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 TOLERANSI OPIOID PADA NYERI NEUROPATIK

opioid nyeri morfin obat

            Persepsi nyeri dimodulasi oleh sistem penghambatan nyeri dan sistem fasilitasi. Aktivasi beberapa daerah di kornu dorsal medula spinalis menyebabkan sekresi senyawa modulator yang menghasilkan penekanan nyeri (analgesia) atau fasilitasi nyeri (Hiperalgesia). Fasilitasi nyeri dimediasi oleh banyak agen, termasuk cholecystokinin (CCK), prostaglandin, dinorfin, substansi P, dan amina simpatik (Mayer et al, 1999.; Verri et al., 2006), dan dapat diblokir oleh antagonis NMDA-reseptor (Ben-Eliyahu et al., 1992; Parsons, 2001). Para peneliti sedang bekerja untuk mengkarakterisasi perubahan yang terjadi dalam sistem saraf selama perkembangan nyeri neuropatik pada hewan model. Sebuah pemahaman tentang bagaimana nyeri neuropatik berkembang diperlukan untuk mengarahkan pengembangan terapi nyeri baru. Sayangnya, nyeri neuropatik umumnya resisten terhadap pilihan terapi yang ada pada saat ini, sehingga pengobatan untuk pasien neuropatik terbatas, seperti opioid dan pengobatan farmakologis lain yang tersedia tidak mampu mengendalikan nyeri spontan secara memadai (Colburn et al., 1999). 

            Obat anti-inflamasi non-steroid, antidepresan dan agen anestesi lokal umumnya tidak efektif atau memiliki kelemahan substansial karena efek samping, terapi ini tidak melindungi neuron dari stres atau kematian. Bukti terbaru menunjukkan bahwa antagonis reseptor NMDA mungkin memiliki peran dalam pelemahan gambaran nyeri neuropatik. Peningkatan konsentrasi glutamat di kornu dorsal ipsilateral setelah CCI (Kawamata & Omote, 1996). Telah diketahui bahwa hiperalgesia dapat dicegah dalam model CCI dengan administrasi antagonis reseptor NMDA MK-801 terus-menerus pra-dan pasca-cedera (Davar et al., 1991). Sistem opioid endogen memainkan peran penting dalam penekanan nyeri. Administrasi obat opioid eksogen juga dapat mengaktifkan sistem ini (Shavit et al., 2007). Senyawa opioid (misalnya, morfin) telah digunakan selama berabad-abad untuk memerangi kondisi yang sangat menyakitkan. Opioid adalah salah satu analgesik yang paling efektif untuk berbagai jenis nyeri (Rashid et al., 2004). Namun, opioid dilaporkan memiliki kemampuan suboptimal terhadap nyeri neuropatik (Bleeker et al, 2001; Cherny et al, 1994). Ada laporan bahwa pengobatan morfin secara kronis dapat mengarah ke 'toleransi morfin' yang dapat menyebabkan kematian neuron (Hameed et al, 2010; Mao et al, 2002). Belum efektifnya morfin dalam konteks nyeri neuropatik mungkin karena berkurangnya jumlah reseptor opioid pre-sinaptik akibat degenerasi neuron aferen primer, yang mana disebabkan oleh kerusakan saraf. Dalam penelitian kami, diperlakukan tikus dengan morfin dan MK-801 baik secara terpisah dan kombinasi sebelum CCI cedera. Pengobatan anti-nosiseptif ini mencegah perubahan proses sentral, yang menguatkan nyeri pasca CCI. Oleh karena itu pemberian morfin atau MK-801 memberikan sebuah efek minimal terhadap fenomena allodinia dan hiperalgesia. Pemberian kombinasi morfin dan MK-801 secara efektif memodulasi beberapa aspek nyeri neuropatik yang berhubungan dengan perilaku nyeri terutama pada allodinia yang disebabkan oleh suhu dingin yang ekstrim (Hamidi et al, 2006; Nichols et al, 1997). Telah dihipotesiskan bahwa nyeri neuropatik berlangsung mekanisme seluler dan molekuler yang sama antara proses plastisitas saraf dengan toleransi opioid. Bukti tambahan untuk hipotesis ini berasal dari sebuah studi oleh (Ossipov et al. 1995), yang mengamati hasil yang sama pada model hewan percobaan nyeri neuropatik. Pengurangan jumlah reseptor μ-opioid mungkin merupakan faktor penting dalam penurunan kemampuan morfin dan agonis reseptor μ-opioid (Przewlocki & Przewlocka, 2001). Cedera saraf siatik parsial menyebabkan penurunan drastis dalam ekspresi reseptor μ-opioid di neuron DRG (Rashid et al., 2004). Kebanyakan penelitian sebelumnya meneliti alasan di balik penurunan efektivitas morfin spinal pada nyeri neuropatik, yang termasuk juga penurunan ekspresi μ-reseptor opioid (MOR) dalam kornu dorsal spinal (Porreca et al., 1998). Hal ini juga diketahui bahwa ekspresi MOR sangat menurun dalam neuron ganglion radik dorsal setelah cedera saraf perifer (Zang et al., 1998). Sebaliknya, aktivitas fungsional dari sistem opioid sentral dan perifer ditingkatkan oleh peradangan (Bilevicute-Ljungar et al., 2006). Telah terbukti bahwa selama peradangan, efek agonis reseptor μ-opioid meningkat sekitar 10 kali lipat (Cook & Nickerson, 2005). Dalam sebuah studi dari laboratorium kami, efek peradangan arthritis persisten pada ekspresi reseptor μ-opioid spinal dan variasi dalam hiperalgesia. Hasil menunjukkan peningkatan signifikan ekspresi reseptor mRNA μ-opioid spinal, yang ditunjukkan oleh RT-PCR semikuantitatif pada minggu pertama setelah induksi arthritis. Ada juga perubahan signifikan ipsilateral dalam hiperalgesia termal setelah arthritis. Namun, dalam 21 hari studi, baik ekspresi reseptor mRNA μ-opioid dan hiperalgesia termal secara bertahap menurun dan mencapai tingkat yang dekat dengan normal. Tampaknya fluktuasi reseptor μ-opioid mungkin terlibat dalam perubahan hiperalgesia selama 21 hari setelah arthritis (Lihat Gambar. 3).
Gambar. 3. Perbandingan variasi dalam hiperalgesia termal setelah injeksi nalokson pada hari ke 6 dan 21 hari setelah induksi adjuvant arthritis (AA). (□), AA; (■), AA + nalokson. Data mean ± SEM (n = 6-7 / group). P <0,001. *** P <0,01, ** P <0,05, *

Hasil penelitian kami menunjukkan bahwa dalam hiperalgesia ekspresi reseptor mRNA opioid dan variasinya ternyata tergantung waktu (Zaringhalam et al., 2008). Sitokin mungkin memainkan peranan penting dalam mekanisme ini dengan mengatur ekspresi MOR dalam SSP. Dipercaya bahwa IL-6 memainkan peran patogenik dalam peradangan. Dalam percobaan di laboratorium, kami menemukan ada peran IL-6 pada arthritis. IL-6 adalah sebuah sitokin multifungsi dengan sifat pro-dan anti-inflamasi. IL-6 sebagai perantara baik respon inflamasi fase akut dan kronis dan karena itu terlibat dalam kedua tahap awal dan akhir peradangan (Moller & Villiger, 2006). Studi kami menunjukkan bahwa serum IL-6 dan Ekspresi MOR spinal meningkat seiring dengan penurunan hiperalgesia selama fase kronis arthritis. Temuan ini mendukung peran hiperalgesi dari IL-6 selama peradangan kronis. Studi kami sebelumnya menunjukkan bahwa administrasi IL-6 mengakibatkan analgesia, yang dihambat oleh nalokson. Analgesia untuk nyeri inflamasi berkelanjutan ini disebabkan oleh pelepasan endogen peptide opioid lokal oleh sel-sel imun setelah aktivasi IL-6 (Tekieh et al., 2011). Hasil ini menunjukkan efek anti-inflamasi serum IL-6 selama fase kronis arthritis (lihat Gambar. 4). Telah di kemukakan bahwa IL-6 dapat berfungsi sebagai regulator nyeri inflamasi dan mungkin penting dalam jalur imun-opioid (De Jongh et al., 2003). Pemberian antibodi anti-IL-6 sistemik menurunkan Ekspresi MOR spinal dan kemudian meningkat hiperalgesia. IL-6 adalah sitokin penting untuk transisi antara radang akut dan kronis dan terlibat dalam tahapan berbeda dari arthritis (Nishimoto & Kishimot, 2006). Dalam studi lain kami mengungkapkan peningkatan kadar serum IL-6 pada hewan CCI yang diblokir oleh minocyline dan menghasilkan antinocicepion (Zanjani et al., 2006). Hasil ini menunjukkan bahwa tahapan peradangan pada arthritis dan perilaku nyeri di CCI harus dipertimbangkan untuk mencapai anti-hiperalgesi yang efektif dan intervensi anti-inflamasi melalui antibodi anti-IL-6 dan efek analgesik pengobatan minocycline.
Gambar. 4. Injeksi CFA menyebabkan peningkat signifikan waktu ekspresi pada MOR spinal. Administrasi antibodi Anti-IL-6 secara signifikan mengurangi ekspresi spinal MOR selama tahapan yang berbeda dari AA. Rasio intensitas MOR spinal di kelompok AA secara signifikan menurun pada hari ke-14 dan ke-21 setelah pengobatan antibodi anti-IL-6 dibandingkan dengan kelompok kontrol AA. Data disajikan sebagai mean ± SEM (n = 6 / group). + + + P <0.001 perbandingan rasio intensitas protein MOR spinal antara hari yang berbeda AA. ** P <0,01, *** P <0.001 perbandingan intensitas protein MOR spinal antara AA dan AA + anti-IL-6 antibodi tikus diobati. # # # P <0.001 menunjukkan perbedaan Intensitas protein MOR spinal AA dan AA + anti-IL-6 antibodi tikus yang diobati antara 14 dan Hari 21th.

2.      GLIAL DAN TOLERANSI OPIOID
Sebagaimana mekanisme perifer, banyak bukti yang mendukung bahwa mekanisme imunologi berperan dalam inisiasi tetapi tidak terhadap pemeliharaan yang berhubungan dengan nyeri neuropatik (Xu et al., 2006). Aktivasi sentral sel glial berperan dalam kaskade sinyal nosiseptif. Hal ini telah menjadi jelas bahwa sel-sel glial medula spinalis memainkan peran utama dalam fasilitasi nyeri (Campbell & Meyer, 2006; Watkins & Maier, 2002). Diperkirakan bahwa nyeri neuropatik menyebabkan berkurangnya kemampuan morfin dan munculnya toleransi morfin. Hasil dari banyak penelitian mendukung gagasan bahwa modulasi glial dan aktivasi neuroimmunologi merupakan salah satu mekanisme terapi yang potensial untuk meningkatkan kemampuan analgesik morfin (Mika, 2008). Potensi analgesik morfin baik sistemik dan intratekal sangat berkurang pada hewan model nyeri neuropatik (Idanpaan et al., 1997). Bukti terbaru menunjukkan bahwa kerusakan saraf membangkitkan respon imun dan ternyata glia memainkan peran penting dalam pemeliharaan homeostasis neuronal di sistem saraf pusat (Nakajima & Kohsaka, 2001; Stoll & Jander, 1999). Bukti bahwa sel glial berperan dalam nyeri kronis adalah adanya salah satu temuan yang paling penting bahwa reseptor P2X ditemukan pada sel-sel glial, bukan pada neuron (Sutherland, 2004). Reseptor P2X, atau sinyal molekul nyeri, telah lama berhubungan dengan nyeri, tetapi dianggap berhubungan dengan sel-sel saraf. Sebagai hasil dari penemuan ini, para peneliti mulai memeriksa mekanisme aktivasi glial lebih dekat (DeLeo, 2006). Mekanisme untuk aktivasi ini mungkin multifaktorial. Glia menjadi aktif dalam menanggapi pemberian morfin yang berulang, yang mengarah ke pelepasan mediator proinflamasi dan mungkin berlawanan dengan analgesia opioid melalui cara mengubah tingkat rangsangan saraf. Telah semakin diakui bahwa sel-sel glial medula spinalis seperti mikroglia dan astrosit memainkan peran penting dalam induksi dan pemeliharaan nyeri neuropatik dengan melepaskan neuromodulators kuat seperti sitokin proinflamasi dan kemokin. Bukti terbaru mengidentifikasi bahwa kemokin sebagai pemain baru dalam kontrol nyeri (Gao Ji & 2010). Pengobatan dengan target aktivasi glial secara klinis merupakan metode yang menjanjikan untuk pengobatan nyeri neuropatik (Mika, 2008). Sel glial merupakan 70% dari sel-sel dalam sistem saraf pusat (SSP), dan mikroglia mewakili 5-10% dari Sel-sel glial dalam kondisi normal. Sel mikroglia jika dalam kondisi normal memiliki soma kecil dengan lapisan tipis dan prosessus yang bercabang. Glial adalah sel-sel non-saraf pertama yang menanggapi gangguan SSP seperti cedera saraf atau pemberian opioid kronis (Raghavendra et al., 2002; Tanga et al., 2004). Mikroglia memainkan peran penting dalam pemeliharaan homeostasis neuronal dalam sistem saraf pusat. Tampaknya mikroglia mungkin bertanggung jawab atas inisiasi kondisi nyeri neuropatik (Marchand et al., 2005), dan faktor imunologi yang mereka produksi diyakini memainkan peran penting dalam transmisi nosiseptif (Colburn, 1999; Watkins, et al., 2001). Cedera saraf daerah distal dari ganglia radik dorsal menyebabkan aktivasi mikroglia. Namun, aktivasi dorsal rhizotomy jauh berkurang, sesuai dengan pengamatan bahwa bagian belakang rhizotomy menyebabkan hiperalgesia yang lebih kurang dibandingkan dengan lesi saraf spinal yang melibatkan radik yang identik (Willis et al., 2006). Setelah aktivasi sel mikroglia akan mengubah morfologi dari bentuk istirahat menjadi aktif, bercabang berbentuk amoeboid (Stoll & Jander, 1999). Activasi mikroglia  memiliki fungsi regulasi ganda dalam pemeliharaan dan fasilitasi homeostasis jaringan SSP. Mikroglia mengangkat sel mati atau bahan berbahaya dengan melepaskan faktor toksin dan fagositosis, tetapi mereka juga memperbaiki sel cedera dengan melepaskan faktor neurotropik (Quattrini et al., 1996). Mekanisme yang tepat aktivasi sel mikroglia mungkin melibatkan pelepasan faktor algesia seperti ATP, glutamat dan nitrat oksida dari neuron yang terluka atau hiperaktif (Inoue, 2006; Watkins & Maier, 2005). Aktivasi mikroglial dapat mengubah aktivitas sistem opioid, dan nyeri neuropatik yang ditandai dengan resistensi terhadap morfin. Sitokin proinflamasi utama (IL-1, IL-6 dan TNF-α) menghambat analgesia opioid akut. Efek tersebut dapat berinteraksi karena menekan aktivitas sitokin tunggal (Hutchinson et al., 2008). Sumber selular spinal dari sinyal proinflamasi juga menarik. Studi medula spinalis normal yang mendokumentasikan ekspresi sitokin basal proinflamasi di glia dan pada beberapa neuron menunjukkan bahwa dalam kondisi akut baik glial dan saraf mungkin mampu untuk melawan analgesia opioid. Potensiasi analgesia morfin akut dengan minocycline menunjukkan bahwa mikroglia mungkin terbukti menjadi mediator utama yang melawan analgesia opioid (Fu et al., 2006). Namun demikian, penelitian setelahnya tentang hiperalgesia di medula spinalis mengungkapkan bahwa sitokin disekresikan dalam keadaan nyeri kronis (Wieseler-Frank et al., 2005). Sitokin proinflamasi, khususnya tumor necrosis Faktor (КB-TNF-α), interleukin-1 (IL-1), dan interleukin-6 (IL-6), adalah protein yang sangat penting dalam komunikasi sistem imun-otak (Sweitzer et al, 2002;. Watkins & Maier, 2005; Watkins & Milligan, 2001). Telah ditemukan bahwa propentofylline, pentoxifylline, fluorocitrate, ibudilast dan minocycline mengurangi microglial, aktivasi astroglial dan menghambat sitokin proinflamasi, sehingga menekan perkembangan nyeri neuropatik (Mika, 2008; Raghavendra et al., 2004). Pemberian antibiotik minocycline interathecal mampu menghambat aktivasi mikroglial, memperlambat munculnya nyeri neuropatik (Raghavendra et al., 2003). Beberapa inhibitor glial, yang aman dan ditoleransi dengan baik secara klinis, berpotensi berguna untuk pengobatan nyeri neuropatik dan untuk pencegahan toleransi terhadap analgesia morfin. Ada bukti untuk peran reseptor ATP P2X4 atau P2X7, yang disajikan dalam mikroglia. Kemokin fractalkine juga mungkin terlibat, sebagai blokade reseptor, CX3CR1, melemahkan hiperalgesia pada model nyeri neuropatik (Milligan et al., 2005).
Pentoxifylline adalah inhibitor sitokin non-spesifik dan penghambat phosphodiesterase yang dapat menghambat sintesis TNF-α, IL-1β dan IL-6. Beberapa penelitian telah menunjukkan bahwa pentoxifylline mempengaruhi perkembangan perilaku nyeri neuropatik pada tikus dan mencit (J. Liu et al, 2007.; Mika et al., 2007). Injeksi lokal pentoxifyllin mengurangi inflamasi nyeri dengan mengurangi TNF-α (Dorazil-Dudzik et al., 2004). Ketika disuntikkan sebagai  preemptive analgesia, mengurangi nyeri pasca operasi (Dobrogowski et al., 2005). Efek anti-nosiseptif pentoxifyllin berkorelasi dengan berkurangnya produksi TNF-α, IL-1 β, dan IL-6 melalui penghambatan nuclear factor-КB serta stimulasi ekspresi IL-10 di medula spinalis dan otak (Vale et al., 2004). Namun efek terapi pentoxifylline pada nyeri neuropatik tetap ditentukan oleh penelitian yang akan datang.
Minocycline, sebuah tetrasiklin semi-sintetik generasi kedua mempunyai kemampuan penetrasi yang cukup dalam baik otak dan cairan serebrospinal (Colovic & Caccia, 2003),  muncul sebagai inhibitor ampuh aktivasi mikroglial dan proliferasi tanpa diketahui efek pada astrosit atau neuron (Tikka et al., 2001). Efek dari minocycline dimediasi oleh sel mikroglia dan berbeda dari kemampuan antimikroba obat ini (Dia et al., 2001). Pemberian minocycline baik secara sistemik atau intratekal melemahkan hiperalgesia tikus model neuropati. Kemampuannya dikaitkan dengan penghambatan aktivasi mikroglial spinal dan melemahkan ekspresi sitokin pro-inflamasi (Ledeboer et al, 2005;. Mika et al, 2007.). Ditekankan bahwa minocycline melawan perkembangan perilaku hipersensitivitas dalam tikus model nyeri neuropatik ketika inhibitor disuntikkan preemptive (Raghavendra et al., 2003). Namun, efek analgesik minocycline dalam tikus model nyeri neuropatik melalui pelemahan ekspresi IL-1β, IL-6, TNF-α, IL-1β-converting enzyme, TNF-α-converting enzyme, reseptor antagonis IL-1β, dan IL-10 di medula spinalis lumbar dorsal .
Aktivasi sel mikroglial terjadi di kornu dorsal, dan aktivasi ini dapat memainkan peran penting untuk memulai sensitisasi sentral. Peran aktivasi ini dalam nyeri neuropatik berlangsung belum jelas. Sensasi nyeri dimulai dengan tesis sederhana: nosiseptor mengkodekan informasi tentang rangsangan noksius dan menyampaikan pesan ini ke SSP; kemudian, nyeri mampu dirasakan. Dalam kasus nyeri neuropatik, kami melihat terjadi mekanisme biologi yang kompleks (Campbell et al., 2006). Studi terbaru menunjukkan bahwa pengobatan preemptive dengan inhibitor glial tampaknya lebih efektif daripada pemberian setelah sel-sel glial telah diaktifkan (Raghavendra et al., 2003). Kami mengamati hasil yang sama dengan minocycline. Pengobatan preemptive dengan minocycline dalam penelitian kami melemahkan hiperalgesia dan allodinia pada CCI. Kami mengamati bahwa minocycline, yang dilaporkan memiliki efek pada beberapa penyakit neurodegenerative, mampu memperbaiki hiperalgesia dan allodinia karena ligasi saraf skiatik dan menghambat produksi interleukin-6 (lihat Gambar. 5).


Tampaknya minocycline bisa memiliki efek anti-inflamasi dan analgesik dalam beberapa kondisi nyeri kronis (Zanjani et al., 2006). Seperti morfin secara kronis mengaktifkan glia medula spinalis, aktivasi glial menyebabkan toleransi morfin, dan keduanya nyeri neuropatik dan toleransi morfin berbagi mekanisme yang sama (Mayer et al., 1999), kami berusaha untuk memahami peran mikroglia dalam toleransi morfin yang diamati setelah pemberian inhibitor glial (Pentoxifylline dan minocycline) setelah sel-sel glial diaktifkan. Diberikan Pentoxifylline dan Minocyclines i.p. setelah pengobatan opioid jangka lama dalam model CCI. Menariknya, hasil menunjukkan pelemahan hiperalgesia dan allodinia. Ini menunjukkan kontribusi glial dalam mengubah proses nosiseptif, yang bisa diblok oleh agen inhibitor glial dan meningkatkan efek analgesik morfin. Beberapa penelitian menjelaskan bahwa glial dari fractalkine merupakan regulator analgesia morfin endogen yang terlibat dalam meningkatkan sensitivitas nyeri yang terjadi setelah pengobatan opioid kronis (Verge et al., 2004). Beberapa mekanisme lain yang mungkin melibatkan aktivitas sel glia telah diteliti, seperti morfin-induced aktivasi p38 MAPK di mikroglia, merubah glial yang mengatur reseptor NMDA glutamatergic dan pelepasan asam amino, prostaglandin dan dinorfin (Svensson et al., 2006). Penelitian terbaru telah menunjukkan bahwa mikroglia bertanggung jawab untuk toleransi opioid dan ketergantungan (Guo & Schluesener, 2007). Tidak jelas bagaimana opioid mengaktifkan mikroglia di medula spinalis, tapi penelitian sebelumnya oleh Hutchinson menujukkan kemungkinan keterlibatan toll-like receptor 4 (TLR4). Hasil penelitian menunjukkan peran pengenalan pola reseptor TLR4 untuk aktivasi mikroglial, yang menyediakan hubungan antara sensitisasi sentral dan respon imun bawaan. Kadar mRNA spinal untuk TLR4 meningkat setelah SNL L5 (Tanga et al, 2005). TLR4 terlibat dalam nyeri neuropatik dan disregulasi aksi opioid (Hutchinson et al, 2008). Morfin meningkatkan regulasi ekspresi TLR4 di mikroglia (Hutchinson et al., 2007). Nyeri neuropatik yang timbul dari CCI melalui aktivasi TLR4 memberikan kontribusi untuk aktivasi mikroglia. Data ini menunjukkan bahwa TLR4 mungkin menjadi sasaran untuk meningkatkan klinis kontrol nyeri (Hutchinson et al., 2008).

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