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Neospinotalamik Yolda COX/5-LOX ve TRPV1 Aracılı Sensitizasyona Yönelik İkili İnhibisyon ve Optogenetik Regülasyon

Dual Inhibition and Optogenetic Regulation Targeting COX/5-LOX and TRPV1-Mediated Sensitization in the Neospinothalamic Pathway

Tayfun Başer(SULEYMAN DEMIREL UNIVERSITY)0000-0002-8526-7737
Mustafa Saygın(SULEYMAN DEMIREL UNIVERSITY)0000-0003-4925-3503
Sayfa
632–652
Yayın Tarihi
2026-09-30
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⚡ TL;DR(1 Cümlede Hızlı Çıkarım)

Sonuç: Gelecekteki terapötik stratejilerin, daha kapsamlı analjezi sağlamak için siklooksijenaz ve 5-Lipoksijenazı eş zamanlı hedefleyen ikili inhibitörler ile Transient Receptor Potential Vanilloid-1 antagonistleri üzerine odaklanılması önerilmektedir.

📌 3 Maddede Bu Makale

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Amaç & Hipotez:Amaç: Çalışmanın amacı neospinotalamik yoldaki moleküler sensitizasyon mekanizmalarının anlaşılması, mevcut tek hedefli tedavilerin sınırlılıklarının yeni deneysel yöntem optogenetik ile aşılabileceğini vurgulamaktır.
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Temel Bulgular & Veri:Bu çalışmada, hızlı ve lokalize ağrı iletiminden sorumlu neospinotalamik yolak eksenindeki ağrı algısının nörofizyolojik dinamikleri, moleküler temelleri ve optogenetik yöntem ile yeni terapötik stratejileri incelendi.
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Sonuç & Katkı:Sonuç: Gelecekteki terapötik stratejilerin, daha kapsamlı analjezi sağlamak için siklooksijenaz ve 5-Lipoksijenazı eş zamanlı hedefleyen ikili inhibitörler ile Transient Receptor Potential Vanilloid-1 antagonistleri üzerine odaklanılması önerilmektedir.
🔬Tür:Derleme
📍Kapsam:Genişletilmiş Akademik Örneklem
⚙️Değişkenler:Neospinotalamik Yolak · Nosisepsiyon · COX

Özet

Amaç: Çalışmanın amacı neospinotalamik yoldaki moleküler sensitizasyon mekanizmalarının anlaşılması, mevcut tek hedefli tedavilerin sınırlılıklarının yeni deneysel yöntem optogenetik ile aşılabileceğini vurgulamaktır. Bu çalışmada, hızlı ve lokalize ağrı iletiminden sorumlu neospinotalamik yolak eksenindeki ağrı algısının nörofizyolojik dinamikleri, moleküler temelleri ve optogenetik yöntem ile yeni terapötik stratejileri incelendi. Giriş: Ağrı sinyalinin başlangıç aşaması olan transdüksiyonda, nosiseptörler (A-delta ve C lifleri) inflamasyon sonrası salınan araşidonik asit metabolitleri ile hassaslaşır. Bu sensitizasyonda temel rolü, siklooksijenaz ve 5-Lipoksijenaz enzimlerinin ürettiği prostaglandinler ve lökotrienler üstlenir. Bu moleküller, termal ve kimyasal uyarılara yanıt veren Transient Receptor Potential Vanilloid-1 iyon kanallarını modüle ederek nosiseptörlerin duyarlılığını artırır ve depolarizasyona yol açar. Ortaya çıkan elektriksel sinyal, omuriliğin dorsal boynuzunda modülasyon aşamasından geçerek talamus ve somatosensöriyel kortekste persepsiyon olarak sonuçlanır. Sonuç: Gelecekteki terapötik stratejilerin, daha kapsamlı analjezi sağlamak için siklooksijenaz ve 5-Lipoksijenazı eş zamanlı hedefleyen ikili inhibitörler ile Transient Receptor Potential Vanilloid-1 antagonistleri üzerine odaklanılması önerilmektedir.

Abstract

Objective: The aim of this study is to elucidate the molecular sensitization mechanisms in the neospinothalamic pathway and to highlight that the limitations of current single-target therapies can be overcome with the novel experimental method of optogenetics. This study examines the neurophysiological dynamics, molecular basis, and novel therapeutic strategies involving optogenetics for pain perception within the neospinothalamic pathway, which is responsible for fast and localized pain transmission. Introduction: During transduction, the initial phase of the pain signal, nociceptors (A-delta and C fibers) become sensitized by arachidonic acid metabolites released following inflammation. A key role in this sensitization is played by prostaglandins and leukotrienes, which are produced by the cyclooxygenase and 5-Lipoxygenase enzymes. These molecules modulate the Transient Receptor Potential Vanilloid-1 ion channels, which respond to thermal and chemical stimuli, thereby increasing nociceptor excitability and leading to depolarization. The resulting electrical signal passes through a modulation phase in the dorsal horn of the spinal cord, culminating in perception in the thalamus and somatosensory cortex. Conclusion: It is suggested that future therapeutic strategies should focus on dual inhibitors that simultaneously target the cyclooxygenase and 5-Lipoxygenase enzymes, alongside Transient Receptor Potential Vanilloid-1 antagonists, to provide more comprehensive analgesia.

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Bu Makaleye Atıf Yap

Başer, T., Saygın, M. (2026). Neospinotalamik Yolda COX/5-LOX ve TRPV1 Aracılı Sensitizasyona Yönelik İkili İnhibisyon ve Optogenetik Regülasyon. Çukurova Anestezi ve Cerrahi Bilimler Dergisi, Cilt: 9 Sayı: 3, 632–652. https://doi.org/10.36516/jocass.1840651

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Kaynakça (110)

  1. Świeboda P, Filip R, Prystupa A, Drozd M. Assessment of pain, types, mechanism.pdf. Ann Agric Env Med. 2013;20(1):2-7. https://www.aaem.pl/Assessment-of-pain-types-mechanism-and-treatment,106177,0,2.html
  2. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2011;152(3):1-31. doi:10.1016/j.pain.2010.09.030.Central
  3. Ghatak S, Vyas A, Misra S, et al. Novel di-tertiary-butyl phenylhydrazones as dual cyclooxygenase-2/5- lipoxygenase inhibitors: Synthesis, COX/LOX inhibition, molecular modeling, and insights into their cytotoxicities. Bioorganic Med Chem Lett. 2014;24(1):317-324. doi:10.1016/j.bmcl.2013.11.015
  4. Pamplona FA, Menezes-de-Lima O, Takahashi RN. Aspirin-triggered lipoxin induces CB1-dependent catalepsy in mice. Neurosci Lett. 2010;470(1):33-37. doi:10.1016/j.neulet.2009.12.050
  5. Park HJ, Moon DE. Pharmacologic Management of Chronic Pain. Korean J Pain. 2010;23(June):99-108. doi:10.1016/j.gtc.2010.08.001
  6. Espinosa-Juárez JV, Chiquete E, Estañol B, Aceves J de J. Optogenetic and Chemogenic Control of Pain Signaling: Molecular Markers. Int J Mol Sci. 2023;24(12):1-16. doi:10.3390/ijms241210220
  7. Hannibal KE, Bishop MD. Chronic stress, cortisol dysfunction, and pain: A psychoneuroendocrine rationale for stress man-agement in pain rehabilitation. Phys Ther. 2014;94(12):1816-1825. doi:10.2522/ptj.20130597
  8. Dubin AE, Patapoutian A. Nociceptors: The sensors of the pain pathway. J Clin Invest. 2010;120(11):3760-3772. doi:10.1172/JCI42843
  9. Todorovic SM, Jevtovic-Todorovic V. Regulation of T-type calcium channels in the peripheral pain pathway. Channels. 2007;1(4):238-245. doi:10.4161/chan.4953
  10. Saito N, Shima R, Yamada Y, Nagaoka M, Ito E, Yoshioka T. A Proposed Molecular Mechanism for Physical Analgesia in Chronic Pain. Neural Plast. 2018;2018. doi:10.1155/2018/1260285
  11. Haghparast A, Azhdari-Zarmehri H, Reisi Z, Vaziri A, Haghparast A, Shaigani P. Involvement of orexin-2 receptors in the ventral tegmental area and nucleus accumbens in the antinociception induced by the lateral hypothalamus stimulation in rats. Peptides. 2013;47:94-98. doi:10.1016/j.peptides.2013.07.012
  12. Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N. Attenuation of morphine antinociceptive tolerance by can-nabinoid CB1 and CB2 receptor antagonists. J Physiol Sci. 2015;65(5):407-415. doi:10.1007/s12576-015-0379-2
  13. Argoff CE, Albrecht P, Irving G, Rice F. Multimodal analgesia for chronic pain: Rationale and future directions. Pain Med. 2009;10(SUPPL. 2). doi:10.1111/j.1526-4637.2009.00669.x
  14. Ignorro L. NO İle Kalp Hastalıklarına Son. Özbay Yayıncılık; 2007.
  15. Karcz M, Abd-elsayed A, Chakravarthy K, et al. Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review ( A Neuron Project ). J Pain Res. 2024;17:3757-3790.
  16. Rashmi BR, Ebrahim NKC. A review on pain and its signals modulation by body. Int J Compr Adv Pharmacol. 2019;4(3):84-90.
  17. Gonzalez-Hermosillo DC, Gonzalez-Hermosillo LM, Villaseñor-Almaraz M, et al. Current Concepts of Pain Pathways: A Brief Review of Anatomy, Physiology, and Medical Imaging. Curr Med Imaging. 2024;20:1-17. doi:10.2174/1573405620666230519144112
  18. Yang D, Jacobson A, Meerschaert KA, et al. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell. 2022;185(22):4190-4205.e25. doi:10.1016/j.cell.2022.09.024
  19. Lefaucheur JP. Clinical Neurophysiology of Pain. Vol 161. 1st ed. Elsevier B.V.; 2019. doi:10.1016/B978-0-444-64142-7.00045-X
  20. Bell A. The neurobiology of acute pain. Vet J. 2018;237:55-62. doi:10.1016/j.tvjl.2018.05.004
  21. Cohen SP, Mao J. Neuropathic pain: Mechanisms and their clinical implications. BMJ. 2014;348:1-12. doi:10.1136/bmj.f7656
  22. Mertens P, Blond S, David R, Rigoard P. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain (part A). Neurochirurgie. 2015;61(S1):S22-S34. doi:10.1016/j.neuchi.2014.09.001
  23. Middleton SJ, Barry AM, Comini M, et al. Studying human nociceptors: From fundamentals to clinic. Brain. 2021;144(5):1312-1335. doi:10.1093/brain/awab048
  24. Welters ID, Menzebach A, Goumon Y, et al. Morphine inhibits AP-1 activity and CD14 expression in leukocytes by a nitric oxide and opioid receptor-dependent mechanism. Eur J Anaesthesiol. 2007;24(11):958-965. doi:10.1017/S026502150700083X
  25. Robert Cronin Yung Peng, Rose Khavari ND. Select noxious stimuli induce changes on corneal nerve morphology. Physiol Behav. 2017;176(3):139-148. doi:10.1159/000444169.Carotid
  26. Russo MM, Sundaramurthi T. An Overview of Cancer Pain: Epidemiology and Pathophysiology. Semin Oncol Nurs. 2019;35(3):223-228. doi:10.1016/j.soncn.2019.04.002
  27. Ong WY, Stohler CS, Herr DR. Role of the Prefrontal Cortex in Pain Processing. Mol Neurobiol. 2019;56(2):1137-1166. doi:10.1007/s12035-018-1130-9
  28. Possomato-Vieira, José S. and Khalil RAK, Modeling O 2. 0. ESE and S. Phospholipase A2 Inhibitor-Loaded Phospholipid Micelles Abolish Neuropathic Pain. Physiol Behav. 2017;176(12):139-148. doi:10.1021/acsnano.0c00999.Additional
  29. Oehler B, Brack A, Blum R, Rittner HL. Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives. Front Endocrinol (Lausanne). 2021;11(January):1-9. doi:10.3389/fendo.2020.613868
  30. Lee GI, Neumeister MW. Pain: Pathways and Physiology. Clin Plast Surg. 2020;47(2):173-180. doi:10.1016/j.cps.2019.11.001
  31. Bourne S, Machado AG, Nagel SJ. Basic anatomy and physiology of pain pathways. Neurosurg Clin N Am. 2014;25(4):629-638. doi:10.1016/j.nec.2014.06.001
  32. Duan WR, Xie YK. Modulation of C-nociceptive activities by inputs from myelinated fibers. Adv Exp Med Biol. 2016;904:33-40. doi:10.1007/978-94-017-7537-3_3
  33. Sopacua M, Hoeijmakers JGJ, Merkies ISJ, Lauria G, Waxman SG, Faber CG. Small-fiber neuropathy: Expanding the clinical pain universe. J Peripher Nerv Syst. 2019;24(1):19-33. doi:10.1111/jns.12298
  34. Cashman JN. The mechanisms of action of NSAIDs in analgesia. Drugs. 1996;52(SUPPL. 5):13-23. doi:10.2165/00003495-199600525-00004
  35. Baser T. Ghrelin ve Oreksin Reseptör Agonistlerinin Morfin Analjezisi ve Toleransı Üzerine Etkileri. Sivas Cumhuriyet Ün-iversitesi; 2018.
  36. Peng SY, Liu Y, Bao XH, et al. Inhibition of 5-lipoxygenase and cyclooxygenase-2 pathways by pain-relieving plaster in mac-rophages. Pharm Biol. 2011;49(7):716-726. doi:10.3109/13880209.2010.544043
  37. Burnett BP, Levy RM. 5-Lipoxygenase metabolic contributions to NSAID-induced organ toxicity. Adv Ther. 2012;29(2):79-98. doi:10.1007/s12325-011-0100-7
  38. Bjordal JM, Ljunggren AE, Klovning A, Slørdal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhib-itors, in osteoarthritic knee pain: Meta-analysis of randomised placebo controlled trials. Br Med J. 2004;329(7478):1317-1320. doi:10.1136/bmj.38273.626655.63
  39. Cortes-Burgos LA, Zweifel BS, Settle SL, et al. CJ-13610, an orally active inhibitor of 5-lipoxygenase is efficacious in preclinical models of pain. Eur J Pharmacol. 2009;617(1-3):59-67. doi:10.1016/j.ejphar.2009.06.058
  40. Kanjhan R. Opioids and Pain. Clin Exp Pharmacol Physiol. 1995;22(6-7):397-403. doi:10.1111/j.1440-1681.1995.tb02029.x
  41. Meshram MA, Bhise UO, Makhal PN, Kaki VR. Synthetically-tailored and nature-derived dual COX-2/5-LOX inhibitors: Struc-tural aspects and SAR. Eur J Med Chem. 2021;225:113804. doi:10.1016/j.ejmech.2021.113804
  42. Metkin G, Süntar İ, Şenol Deniz FS, Tugay O, Demiralp M, Pittalà V. Investigating COX-2 and 5-LOX Enzyme-Related An-ti-Inflammatory and Antioxidant Activities and Phytochemical Features of Scutellaria salviifolia Benth. Int J Mol Sci. 2025;26(12):1-17. doi:10.3390/ijms26125608
  43. Xie L, Lee DY wei, Shang Y, et al. Phytomedicine Characterization of spirostanol glycosides and furostanol glycosides from anemarrhenae rhizoma as dual targeted inhibitors of 5-lipoxygenase and Cyclooxygenase-2 by employing a combination of a ffi nity ultra fi ltration and HPLC / MS. Phytomedicine. 2020;77:1-10. doi:10.1016/j.phymed.2020.153284
  44. Ji G, Zhou S, MY K, Westlund K, Carlton S. Plasticity in Intact Aδ- and C-Fibers Contributes to Cold Hypersensitivity in Neu-ropathic Rats. Neuroscience. 2008;150(1):182-193.
  45. Kawabata A. Lipid Mediators and Pain Signaling Prostaglandin E 2 and Pain — An Update. Biol Pharm Bull 34(8). 2011;34(8):1170-1173.
  46. Basbaum A. History of Spinal Cord “ Pain ” Pathways Including the Pathways Not Taken. Front Pain Res. 2022;3:1-6. doi:10.3389/fpain.2022.910954
  47. Premkumar LS, Sikand P. TRPV1: A Target for Next Generation Analgesics. Curr Neuropharmacol. 2008;6:151-163.
  48. Zhang X, Li L, Mcnaughton PA. Proinflammatory Mediators Modulate the Heat-Activated Ion Channel TRPV1 via the Scaf-folding Protein AKAP79 / 150. Neuron. 2008;(59):450-461. doi:10.1016/j.neuron.2008.05.015
  49. Darre L, Domene C. Binding of Capsaicin to the TRPV1 Ion Channel. Mol Pharm. 2015;(12):4454-4465. doi:10.1021/acs.molpharmaceut.5b00641
  50. Crofford LJ. Chronic Pain: Where the Body Meets the Brain. Trans Am Clin Climatol Assoc. 2015;126:167-183.
  51. Kitahata LM. Pain pathways and transmission. Yale J Biol Med. 1993;66(5):437-442.
  52. Argoff C. Mechanisms of pain transmission and pharmacologic management. Curr Med Res Opin. 2011;27(10):2019-2031. doi:10.1185/03007995.2011.614934
  53. Maio G Di, Villano I, Ilardi CR, et al. Mechanisms of Transmission and Processing of Pain: A Narrative Review. Int J Environ Res Public Health. 2023;20(4). doi:10.3390/ijerph20043064
  54. Kağan Yücel R, Özdemir F, Ural Ulucan H, Hizli Yücel S. Endogenous opioid system in pain management: Mechanisms, in-fluences, and clinical implications. J Exp Clin Med. 2025;42(2):207-211. doi:10.52142/omujecm.42.2.15
  55. Kaye AD, Urman RD, Vadivelu N. Essentials of Regional Anesthesia.; 2012. doi:10.1007/978-1-4614-1013-3
  56. Xie YF, Wang J, Bonin RP. Optogenetic exploration and modulation of pain processing. Exp Neurol. 2018;306(April):117-121. doi:10.1016/j.expneurol.2018.05.003
  57. Yağcı Ü, Saygın M. Ağri fi̇zyopatoloji̇si̇. Med J SDU. 2019;26(2):209-220. doi:10.17343/sdutfd.444237
  58. Willis W, Westlund K. Neuroanatomy of the Pain System and of the Pathways That Modulate Pain. J Clin Neurophysiol. 2021;14(1):2-31. doi:10.1097/00004691-199701000-00002.Neuroanatomy
  59. Cross SA. Pathophysiology of Pain. Mayo Clin Proc. 1994;69(4):375-383. doi:10.1016/S0025-6196(12)62225-3
  60. Bodnar R, Heinricher MM. Central Mechanisms of Pain Modulation. Curr Opin Neurobiol. 1999;9:436-441. doi:10.1007/978-3-030-88832-9_102
  61. Liu D, Hu SW, Wang D, et al. An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain. J Neurosci. 2024;44(4):1-21. doi:10.1523/JNEUROSCI.0869-23.2023
  62. Mwendwa. Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review. Physiol Behav. 2019;176(3):139-148. doi:10.1016/j.jpain.2021.02.005.Mechanisms
  63. Leung RH, Stroman PW. Neural correlates of cognitive modulation of pain perception in the human brainstem and cervical spinal cord using functional magnetic resonance imaging: A review. Crit Rev Biomed Eng. 2016;44(1-2):33-45. doi:10.1615/CritRevBiomedEng.2016016540
  64. Justin I. Odegaard, Chawla A. Constructing and Deconstructing the Gate Theory of Pain Lorne. Bone. 2008;23(1):1-7. doi:10.1016/j.pain.2013.12.010.Constructing
  65. Congress I. The gate control theory of pain. Br Med J. 1978;2(6137):586-587. doi:10.1136/bmj.2.6137.586-a
  66. Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology. 2008;23(6):371-380. doi:10.1152/physiol.00024.2008
  67. Braz J, Solorzano C, Wang X, Basbaum AI. Transmitting Pain and Itch Messages: A Contemporary View of the Spinal Cord Circuits that Generate Gate Control. Neuron. 2014;82(3):522-536. doi:10.1016/j.neuron.2014.01.018
  68. Fuller AM, Luiz A, Tian N, et al. Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons. Brain. 2023;146(10):4033-4039. doi:10.1093/brain/awad182
  69. Petersen-Zeitz KR, Basbaum AI. Second messengers, the substantia gelatinosa and injury-induced persistent pain. Pain. 1999;82(SUPPL.1). doi:10.1016/S0304-3959(99)00132-3
  70. Shanley KJ. Pathophysiology of pruritus. Vet Clin North Am Small Anim Pract. 1988;18(5):971-981. doi:10.1016/S0195-5616(88)50101-8
  71. Ropero Peláez FJ, Taniguchi S. The gate theory of pain revisited: Modeling different pain conditions with a parsimonious neurocomputational model. Neural Plast. 2016;2016. doi:10.1155/2016/4131395
  72. Pereira PJS, Lerner EA. Gate Control Theory Springs a Leak. Neuron. 2017;93(4):723-724. doi:10.1016/j.neuron.2017.02.016
  73. Moayedi M, Davis KD. Theories of pain: From specificity to gate control. J Neurophysiol. 2013;109(1):5-12. doi:10.1152/jn.00457.2012
  74. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120(11):3779-3787. doi:10.1172/JCI43766.reduced
  75. De Felice M, Ossipov MH. Cortical and subcortical modulation of pain. Pain Manag. 2016;6(2):111-120. doi:10.2217/pmt.15.63
  76. Medoff ZM, Colloca L. Placebo analgesia: understanding the mechanisms. Pain Manag. 2016;5(2):89-96. doi:10.2217/pmt.15.3.Placebo
  77. Chen C, Niehaus JK, Dinc F, et al. Neural circuit basis of placebo pain relief. Nature. 2024;632:1092-1125. doi:10.1038/s41586-024-07816-z
  78. Pagliusi M, Gomes F V. The Role of The Rostral Ventromedial Medulla in Stress Responses. Brain Sci. 2023;13(5):1-10. doi:10.3390/brainsci13050776
  79. Benarroch EE. Descending monoaminergic pain modulation: Bidirectional control and clinical relevance. Neurology. 2008;71(3):217-221. doi:10.1212/01.wnl.0000318225.51122.63
  80. Lockwood S, Dickenson AH. What goes up must come down: insights from studies on descending controls acting on spinal pain processing. J Neural Transm. 2020;127(4):541-549. doi:10.1007/s00702-019-02077-x
  81. Colloca L, Klinger R, Flor H, Bingel U. Placebo analgesia: Psychological and neurobiological mechanisms. Pain. 2013;154(4):511-514. doi:10.1016/j.pain.2013.02.002
  82. Neyama H, Wu Y, Nakaya Y, et al. Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia. Sci Adv. 2025;11(3):1-16. doi:10.1126/sciadv.adp8494
  83. Fenton BWF, Shih E, Zolton J. The neurobiology of pain perception in normal and persistent pain Bradford W Fenton, Elim Shih and Jessica Zolton. Pain Manag. 2015;4(July 2015):1-26.
  84. Gallace A, Bellan V. The Parietal Cortex and Pain Perception: A Body Protection System. Vol 151. 1st ed. Elsevier B.V.; 2018. doi:10.1016/B978-0-444-63622-5.00005-X
  85. Benarroch EE. Involvement of the nucleus accumbens and dopamine system in chronic pain. Neurology. 2016;87(16):1720-1726. doi:10.1212/WNL.0000000000003243
  86. Guénette SA, Giroux MC, Vachon P. Pain perception and anaesthesia in research frogs. Exp Anim. 2013;62(2):87-92. doi:10.1538/expanim.62.87
  87. Meng J, Li X, Peng W, Li Z, Shen L. The interaction between pain and attractiveness perception in others. Sci Rep. 2020;10(1):1-11. doi:10.1038/s41598-020-62478-x
  88. Taesler P, Rose M. Multivariate prediction of pain perception based on pre-stimulus activity. Sci Rep. 2022;12(1):1-9. doi:10.1038/s41598-022-07208-1
  89. Müller R, Segerer W, Ronca E, et al. Inducing positive emotions to reduce chronic pain: a randomized controlled trial of positive psychology exercises. Disabil Rehabil. 2022;44(12):2691-2704. doi:10.1080/09638288.2020.1850888
  90. Kaur A, Guan Y. Phantom limb pain: A literature review. Chinese J Traumatol - English Ed. 2018;21(6):366-368. doi:10.1016/j.cjtee.2018.04.006
  91. Flor H. Phantom-limb pain:characteristics, causes, and treatmentH et al 2002b. Lancet. 2002;1(July):182-189.
  92. Urits I, Seifert D, Seats A, et al. Treatment Strategies and Effective Management of Phantom Limb–Associated Pain. Curr Pain Headache Rep. 2019;23(9):1-7. doi:10.1007/s11916-019-0802-0
  93. Kato F, Sugimura YK, Takahashi Y. Pain-associated neural plasticity in the parabrachial to central amygdala circuit: Pain changes the brain, and the brain changes the pain. Adv Exp Med Biol. 2018;1099:157-166. doi:10.1007/978-981-13-1756-9_14
  94. Afridi B, Khan H, Akkol EK, Aschner M. Pain Perception and Management. J Curr Mol Pharmacol. 2021;14(5):678-688. doi:10.2174/1874467213666200611142438.Pain
  95. Wu H, Saini C, Medina R, Hsieh SL, Meshkati A, Sung K. Pain without presence: a narrative review of the pathophysiological landscape of phantom limb pain. Front Pain Res. 2025;(February):1-10. doi:10.3389/fpain.2025.1419762
  96. Melzack R. From the gate to the neuromatrix. Pain. 1999;6(1):121-126.
  97. Trout KK. The Neuromatrix Theory of Pain: Implications for Selected Nonpharmacologic Methods of Pain Relief for Labor. J Midwifery Womens Heal. 2004;49(6):482-488. doi:10.1016/j.jmwh.2004.07.009
  98. Copits BA, Pullen MY, W. GIR. Spotlight on pain: optogenetic approaches for interrogating somatosensory circuits. Pain. 2017;157(11):2424-2433. doi:10.1097/j.pain.0000000000000620.Spotlight
  99. Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci. 2015;18(9):1213-1225.
  100. Baier H, Scott EK. Genetic and Optical Targeting of Neural Circuits and Behavior – Zebrafish in the Spotlight. Curr Opin Neurobiol. 2010;19(5):553-560. doi:10.1016/j.conb.2009.08.001.Genetic
  101. Wang Y, Hu Z, Ju P, et al. Viral vectors as a novel tool for clinical and neuropsychiatric research applications. Gen Psychiatry. 2018;(31):1-9. doi:10.1136/gpsych-2018-000015
  102. Zhang C, Hong Z, Li H, et al. Optogenetic activation of mechanical nociceptions to enhance implant osseointegration. Nat Commun. 2025;16:1-21. doi:10.1038/s41467-025-58336-x
  103. Montgomery KL, Iyer SM, Christensen AJ, Deisseroth K, Delp SL. Beyond the brain: Optogenetic control in the spinal cord and peripheral nervous system. Science (80- ). 2016;8(337):1-13.
  104. Shen Y, Campbell RE, Cote DC, Paquet ME. Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans. Front Neural Circuits. 2020;14(July):1-11. doi:10.3389/fncir.2020.00041
  105. Karcz M, Abd-elsayed A, Chakravarthy K, et al. Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review ( A Neuron Project ). J Pain Res. 2024;17:3757-3790.
  106. Premkumar LS, Sikand P. TRPV1: A Target for Next Generation Analgesics. Curr Neuropharmacol. 2008;6:151-163.
  107. Neyama H, Wu Y, Nakaya Y, et al. Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia. Sci Adv. 2025;11(3):1-16. doi:10.1126/sciadv.adp8494
  108. Trout KK. The Neuromatrix Theory of Pain: Implications for Selected Nonpharmacologic Methods of Pain Relief for Labor. J Midwifery Womens Heal. 2004;49(6):482-488. doi:10.1016/j.jmwh.2004.07.009
  109. Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci. 2015;18(9):1213-1225.
  110. Montgomery KL, Iyer SM, Christensen AJ, Deisseroth K, Delp SL. Beyond the brain: Optogenetic control in the spinal cord and peripheral nervous system. Science (80- ). 2016;8(337):1-13.