Effects of Endogenous Opioids on Pain Mechanism

Abstract

Pain is defined as an unpleasant sensory and emotional experi-ence, associated with potential tissue damage. Many studies have been conducted to reveal the effects of opioids on the pain mech-anism. These studies have focused primarily on opioid peptides and opioid receptor agonists. In general, it is declared that dopa-minergic, serotonergic, and glutaminergic systems as well as the opioid system are closely associated with pain.Morphine, an opioid type obtained from Papaver somniferum, has been used for pain relief for many years. Morphine and other exog-enous opioids show their activity by binding to opioid receptors in living organisms. These receptors respond to opioid peptides ex-pressed as inactive polypeptide hormones activated by proteolytic cleavage. These opioids found in living organisms are referred as endogenous opioids. Endogenous opioids and their peptides are expressed throughout the peripheral and central nervous system and regulate many different systems and functions. One of the main functions of the endogenous opioid peptide is to modulate our pain response through a descending pain modifying pathway. In light of this data, the mechanism of pain has been elucidated by studying the endogenous opioid mechanism. In this review, after the definition of pain, endogenous opioids and their receptors will be mentioned, the methodology and recent findings in pain re-search will be explained

Keywords

• Pain
• Opioids
• Opioid receptors

Endojen Opioidlerin Ağrı Mekanizması Üzerine Etkileri

Abstract

Ağrı, “gerçek veya potansiyel doku hasarı ile ilişkili tarif edilen hoş olmayan bir duyusal ve duygusal deneyimdir” şeklinde tanımlan-maktadır. Opioidlerin ağrı mekanizması üzerine etkilerini ortaya koymak amacıyla birçok çalışma yapılmıştır. Bu çalışmaların çoğun-da opioid peptidleri ve opioid reseptör agonistleri üzerine odakla-nılmıştır. Ağrı ile dopaminerjik, serotonerjik, glutaminerjik sistem-lerin yanı sıra opioid sisteminin de ilişkili olduğu belirtilmektedir.Papaver somniferum bitkisinden elde edilen ve bir opioid çeşidi olan morfin uzun yıllardır ağrı tedavisinde kullanılmaktadır. Morfin ve diğer ekzojen opioidler canlı organizmada opioid reseptörleri-ne bağlanarak aktivite gösterirler. Bu reseptörler, proteolitik par-çalanma yoluyla aktive olan inaktif polipeptit hormonları olarak ifade edilen opioid peptitlere yanıt verir. Ekzojen opioidlerin yanı sıra canlı organizmalarda bulunan bu opioidlere endojen opioidler denir. Endojen opioidler ve onların peptidleri, periferik ve merkezi sinir sistemi boyunca eksprese edilir ve birçok farklı sistem ve işlevi düzenler. Endojen opioid peptidlerin temel işlevlerinden biri, ağrı-ya verilen yanıtı, azalan ağrı yolağı ile modüle etmektir. Bu bilgile-rin ışığında endojen opioid mekanizması üzerinden hareketle ağrı mekanizması aydınlatılmaya çalışılmıştır. Bu derlemede ağrı tanımı yapıldıktan sonra endojen opioidler ve reseptörlerinden bahse-dilecek ve ağrı araştırmalarında uygulanan metodoloji ve güncel bulgular anlatılacaktır

Keywords

• Ağrı
• Opioidler
• Opioid reseptörleri

References

1. 1. Loeser JD, Treede RD. The Kyoto protocol of IASP Basic Pain Termi-nology. Pain 2008; 137(3): 473-7. [CrossRef] google scholar
2. 2. Ban EG, Brassai A, Vizi ES. The role of the endogenous neurotrans-mitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system. Brain Res Bull 2020; 155: 129-36. [CrossRef] google scholar
3. 3. Aydın ON. Ağrı ve ağrı mekanizmalarına güncel bakış. ADÜ Tıp Fakültesi Dergisi 2002; 3(2): 37-48. google scholar
4. 4. Fundytus ME. Glutamate Receptors and Nociception. CNS Drugs 2001; 15(1): 29-58. [CrossRef] google scholar
5. 5. Bannister K, Bee LA, Dickenson AH. Preclinical and Early Clinical In-vestigations Related to Monoaminergic Pain Modulation. Neurot-herapeutics 2009; 6(4): 703-12. [CrossRef] google scholar
6. 6. Seol Hee Im, Galko MJ. Model for the Biology of Nociception. 2012; 241(1): 16-26. [CrossRef] google scholar
7. 7. Smith ESJ, Lewin GR. Nociceptors: a phylogenetic view. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2009; 195(12): 1089-106. [CrossRef] google scholar
8. 8. Lawson SN, Waddell PJ. Soma neurofilament immunoreactivity is related to cell size and fibre conduction velocity in rat primary sensory neurons. J Physiol 1991; 435: 41-63. [CrossRef] google scholar

9. 9. Lee KH, Chung K, Chung JM, Coggeshall RE. Correlation of cell body size, axon size, and signal conduction velocity for individu-ally labelled dorsal root ganglion cells in the cat. J Comp Neurol 1986; 243(3): 335-46. [CrossRef] google scholar
10. 10. Muzny DM, Bainbridge MN, Chang K, Dinh HH, Drummond JA, Fowler G, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487(7407): 330-7. [CrossRef] google scholar
11. 11. McDougall JJ. Peripheral analgesia: Hitting pain where it hurts. Biochim Biophys Acta Mol Basis Dis 2011; 1812(4): 459-67. [CrossRef] google scholar
12. 12. Olesen AE, Andresen T, Staahl C, Drewes AM. Human experimen-tal pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev 2012; 64(3): 722-79. [CrossRef] google scholar
13. 13. Woolf CJ, Ma Q. Nociceptors-Noxious Stimulus Detectors. Neuron 2007; 55(3): 353-64. [CrossRef] google scholar
14. 14. Bao W, Volgin AD, Alpyshov ET, Friend AJ, Strekalova T V, de Abreu MS, et al. Opioid Neurobiology, Neurogenetics and Neuropharma-cology in Zebrafish. Neuroscience 2019; 404: 218-32. [CrossRef] google scholar
15. 15. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid recep-tor-dependent signaling and behavior Anesthesiology 2011; 115: 1363-81. [CrossRef] google scholar
16. 16. Mistry C, Bawor M, Desai D, Marsh D, Samaan Z. Genetics of Opi-oid Dependence: A Review of the Genetic Contribution to Opioid Dependence. Curr Psychiatry Rev 2014; 10(2): 156-67. [CrossRef] google scholar
17. 17. Machelska H, Celik MO. Opioid Receptors in Immune and Glial Cel-ls—Implications for Pain Control. Front Immunol. 2020; 11: 300. [CrossRef] google scholar
18. 18. Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Progr in Neurobiol 2002; 66: 285-306. [CrossRef] google scholar
19. 19. Clarke S, Zimmer A, Zimmer AM, Hill RG, Kitchen I. Region selec-tive up-regulation of p-, ö- and K-opioid receptors but not opioid receptor-like 1 receptors in the brains of enkephalin and dynorp-hin knockout mice. Neuroscience 2003; 122(2): 479-89. [CrossRef] google scholar
20. 20. Ganesh CB. The stress - Reproductive axis in fish: The involve-ment of functional neuroanatomical systems in the brain. J Chem Neuroanat 2021; 112: 101904. [CrossRef] google scholar
21. 21. Herrero-Turrion MJ. Opioids and Opioid Receptors in Fishes . In: Reference Module in Life Sciences. Elsevier; 2017. p:1-15. [CrossRef] google scholar
22. 22. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the p-opiate receptor. Nature 1997; 386(6624): 499-502. [CrossRef] google scholar
23. 23. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Mor-ris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975; 258(5536): 577-9. [CrossRef] google scholar
24. 24. Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN clinical issues 2005; 16: 291301. [CrossRef] google scholar
25. 25. Laycock H, Bantel C. Opioid mechanisms and opioid drugs. Ana-esth Intensive Care Med 2019; 20(8): 450-5. [CrossRef] google scholar
26. 26. Friedman A, Nabong L. Opioids: Pharmacology, Physiology, and Clinical Implications in Pain Medicine. Phys Med Rehabil Clin N Am 2020; 31(2): 289-303. [CrossRef] google scholar
27. 27 Bodnar RJ Endogenous opiates and behavior: 2012 Peptides 2013; 50: 55-95 [CrossRef] google scholar
28. 28 Rosemann M, Ivashkevich A, Favor J, Dalke C, Hölter SM, Becker L, et al Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice Mamm Genome 2010; 21(1-2): 13-27 [CrossRef] google scholar
29. 29 Karkhanis AN, Al-Hasani R Dynorphin and its role in alcohol use disorder Brain Res 2020; 1735: 146742 [CrossRef] google scholar
30. 30 Navratilova E, Ji G, Phelps C, Qu C, Hein M, Yakhnitsa V, et al Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain Pain 2019; 160(4): 824-32 [CrossRef] google scholar
31. 31 Hackler L, Zadina JE, Ge LJ, Kastin AJ Isolation of relatively large amounts of endomorphin-1 and endomorphin- 2 from human brain cortex Peptides 1997; 18(10): 1635-9 [CrossRef] google scholar
32. 32 Zadina JE Isolation and distribution of endomorphins in the cent-ral nervous system Japanese Journal of Pharmacology 2002; 89: 203-8 [CrossRef] google scholar
33. 33 Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, et al Isolation and structure of the endogenous agonist of opio-id receptor-like ORL1 receptor Nature 1995; 377: 532-5 [CrossRef] google scholar
34. 34 Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, et al Orphanin FQ: A neuropeptide that activates an opioidlike G protein-coupled receptor Science 1995; 270(5237): 792-4 [CrossRef] google scholar
35. 35 Reinscheid RK, Nothacker HP, Civelli O The orphanin FQ/nocicep-tin gene: Structure, tissue distribution of expression and functi-onal implications obtained from knockout mice Peptides 2000; 21(7): 901-6 [CrossRef] google scholar
36. 36 Zhang L, Zhang J-T, Hang L, Liu T Mu Opioid Receptor Heterodi-mers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective Front Pharmacol 2020; 11: 1078 [CrossRef] google scholar
37. 37 . Chavkin C .Thetherapeutic potential ofK-opioids for treatment of pain and addiction Neuropsychopharmacology. Neuropsychop-harmacology 2011; 36: 369-70. [CrossRef] google scholar
38. 38. Pradhan AA, Befort K, Nozaki C, Gaveriaux-Ruff C, Kieffer BL. The delta opioid receptor: An evolving target for the treatment of bra-in disorders. Trends Pharmacol Sci 2011; 32: 581-90. [CrossRef] google scholar
39. 39. Pan ZZ, Hirakawa N, Fields HL. A cellular mechanism for the bi-directional pain-modulating actions of orphanin FQ/nociceptin. Neuron 2000; 26(2): 515-22. [CrossRef] google scholar
40. 40. Fürst S, Riba P, Friedmann T, Tımar J, Al-Khrasani M, Obara I, et al. Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acu-te and inflammatory pain in the rat. J Pharmacol Exp Ther 2005; 312(2): 609-18. [CrossRef] google scholar
41. 41. Pacheco DF, Reis GML, Francischi JN, Castro MSA, Perez AC, Duarte IDG. y-Opioid receptor agonist SNC80 elicits peripheral antinoci-ception via y 1 and y 2 receptors and activation of the l-arginine/ nitric oxide/cyclic GMP pathway Life Sciences 2005; 78(1): 54-60. [CrossRef] google scholar
42. 42. Binder W, Machelska H, Mousa S, SchmittT, Riviere PJM,Junien JL, et al. Analgesic and antiinflammatory effects oftwo novel K-opio-id peptides. Anesthesiology 2001; 94(6): 1034-44. [CrossRef] google scholar
43. 43. Sengupta JN, Snider A, Su X, Gebhart GF. Effects of kappa opioids in the inflamed rat colon. Pain 1999; 79(2-3): 175-85. [CrossRef] google scholar
44. 44. Pannell M, Labuz D, Celik M, Keye J, Batra A, Siegmund B, et al. Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation 2016; 13(1): 262-89. [CrossRef] google scholar
45. 45. Aggarwal S, DeBerry JJ, Ahmad I, Lynn P, Dewitte C, Malik S, et al. Heme attenuates beta-endorphin levels in leukocytes of HIV po-sitive individuals with chronic widespread pain. Redox Biol 2020; 36: 101684. [CrossRef] google scholar
46. 46. Mouradov D, Domingo E, Gibbs P, Jorissen RN, Li S, Soo PY, et al. Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by speci-fic driver mutations. Am J Gastroenterol. 2013; 108(11): 1785-93. [CrossRef] google scholar
47. 47. Schnörr SJ, Steenbergen PJ, Richardson MK, Champagne DL. Measuring thigmotaxis in larval zebrafish. Behav Brain Res 2012; 228(2): 367-74. [CrossRef] google scholar
48. 48. Deakin AG, Buckley J, AlZu’bi HS, Cossins AR, Spencer JW, Al’Nua-imy W, et al. Automated monitoring of behaviour in zebrafish after invasive procedures. Sci Rep 2019; 9(1): 1-13. [CrossRef] google scholar
49. 49. Ali U, Apryani E, Wu HY, Mao XF, Liu H, Wang YX. Low frequency electroacupuncture alleviates neuropathic pain by activation of spinal microglial IL-10/p—endorphin pathway. Biomed Pharmacot-her 2020; 125: 109898. [CrossRef] google scholar