The Journal of Pain
Volume 10, Issue 10 , Pages 1088-1098 , October 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

  • Kieran Rea
  • ,
  • Yvonne Lang
  • ,
  • David P. Finn

      Affiliations

    • Corresponding Author InformationAddress reprint requests to: David P. Finn, Department of Pharmacology & Therapeutics, University Road, National University of Ireland, Galway, Ireland.

Received 16 October 2008 ,Revised 17 March 2009 ,Accepted 14 April 2009.

References 

  1. Amaral DG, Price JL. Amygdalo-cortical projections in the monkey (Macaca fascicularis). Comp Neurol. 1984;230:465–496
  2. Beitz AJ. The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience. 1982;7:133–159
  3. Berlau DJ, McGaugh JL. Enhancement of extinction memory consolidation: The role of the noradrenergic and GABAergic systems within the basolateral amygdala. Neurobiol Learn Mem. 2006;86:123–132
  4. Berrino L, Oliva P, Rossi F, Palazzo E, Nobili B, Maione S. Interaction between metabotropic and NMDA glutamate receptors in the periaqueductal grey pain modulatory system. Naunyn Schmiedebergs Arch Pharmacol. 2001;364:437–443
  5. Blair HT, Sotres-Bayon F, Moita MA, Ledoux JE. The lateral amygdala processes the value of conditioned and unconditioned aversive stimuli. Neuroscience. 2005;133:561–569
  6. Brandao ML, Zanoveli JM, Ruiz-Martinez RC, Oliveira LC, Landeira-Fernandez J. Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety. Behav Brain Res. 2008;188:1–13
  7. Broiz AC, Oliveira LC, Brandao ML. Regulation of conditioned and unconditioned fear in rats by 5-HT1A receptors in the dorsal periaqueductal gray. Pharmacol Biochem Behav. 2008;89:76–84
  8. Butler RK, Rea K, Lang Y, Gavin AM, Finn DP. Endocannabinoid-mediated enhancement of fear-conditioned analgesia in rats: Opioid receptor dependency and molecular correlates. Pain. 2008;140:491–500
  9. Campbell K, Kalen P, Lundberg C, Wictorin K, Rosengren E, Bjorklund A. Extracellular gamma-aminobutyric acid levels in the rat caudate-putamen: Monitoring the neuronal and glial contribution by intracerebral microdialysis. Brain Res. 1993;614:241–250
  10. Carrive P, Leung P, Harris J, Paxinos G. Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray. Neuroscience. 1997;78:165–177
  11. Castilho VM, Brandao ML. Conditioned antinociception and freezing using electrical stimulation of the dorsal periaqueductal gray or inferior colliculus as unconditioned stimulus are differentially regulated by 5-HT2A receptors in rats. Psychopharmacology (Berl). 2001;155:154–162
  12. Castilho VM, Macedo CE, Brandao ML. Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats. Psychopharmacology (Berl). 2002;165:77–85
  13. Collins DR, Pare D. Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS(+) and CS(-). Learn Mem. 2000;7:97–103
  14. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353–375
  15. Davis M, Myers KM. The role of glutamate and gamma-aminobutyric acid in fear extinction: Clinical implications for exposure therapy. Biol Psychiatry. 2002;52:998–1007
  16. Davis M, Rainnie D, Cassell M. Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 1994;17:208–214
  17. Davis M, Walker DL, Myers KM. Role of the amygdala in fear extinction measured with potentiated startle. Annals of the New York Academy of Sciences. 2003;985:218–232
  18. de Novellis V, Mariani L, Palazzo E, Vita D, Marabese I, Scafuro M, et al. Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. Neuroscience. 2005;134:269–281
  19. De Oca BM, DeCola JP, Maren S, Fanselow MS. Distinct regions of the periaqueductal gray are involved in the acquisition and expression of defensive responses. J Neurosci. 1998;18:3426–3432
  20. Drew KL, Pehek EA, Rasley BT, Ma YL, Green TK. Sampling glutamate and GABA with microdialysis: Suggestions on how to get the dialysis membrane closer to the synapse. J Neurosci Methods. 2004;140:127–131
  21. Enna SJ, McCarson KE. The role of GABA in the mediation and perception of pain. Adv Pharmacol. 2006;54:1–27
  22. Fanselow MS, LeDoux JE. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron. 1999;23:229–232
  23. Fendt M, Fanselow MS. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev. 1999;23:743–760
  24. Finn DP, Beckett SR, Richardson D, Kendall DA, Marsden CA, Chapman V. Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci. 2004;20:848–852
  25. Finn DP, Jhaveri MD, Beckett SR, Madjd A, Kendall DA, Marsden CA, et al. Behavioral, central monoaminergic and hypothalamo-pituitary-adrenal axis correlates of fear-conditioned analgesia in rats. Neuroscience. 2006;138:1309–1317
  26. Finn DP, Jhaveri MD, Beckett SR, Roe CH, Kendall DA, Marsden CA, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology. 2003;45:594–604
  27. Fox RJ, Sorenson CA. Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res. 1994;648:215–221
  28. Geuze E, Westenberg HG, Jochims A, de Kloet CS, Bohus M, Vermetten E, et al. Altered pain processing in veterans with posttraumatic stress disorder. Arch Gen Psychiatry. 2007;64:76–85
  29. Harris JA, Westbrook RF. Effects of midazolam and naloxone in rats tested for sensitivity/reactivity to formalin pain in a familiar, novel or aversively conditioned environment. Psychopharmacology (Berl). 1994;115:65–72
  30. Harris JA, Westbrook RF. Effects of benzodiazepine microinjection into the amygdala or periaqueductal gray on the expression of conditioned fear and hypoalgesia in rats. Behav Neurosci. 1995;109:295–304
  31. Harris JA, Westbrook RF. Midazolam impairs the acquisition of conditioned analgesia if rats are tested with an acute but not a chronic noxious stimulus. Brain Res Bull. 1996;39:227–233
  32. Helmstetter FJ. The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci. 1992;106:518–528
  33. Helmstetter FJ. Stress-induced hypoalgesia and defensive freezing are attenuated by application of diazepam to the amygdala. Pharmacol Biochem Behav. 1993;44:433–438
  34. Helmstetter FJ, Bellgowan PS. Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res. 1993;612:253–257
  35. Helmstetter FJ, Bellgowan PS. Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats. Behav Neurosci. 1994;108:1005–1009
  36. Helmstetter FJ, Tershner SA. Lesions of the periaqueductal gray and rostral ventromedial medulla disrupt antinociceptive but not cardiovascular aversive conditional responses. J Neurosci. 1994;14:7099–7108
  37. Helmstetter FJ, Tershner SA, Poore LH, Bellgowan PS. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res. 1998;779:104–118
  38. Hopkins DA, Holstege G. Amygdaloid projections to the mesencephalon, pons and medulla oblongata in the cat. Exp Brain Res. 1978;32:529–547
  39. Kim JJ, Rison RA, Fanselow MS. Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. Behav Neurosci. 1993;107:1093–1098
  40. LeDoux JE. Emotion: Clues from the brain. Annu Rev Psychol. 1995;46:209–235
  41. LeDoux JE, Farb C, Ruggiero DA. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci. 1990;10:1043–1054
  42. Lei LG, Zhang YQ, Zhao ZQ. Pain-related aversion and Fos expression in the central nervous system in rats. Neuroreport. 2004;15:67–71
  43. Li YQ, Jia HG, Rao ZR, Shi JW. Serotonin-, substance P- or leucine-enkephalin-containing neurons in the midbrain periaqueductal gray and nucleus raphe dorsalis send projection fibers to the central amygdaloid nucleus in the rat. Neurosci Lett. 1990;120:124–127
  44. Maione S, Marabese I, Oliva P, de Novellis V, Stella L, Rossi F, et al. Periaqueductal gray matter glutamate and GABA decrease following subcutaneous formalin injection in rat. Neuroreport. 1999;10:1403–1407
  45. Maione S, Oliva P, Marabese I, Palazzo E, Rossi F, Berrino L, et al. Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception. Pain. 2000;85:183–189
  46. Manning BH. A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J Neurosci. 1998;18:9453–9470
  47. Mantyh PW. Forebrain projections to the periaqueductal gray in the monkey, with observations in the cat and rat. J Comp Neurol. 1982;206:146–158
  48. Maren S. Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci. 2001;24:897–931
  49. Martinez RC, de Oliveira AR, Brandao ML. Conditioned and unconditioned fear organized in the periaqueductal gray are differentially sensitive to injections of muscimol into amygdaloid nuclei. Neurobiol Learn Mem. 2006;85:58–65
  50. Mendes-Gomes J, Nunes-de-Souza RL. Concurrent nociceptive stimulation impairs the anxiolytic effect of midazolam injected into the periaqueductal gray in mice. Brain Res. 2005;1047:97–104
  51. Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66:355–474
  52. Monhemius R, Green DL, Roberts MH, Azami J. Periaqueductal grey mediated inhibition of responses to noxious stimulation is dynamically activated in a rat model of neuropathic pain. Neurosci Lett. 2001;298:70–74
  53. Morgan MM, Clayton CC. Defensive behaviors evoked from the ventrolateral periaqueductal gray of the rat: Comparison of opioid and GABA disinhibition. Behav Brain Res. 2005;164:61–66
  54. Muller J, Corodimas KP, Fridel Z, LeDoux JE. Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli. Behav Neurosci. 1997;111:683–691
  55. Nader K, Majidishad P, Amorapanth P, LeDoux JE. Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learning Mem. 2001;8:156–163
  56. Oliva P, Berrino L, de Novellis V, Palazzo E, Marabese I, Siniscalco D, et al. Role of periaqueductal grey prostaglandin receptors in formalin-induced hyperalgesia. Eur J Pharmacol. 2006;530:40–47
  57. Oliveira LC, Broiz AC, de Macedo CE, Landeira-Fernandez J, Brandao ML. 5-HT2 receptor mechanisms of the dorsal periaqueductal gray in the conditioned and unconditioned fear in rats. Psychopharmacology (Berl). 2007;191:253–262
  58. Oliveira MA, Prado WA. Role of PAG in the antinociception evoked from the medial or central amygdala in rats. Brain Res Bull. 2001;54:55–63
  59. Osborne PG, O'Connor WT, Drew KL, Ungerstedt U. An in vivo microdialysis characterization of extracellular dopamine and GABA in dorsolateral striatum of awake freely moving and halothane anaesthetised rats. J Neurosci Methods. 1990;34:99–105
  60. Pare D, Quirk GJ, Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol. 2004;92:1–9
  61. Pavlovic ZW, Bodnar RJ. Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats. Brain Res. 1998;779:158–169
  62. Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods. 1985;13:139–143
  63. Pitkanen A, Savander V, LeDoux JE. Organization of intra-amygdaloid circuitries in the rat: An emerging framework for understanding functions of the amygdala. Trends Neurosci. 1997;20:517–523
  64. Porro CA, Cavazzuti M, Galetti A, Sassatelli L. Functional activity mapping of the rat brainstem during formalin-induced noxious stimulation. Neuroscience. 1991;41:667–680
  65. Quirk GJ, Likhtik E, Pelletier JG, Pare D. Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci. 2003;23:8800–8807
  66. Rakovska A, Giovannini MG, Della Corte L, Kalfin R, Bianchi L, Pepeu G. Neurotensin modulation of acetylcholine and GABA release from the rat hippocampus: An in vivo microdialysis study. Neurochem Int. 1998;33:335–340
  67. Rea K, Cremers TI, Westerink BH. HPLC conditions are critical for the detection of GABA by microdialysis. J Neurochem. 2005;94:672–679
  68. Rea K, Roche M, Finn DP. Supraspinal modulation of pain by cannabinoids: The role of GABA and glutamate. Br J Pharmacol. 2007;152:633–648
  69. Reimer AE, Oliveira AR, Brandao ML. Selective involvement of GABAergic mechanisms of the dorsal periaqueductal gray and inferior colliculus on the memory of the contextual fear as assessed by the fear potentiated startle test. Brain Res Bull. 2008;76:545–550
  70. Repa JC, Muller J, Apergis J, Desrochers TM, Zhou Y, LeDoux JE. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat Neurosci. 2001;4:724–731
  71. Resstel LB, Lisboa SF, Aguiar DC, Correa FM, Guimaraes FS. Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats. Psychopharmacology (Berl). 2008;198:405–411
  72. Rizvi TA, Ennis M, Behbehani MM, Shipley MT. Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: Topography and reciprocity. J Comp Neurol. 1991;303:121–131
  73. Roche M, O'Connor E, Diskin C, Finn DP. The effect of CB(1) receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats. Eur J Neurosci. 2007;26:2643–2653
  74. Rodriguez Manzanares PA, Isoardi NA, Carrer HF. Molina VA: Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci. 2005;25:8725–8734
  75. Royer S, Pare D. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience. 2002;115:455–462
  76. Stork O, Ji FY, Obata K. Reduction of extracellular GABA in the mouse amygdala during and following confrontation with a conditioned fear stimulus. Neurosci Lett. 2002;327:138–142
  77. Stutzmann GE, LeDoux JE: GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: A mechanism for modulation of sensory inputs related to fear conditioning. J Neurosci 19:RC8, 1999
  78. Timmerman W, Westerink BH. Brain microdialysis of GABA and glutamate: What does it signify?. Synapse. 1997;27:242–261
  79. Twillman RK. Mental disorders in chronic pain patients. J Pain Palliat Care Pharmacother. 2007;21:13–19
  80. Vaccarino AL, Clemmons HR, Mader GJ, Magnusson JE. A role of periaqueductal grey NMDA receptors in mediating formalin-induced pain in the rat. Neurosci Lett. 1997;236:117–119
  81. Van Nobelen M, Kokkinidis L. Amygdaloid GABA, not glutamate neurotransmission or mRNA transcription controls footshock-associated fear arousal in the acoustic startle paradigm. Neuroscience. 2006;137:707–716
  82. Venton BJ, Robinson TE, Kennedy RT, Maren S. Dynamic amino acid increases in the basolateral amygdala during acquisition and expression of conditioned fear. Eur J Neurosci. 2006;23:3391–3398
  83. Vianna DM, Brandao ML. Anatomical connections of the periaqueductal gray: Specific neural substrates for different kinds of fear. Braz J Med Biol Res. 2003;36:557–566
  84. Vianna DM, Graeff FG, Brandao ML, Landeira-Fernandez J. Defensive freezing evoked by electrical stimulation of the periaqueductal gray: Comparison between dorsolateral and ventrolateral regions. Neuroreport. 2001;12:4109–4112
  85. Vianna DM, Graeff FG, Landeira-Fernandez J, Brandao ML. Lesion of the ventral periaqueductal gray reduces conditioned fear but does not change freezing induced by stimulation of the dorsal periaqueductal gray. Learn Mem. 2001;8:164–169
  86. Vianna DM, Landeira-Fernandez J, Brandao ML. Dorsolateral and ventral regions of the periaqueductal gray matter are involved in distinct types of fear. Neurosci Biobehav Rev. 2001;25:711–719
  87. Walker DL, Cassella JV, Lee Y, De Lima TC, Davis M. Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle. Neurosci Biobehav Rev. 1997;21:743–753
  88. Watkins LR, Wiertelak EP, Maier SF. The amygdala is necessary for the expression of conditioned but not unconditioned analgesia. Behav Neurosci. 1993;107:402–405
  89. Watson GS, Sufka KJ, Coderre TJ. Optimal scoring strategies and weights for the formalin test in rats. Pain. 1997;70:53–58
  90. Zanoveli JM, Ferreira-Netto C, Brandao ML. Conditioned place aversion organized in the dorsal periaqueductal gray recruits the laterodorsal nucleus of the thalamus and the basolateral amygdala. Exp Neurol. 2007;208:127–136

 This work was supported by a research grant from Science Foundation Ireland.

PII: S1526-5900(09)00636-1

doi: 10.1016/j.jpain.2009.04.019

The Journal of Pain
Volume 10, Issue 10 , Pages 1088-1098 , October 2009