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

Abstract

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.

Keywords

• Amantadine
• Hyperalgesia
• Ketamine
• Neuropathic pain
• NMDAR

NMDA Reseptörleri ve Ligandları Nöropatik Ağrının Tedavisinde Neden Önemlidir?

Abstract

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.

Keywords

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

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