title: Descending pain modulation and chronification of pain.
abstract: OBJECTIVE
  Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain 'chronification'. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition.
  
  
  RESULTS
  Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual.
  
  
  CONCLUSIONS
  Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain 'chronification'. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Kozo
authors.initials: K
authors.lastname: Morimura
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D059350:Chronic Pain / Q000503:physiopathology / Q000523:psychology; D004644:Emotions / Q000502:physiology; D006801:Humans; D009042:Motivation / Q000502:physiology; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000503:physiopathology* / Q000523:psychology*; D011788:Quality of Life; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism; D013131:Spine / Q000378:metabolism
chemical_list: D012701:Serotonin
references.citation: Prog Neurobiol. 2013 May;104:93-105
references.pmid: 23499729
references.citation: Ann Neurol. 2013 Aug;74(2):257-65
references.pmid: 23686557
references.citation: Lancet. 2012 Feb 4;379(9814):482-91
references.pmid: 21982256
references.citation: Neuroscience. 2010 Dec 29;171(4):1341-56
references.pmid: 20888891
references.citation: Pain. 2008 Nov 15;140(1):209-223
references.pmid: 18809257
references.citation: J Neurosci. 2006 Jan 4;26(1):126-37
references.pmid: 16399679
references.citation: Pain Med. 2013 Nov;14(11):1757-68
references.pmid: 23924369
references.citation: J Pain. 2008 Oct;9(10):883-91
references.pmid: 18602869
references.citation: Br J Cancer. 2012 Oct 23;107(9):1459-66
references.pmid: 23093294
references.citation: Prog Neurobiol. 2013 Oct;109:1-27
references.pmid: 23827972
references.citation: Neuroscience. 1999;91(3):979-90
references.pmid: 10391476
references.citation: J Neurosci. 2010 Jun 23;30(25):8624-36
references.pmid: 20573908
references.citation: Maturitas. 2013 Aug;75(4):335-40
references.pmid: 23742873
references.citation: J Neurosci. 2003 Sep 10;23(23):8370-9
references.pmid: 12967999
references.citation: Pain. 1979 Jun;6(3):305-327
references.pmid: 460936
references.citation: Pain. 2013 Sep;154(9):1680-1690
references.pmid: 23707289
references.citation: Nat Neurosci. 2012 Jul 01;15(8):1117-9
references.pmid: 22751038
references.citation: Science. 1969 Apr 25;164(3878):444-5
references.pmid: 4887743
references.citation: Hernia. 2013 Jun;17(3):293-7
references.pmid: 23686405
references.citation: Neurosurgery. 1977 Sep-Oct;1(2):199-202
references.pmid: 308192
references.citation: Pain Res Manag. 2012 Mar-Apr;17(2):98-102
references.pmid: 22518372
references.citation: Neuroscience. 2007 Jul 13;147(3):786-93
references.pmid: 17570596
references.citation: Pain Med. 2008 Mar;9(2):166-74
references.pmid: 18298699
references.citation: J Neurosci. 2002 Jun 15;22(12):5129-36
references.pmid: 12077208
references.citation: J Neurophysiol. 2006 Dec;96(6):3465-73
references.pmid: 17005613
references.citation: Sleep Med Rev. 2003 Apr;7(2):145-54
references.pmid: 12628215
references.citation: Anesth Analg. 1998 Sep;87(3):591-6
references.pmid: 9728835
references.citation: Nihon Igaku Hoshasen Gakkai Zasshi. 2002 Dec;62(14):834-5
references.pmid: 12607953
references.citation: Nat Neurosci. 2014 Feb;17(2):192-200
references.pmid: 24473267
references.citation: Brain Res. 1998 Jan 1;779(1-2):104-18
references.pmid: 9473612
references.citation: Pain. 2002 Nov;100(1-2):1-6
references.pmid: 12435453
references.citation: Exp Physiol. 2002 Mar;87(2):267-74
references.pmid: 11856973
references.citation: Clin Exp Rheumatol. 2010 Nov-Dec;28(6 Suppl 63):S110-6
references.pmid: 21176430
references.citation: Gastroenterology. 2006 Sep;131(3):900-10
references.pmid: 16952558
references.citation: Brain Res Rev. 2009 Apr;60(1):214-25
references.pmid: 19146877
references.citation: Sci Sin. 1964 Jul;13:1099-109
references.pmid: 14196479
references.citation: Pain. 2010 Mar;148(3):359-360
references.pmid: 20080346
references.citation: Brain Res. 1997 Mar 28;752(1-2):239-49
references.pmid: 9106463
references.citation: Brain Res. 2003 Apr 25;970(1-2):110-8
references.pmid: 12706252
references.citation: Lancet. 2006 May 13;367(9522):1618-25
references.pmid: 16698416
references.citation: J Physiol. 2010 Nov 1;588(Pt 21):4177-88
references.pmid: 20837643
references.citation: PLoS One. 2012;7(4):e35293
references.pmid: 22558137
references.citation: Pain. 2011 Dec;152(12):2701-2709
references.pmid: 21745713
references.citation: Br J Pharmacol. 2012 Jun;166(3):1047-57
references.pmid: 22188400
references.citation: Pain. 2010 Jun;149(3):573-581
references.pmid: 20418016
references.citation: Nat Rev Neurosci. 2008 Apr;9(4):314-20
references.pmid: 18354400
references.citation: Nat Rev Neurosci. 2013 Jul;14(7):502-11
references.pmid: 23719569
references.citation: Brain Res Brain Res Rev. 2004 Nov;46(3):295-309
references.pmid: 15571771
references.citation: J Pharmacol Exp Ther. 2002 Jan;300(1):282-90
references.pmid: 11752127
references.citation: J Neurosci. 1997 May 1;17(9):3285-92
references.pmid: 9096161
references.citation: Pain. 1977 Oct;4(1):23-40
references.pmid: 927879
references.citation: Curr Pain Headache Rep. 2013 Sep;17(9):361
references.pmid: 23943407
references.citation: Science. 2002 Mar 1;295(5560):1737-40
references.pmid: 11834781
references.citation: Pain. 1995 Jun;61(3):391-399
references.pmid: 7478682
references.citation: Trends Pharmacol Sci. 2004 Dec;25(12):613-7
references.pmid: 15530638
references.citation: Prog Neurobiol. 2006 Oct;80(2):53-83
references.pmid: 17030082
references.citation: Pain. 2012 Dec;153(12):2309-2310
references.pmid: 23059053
references.citation: J Neurosci. 2004 Nov 17;24(46):10410-5
references.pmid: 15548656
references.citation: J Pain. 2010 Nov;11(11):1230-9
references.pmid: 20797916
references.citation: J Neurosurg. 1977 Aug;47(2):178-83
references.pmid: 327030
references.citation: Nat Commun. 2013;4:1979
references.pmid: 23752667
references.citation: Curr Pain Headache Rep. 2006 Feb;10(1):34-8
references.pmid: 16499828
references.citation: Expert Opin Pharmacother. 2012 Jul;13(10):1437-49
references.pmid: 22698264
references.citation: Anesthesiology. 1990 Dec;73(6):1227-35
references.pmid: 1978990
references.citation: J Pharmacol Exp Ther. 1990 Dec;255(3):1107-16
references.pmid: 2262895
references.citation: PLoS One. 2013;8(2):e55460
references.pmid: 23405154
references.citation: Rambam Maimonides Med J. 2013 Oct 29;4(4):e0024
references.pmid: 24228167
references.citation: Pancreatology. 2010;10(6):742-51
references.pmid: 21273802
references.citation: J Neurophysiol. 1998 Nov;80(5):2244-54
references.pmid: 9819240
references.citation: Neuroscience. 2006 Jun 30;140(2):577-95
references.pmid: 16563637
references.citation: Eur J Pharmacol. 1999 Jan 29;366(1):41-5
references.pmid: 10064150
references.citation: J Comp Neurol. 2012 Jun 15;520(9):1985-2001
references.pmid: 22173709
references.citation: J Pain. 2011 Jul;12(7):725-46
references.pmid: 21435953
references.citation: Ann N Y Acad Sci. 2013 Apr;1282:1-11
references.pmid: 23496247
references.citation: Pain. 2000 Dec 15;89(1):81-88
references.pmid: 11113296
references.citation: J Neurosci. 2006 Feb 8;26(6):1787-94
references.pmid: 16467527
references.citation: Psychosom Med. 2008 Oct;70(8):890-7
references.pmid: 18799425
references.citation: Pain. 2008 Nov 30;140(2):376-386
references.pmid: 18926635
references.citation: Pain. 1999 Aug;Suppl 6:S61-S69
references.pmid: 10491974
references.citation: Pain Med. 2008 Oct;9(7):803-12
references.pmid: 18346058
references.citation: Nat Neurosci. 2009 Nov;12(11):1364-6
references.pmid: 19783992
references.citation: Neurotherapeutics. 2009 Oct;6(4):703-12
references.pmid: 19789074
references.citation: Br J Anaesth. 2013 Jul;111(1):13-8
references.pmid: 23794640
references.citation: J Neurosci. 2008 Nov 5;28(45):11642-9
references.pmid: 18987200
references.citation: Brain Res. 2009 Jul 14;1280:52-9
references.pmid: 19427839
references.citation: Pain. 1978 Apr;4(4):299-359
references.pmid: 25403
references.citation: Eur J Pain. 2005 Aug;9(4):463-84
references.pmid: 15979027
references.citation: Brain. 2013 Sep;136(Pt 9):2751-68
references.pmid: 23983029
references.citation: Nat Med. 2010 Nov;16(11):1277-83
references.pmid: 20948533
references.citation: J Pain. 2013 Oct;14(10):1185-95
references.pmid: 23890847
references.citation: Brain Res. 1977 Mar 25;124(2):283-303
references.pmid: 191150
references.citation: Pain Pract. 2015 Feb;15(2):98-106
references.pmid: 24528544
references.citation: N Engl J Med. 2013 Apr 11;368(15):1388-97
references.pmid: 23574118
references.citation: Eur J Neurosci. 2007 Jun;25(12):3576-82
references.pmid: 17610577
references.citation: Diabetes Care. 2011 Oct;34(10):2220-4
references.pmid: 21852677
references.citation: Vasc Health Risk Manag. 2007;3(6):833-44
references.pmid: 18200804
references.citation: Biol Res Nurs. 2014 Oct;16(4):368-77
references.pmid: 24463504
references.citation: Pain. 2006 May;122(1-2):130-6
references.pmid: 16527395
references.citation: Curr Psychiatry Rep. 2008 Aug;10(4):318-22
references.pmid: 18627670
references.citation: Exp Physiol. 2002 Mar;87(2):251-8
references.pmid: 11856971
references.citation: Pain Med. 2007 Sep;8 Suppl 2:S63-74
references.pmid: 17714117
references.citation: Pain. 2009 Feb;141(3):239-247
references.pmid: 19118950
references.citation: Brain. 2009 Mar;132(Pt 3):778-87
references.pmid: 19050032
references.citation: Neuroscience. 1998 Apr;83(3):929-47
references.pmid: 9483575
references.citation: Science. 1977 Jul 8;197(4299):183-6
references.pmid: 301658
references.citation: Physiology (Bethesda). 2008 Dec;23:371-80
references.pmid: 19074744
references.citation: Transfusion. 2000 Sep;40(9):1036-40
references.pmid: 10988302
references.citation: Discov Med. 2011 Mar;11(58):197-207
references.pmid: 21447279
references.citation: Neuron. 2010 Apr 15;66(1):149-60
references.pmid: 20399736
references.citation: Mol Pain. 2009 Aug 07;5:45
references.pmid: 19664204
references.citation: J Pain. 2013 Sep;14(9):921-30
references.pmid: 23685184
references.citation: Eur J Pharmacol. 2008 Sep 11;592(1-3):62-6
references.pmid: 18625215
references.citation: Pain. 2010 Sep;150(3):573-581
references.pmid: 20705215
references.citation: J Comp Neurol. 1999 Mar 15;405(3):359-79
references.pmid: 10076931
references.citation: Anesthesiology. 2010 Mar;112(3):514-5
references.pmid: 20124977
references.citation: Brain Res. 1979 Jul 6;170(1):85-93
references.pmid: 223721
references.citation: Neuron. 2009 Aug 27;63(4):533-43
references.pmid: 19709634
references.citation: Exp Neurol. 1977 Dec;57(3):934-55
references.pmid: 923683
references.citation: J Neurosci. 2009 Dec 16;29(50):15828-35
references.pmid: 20016098