![[PDF]](/pb-assets/Icons/adobe-pdf-icon-1498649896243.png){kind=icon}
Abstract
A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the “nociceptive amygdala” and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.
Keywords Pain, Nociception, Emotion, Affect, Plasticity, Amygdala
| Aggleton JP . 2000. The amygdala: a functional analysis. 2nd ed. Oxford: Oxford University Press. Google Scholar | |
| Augustine JR . 1996. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 22:229-244. Google Scholar, Crossref, Medline | |
| Basbaum AI . 1999. Distinct neurochemical features of acute and persistent pain. Proc Natl Acad Sci U S A 96:7739-7743. Google Scholar, Crossref, Medline, ISI | |
| Becerra LR , Breiter HC , Stojanovic M , Fishman S , Edwards A , Comite AR , and others . 1999. Human brain activation under controlled thermal stimulation and habituation of noxious heat: an fMRI study. Mag Reson Med 41:1044-1057. Google Scholar, Crossref, Medline, ISI | |
| Bernard J-F , Bester H , Besson JM . 1996. Involvement of the spino-parabrachio-amygdaloid and -hypothalamic pathways in the autonomic and affective emotional aspects of pain. Prog Brain Res 107:243-255. Google Scholar, Crossref, Medline, ISI | |
| Bernard J-F , Huang GF , Besson JM . 1992. Nucleus centralis of the amygdala and the globus pallidus ventralis: electrophysiological evidence for an involvement in pain processes. J Neurophysiol 68:551-569. Google Scholar, Medline, ISI | |
| Besson JM . 1999. The neurobiology of pain. Lancet 353:1610-1615. Google Scholar, Crossref, Medline, ISI | |
| Bingel U , Quante M , Knab R , Bromm B , Weiller C , Buchel C. 2002. Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 99:313-321. Google Scholar, Crossref, Medline, ISI | |
| Blood AJ , Zatorre RJ . 2001. Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci U S A 98:11818-11823. Google Scholar, Crossref, Medline, ISI | |
| Bonaz B , Baciu M , Papillon E , Bost R , Gueddah N , Le Bas JF , and others . 2002. Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol 97:654-661. Google Scholar, Crossref, Medline, ISI | |
| Bornhovd K , Quante M , Glauche V , Bromm B , Weiller C , Buchel C. 2002. Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain 125:1326-1336. Google Scholar, Crossref, Medline, ISI | |
| Borszcz GS . 1999. Differential contributions of medullary, thalamic, and amygdaloid serotonin to the antinociceptive action of morphine administered into the periaqueductal gray: a model of morphine analgesia. Behav Neurosci 113:612-631. Google Scholar, Crossref, Medline, ISI | |
| 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 14:229-255. Google Scholar, Crossref, Medline, ISI | |
| Burstein R , Potrebic S. 1993. Retrograde labeling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat. J Comp Neurol 335:469-485. Google Scholar, Crossref, Medline, ISI | |
| Calvino B , Levesque G , Besson JM . 1982. Possible involvement of the amygdaloid complex in morphine analgesia as studied by electrolytic lesions in rats. Brain Res 233:221-226. Google Scholar, Crossref, Medline, ISI | |
| Cardinal RN , Parkinson JA , Hall J , Everitt BJ . 2002. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26:321-352. Google Scholar, Crossref, Medline, ISI | |
| Charpentier J. 1967. Modifications de la réaction à la douleur provoquées par diverses lésions cérébrales, et leurs effets sur la sensibilitè á la morphine. Psychopharmacologia 11:95-121. Google Scholar, Crossref, Medline | |
| Crown ED , King TE , Meagher MW , Grau JW . 2000. Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei. Behav Neurosci 114:561-573. Google Scholar, Crossref, Medline, ISI | |
| Da Costa Gomez TM , Behbehani MM . 1995. An electrophysiological characterization of the projection from the central nucleus of the amygdala to the periaqueductal gray of the rat: the role of opioid receptors. Brain Res 689:21-31. Google Scholar, Crossref, Medline, ISI | |
| Davidson RJ . 2002. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 51:68-80. Google Scholar, Crossref, Medline, ISI | |
| Davis KD . 2003. Neurophysiological and anatomical considerations in functional imaging of pain. Pain 105:1-3. Google Scholar, Crossref, Medline, ISI | |
| Davis M. 1998. Anatomic and physiologic substrates of emotion in an animal model. J Clin Neurophysiol 15:378-387. Google Scholar, Crossref, Medline, ISI | |
| Derbyshire SWG , Jones AKP , Gyulai F , Clark S , Townsend D , Firestone LL . 1997. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 73:431-445. Google Scholar, Crossref, Medline, ISI | |
| Dubner R , Gold M. 1999. The neurobiology of pain. Proc Natl Acad Sci U S A 96:7627-7630. Google Scholar, Crossref, Medline, ISI | |
| Fields HL . 2000. Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 122:245-253. Google Scholar, Crossref, Medline, ISI | |
| Fields HL , Basbaum AI . 1999. Central nervous system mechanisms of pain modulation. In: Wall PD , Melzack R , editors. Textbook of pain. London: Churchill Livingstone. p 309-329. Google Scholar | |
| Fox RJ , Sorenson CA . 1994. Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res 648:215-221. Google Scholar, Crossref, Medline, ISI | |
| Gallagher M , Schoenbaum G. 1999. Functions of the amygdala and related forebrain areas in attention and cognition. Ann N Y Acad Sci 877:397-411. Google Scholar, Crossref, Medline, ISI | |
| Gauriau C , Bernard J-F. 2002. Pain pathways and parabrachial circuits in the rat. Exp Physiol 87:251-258. Google Scholar, Crossref, Medline, ISI | |
| Greenwood-Van Meerveld B , Gibson M , Gunder W , Shepard J , Foreman R , Myers D. 2001. Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats. Brain Res 893:135-142. Google Scholar, Crossref, Medline, ISI | |
| Haythornthwaite JA , Sieber WJ , Kerns RD . 1991. Depression and the chronic pain experience. Pain 46:177-184. Google Scholar, Crossref, Medline, ISI | |
| Heinricher MM , McGaraughty S. 1999. Pain-modulating neurons and behavioral state. In: Lydic R , Baghdoyan HA , editors. Handbook of behavioral state control. New York: CRC Press. p 487-503. Google Scholar | |
| Helmstetter FJ . 1992. The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci 106:518-528. Google Scholar, Crossref, Medline, ISI | |
| Helmstetter FJ , Bellgowan PS . 1993. Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res 612:253-257. Google Scholar, Crossref, Medline, ISI | |
| Helmstetter FJ , Tershner SA , Poore LH , Bellgowan PSF . 1998. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res 779:104-118. Google Scholar, Crossref, Medline, ISI | |
| Henry JL , Yashpal K , Pitcher GM , Coderre TJ . 1999. Physiological evidence that the “interphase” in the formalin test is due to active inhibition. Pain 82:57-63. Google Scholar, Crossref, Medline, ISI | |
| Huyser BA , Parker JC . 1999. Negative affect and pain in arthritis. Rheum Dis Clin North Am 25:105-121. Google Scholar, Crossref, Medline, ISI | |
| Jurgens U. 1982. Amygdalar vocalization pathways in the squirrel monkey. Brain Res 241:189-196. Google Scholar, Crossref, Medline, ISI | |
| Jurgens U , Maurus M , Ploog D , Winter P. 1967. Vocalization in the squirrel monkey (Saimiri sciureus) elicited by brain stimulation. Exp Brain Res 4:114-117. Google Scholar, Crossref, Medline, ISI | |
| LeDoux JE . 2000. Emotion circuits in the brain. Annu Rev Neurosci 23:155-184. Google Scholar, Crossref, Medline, ISI | |
| Li W , Neugebauer V. 2003. Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in the amygdala. J Neurophysiol (in press). Google Scholar, Crossref, ISI | |
| Maier SF , Grahn RE , Kalman BA , Sutton LC , Wiertelak EP , Watkins LR . 1993. The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock. Behav Neurosci 107:377-388. Google Scholar, Crossref, Medline, ISI | |
| Manning BH . 1998. A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J Neurosci 18:9453-9470. Google Scholar, Medline, ISI | |
| Manning BH , Martin WJ , Meng ID . 2003. The rodent amygdala contributes to the production of cannabinoid-induced antinociception. Neuroscience 120:1157-1170. Google Scholar, Crossref, Medline, ISI | |
| Manning BH , Mayer DJ . 1995a. The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test. Pain 63:141-152. Google Scholar, Crossref, Medline, ISI | |
| 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 15:8199-8213. Google Scholar, Medline, ISI | |
| Maren S. 1999. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci 22:561-567. Google Scholar, Crossref, Medline, ISI | |
| McKernan MG , Shinnick-Gallagher P. 1997. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390:607-611. Google Scholar, Crossref, Medline, ISI | |
| McWilliams LA , Cox BJ , Enns MW . 2003. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain 106:127-133. Google Scholar, Crossref, Medline, ISI | |
| Meagher MW , Arnau RC , Rhudy JL . 2001. Pain and emotion: effects of affective picture modulation. Psychosom Med 63:79-90. Google Scholar, Crossref, Medline, ISI | |
| Mena NB , Mathur R , Nayar U. 1995. Amygdalar involvement in pain. Indian J Physiol Pharmacol 39:339-346. Google Scholar, Medline | |
| Millan MJ . 1999. The induction of pain: an integrative review. Progr Neurobiol. 57:1-164. Google Scholar, Crossref, Medline, ISI | |
| Nakagawa T , Katsuya A , Tanimoto S , Yamamoto J , Yamauchi Y , Minami M , and others . 2003. Differential patterns of c-fos mRNA expression in the amygdaloid nuclei induced by chemical somatic and visceral noxious stimuli in rats. Neurosci Lett 344:197-200. Google Scholar, Crossref, Medline, ISI | |
| Naliboff BD , Berman S , Chang L , Derbyshire SWG , Suyenobu B , Vogt BA , and others . 2003. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 124:1738-1747. Google Scholar, Crossref, Medline, ISI | |
| National Institutes of Health . 2001. NIH guide, management of chronic pain. PA-01-115. Bethesda (MD): National Institutes of Health. Google Scholar | |
| Neugebauer V. 2002. Metabotropic glutamate receptors—important modulators of nociception and pain behavior. Pain 98:1-8. Google Scholar, Crossref, Medline, ISI | |
| Neugebauer V , Keele NB , Shinnick-Gallagher P. 1997. Epileptogenesis in vivo enhances the sensitivity of inhibitory presynaptic metabotropic glutamate receptors in basolateral amygdala neurons in vitro. J Neurosci 17:983-995. Google Scholar, Medline, ISI | |
| Neugebauer V , Li W. 2002. Processing of nociceptive mechanical and thermal information in central amygdala neurons with knee-joint input. J Neurophysiol 87:103-112. Google Scholar, Crossref, Medline, ISI | |
| Neugebauer V , Li W. 2003. Differential sensitization of amygdala neurons to afferent inputs in a model of arthritic pain. J Neurophysiol 89:716-727. Google Scholar, Crossref, Medline, ISI | |
| 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 23:52-63. Google Scholar, Medline, ISI | |
| 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 84:759-770. Google Scholar, Medline, ISI | |
| Paulson PE , Casey KL , Morrow TJ . 2002. Long-term changes in behavior and regional cerebral blood flow associated with painful peripheral mononeuropathy in the rat. Pain 95:31-40. Google Scholar, Crossref, Medline, ISI | |
| Pavlovic ZW , Bodnar RJ . 1998. Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats. Brain Res 779:158-169. Google Scholar, Crossref, Medline, ISI | |
| Petrovic P , Ingvar M , Stone-Elander S , Petersson KM , Hansson P. 1999. A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 83:447-457. Google Scholar, Crossref, Medline, ISI | |
| Pitkanen A , Savander V , LeDoux JE . 1997. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 20:517-523. Google Scholar, Crossref, Medline, ISI | |
| Ploghaus A , Tracey I , Gati JS , Clare S , Menon RS , Matthews PM , and others . 1999. Dissociating pain from its anticipation in the human brain. Science 284:1979-1981. Google Scholar, Crossref, Medline, ISI | |
| Porreca F , Ossipov MH , Gebhart GF . 2002. Chronic pain and medullary descending facilitation. Trends Neurosci 25:319-325. Google Scholar, Crossref, Medline, ISI | |
| Price DD . 2000. Psychological and neural mechanisms of the affective dimension of pain. Science 288:1769-1772. Google Scholar, Crossref, Medline, ISI | |
| Price JL . 2003. Comparative aspects of amygdala connectivity. In: Shinnick-Gallagher P , Pitkanen A , Shekhar A , Cahill L , editors. The amygdala in brain function. Basic and clinical approaches. New York: New York Academy of Sciences. p 50-58. Google Scholar, Crossref | |
| Qin C , Greenwood-Van Meerveld B , Foreman RD . 2003. Spinal neuronal responses to urinary bladder stimulation in rats with corticosterone or aldosterone onto the amygdala. J Neurophysiol 90:2180-2189. Google Scholar, Crossref, Medline, ISI | |
| Qin C , Greenwood-Van Meerveld B , Myers DA , Foreman RD . 2003. Corticosterone acts directly at the amygdala to alter spinal neuronal activity in response to colorectal distension. J Neurophysiol 89:1343-1352. Google Scholar, Crossref, Medline, ISI | |
| Qin C , Meerveld BG-V , Foreman RD . 2003. Visceromotor and spinal neuronal responses to colorectal distension in rats with aldosterone onto the amygdala. J Neurophysiol 90:2-11. Google Scholar, Crossref, Medline, ISI | |
| Rhudy JL , Meagher MW . 2000. Fear and anxiety: divergent effects on human pain thresholds. Pain 84:65-75. Google Scholar, Crossref, Medline, ISI | |
| Rhudy JL , Meagher MW . 2003. Negative affect: effects on an evaluative measure of human pain. Pain 104:617-626. Google Scholar, Crossref, Medline, ISI | |
| Schaible H-G , Ebersberger A , von Banchet GS . 2002. Mechanisms of pain in arthritis. Ann N Y Acad Sci 966:343-354. Google Scholar, Crossref, Medline, ISI | |
| Schneider F , Habel U , Holthusen H , Kessler C , Posse S , Muller-Gartner HW , and others . 2001. Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study. Neuropsychobiology 43:175-185. Google Scholar, Crossref, Medline, ISI | |
| Schoepp DD , Jane DE , Monn JA . 1999. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38:1431-1476. Google Scholar, Crossref, Medline, ISI | |
| Shi C , Davis M. 1999. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J Neurosci 19:420-430. Google Scholar, Medline, ISI | |
| Stam R , Ekkelenkamp K , Frankhuijzen AC , Bruijnzeel AW , Akkermans LM , Wiegant VM . 2002. Long-lasting changes in central nervous system responsivity to colonic distention after stress in rats. Gastroenterology 123:1216-1225. Google Scholar, Crossref, Medline, ISI | |
| Stefanacci L , Amaral DG . 2000. Topographic organization of cortical inputs to the lateral nucleus of the macaque monkey amygdala: a retrograde tracing study. J Comp Neurol 421:52-79. Google Scholar, Crossref, Medline, ISI | |
| Stucky CL , Gold MS , Zhang X. 2001. Mechanisms of pain. Proc Natl Acad Sci U S A 98:11845-11846. Google Scholar, Crossref, Medline, ISI | |
| Tershner SA , Helmstetter FJ . 2000. Antinociception produced by mu opioid receptor activation in the amygdala is partly dependent on activation of mu opioid and neurotensin receptors in the ventral periaqueductal gray. Brain Res 865:17-26. Google Scholar, Crossref, Medline, ISI | |
| Traub RJ , Silva E , Gebhart GF , Solodkin A. 1996. Noxious colorectal distension induced-c-Fos protein in limbic brain structures in the rat. Neurosci Lett 215:165-168. Google Scholar, Crossref, Medline, ISI | |
| Varney MA , Gereau RW . 2002. Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Current Drug Targets 1:215-225. Google Scholar | |
| Villemure C , Slotnick BM , Bushnell MC . 2003. Effects of odors on pain perception: deciphering the roles of emotion and attention. Pain 106:101-108. Google Scholar, Crossref, Medline, ISI | |
| Wang C-C , Willis WD , Westlund KN . 1999. Ascending projections from the area around the spinal cord central canal: a Phaseolus vulgaris leucoagglutinin study in rats. J Comp Neurol 415:341-367. Google Scholar, Crossref, Medline, ISI | |
| Watkins LR , Wiertelak EP , McGorry M , Martinez J , Schwartz B , Sisk D , and others . 1998. Neurocircuitry of conditioned inhibition of analgesia: effects of amygdala, dorsal raphe, ventral medullary, and spinal cord lesions on antianalgesia in the rat. Behav Neurosci 112:360-378. Google Scholar, Crossref, Medline, ISI | |
| Werka T. 1997. The effects of the medial and cortical amygdala lesions on post-stress analgesia in rats. Behav Brain Res 86:59-65. Google Scholar, Crossref, Medline, ISI | |
| Willis WD . 2002. Long-term potentiation in spinothalamic neurons. Brain Res Rev 40:202-214. Google Scholar, Crossref, Medline | |
| Wilson KG , Mikail SF , D’Eon JL , Minns JE . 2001. Alternative diagnostic criteria for major depressive disorder in patients with chronic pain. Pain 91:227-234. Google Scholar, Crossref, Medline, ISI | |
| Wood JN , Perl ER . 1999. Pain. Curr Opin Genet Dev 9:328-332. Google Scholar, Crossref, Medline, ISI | |
| Woolf CJ , Salter MW . 2000. Neuronal plasticity: increasing the gain in pain. Science 288:1765-1769. Google Scholar, Crossref, Medline, ISI | |
| Yaksh TL , Hua XY , Kalcheva I , Nozaki-Taguchi N , Marsala M. 1999. The spinal biology in humans and animals of pain states generated by persistent small afferent input. Proc Natl Acad Sci U S A 96:7680-7686. Google Scholar, Crossref, Medline, ISI | |
| Zald DH . 2003. The human amygdala and the emotional evaluation of sensory stimuli. Brain Res Rev 41:88-123. Google Scholar, Crossref, Medline |
