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Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications

Year 2025, Volume: 42 Issue: 2, 207 - 211, 30.06.2025

Remzi Kağan Yücel , Fulya Özdemir , Hesna Ural Ulucan , Serap Hızlı Yücel

Abstract

This manuscript discusses the role of the endogenous opioid system in pain management and its potential clinical applications. The endogenous opioid system is a network of naturally produced painkillers, known as opioid peptides, and the receptors to which they bind. The main components of this system are endorphins, enkephalins, and dynorphins. Opioid receptors (mu, delta, and kappa) interact with these peptides to regulate various physiological and psychological processes, such as analgesia, euphoria, and stress responses. The article provides detailed explanations of the biosynthesis, secretion, and receptor activation mechanisms of opioid peptides. Additionally, the effects of stress, exercise, and alternative treatment methods (acupuncture, meditation) on the endogenous opioid system are discussed. In clinical applications, dysfunction of the endogenous opioid system is noted to be associated with the risk of opioid misuse in chronic pain patients. The article also presents recommendations for future research to develop more effective pain management strategies.

Keywords

Endogenous Opioid System Pain Management Opioid Peptides

References

  • Ilana E. Pain terms; a list with definitions and notes on usage. Pain. 1979;6:249.
  • Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287–333.
  • Gaskin DJ, Richard P. The economic costs of pain in the United States. J pain. 2012;13(8):715–24. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev. 2004;8(2):119–32.
  • Pizzo P, Clark NM, Carter-Pokras O, Christopher M, Farrar JT, Follett KA, et al. Relieving Pain in America: A Blueprint for Transforming Prevention, Care. Educ Res Inst Med. 2011;
  • Bodnar RJ. Endogenous opiates and behavior: 2016. Peptides. 2018;101:167–212.
  • Przewłocki R, Przewłocka B. Opioids in chronic pain. Eur J Pharmacol. 2001;429(1–3):79–91.
  • Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/κ-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69(6):857–96.
  • Pasternak GW. Mu opioid pharmacology: 40 years to the promised land. Adv Pharmacol. 2018;82:261–91.
  • Stein C. Opioid receptors. Annu Rev Med. 2016;67:433–51.
  • Zadina JE, Hackler L, Ge L-J, Kastin AJ. A potent and selective endogenous agonist for the µ-opiate receptor. Nature. 1997;386(6624):499–502.
  • Pradhan AA, Befort K, Nozaki C, Gavériaux-Ruff C, Kieffer BL. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32(10):581–90.
  • Nakanishi S, Inoue A, Kita T, Inoue A, Nakamura M, Chang ACY, et al. Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor. Nature. 1979;278(5703):423–7.
  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM. Endogenous opioids: biology and function. Annu Rev Neurosci. 1984;7(1):223–55.
  • Hökfelt T, Kellerth JO, Nilsson G, Pernow B. Substance P: localization in the central nervous system and in some primary sensory neurons. Science (80- ). 1975;190(4217):889–90.
  • Mansour A, Fox CA, Burke S, Akil H, Watson SJ. Immunohistochemical localization of the cloned μ opioid receptor in the rat CNS. J Chem Neuroanat. 1995;8(4):283–305.
  • Yaksh TL, Noueihed R. The physiology and pharmacology of spinal opiates. Annu Rev Pharmacol Toxicol. 1985;25(1):433–62.
  • Liu J-G, Anand KJS. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. Brain Res Rev. 2001;38(1–2):1–19.
  • Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. J Am Soc Anesthesiol. 2011;115(6):1363–81.
  • Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev. 2001;81(1):299–343.
  • Gutstein HB, Akil H. Opioid analgesics. Goodman Gilman’s Pharmacol basis Ther. 2006;11:547–90.
  • Bohn LM, Gainetdinov RR, Lin F-T, Lefkowitz RJ, Caron MG. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000;408(6813):720–3.
  • Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Adv Crit Care. 2005;16(3):291–301.
  • Mani AR, Moore KP. New insights into the role of endogenous opioids in the pathogenesis of gastrointestinal and liver disease. Gut. 2009;58(7):893–5.
  • Bruehl S, Burns JW, Chung OY, Quartana P. Anger management style and emotional reactivity to noxious stimuli among chronic pain patients and healthy controls: the role of endogenous opioids. Heal Psychol. 2008;27(2):204.
  • Ma Y, Luo J, Wang X-Q. The effect and mechanism of exercise for post-stroke pain. Front Mol Neurosci. 2022;15:1074205.
  • Ballester J, Baker AK, Martikainen IK, Koppelmans V, Zubieta J-K, Love TM. Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation. Transl Psychiatry. 2022;12(1):20.
  • Abou-Kassem D, Kurita GP, Sjøgren P, Diasso PDK. Long-term opioid treatment and endocrine measures in patients with cancer-related pain: a systematic review. Scand J Pain. 2022;22(3):421–35.
  • Clauw D. Hijacking the endogenous opioid system to treat pain: who thought it would be so complicated? Pain. 2017;158(12):2283–4.
  • Dworsky-Fried Z, Chadwick CI, Kerr BJ, Taylor AMW. Multiple sclerosis and the endogenous opioid system. Front Neurosci. 2021;15:741503.
  • Gersch WD, Delate T, Bergquist KM, Smith K. Clinical effectiveness of an outpatient multidisciplinary chronic pain management telementoring service. Clin J Pain. 2021;37(10):740–6.
  • Sher L. The role of the endogenous opioid system in the effects of acupuncture on mood, behavior, learning, and memory. Med Hypotheses. 1998;50(6):475–8.
  • Zhao J, Liu W. Relatıonshıp Between Acupuncture-Induced Immunıty and the Regulatıon of Central Neurotransmıtter System In Rabbıts---Iı. Effect of The Endogenous Opıoıd Peptıdes On The Regulatıon of Acupuncture-Induced Immune Reactıon. Acupunct Electrother Res. 1989;14(1):1–7.
  • Wang XJ, Wang L-L. A mechanism of endogenous opioid peptides for rapid onset of acupuncture effect in treatment of depression. Zhong xi yi jie he xue bao= J Chinese Integr Med. 2010;8(11):1014–7.
  • Sharon H, Maron-Katz A, Simon E Ben, Flusser Y, Hendler T, Tarrasch R, et al. Mindfulness meditation modulates pain through endogenous opioids. Am J Med. 2016;129(7):755–8.
  • Adler A, Wells R, Stagnaro E, Barber L, Porter A, Garcia K, et al. (551) Mindfulness meditation-induced pain relief does not require endogenous opioidergic systems. J Pain. 2016;17(4):S112.
  • Reid LD. Endogenous opioid peptides and regulation of drinking and feeding. Am J Clin Nutr. 1985;42(5):1099–132.
  • Higginbotham JA, Markovic T, Massaly N, Morón JA. Endogenous opioid systems alterations in pain and opioid use disorder. Front Syst Neurosci. 2022;16:1014768.
  • Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta J-K. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2019;24(4):576–87.
  • Muñoa I, Urizar I, Casis L, Irazusta J, Subirán N. The epigenetic regulation of the opioid system: New individualized prompt prevention and treatment strategies. J Cell Biochem. 2015;116(11):2419–26.
  • DosSantos MF, Martikainen IK, Nascimento TD, Love TM, DeBoer MD, Schambra HM, et al. Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report. PLoS One. 2014;9(7):e102350.
  • Li S-K, Liao W-D, Zhao J, Cao X-W. Effects of acupuncture on plasma endogenous opioid peptides in patients with stroke-associated headache in convalescence. Zhen ci yan jiu= Acupunct Res. 2020;45(12):995–9.
  • Maldonado R, Baños JE, Cabañero D. Usefulness of knockout mice to clarify the role of the opioid system in chronic pain. Br J Pharmacol. 2018;175(14):2791–808.
  • Shimizu S, Shiraki A. CRISPR/Cas9 unveils the dynamics of the endogenous µ‐opioid receptors on neuronal cells under continuous opioid stimulation. Pharmacol Res Perspect. 2022;10(2):e00933.

Year 2025, Volume: 42 Issue: 2, 207 - 211, 30.06.2025

Remzi Kağan Yücel , Fulya Özdemir , Hesna Ural Ulucan , Serap Hızlı Yücel

Abstract

References

  • Ilana E. Pain terms; a list with definitions and notes on usage. Pain. 1979;6:249.
  • Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287–333.
  • Gaskin DJ, Richard P. The economic costs of pain in the United States. J pain. 2012;13(8):715–24. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev. 2004;8(2):119–32.
  • Pizzo P, Clark NM, Carter-Pokras O, Christopher M, Farrar JT, Follett KA, et al. Relieving Pain in America: A Blueprint for Transforming Prevention, Care. Educ Res Inst Med. 2011;
  • Bodnar RJ. Endogenous opiates and behavior: 2016. Peptides. 2018;101:167–212.
  • Przewłocki R, Przewłocka B. Opioids in chronic pain. Eur J Pharmacol. 2001;429(1–3):79–91.
  • Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/κ-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69(6):857–96.
  • Pasternak GW. Mu opioid pharmacology: 40 years to the promised land. Adv Pharmacol. 2018;82:261–91.
  • Stein C. Opioid receptors. Annu Rev Med. 2016;67:433–51.
  • Zadina JE, Hackler L, Ge L-J, Kastin AJ. A potent and selective endogenous agonist for the µ-opiate receptor. Nature. 1997;386(6624):499–502.
  • Pradhan AA, Befort K, Nozaki C, Gavériaux-Ruff C, Kieffer BL. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32(10):581–90.
  • Nakanishi S, Inoue A, Kita T, Inoue A, Nakamura M, Chang ACY, et al. Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor. Nature. 1979;278(5703):423–7.
  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM. Endogenous opioids: biology and function. Annu Rev Neurosci. 1984;7(1):223–55.
  • Hökfelt T, Kellerth JO, Nilsson G, Pernow B. Substance P: localization in the central nervous system and in some primary sensory neurons. Science (80- ). 1975;190(4217):889–90.
  • Mansour A, Fox CA, Burke S, Akil H, Watson SJ. Immunohistochemical localization of the cloned μ opioid receptor in the rat CNS. J Chem Neuroanat. 1995;8(4):283–305.
  • Yaksh TL, Noueihed R. The physiology and pharmacology of spinal opiates. Annu Rev Pharmacol Toxicol. 1985;25(1):433–62.
  • Liu J-G, Anand KJS. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. Brain Res Rev. 2001;38(1–2):1–19.
  • Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. J Am Soc Anesthesiol. 2011;115(6):1363–81.
  • Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev. 2001;81(1):299–343.
  • Gutstein HB, Akil H. Opioid analgesics. Goodman Gilman’s Pharmacol basis Ther. 2006;11:547–90.
  • Bohn LM, Gainetdinov RR, Lin F-T, Lefkowitz RJ, Caron MG. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000;408(6813):720–3.
  • Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Adv Crit Care. 2005;16(3):291–301.
  • Mani AR, Moore KP. New insights into the role of endogenous opioids in the pathogenesis of gastrointestinal and liver disease. Gut. 2009;58(7):893–5.
  • Bruehl S, Burns JW, Chung OY, Quartana P. Anger management style and emotional reactivity to noxious stimuli among chronic pain patients and healthy controls: the role of endogenous opioids. Heal Psychol. 2008;27(2):204.
  • Ma Y, Luo J, Wang X-Q. The effect and mechanism of exercise for post-stroke pain. Front Mol Neurosci. 2022;15:1074205.
  • Ballester J, Baker AK, Martikainen IK, Koppelmans V, Zubieta J-K, Love TM. Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation. Transl Psychiatry. 2022;12(1):20.
  • Abou-Kassem D, Kurita GP, Sjøgren P, Diasso PDK. Long-term opioid treatment and endocrine measures in patients with cancer-related pain: a systematic review. Scand J Pain. 2022;22(3):421–35.
  • Clauw D. Hijacking the endogenous opioid system to treat pain: who thought it would be so complicated? Pain. 2017;158(12):2283–4.
  • Dworsky-Fried Z, Chadwick CI, Kerr BJ, Taylor AMW. Multiple sclerosis and the endogenous opioid system. Front Neurosci. 2021;15:741503.
  • Gersch WD, Delate T, Bergquist KM, Smith K. Clinical effectiveness of an outpatient multidisciplinary chronic pain management telementoring service. Clin J Pain. 2021;37(10):740–6.
  • Sher L. The role of the endogenous opioid system in the effects of acupuncture on mood, behavior, learning, and memory. Med Hypotheses. 1998;50(6):475–8.
  • Zhao J, Liu W. Relatıonshıp Between Acupuncture-Induced Immunıty and the Regulatıon of Central Neurotransmıtter System In Rabbıts---Iı. Effect of The Endogenous Opıoıd Peptıdes On The Regulatıon of Acupuncture-Induced Immune Reactıon. Acupunct Electrother Res. 1989;14(1):1–7.
  • Wang XJ, Wang L-L. A mechanism of endogenous opioid peptides for rapid onset of acupuncture effect in treatment of depression. Zhong xi yi jie he xue bao= J Chinese Integr Med. 2010;8(11):1014–7.
  • Sharon H, Maron-Katz A, Simon E Ben, Flusser Y, Hendler T, Tarrasch R, et al. Mindfulness meditation modulates pain through endogenous opioids. Am J Med. 2016;129(7):755–8.
  • Adler A, Wells R, Stagnaro E, Barber L, Porter A, Garcia K, et al. (551) Mindfulness meditation-induced pain relief does not require endogenous opioidergic systems. J Pain. 2016;17(4):S112.
  • Reid LD. Endogenous opioid peptides and regulation of drinking and feeding. Am J Clin Nutr. 1985;42(5):1099–132.
  • Higginbotham JA, Markovic T, Massaly N, Morón JA. Endogenous opioid systems alterations in pain and opioid use disorder. Front Syst Neurosci. 2022;16:1014768.
  • Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta J-K. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2019;24(4):576–87.
  • Muñoa I, Urizar I, Casis L, Irazusta J, Subirán N. The epigenetic regulation of the opioid system: New individualized prompt prevention and treatment strategies. J Cell Biochem. 2015;116(11):2419–26.
  • DosSantos MF, Martikainen IK, Nascimento TD, Love TM, DeBoer MD, Schambra HM, et al. Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report. PLoS One. 2014;9(7):e102350.
  • Li S-K, Liao W-D, Zhao J, Cao X-W. Effects of acupuncture on plasma endogenous opioid peptides in patients with stroke-associated headache in convalescence. Zhen ci yan jiu= Acupunct Res. 2020;45(12):995–9.
  • Maldonado R, Baños JE, Cabañero D. Usefulness of knockout mice to clarify the role of the opioid system in chronic pain. Br J Pharmacol. 2018;175(14):2791–808.
  • Shimizu S, Shiraki A. CRISPR/Cas9 unveils the dynamics of the endogenous µ‐opioid receptors on neuronal cells under continuous opioid stimulation. Pharmacol Res Perspect. 2022;10(2):e00933.
There are 43 citations in total.

Details

Primary Language English
Subjects Pain, Clinical Chemistry, Medical Biochemistry - Proteins, Peptides and Proteomics
Journal Section Review Articles
Authors

Remzi Kağan Yücel 0009-0005-4228-5838

Fulya Özdemir 0000-0001-8937-9130

Hesna Ural Ulucan 0000-0003-1885-6766

Serap Hızlı Yücel 0009-0009-6900-2083

Publication Date June 30, 2025
Submission Date June 11, 2024
Acceptance Date June 30, 2025
Published in Issue Year 2025 Volume: 42 Issue: 2

Cite

APA Yücel, R. K., Özdemir, F., Ural Ulucan, H., Hızlı Yücel, S. (2025). Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications. Deneysel Ve Klinik Tıp Dergisi, 42(2), 207-211.
AMA Yücel RK, Özdemir F, Ural Ulucan H, Hızlı Yücel S. Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications. J. Exp. Clin. Med. June 2025;42(2):207-211.
Chicago Yücel, Remzi Kağan, Fulya Özdemir, Hesna Ural Ulucan, and Serap Hızlı Yücel. “Endogenous Opioid System in Pain Management: Mechanisms, Influences, and Clinical Implications”. Deneysel Ve Klinik Tıp Dergisi 42, no. 2 (June 2025): 207-11.
EndNote Yücel RK, Özdemir F, Ural Ulucan H, Hızlı Yücel S (June 1, 2025) Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications. Deneysel ve Klinik Tıp Dergisi 42 2 207–211.
IEEE R. K. Yücel, F. Özdemir, H. Ural Ulucan, and S. Hızlı Yücel, “Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications”, J. Exp. Clin. Med., vol. 42, no. 2, pp. 207–211, 2025.
ISNAD Yücel, Remzi Kağan et al. “Endogenous Opioid System in Pain Management: Mechanisms, Influences, and Clinical Implications”. Deneysel ve Klinik Tıp Dergisi 42/2 (June 2025), 207-211.
JAMA Yücel RK, Özdemir F, Ural Ulucan H, Hızlı Yücel S. Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications. J. Exp. Clin. Med. 2025;42:207–211.
MLA Yücel, Remzi Kağan et al. “Endogenous Opioid System in Pain Management: Mechanisms, Influences, and Clinical Implications”. Deneysel Ve Klinik Tıp Dergisi, vol. 42, no. 2, 2025, pp. 207-11.
Vancouver Yücel RK, Özdemir F, Ural Ulucan H, Hızlı Yücel S. Endogenous opioid system in pain management: Mechanisms, influences, and clinical Implications. J. Exp. Clin. Med. 2025;42(2):207-11.
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