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Stress and pain: modality-specific opioid mediation of stress-induced analgesia

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Preclinical research has demonstrated that exposure to acute stress is associated with attenuated pain perception, so called stress-induced analgesia (SIA). Mechanisms of SIA in humans have not been reliably demonstrated. This study examined the role of the endogenous opioid system in the impact of combined interpersonal and mental stressors on evoked pain responses in 84 participants (34 women). Using a within-subject, double-blinded, counterbalanced design, participants were administered either oral placebo or the opioid antagonist naltrexone (50 mg) across two testing sessions. In each session, they experienced two evoked pain stimuli (cold pressor test [CPT], heat pain) after an extended rest period (rest condition) and after exposure to an acute stressor (a combination of public speaking and mental arithmetic challenge; stress condition). Results showed that both stress and opioid blockade produced significant changes in hormonal and cardiovascular measures, consistent with successful induction of acute stress. Stress was associated with attenuated pain perception (SIA) as indicated by significantly increased CPT tolerance. These effects were particularly pronounced in individuals experiencing the stress condition first. More importantly, SIA effects on CPT tolerance were abolished by opioid blockade. There were no significant SIA effects on heat pain responses. This study demonstrates that the endogenous opioid system may mediate effects of acute stress on pain perception, although this effect seems to be qualified by the type of evoked pain stimuli experienced.

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References

  • Ahmad AH, Zakaria R (2015) Pain in times of stress. Malays J Med Sci 22:52–61

    PubMed  PubMed Central  Google Scholar 

  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255

    Article  CAS  PubMed  Google Scholar 

  • al’Absi M, Petersen KL (2003) Blood pressure but not cortisol mediates stress effects on subsequent pain perception in healthy men and women. Pain 106:285–295

    Article  PubMed  CAS  Google Scholar 

  • al’Absi M, Rokke PD (1991) Can anxiety help us tolerate pain? Pain 46:43–51

    Article  Google Scholar 

  • al’Absi M, Bongard S, Buchanan T, Pincomb G, Licinio J, Lovallo WR (1997a) Neuroendocrine and hemodynamic responses to extended mental and interpersonal stressors. Psychophysiology 34:266–275

    PubMed  Google Scholar 

  • al’Absi M, Bongard S, Buchanan T, Pincomb GA, Licinio J, Lovallo WR (1997b) Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Psychophysiology 34:266–275

    Article  PubMed  Google Scholar 

  • al’Absi M, Petersen KL, Wittmers LE (2002) Adrenocortical and hemodynamic predictors of pain perception in men and women. Pain 96:197–204

    Article  PubMed  Google Scholar 

  • al’Absi M, Wittmers LE, Erickson J, Hatsukami D, Crouse B (2003) Attenuated adrenocortical and blood pressure responses to psychological stress in ad libitum and abstinent smokers. Pharmacol Biochem Behav 74:401–410

    Article  PubMed  Google Scholar 

  • al’Absi M, Wittmers LE, Ellestad D, Nordehn G, Kim SW, Kirschbaum C, Grant JE (2004) Sex differences in pain and hypothalamic-pituitary-adrenocortical responses to opioid blockade. Psychosom Med 66:198–206

    Article  PubMed  CAS  Google Scholar 

  • al’Absi M, France CR, Ring C, France J, Harju A, McIntyre D, Wittmers LE (2005) Nociception and baroreceptor stimulation in hypertension-prone men and women. Psychophysiology 42:83–91

    Article  PubMed  Google Scholar 

  • al’Absi M, France C, Harju A, France J, Wittmers L (2006) Adrenocortical and nociceptive responses to opioid blockade in hypertension-prone men and women. Psychosom Med 68:292–298

    Article  PubMed  CAS  Google Scholar 

  • al’Absi M, Nakajima M, Grabowski J (2013) Stress response dysregulation and stress-induced analgesia in nicotine dependent men and women. Biol Psychol 93:1–8

    Article  PubMed  Google Scholar 

  • Angrilli A, Mini A, Mucha RF, Rau H (1997) The influence of low blood pressure and baroreceptor activity on pain responses. Physiol Behav 62:391–397

    Article  CAS  PubMed  Google Scholar 

  • Bandura A, Cioffi D, Taylor CB, Brouillard ME (1988) Perceived self-efficacy in coping with cognitive stressors and opioid activation. J Pers Soc Psychol 55:479–488

    Article  CAS  PubMed  Google Scholar 

  • Bansevicius D, Westgaard RH, Jensen C (1997) Mental stress of long duration: EMG activity, perceived tension, fatigue, and pain development in pain-free subjects. Headache 37:499–510

    Article  CAS  PubMed  Google Scholar 

  • Benarroch EE (2012) Periaqueductal gray: an interface for behavioral control. Neurology 78:210–217

    Article  PubMed  Google Scholar 

  • Bruehl S, Chung OY (2004) Interactions between the cardiovascular and pain regulatory systems: an updated review of mechanisms and possible alterations in chronic pain. Neurosci Biobehav Rev 28:395–414

    Article  PubMed  Google Scholar 

  • Bruehl S, Chung OY, Ward P, Johnson B, McCubbin JA (2002) The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade. Pain 100:191–201

    Article  CAS  PubMed  Google Scholar 

  • Bruehl S, al’Absi M, France CR, France J, Harju A, Burns JW, Chung OY (2007) Anger management style and endogenous opioid function: is gender a moderator? J Behav Med 30:209–219

    Article  PubMed  Google Scholar 

  • Bruehl S, Chung OY, Diedrich L, Diedrich A, Robertson D (2008) The relationship between resting blood pressure and acute pain sensitivity: effects of chronic pain and alpha-2 adrenergic blockade. J Behav Med 31:71–80

    Article  PubMed  Google Scholar 

  • Bruehl S, Burns JW, Chung OY, Magid E, Chont M, Gilliam W, Matsuura J, Somar K, Goodlad JK, Stone K, Cairl H (2010) Hypoalgesia associated with elevated resting blood pressure: evidence for endogenous opioid involvement. J Behav Med 33:168–176

    Article  PubMed  Google Scholar 

  • Butler RK, Finn DP (2009) Stress-induced analgesia. Prog Neurobiol 88:184–202

    Article  CAS  PubMed  Google Scholar 

  • Caceres C, Burns JW (1997) Cardiovascular reactivity to psychological stress may enhance subsequent pain sensitivity. Pain 69:237–244

    Article  PubMed  Google Scholar 

  • Ceballos NA, France CR, al’Absi M (2007) Influence of naltrexone administration on dehydroepiandrosterone sulfate levels in male and female participants. Biol Psychol 74:414–416

    Article  PubMed  Google Scholar 

  • Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25:729–741

    Article  CAS  PubMed  Google Scholar 

  • Edwards L, McIntyre D, Carroll D, Ring C, Martin U (2002) The human nociceptive flexion reflex threshold is higher during systole than diastole. Psychophysiology 39:678–681

    Article  PubMed  Google Scholar 

  • Edwards L, McIntyre D, Carroll D, Ring C, France CR, Martin U (2003) Effects of artificial and natural baroreceptor stimulation on nociceptive responding and pain. Psychophysiology 40:762–769

    Article  PubMed  Google Scholar 

  • Edwards L, Ring C, France CR, al’Absi M, McIntyre D, Carroll D, Martin U (2007) Nociceptive flexion reflex thresholds and pain during rest and computer game play in patients with hypertension and individuals at risk for hypertension. Biol Psychol 76:72–82

    Article  PubMed  PubMed Central  Google Scholar 

  • Fechir M, Breimhorst M, Kritzmann S, Geber C, Schlereth T, Baier B, Birklein F (2012) Naloxone inhibits not only stress-induced analgesia but also sympathetic activation and baroreceptor-reflex sensitivity. Eur J Pain 16:82–92

    Article  CAS  PubMed  Google Scholar 

  • Ferdousi M, Finn DP (2018) Stress-induced modulation of pain: Role of the endogenous opioid system. Prog Brain Res 239:121–177

    Article  PubMed  Google Scholar 

  • Fillingim RB, Maixner W, Kincaid S, Silva S (1998) Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain 75:121–127

    Article  PubMed  Google Scholar 

  • Flor H, Birbaumer N, Schulz R, Grusser SM, Mucha RF (2002) Pavlovian conditioning of opioid and nonopioid pain inhibitory mechanisms in humans. Eur J Pain 6:395–402

    Article  PubMed  Google Scholar 

  • Frew AK, Drummond PD (2007) Negative affect, pain and sex: the role of endogenous opioids. Pain 132(Suppl 1):S77–S85

    Article  CAS  PubMed  Google Scholar 

  • Ghione S (1996) Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences. Hypertension 28:494–504

    Article  CAS  PubMed  Google Scholar 

  • Hargreaves KM, Mueller GP, Dubner R, Goldstein D, Dionne RA (1987) Corticotropin-releasing factor (CRF) produces analgesia in humans and rats. Brain Res 422:154–157

    Article  CAS  PubMed  Google Scholar 

  • Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112

    Article  CAS  PubMed  Google Scholar 

  • Hyson RL, Ashcraft LJ, Drugan RC, Grau JW, Maier SF (1982) Extent and control of shock affects naltrexone sensitivity of stress-induced analgesia and reactivity to morphine. Pharmacol Biochem Behav 17:1019–1025

    Article  CAS  PubMed  Google Scholar 

  • Janssen SA, Arntz A (1997) No evidence for opioid-mediated analgesia induced by phobic fear. Behav Res Ther 35:823–830

    Article  CAS  PubMed  Google Scholar 

  • Janssen SA, Arntz A (1999) No interactive effects of naltrexone and benzodiazepines on pain during phobic fear. Behav Res Ther 37:77–86

    Article  CAS  PubMed  Google Scholar 

  • Janssen SA, Spinhoven P, Brosschot JF (2001) Experimentally induced anger, cardiovascular reactivity, and pain sensitivity. J Psychosom Res 51:479–485

    Article  CAS  PubMed  Google Scholar 

  • Jungkunz G, Engel RR, King UG, Kuss HJ (1983) Endogenous opiates increase pain tolerance after stress in humans. Psychiatry Res 8:13–18

    Article  CAS  PubMed  Google Scholar 

  • King AC, Schluger J, Gunduz M, Borg L, Perret G, Ho A, Kreek MJ (2002) Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone. Preliminary examination of relationship to family history of alcoholism. Neuropsychopharmacology 26:778–788

    Article  CAS  PubMed  Google Scholar 

  • Kirschbaum C, Pirke KM, Hellhammer DH (1993) The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28:76–81

    Article  CAS  PubMed  Google Scholar 

  • Lariviere WR, Melzack R (2000) The role of corticotropin-releasing factor in pain and analgesia. Pain 84:1–12

    Article  CAS  PubMed  Google Scholar 

  • Lautenbacher S, Roscher S, Kohl G, Vedder H, Krieg J (1999) Corticotropin-releasing-hormone lacks analgesic properties: an experimental study in humans, using non-inflammatory pain. Pain 83:1–7

    Article  CAS  PubMed  Google Scholar 

  • Lundberg U (1999) Stress responses in low-status jobs and their relationship to health risks: musculoskeletal disorders. Ann N Y Acad Sci 896:162–172

    Article  CAS  PubMed  Google Scholar 

  • Maier SF (1986) Stressor controllability and stress-induced analgesia. Ann N Y Acad Sci 467:55–72

    Article  CAS  PubMed  Google Scholar 

  • Martin del Campo AF, Dowson JH, Herbert J, Paykel ES (1994) Effects of naloxone on diurnal rhythms in mood and endocrine function: a dose-response study in man. Psychopharmacology 114:583–590

    Article  CAS  PubMed  Google Scholar 

  • McCubbin JA, Wilson JF, Carlson CR, Bruehl S, Ibarra P, Norton JA, Colclough GW (1996) Relaxation training and opioid inhibition of blood pressure response to stress. Consult Clin Psychol 64:593–601

    Article  CAS  Google Scholar 

  • McCubbin JA, Bruehl S, Wilson JF, Sherman JJ, Norton JA, Colclough G (1998) Endogenous opiods inhibit ambulatory blood pressure during naturally occurring stress. Psychosom Med 60:227–231

    Article  CAS  PubMed  Google Scholar 

  • McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873–904

    Article  PubMed  Google Scholar 

  • 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 112:605–617

    Article  CAS  PubMed  Google Scholar 

  • Melzack R (1987) The short-form McGill Pain Questionnaire. Pain 30(2):191–197

    Article  PubMed  Google Scholar 

  • Miguel TT, Nunes-de-Souza RL (2011) Anxiogenic and antinociceptive effects induced by corticotropin-releasing factor (CRF) injections into the periaqueductal gray are modulated by CRF1 receptor in mice. Horm Behav 60:292–300

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474

    Article  CAS  PubMed  Google Scholar 

  • Mogil JS, Bailey AL (2010) Sex and gender differences in pain and analgesia. Prog Brain Res 186:141–157

    PubMed  Google Scholar 

  • Morris M, Salmon P, Steinberg H, Sykes EA, Bouloux P, Newbould E, McLoughlin L, Besser GM, Grossman A (1990) Endogenous opioids modulate the cardiovascular response to mental stress. Psychoneuroendocrinology 15:185–192

    Article  CAS  PubMed  Google Scholar 

  • Morrison MF, Redei E, TenHave T, Parmelee P, Boyce AA, Sinha PS, Katz IR (2000) Dehydroepiandrosterone sulfate and psychiatric measures in a frail, elderly residential care population. Biol Psychiatry 47:144–150

    Article  CAS  PubMed  Google Scholar 

  • Mousa SA, Bopaiah CP, Richter JF, Yamdeu RS, Schäfer M (2007) Inhibition of inflammatory pain by CRF at peripheral, spinal and supraspinal sites: involvement of areas coexpressing CRF receptors and opioid peptides. Neuropsychopharmacology 32:2530–2542

    Article  CAS  PubMed  Google Scholar 

  • Nilsen KB, Westgaard RH, Stovner LJ, Helde G, Rø M, Sand TH (2006) Pain induced by low-grade stress in patients with fibromyalgia and chronic shoulder/neck pain, relation to surface electromyography. Eur J Pain 10:615–627

    Article  CAS  PubMed  Google Scholar 

  • Olsen RB, Bruehl S, Nielsen CS, Rosseland LA, Eggen AE, Stubhaug A (2013) Hypertension prevalence and diminished blood pressure-related hypoalgesia in individuals reporting chronic pain in a general population: the Tromsø study. Pain 154:257–262

    Article  PubMed  Google Scholar 

  • Ossipov MH, Dussor GO, Porreca F (2010) Central modulation of pain. J Clin Investig 120:3779–3787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parikh D, Hamid A, Friedman TC, Nguyen K, Tseng A, Marquez P, Lutfy K (2011) Stress-induced analgesia and endogenous opioid peptides: the importance of stress duration. Eur J Pharmacol 650:563–567

    Article  CAS  PubMed  Google Scholar 

  • Pitman RK, van der Kolk BA, Orr SP, Greenberg MS (1990) Naloxone-reversible analgesic response to combat-related stimuli in posttraumatic stress disorder. A pilot study. Arch Gen Psychiatry 47:541–544

    Article  CAS  PubMed  Google Scholar 

  • Rau H, Elbert T (2001) Psychophysiology of arterial baroreceptors and the etiology of hypertension. Biol Psychol 57:179–201

    Article  CAS  PubMed  Google Scholar 

  • Ring C, France CR, al’Absi M, Edwards L, McIntyre D, Carroll D, Martin U (2008) Effects of naltrexone on electrocutaneous pain in patients with hypertension compared to normotensive individuals. Biol Psychol 77:191–196

    Article  PubMed  Google Scholar 

  • Robertson LJ, Hammond GR, Drummond PD (2008) The effect of subcutaneous naloxone on experimentally induced pain. J Pain 9:79–87

    Article  CAS  PubMed  Google Scholar 

  • Ruscheweyh R, Stumpenhorst F, Knecht S, Marziniak M (2010) Comparison of the cold pressor test and contact thermode-delivered cold stimuli for the assessment of cold pain sensitivity. J Pain 11:728–736

    Article  PubMed  Google Scholar 

  • Rushen J, Schwartze N, Ladewig J, Foxcroft G (1993) Opioid modulation of the effects of repeated stress on A.C.T.H., cortisol, prolactin, and growth hormone in pigs. Physiol Behav 53:923–928

    Article  CAS  PubMed  Google Scholar 

  • Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta JK (2006) Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J Neurosci 26:5777–5785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4:141–194

    Article  CAS  PubMed  Google Scholar 

  • Theorell T, Hasselhorn HM, Vingrd E, Andersson B (2000) Interleukin 6 and cortisol in acute musculoskeletal disorders: results from a case-referent study in Sweden. Stress Med 16:27–35

    Article  Google Scholar 

  • Wand GS, Schumann H (1998) Relationship between plasma adrenocorticotropin, hypothalamic opioid tone, and plasma leptin. J Clin Endocrinol Metab 83:2138–2142

    CAS  PubMed  Google Scholar 

  • Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, McCaul ME (2008) Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology 33:653–665

    Article  CAS  PubMed  Google Scholar 

  • Werner MU, Pereira MP, Andersen LP, Dahl JB (2015) Endogenous opioid antagonism in physiological experimental pain models: a systematic review. PLoS One 10:e0125887

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Willer JC, Albe-Fessard D (1980) Electrophysiological evidence for a release of endogenous opiates in stress-induced ‘analgesia’ in man. Brain Res 198:419–426

    Article  CAS  PubMed  Google Scholar 

  • Willer JC, Ernst M (1986) Somatovegetative changes in stress-induced analgesia in man: an electrophysiological and pharmacological study. Ann N Y Acad Sci 467:256–272

    Article  CAS  PubMed  Google Scholar 

  • Willer JC, Dehen H, Cambier J (1981) Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes. Science 212:689–691

    Article  CAS  PubMed  Google Scholar 

  • Yarushkina NI, Filaretova LP (2018) The peripheral corticotropin-releasing factor (CRF)-induced analgesic effect on somatic pain sensitivity in conscious rats: involving CRF, opioid and glucocorticoid receptors. Inflammopharmacology 26:305–318

    Article  CAS  PubMed  Google Scholar 

  • Yesilyurt O, Seyrek M, Tasdemir S, Kahraman S, Deveci MS, Karakus E, Halici Z, Dogrul A (2015) The critical role of spinal 5-HT7 receptors in opioid and non-opioid type stress-induced analgesia. Eur J Pharmacol 762:402–410

    Article  CAS  PubMed  Google Scholar 

  • Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS (2002) mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 22:5100–5107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to express their appreciation to Deanna Ellestad, and Angie Harju for their assistance on data collection and management of this study.

Funding

This work was supported by grants R01DA16351 and R01DA027232 (MA), and R01AG048915 and R01DA050334 (SB) from the National Institute of Health, and an AHA-Grant-in-Aid (MA) from the American Heart Association—Minnesota.

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Authors and Affiliations

  1. Department of Family Medicine and Biobehavioral Health, University of Minnesota Medical School, 1035 University Drive, Duluth, Minneapolis, MN, 55812, USA

    Mustafa al’Absi & Motohiro Nakajima

  2. Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA

    Stephen Bruehl

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  1. Mustafa al’Absi
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  2. Motohiro Nakajima
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  3. Stephen Bruehl
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Contributions

MaA designed the study. MaA and MN were responsible for data management and analysis. MaA, MN, and SB were responsible for data interpretation, and drafting and revising of the manuscript. All authors approved the final version of manuscript.

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Correspondence to Mustafa al’Absi.

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This study was approved by the Institutional Review Board of the University of Minnesota. The procedures used in this study adhere to the principles of the Declaration of Helsinki.

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al’Absi, M., Nakajima, M. & Bruehl, S. Stress and pain: modality-specific opioid mediation of stress-induced analgesia. J Neural Transm 128, 1397–1407 (2021). https://doi.org/10.1007/s00702-021-02401-4

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