Skip to main content Accessibility help

Opioids: From Physical Pain to the Pain of Social Isolation

  • Dan J. Stein, Jack van Honk, Jonathan Ipser, Mark Solms and Jaak Panksepp...


The opioid systems play an important role in mediating both physical pain and negative affects (eg, the pain of social isolation). From an evolutionary perspective, it is not surprising that the neurocircuitry and neurochemistry of physical pain would overlap with that involved in complex social emotions. Exposure to trauma as well as a range of gene variants in the opioid system may be associated with alterations in opioid systems function, with changes in reward processing, and with vulnerability to substance abuse. A role for interventions with opioid agents in depression and anxiety disorders has been suggested.



Hide All
1.Bodnar, RJ, Hadjimarkou, MM. Endogenous opiates and behavior: 2001. Peptides. 2002;23:23072365.
2.Ribeiro, SC, Kennedy, SE, Smith, YR, Stohler, CS, Zubieta, JK. Interface of physical and emotional stress regulation through the endogenous opioid system and [mu]-opioid receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:12641280.
3.Cross, AJ, Hille, C, Slater, P. Subtraction autoradiography of opiate receptor subtypes in human brain. Brain Res. 1987;418:343348.
4.Frost, JJ, Wagner, HN, Dannals, RF, et al.Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomog. 1985;9:231236.
5.Lever, JR. PET and SPECT imaging of the opioid system: receptors, radioligands and avenues for drug discovery and development. Curr Pharm Des. 2007;13:3349.
6.Sugita, S, North, RA. Opioid actions on neurons of rat lateral amygdala in vitro. Brain Res. 1993;612:151155.
7.Wiedenmayer, CP, Barr, GA. Mu opioid receptors in the ventrolateral periaqueductal gray medíate stress-induced analgesia but not immobility in rat pups. Behav Neurosci. 2000;114:125136.
8.Liberzon, I, Zubieta, JK, Fig, LM, et receptors and limbic responses to aversive emotional stimuli. Proc Natl Acad Sci U S A. 2002;99:70847089.
9.Zubieta, JK, Dannals, RF, Frost, JJ. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry. 1999;156:842848.
10.Apkarian, AV, Bushnell, MC, Treede, RD, Zubieta, JK. Human brain mechanisms of pain perception and regulation in health and disease. Euro J Pain. 2005;9:463484.
11.Nelson, EE, Panksepp, J. Brain substrates of infant-mother attachment: contributions of opioids, oxytocin, and norepinephrine. Neurosci Biobehav Rev. 1998;22:437452.
12.MacDonald, AW, Cohen, JD, Stenger, VA, Carter, CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science. 2000;288:18351838.
13.Sawamoto, N, Honda, M, Okada, T, et al.Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci. 2000;20:74387445.
14.Rainville, P, Duncan, GH, Price, DD, Carrier, B, Bushnell, MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science. 1997;277:968971.
15.Eisenberger, NI, Lieberman, MD, Williams, KD. Does rejection hurt? An FMRI study of social exclusion. Science. 2003;302:290292.
16.Panksepp, J. Feeling the pain of social loss. Science. 2003;302:237239.
17.Schlaepfer, TE, Strain, EC, Greenberg, BD, et al.Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects. Am J Psychiatry. 1998;155:470473.
18.Leppa, M, Korvenoja, A, Carlson, S, et al.Acute opioid effects on human brain as revealed by functional magnetic resonance imaging. Neuroimage. 2006;31:661669.
19.Becerra, L, Harter, K, Gonzalez, RG, Borsook, D. Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioidnaive healthy volunteers. Anesth Analg. 2006;103:208216.
20.Petrovic, P, Kalso, E, Petersson, KM, Ingvar, M. Placebo and opioid analgesia–imaging a shared neuronal network. Science. 2002;295:17371740.
21.Shah, YB, Haynes, L, Prior, MJ, Marsden, CA, Morris, PG, Chapman, V. Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxiousevoked BOLD contrast in rats. Psychopharmacology (Berl). 2005;180:761773.
22.Wagner, KJ, Sprenger, T, Kochs, EF, Tölle, TR, Valet, M, Willoch, F. Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil. Anesthesiology. 2007;106:548556.
23.Zubieta, JK, Smith, YR, Bueller, JA, et al.Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311315.
24.Kennedy, SE, Koeppe, RA, Young, EA, Zubieta, JK. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63:11991208.
25.Herman, BH. A possible role of proopiomelanocortin peptides in self-injurious behavior. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:S109S139.
26.Liberzon, I, Taylor, SF, Phan, KL, et al.Altered central micro-opioid receptor binding after psychological trauma. Biol Psychiatry. 2007;61:10301038.
27.Ikeda, K, Ide, S, Han, W, Hayashida, M, Uhl, GR, Sora, I. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci. 2005;26:311317.
28.Somogyi, AA, Barratt, DT, Coller, JK. Pharmacogenetics of opioids. Clin Pharmacol Ther. 2007;81:429444.
29.Mayer, P, Höllt, V. Pharmacogenetics of opioid receptors and addiction. Pharmacogenet Genomics. 2006;16:17.
30.Arias, A, Feinn, R, Kranzler, HR, Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend. 2006;83:262268.
31.Max, MB, Wu, T, Atlas, SJ, Edwards, RR, Haythornthwaite, JA, Bollettino, AF. A clinical genetic method to identify mechanisms by which pain causes depression and anxiety. Mol Pain. 2006;2:14.
32.Stein, DJ, Newman, TK, Savitz, J, Ramesar, R. Warriors vs worriers: the role of COMT gene variants. CNS Spectr. 2006;11:745748.
33.Zubieta, JK, Heitzeg, MM, Smith, YR, et al.COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:12401243.
34.Panksepp, J. Why does separation distress hurt? Comment on MacDonald and Leary (2005). Psychol Bull. 2005;131:224230.
35.Panksepp, J, Panksepp, JB. The seven sins of evolutionary psychology. Evolution and Cognition. 2000;6:108131.
36.Macdonald, G, Leary, MR. Why does social exclusion hurt? The relationship between social and physical pain. Psychol Bull. 2005;131:202223.
37.Panksepp, J, Knutson, B, Burgdorf, J. The role of brain emotional systems in addictions: a neuro-evolutionary perspective and new ‘self-report’ animal model. Addiction. 2002;97:459469.
38.Nesse, RM, Berridge, KC. Psychoactive drug use in evolutionary perspective. Science. 1997;278:6366.
39.Gerald, MS, Higley, JD. Evolutionary underpinnings of excessive alcohol consumption. Addiction. 2002;97:415425.
40.Kross, E, Egner, T, Ochsner, K, Hirsch, J, Downey, G. Neural dynamics of rejection sensitivity. J Cogn Neurosci. 2007;19:945956.
41.Downey, G, Feldman, SI. Implications of rejection sensitivity for intimate relationships. J Pers Soc Psychol. 1996;70:13271343.
42.Panksepp, J. Affective Neuroscience: The Foundations of Human and Animal Emotions. New York, NY: Oxford University Press; 1998.
43.Schwartz, AC, Bradley, R, Penza, KM, et al.Pain medication use among patients with posttraumatic stress disorder. Psychosomatics. 2006;47:136142.
44.Zacny, JRMorphine responses in humans: a retrospective analysis of sex differences. Drug Alcohol Depend. 2001;63:2328.
45.Gowing, L, Ali, R, White, J. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2006;(2):CD002025.
46.Amato, L, Davoli, M, A, Perucci C, Ferri, M, Faggiano, FP, Mattick, R. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat. 2005;28:321329.
47.Boothby, LA, Doering, PL. Buprenorphine for the treatment of opioid dependence. Am J Health Syst Pharm. 2007;64:266272.
48.Amato, L, Minozzi, S, Davoli, M, Vecchi, S, Ferri, M, Mayet, S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2004;(4):CD005031.
49.Amato, L, Minozzi, S, Davoli, M, Vecchi, S, Ferri, M, Mayet, S. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst Rev. 2004;(4):CD004147.
50.Grant, JE, Kim, SW. Medication management of pathological gambling. Minn Med. 2006;89:4448.
51.Srisurapanont, M, Jarusuraisin, N. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2005;(1):CD001867.
52.Elchaar, GM, Maisch, NM, Augusto, LM, Wehring, HJ. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother. 2006;40:10861095.
53.Symons, FJ, Thompson, A, Rodriquez, MC. Self-injurious behavior and the efficacy of naltrexone treatment: a quantitative synthesis. Ment Retard Dev Disabil Res Rev. 2004;10:193200.
54.Kosten, TR, Morgan, C, Kosten, TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7:5154.
55.Gerra, G, Leonardi, C, D'Amore, A, et al.Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: a retrospective study. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:265272.
56.Emrich, HM, Vogt, P, Herz, A. Possible antidepressive effects of opioids: action of buprenorphine. Ann N Y Acad Sci. 1982;398:108112.
57.Bodkin, JA, Zornberg, GL, Lukas, SE, Cole, JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:4957.
58.Saxe, G, Geary, M, Bedard, K, et al.Separation anxiety as a mediator between acute morphine administration and PTSD symptoms in injured children. Ann N Y Acad Sci. 2006;1071:4145.
59.Bohus, MJ, Landwehrmeyer, GB, Stiglmayr, CE, Limberger, MF, Böhme, R, Schmahl, CG. Naltrexone in the treatment of dissociative symptoms in patients with borderline personality disorder: an open-label trial. J Clin Psychiatry. 1999;60:598603.
60.Glover, H. A preliminary trial of nalmefene for the treatment of emotional numbing in combat veterans with post-traumatic stress disorder. Isr J Psychiatry Relat Sci. 1993;30:255263.
61.Lubin, G, Weizman, A, Shmushkevitz, M, Valevski, A. Short-term treatment of posttraumatic stress disorder with naltrexone: an open-label preliminary study. Hum Psychopharmacol. 2002;17:181185.
62.Koran, LM, Aboujaoude, E, Bullock, KD, Franz, B, Gamel, N, Elliott, M. Double-blind treatment with oral morphine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2005;66:353359.
63.Panksepp, J. Brain opioids: a neurochemical substrate for narcotic and social dependence. In: Cooper, SJ, ed. Progress in Theory in Psychopharmacology. London, England: Academic Press; 1981:149175.
64.Panksepp, J, Herman, BH, Vilberg, T, Bishop, P, DeEskinazi, FG. Endogenous opioids and social behavior. Neurosci Biobehav Revs. 1980;4:473487.


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed