Why are NMDA Receptors and Ligands Important in Treating Neuropathic Pain?

Öz

ABSTRACT Neuropathic pain (NP) is characterized by heightened sensitivity to stimuli, known as hyperalgesia, and nociceptive responses to normally non-harmful stimuli, referred to as allodynia. NP is reported to affect 5-10% of the world's human population and is often accompanied by conditions that negatively affect life, such as depression and sleep disorders. NP, which negatively affects quality of life, is tough to manage. Current treatments for NP are only moderately effective and have significant side effects, necessitating alternative therapeutic approaches for patients. Spinal glutamate N-methyl-D-aspartate receptor (NMDAR) hyperactivity is an important mechanism of chronic NP. NMDARs in primary afferent terminals may contribute to hyperalgesia by increasing neurotransmitter release. Therefore, antagonizing these receptors is of interest in the treatment of NP. Following nerve injury, increased activation of NMDARs in the spinal cord and brain results in increased calcium ion influx. This also enhances pain signals. Increased NMDAR activity also plays a role in the initiation and maintenance of chronic pain states. Therefore, modulating NMDAR activity is one of the cornerstones of pharmacological therapy in the management of neuropathic pain.Several drugs with (variable) antagonistic activity at NMDAR are available in clinical practice. These include xenon, nitrous oxide, magnesium, methadone, amantadine, riluzole, memantine, phenytoin, carbamazepine, valproic acid, and ketamine. Among these, antagonists that do not have motor side effects such as sedation and motor impairment, which are frequently associated with NMDAR antagonism, are attracting attention as targets for the treatment of NP.Pharmacological approaches emerging from phase III clinical trials and preclinical studies hold promise for effective treatment.

Anahtar Kelimeler

• Amantadine
• Hyperalgesia
• Ketamine
• Neuropathic pain
• NMDAR

NMDA Reseptörleri ve Ligandları Nöropatik Ağrının Tedavisinde Neden Önemlidir?

Öz

ÖZ Nöropatik ağrı, hiperaljezi olarak bilinen uyaranlara karşı artan hassasiyet ve allodini olarak adlandırılan, normalde zararlı olmayan uyaranlara karşı nosiseptif tepkiler ile karakterize edilir.Nöropatik ağrının, dünyadaki insan nüfusunun %5-10'unu etkilediği ve sıklıkla depresyon, uyku bozuklukları gibi yaşamı olumsuz etkileyen durumlarla birlikte görüldüğü bildirilmektedir. Yaşam kalitesini olumsuz etkileyen nöropatik ağrının yönetimi oldukça güçtür. Nöropatik ağrı için mevcut tedavilerin çoğunun orta düzeyde etkililiğe sahip olması ve kullanımlarını sınırlayan ciddi yan etkilere sahip olması nedeniyle hastalar için başka terapötik yaklaşımlara ihtiyaç vardır. Spinal glutamat N-metil-D-aspartat reseptör (NMDAR) hiperaktivitesi kronik nöropatik ağrının önemli bir mekanizmasıdır. Primer afferent terminallerdeki NMDAR’leri nörotransmitter salınımını artırarak hiperaljeziye katkıda bulunabilmektedir. Dolayısıyla nöropatik ağrı tedavisinde bu reseptörlerin antagonize edilmesi durumu göze çarpmaktadır. Sinir yaralanmasının ardından, omurilik ve beyindeki NMDAR’lerinin artan aktivasyonu, artan kalsiyum iyon akışıyla sonuçlanır. Ayrıca bu durum, ağrı sinyallerini de güçlendirmektedir. Artan NMDA reseptör aktivitesi, kronik ağrı durumlarının başlatılmasında ve sürdürülmesinde de rol oynamaktadır. Bu nedenle, NMDAR aktivitesini modüle etmek, nöropatik ağrının yönetiminde farmakolojik tedavinin temel taşlarından biridir. Klinik uygulamada NMDAR'de (değişken) antagonistik aktiviteye sahip birkaç ilaç mevcuttur. Bunlar arasında ksenon, nitröz oksit, magnezyum, metadon, amantadin, riluzol, memantin, fenitoin, karbamazepin, valproik asit ve ketamin bulunur. Bunlardan özellikle NMDAR antagonizmasıyla sıklıkla ilişkilendirilen sedasyon ve motor bozukluğu gibi motor yan etkilere sahip olmayan antagonistler nöropatik ağrı tedavisinde hedef olabilmesi açısından dikkat çekmektedir. Faz III klinik çalışmalar ve klinik öncesi çalışmalardan ortaya çıkan farmakolojik yaklaşımlar etkili tedavi için ümit vaat etmektedir.

Anahtar Kelimeler

• Amantadin
• Hiperaljezi
• Ketamine
• Neuropathic pain
• NMDAR.

Kaynakça

1. 1.Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol.2019;33:2058738419838383.
2. 2.Deng M, Chen SR, Pan HL. Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain. Cell Mol Life Sci. 2019;76(10):1889-99.
3. 3.Smith PA. Neuropathic pain; what we know and what we should do about it. Frontiers in Pain Research, 2023;4:1220034.
4. 4.Moisset X, Bouhassira D, Couturier JA, Alchaar H, Conradi S, Delmotte MH,Attal N. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020;176(5):325-52.
5. 5.Kamp J, Van Velzen M, Olofsen E, Boon M, Dahan A, Niesters M. Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature. Expert Opin Drug Metab & Toxicol. 2019;15(12):1033-41.
6. 6.Bannister K, Sachau J, Baron R, Dickenson AH. Neuropathic pain: mechanism-based therapeutics. Annu Rev Pharmacol Toxicol. 2020;60(1):257-74.
7. 7.Collins S, Sigtermans MJ, Dahan A, Zuurmond WW, Perez RS. NMDA receptor antagonists for the treatment of neuropathic pain. Pain medicine, 2010;11(11):1726-42.
8. 8.Chen W, Walwyn W, Ennes HS, Kim H, McRoberts JA, Marvizón JCG. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals. Eur J Neurosci. 2014;39(9):1439-54.

9. 9.Huerta MA, Garcia MM, Garcia-Parra B, Serrano-Afonso A, Paniagua N. Investigational drugs for the treatment of postherpetic neuralgia: systematic review of randomized controlled trials. Int J Mol Sci. 2023;24(16):12987.
10. 10. Bernatoniene J, Sciupokas A, Kopustinskiene DM, Petrikonis K. Novel drug targets and emerging pharmacotherapies in neuropathic pain. Pharmaceutics. 2023;15(7):1799.
11. 11. Moisset X, Bouhassira D, Attal N. French guidelines for neuropathic pain: an update and commentary. Revue neurologique. 2021;177(7):834-7.
12. 12.Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiological reviews. Physiol Rev. 2021;101(1):259-301.
13. 13.Fisher R, Clarkson E. Medication Management of Neuropathic Pain Disorders. Dental Clinics of North America. 2023;68(1):121-31.
14. 14.Abdel Shaheed C, Hayes C, Maher CG, Ballantyne JC, Underwood M, McLachlan AJ, Martin JH, Narayan SW, Sidhom MA. Opioid analgesics for nociceptive cancer pain: A comprehensive review. CA: A Cancer Journal for Clinicians. 2024;74(3): 286-13.
15. 15.Koutake Y, Fujimoto A, Nakahara M, Tsuruyama M, Miyoshi T, Yamaguchi Y, Fukazawa M, Kawamata Y, Hanada K, Hashimoto M. Predictors for the Clinical Efficacy of Tramadol for Cancer Pain. American Journal of Hospice and Palliative Medicine®. 2023;40(12):1303-9.
16. 16.Bendtsen L, Zakrzewska JM, Heinskou TB, Hodaie M, Leal PRL, Nurmikko T, Obermann M, Cruccu G, Maarbjerg S. Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia. The Lancet Neurology. 2020;19(9):784-96.
17. 17.Jafarzadeh E, Beheshtirouy S, Aghamohammadzadeh N, Ghaffary S, Sarbakhsh P,Shaseb E. Management of diabetic neuropathy with memantine: A randomized clinical trial. Diabetes & Vascular Disease Research. 2023;20(4):14791641231191093.
18. 18.Rodríguez-Muñoz M, Cortés-Montero E, Onetti Y, Sánchez-Blázquez P, Garzón-Niño J. The σ1 receptor and the HINT1 protein control α2δ1 binding to glutamate NMDA receptors: implications in neuropathic pain. Biomolecules. 2021;11(11):1681.
19. 19.Wu LJ, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics. 2009;6(4):693-702.
20. 20.Bravo D, Zepeda-Morales K, Maturana CJ, Retamal JS, Hernández A, Pelissier T, Constandil L. NMDA and P2X7 receptors require pannexin 1 activation to initiate and maintain nociceptive signaling in the spinal cord of neuropathic rats. International Journal of Molecular Sciences. 2022;23(12):6705.
21. 21.Huang Y, Chen H, Jin D, Chen SR, Pan HL. NMDA Receptors at Primary Afferent–Excitatory Neuron Synapses Differentially Sustain Chemotherapy-and Nerve Trauma-Induced Chronic Pain. J Neurosci. 2023;43(21):3933-48.
22. 22.Pedersen LM, Gjerstad J. Spinal cord long‐term potentiation is attenuated by the NMDA‐2B receptor antagonist Ro 25‐6981. Acta physiologica. 2008;192(3):421-27.
23. 23.Boakye PA, Tang SJ, Smith PA. Mediators of neuropathic pain; focus on spinal microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt ligands, and interleukin 1β. Front Pain Res (Lausanne). 2021;2:698157.
24. 24.Zhou HY, Chen SR, Byun HS, Chen H, Li L, Han HD, Pan HL. N-Methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+–Cl− cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain. J Biol Chem. 2012;287(40):33853–64.
25. 25.Peterson CD, Kitto KF, Verma H, Pflepsen K, Delpire E, Wilcox GL, Fairbanks CA. Agmatine requires GluN2B-containing NMDA receptors to inhibit the development of neuropathic pain. Mol Pain. 2021;17:17448069211029171.
26. 26.Shi T, Hao JX, Wiesenfeld-Hallin Z, Xu XJ. Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain. Scandinavian Journal of Pain. 2018;18(4):687-93.
27. 27.Faísco A, Dinis R, Seixas T, Lopes L. Ketamine in Chronic Pain: A Review. Cureus, 2024;16(2):e53365.
28. 28.Kirby LC. Memantine in the treatment of diabetics with painful peripheral neuropathy: A placebo-controlled trial. In 18th Annual Meeting of the American Academy of Pain Medicine. 2002;3(2):182.
29. 29.Attal N. Pharmacological treatments of neuropathic pain: The latest recommendations. Rev Neurol. 2019;175(1-2):46-50.
30. 30. Zhou C, Tajima N. Structural insights into NMDA receptor pharmacology. Biochem Soc Trans. 2023;51(4):1713-31.
31. 31. Egunlusi AO, Joubert J. NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders. Pharmaceuticals (Basel). 2024;17(5):639.
32. 32. Uzbay T, Göktalay G, Kayır H, Eker SS, Sarandol A, Oral S, Büyükuysal L, Ulusoy G, Kırlı S. Increased plasma agmatine levels in patients with schizophrenia. J Psychiatr Res. 2013;47:1054-60.
33. 33. Yang S,Yu B, Zhang Q, Zhang Y, Fu L,Zhou B,Wu H, Li J, Gong S. Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury. Journal of Translational Medicine. 2025;23(1): 60.
34. 34. Mellone M, Gardoni F. Modulation of NMDA receptor at the synapse: promising therapeutic interventions in disorders of the nervous system. Eur J Pharmacol. 2013;719(1-3):75-83.