJ (1998) Cortical pathways to the mammalian amygdala. Prog Neurobiol 55:257–332PubMedGoogle Scholar
  78. McGaugh JL (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1–28PubMedGoogle Scholar
  79. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339PubMedGoogle Scholar
  80. McNally GP, Akil H (2002) 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 112:605–617PubMedGoogle Scholar
  81. Myers B, Greenwood-Van Meerveld B (2010) Divergent effects of amygdala glucocorticoid and mineralocorticoid receptors in the regulation of visceral and somatic pain. Am J Physiol Gastrointest Liver Physiol 298:G295–G303PubMedGoogle Scholar
  82. Myers DA, Gibson M, Schulkin J, Greenwood Van-Meerveld B (2005) Corticosterone implants to the amygdala and type 1 CRH receptor regulation: effects on behavior and colonic sensitivity. Behav Brain Res 161:39–44PubMedGoogle Scholar
  83. Nakao A, Takahashi Y, Nagase M, Ikeda R, Kato F (2012) Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala. Mol Pain 8:51PubMedCentralPubMedGoogle Scholar
  84. Neugebauer V, Li W (2003) Differential sensitization of amygdala neurons to afferent inputs in a model of arthritic pain. J Neurophysiol 89:716–727PubMedGoogle Scholar
  85. Neugebauer V, Zinebi F, Russell R, Gallagher JP, Shinnick-Gallagher P (2000) Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. J Neurophysiol 84:759–770PubMedGoogle Scholar
  86. Neugebauer V, Li W, Bird GC, Bhave G, Gereau RW (2003) Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J Neurosci 23:52–63PubMedGoogle Scholar
  87. Neugebauer V, Li W, Bird GC, Han JS (2004) The amygdala and persistent pain. Neuroscientist 10:221–234PubMedGoogle Scholar
  88. Neugebauer V, Galhardo V, Maione S, Mackey SC (2009) Forebrain pain mechanisms. Brain Res Rev 60:226–242PubMedCentralPubMedGoogle Scholar
  89. Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041PubMedCentralPubMedGoogle Scholar
  90. Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322PubMedCentralPubMedGoogle Scholar
  91. Ochsner KN, Gross JJ (2005) The cognitive control of emotion. Trends Cogn Sci 9:242–249PubMedGoogle Scholar
  92. Oliver KR, Kane SA, Salvatore CA, Mallee JJ, Kinsey AM, Koblan KS, Keyvan-Fouladi N, Heavens RP, Wainwright A, Jacobson M, Dickerson IM, Hill RG (2001) Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur J Neurosci 14:618–628PubMedGoogle Scholar
  93. Orsini CA, Maren S (2012) Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev 36:1773–1802PubMedCentralPubMedGoogle Scholar
  94. Palazzo E, Fu Y, Ji G, Maione S, Neugebauer V (2008) Group III mGluR7 and mGluR8 in the amygdala differentially modulate nocifensive and affective pain behaviors. Neuropharmacology 55:537–545PubMedCentralPubMedGoogle Scholar
  95. Palazzo E, Marabese I, Soukupova M, Luongo L, Boccella S, Giordano C, de Novellis V, Rossi F, Maione S (2011) Metabotropic glutamate receptor subtype 8 in the amygdala modulates thermal threshold, neurotransmitter release, and rostral ventromedial medulla cell activity in inflammatory pain. J Neurosci 31:4687–4697PubMedGoogle Scholar
  96. Pape HC, Pare D (2010) Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90:419–463PubMedCentralPubMedGoogle Scholar
  97. Pedersen LH, Scheel-Kruger J, Blackburn-Munro G (2007) Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury. Pain 127:17–26PubMedGoogle Scholar
  98. Peng YL, Zhang JN, Chang M, Li W, Han RW, Wang R (2010) Effects of central neuropeptide S in the mouse formalin test. Peptides 31:1878–1883PubMedGoogle Scholar
  99. Pinard CR, Mascagni F, McDonald AJ (2012) Medial prefrontal cortical innervation of the intercalated nuclear region of the amygdala. Neuroscience 205:112–124PubMedGoogle Scholar
  100. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54:233–246PubMedGoogle Scholar
  101. Price JL (2003) Comparative aspects of amygdala connectivity. In: Shinnick-Gallagher P, Pitkanen A, Shekhar A, Cahill L (eds) The amygdala in brain function. Basic and clinical approaches, vol 985. The New York Academy of Sciences, New York, pp 50–58Google Scholar
  102. Qin C, Greenwood-Van Meerveld B, Foreman RD (2003) Visceromotor and spinal neuronal responses to colorectal distension in rats with aldosterone onto the amygdala. J Neurophysiol 90:2–11PubMedGoogle Scholar
  103. Rea K, Lang Y, Finn DP (2009) Alterations in extracellular levels of gamma-aminobutyric acid in the rat basolateral amygdala and periaqueductal gray during conditioned fear, persistent pain and fear-conditioned analgesia. J Pain 10:1088–1098PubMedGoogle Scholar
  104. Reinscheid RK (2008) Neuropeptide S: anatomy, pharmacology, genetics and physiological functions. Results Probl Cell Differ 46:145–158PubMedGoogle Scholar
  105. Ren W, Neugebauer V (2010) Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1. Mol Pain 6:93–106PubMedCentralPubMedGoogle Scholar
  106. Ren W, Palazzo E, Maione S, Neugebauer V (2011) Differential effects of mGluR7 and mGluR8 activation on pain-related synaptic activity in the amygdala. Neuropharmacology 61:1334–1344PubMedCentralPubMedGoogle Scholar
  107. Ren W, Kiritoshi T, Gregoire S, Ji G, Guerrini R, Calo G, Neugebauer V (2013) Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors. J Neurophysiol 110:1765–1781PubMedCentralPubMedGoogle Scholar
  108. Reul JM, Holsboer F (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2:23–33PubMedGoogle Scholar
  109. Robinson SD, Aitken JF, Bailey RJ, Poyner DR, Hay DL (2009) Novel peptide antagonists of adrenomedullin and calcitonin gene-related peptide receptors: identification, pharmacological characterization, and interactions with position 74 in receptor activity-modifying protein 1/3. J Pharmacol Exp Ther 331:513–521PubMedGoogle Scholar
  110. Rouwette T, Vanelderen P, Reus MD, Loohuis NO, Giele J, van Egmond J, Scheenen W, Scheffer GJ, Roubos E, Vissers K, Kozicz T (2011) Experimental neuropathy increases limbic forebrain CRF. Eur J Pain 16(1):61–71Google Scholar
  111. Ruzza C, Pulga A, Rizzi A, Marzola G, Guerrini R, Calo’ G (2012) Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor. Neuropharmacology 62:1999–2009PubMedGoogle Scholar
  112. Sanchez MM, Young LJ, Plotsky PM, Insel TR (1999) Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 408(3):365–377PubMedGoogle Scholar
  113. Schiess MC, Callahan PM, Zheng H (1999) Characterization of the electrophysiological and morphological properties of rat central amygdala neurons in vitro. J Neurosci Res 58:663–673PubMedGoogle Scholar
  114. Schwaber JS, Sternini C, Brecha NC, Rogers WT, Card JP (1988) Neurons containing calcitonin gene-related peptide in the parabrachial nucleus project to the central nucleus of the amygdala. J Comp Neurol 270:416–426PubMedGoogle Scholar
  115. Simons LE, Moulton EA, Linnman C, Carpino E, Becerra L, Borsook D (2012) The human amygdala and pain: evidence from neuroimaging. Hum Brain Mapp 35(2):527–538. doi: 10.1002/hbm.22199 PubMedCentralPubMedGoogle Scholar
  116. Sotres-Bayon F, Quirk GJ (2010) Prefrontal control of fear: more than just extinction. Curr Opin Neurobiol 20:231–235PubMedCentralPubMedGoogle Scholar
  117. Spuz CA, Borszcz GS (2012) NMDA or non-NMDA receptor antagonism within the amygdaloid central nucleus suppresses the affective dimension of pain in rats: evidence for hemispheric synergy. J Pain 13:328–337PubMedCentralPubMedGoogle Scholar
  118. Sun N, Cassell MD (1993) Intrinsic GABAergic neurons in the rat central extended amygdala. J Comp Neurol 330:381–404PubMedGoogle Scholar
  119. Tache Y, Bonaz B (2007) Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest 117:33–40PubMedCentralPubMedGoogle Scholar
  120. Takahashi LK (2001) Role of CRF(1) and CRF(2) receptors in fear and anxiety. Neurosci Biobehav Rev 25:627–636PubMedGoogle Scholar
  121. Tillisch K, Mayer EA, Labus JS (2010) Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology 140:91–100PubMedCentralPubMedGoogle Scholar
  122. Ulrich-Lai YM, Xie W, Meij JTA, Dolgas CM, Yu L, Herman JP (2006) Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav 88:67–76PubMedGoogle Scholar
  123. Uryu K, Okumura T, Shibasaki T, Sakanaka M (1992) Fine structure and possible origins of nerve fibers with corticotropin-releasing factor-like immunoreactivity in the rat central amygdaloid nucleus. Brain Res 577:175–179PubMedGoogle Scholar
  124. Van Rossum D, Hanish U-K, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678PubMedGoogle Scholar
  125. Wimalawansa SJ (1996) Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 17:533–585PubMedGoogle Scholar
  126. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, De LL, Civelli O (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43:487–497PubMedGoogle Scholar
  127. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK (2007) Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. J Comp Neurol 500:84–102PubMedGoogle Scholar
  128. Zhang RX, Zhang M, Li A, Pan L, Berman BM, Ren K, Lao L (2013) DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia. Neuroscience 252:359–366PubMedGoogle Scholar
  129. Zhu W, Pan ZZ (2004) Synaptic properties and postsynaptic opioid effects in rat central amygdala neurons. Neuroscience 127:871–879PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Pharmacology and Neuroscience, Center for Translational Neuroscience and TherapeuticsTexas Tech University Health Sciences CenterLubbockUSA

Personalised recommendations