Batho ba amohelang Orexin1 ba nang le boikutlo ba ho qobella le ho tšoenyeha: ho ka etsahala hore na mokhoa oa phekolo o sebelisoa (2014)

Eya ho:

inahaneloang

Selelekela

Hypocretin / orexin ke hypothalamic neuropeptide e nang le mefuta e 'meli, A le B, e nang le li-amino acid tsa 33 le 28 ka ho latellana, hape e tlama ho li-receptor tse peli tsa G-protein, OX1 (kapa hcrt-1) kapa OX2 (kapa hcrt-2) ( de Lecea et al., 1998; Sakurai et al., 1998).

Hypocretin / orexin peptide e hlahisoa ka palo e nyane ea li-neuron tse sebakeng sa dorsomedial-pericileical hypothalamic area (DMH / PeF) le ho latela lateral hypothalamic nucleus (LH). Lisebelisoa tsa methapo ea kutlo le liteishene tse sebetsang li ka fumaneha libakeng tse 'maloa tsa methapo ea methapo e bohareng le e phelisang, ho kenyelletsa le vagus nerve, lesapo la mokokotlo, brainstem, hypothalamus, thalamus, limbic system, le libakeng tse ling tsa cortical (Peyron et al., 1998; Heinonen et al., 2008). Li-receptors tsa OX / hcrt li bontša kabo e tšoanang e atolositsoeng (Marcus et al., 2001), ho fana ka maikutlo a karolo e ka bang teng ea li-hypocretins / orexins e le li-peptide tse laoloang bakeng sa mesebetsi e laoloang e tsamaeang le methapo ea maoto (Johnson et al., 2012a,b; Mahler et al., 2012; Boutrel et al., 2013; Tsujino le Sakurai, 2013).

Receptor ea OX1 e na le li-amino acid tsa 425 ha li-receptor tsa OX2 li na le li-amino acid tsa 444 ka tatellano e tšoanang pakeng tsa li-receptor tse peli tsa 68% (Sakurai et al., 1998). Le ha li-receptor ka bobeli li kopantsoe le Gq-protheine, ke feela "G" receptor ea OX1 e kopantsoeng le Gs-protein. Ts'ebetso ea li-receptor e eketsa maemo a calcium a kenang ka bongata ka Gq -dependent phospholipase C (PLC) - keketseho e ikemetseng ea inositol-1,4,5-triphosphate (Lund et al., 2000) le diacylglycerol, e hlahisang ts'ebetso ea δ ea protheine kinase C, qetellong e kenyelletsa tsela ea phosphorylation ea ERK (Ekholm et al., 2007).

Li-receptors tsa OX1 le OX2 li ajoa ka mokhoa o fapaneng ho pholletsa le boko ba mammary (Marcus et al., 2001), e tsamaellanang le kabo ea lits'oants'o tsa hypocretin / orexin. Bopaki ba karohano e sebetsang ea li-receptor tse peli bo sa tsoa fumanoa bo sebelisa li-pharmacological magnetic resonance imaging (phMRI) ka litekong. Litlamorao tse sebetsang tsa amphetamine li ile tsa bonts'oa ka mokhoa o fapaneng ka kalafo ea pele ea OX2 receptor antagonist JNJ-1037049 kapa ka pale ea OX1 receptor antagonist GSK1059865: JNJ-1037049 e fumane phello ea amphetamine libakeng tse ka pele tsa GNXX, GNXXous, GNLX fokotsa ts'ebetso ho amygdala e atolositsoeng, BNST le ventral striatum; libaka tsohle tsa boko tse kenyelletsang khatello ea maikutlo le tšusumetso (Gozzi et al., 2011). Phapang ena ea limmapa tse sebetsang, hammoho le phapang lipapatsong tsa boits'oaro li ts'ehetsa mabaka a ho hlahloba matšoao a fapaneng a lingaka tsa bongaka tse ikemiselitseng ho khetha li-OX1 kapa li-receptors tsa OX2. Leha ho le joalo, ha karolo ea "receptor" ea OX2 boroko le tsoho e tšehetsoa ka matla ke bopaki bo fumanehang ba liteko (Gatfield et al., 2010), menyetla ea ho phekola ea ho khetha ho khetha motsoako oa OX1 receptor e ntse e hlahlojoa (Gotter et al., 2012).

Kutloisiso e ntlafalitsoeng ea biology ea hypocretin / orexin e ntlafalitse mananeo a ho sibolla lithethefatsi ho lik'hamphani tse 'maloa tsa meriana, e hlahisang letoto la litokelo le likhomphutha tse fapaneng le khethollo e fapaneng. a vitro litšobotsi (Faedo et al., 2012; Lebold et al., 2013). Joalokaha ho bontšitsoe kaholimo, metsoako e meng e ne e sebelisoa e le lisebelisoa tsa pharmacologic ho hlahloba OX1- le neurotransuction e itšetlehileng ka OX2 Ka vivo. Lik'hemik'hale tse 'maloa li hatetse pele ka katleho bathong, haholo-holo li-octxonist tse peli tsa OX1-OX2 receptor antagonist (DORA) almorexant (Hoever et al., 2012), SB-649868 (Bettica et al., 2012), le suvorexant (Hfer et al., 2012). Ke suvorexant feela e ileng ea atleha ka katleho ho nts'etsopele ea Phase 3 mme e hlahisitsoe USA e le kalafo e ncha ea ho hloka boroko ho 2013.

Sesebelisoa sa pele sa pharmacological se sebelisitsoeng e le mohanyetsi oa li-receptor oa OX1 e ne e le SB-334867 (Jones et al., 2001; Smart et al., 2001). Haufinyane, likhakanyo tse ling li hlahisitsoe: GSK1059865 (Alvaro et al., 2009; Gozzi et al., 2011), Li-piperidines tse nkiloeng ka 2,5 (Jiang et al., 2012) le ACT-335827 (Steiner et al., 2013).

Thutong ena re sebetsana le bopaki, bo hlophisitsoeng haholo ka lisebelisoa tsa pharmacologic, bakeng sa karolo e ikhethileng ea ts'ebeliso ea methapo ea methapo ea methapo ea kutlo ea OX1 ka boitšoaro bo qobelloang, haholo-holo mabapi le ho lemalla ho ja le ho itlopa joala le ka ho tšoenyeha.

Hypocretin / orexin le receptor ea OX1 liketsong tsa bokhoba ba lithethefatsi le litloaelo tse tlamang tsa ho ja.

Liphumano tse 'maloa tsa tlhahlobo ea pele li bonts'a karolo ea ts'ebetso ea hypocretin / orexin ts'ebetsong e phehellang le e pheta-phetoang hammoho le taolong ea boitšoaro bo nang le sepheo. Maikutlo a morao-rao a akaretsa bopaki bo bokelletsoeng linthong tse fetang lekholo tse fanang ka maikutlo a hore tsamaiso ea hypocretin / orexin ho hypothalamus ea morao (Harris et al., 2005) e kenella litloaelisong tse joalo tsa bokhoba ba tahi bo amanang le ho pepesetsoa koae, amphetamine, morphine, heroin, nicotine, ethanol le cannabinoids ka litoeba (Espana et al., 2011; Mahler et al., 2012; Boutrel et al., 2013; Flores et al., 2013), hammoho le ho ja lijo tse matlafatsang tse amanang le ho ja ho itlopa joala (Tsujino le Sakurai, 2013).

Lintlha tse tšehetsang ts'ebetso ea hypocretin / orexin litlamorao tsa lithethefatsi tse lemalloang li fumanoe qalong litoeba tse nkileng nut mutation (KO) ea hypocretin / orexin peptide, e bonts'ang matšoao a fokotsehileng a ho tlohela morphine (Georgescu et al., 2003). Kamora moo, mathata a sebaka a sa rateheng a morphine (Narita et al., 2006) le bakeng sa nikotine (Plaza-Zabala et al., 2012) e bontšitsoe ka litoeba. Haufinyane tjena, liphuputso tse tsoang ho litoeba tsa KO ka ho hlakoloa ha sefuba sa OX1 li bonts'itse ts'ebetso e fokolisitsoeng ea koae le ho ts'oara "cannabinoid" le blockade ea ho khutlisetsoa hoa lithethefatsi kamora ho khaotsa (Hollander et al., 2012; Flores et al., 2013), e bonts'a karolo e mahlonoko ea li-receptors tsa OX1 ho phehellang ho khutlisetsoa ha takatso ea lithethefatsi.

Ho litoeba SB-334867, mohanyetsi ea amohelang motho ea amohelang OX1, o fokolisitse maikutlo, tloaelo ea ho batla lithethefatsi le lefu la ho tlohela ho litoeba tse pepesitsoeng ke ethanol, nicotine, morphine le cocaine. Liphumano tsena le tse ling li hlalositsoe haholo litlhahlobo tsa morao-rao (Mahler et al., 2012; Boutrel et al., 2013). Ho khahlisang haholo ke taba ea hore SB-334867 e lula e pheta boitšoaro bo qobelloang bo amanang le ho khutlisetsoa ha lithethefatsi, bo bakiloeng ke khatello ea maikutlo kapa litloaelo tse amanang le tšebeliso ea lithethefatsi, ketsahalo e bonoang ethanol, nicotine, cocaine, cannabinoids le morphine.

Haufinyane, GSK1 e khethiloeng haholo ke li-receptor antagonist GSK1059865 (5-bromo-N - [(2S, 5S) -1- (3-fluoro-2-methoxybenzoyl) -5-methylpiperidin-2LLUMXLLXXLXLXXLXXLXXLXXLXXLXLUMXLUMXL-2-methylpiperidin ) e tšoauoa kahare ho pokello ea GSK (Alvaro et al., 2009). GSK1059865 ka tekanyo ea 25 mg / kg ip (e hakantsoeng ho lula ka botlalo li-receptor tsa OX1 bokong ba rat) e mpa e fetotse feela boroko ba 'mele ba litoeba, bo bontšang phello e fokolang ea hypnotic (Gozzi et al., 2011; Piccoli et al., 2012) le netefatso ea phapanyetsano khahlanong le OX2 receptor blockade (Mieda et al., 2011). Ka lehlakoreng le leng, ho litekanyetso tsa 10 le 30 mg / kg ip, GSK1059865 e rarolotse phello ea koae ka mokhoa o ikhethileng oa paradigm (Gozzi et al., 2011). Liphetho tsena li tsamaisana le karolo e reriloeng ea ho khetha ho amohela li-receptor tsa OX1 ho thibela ho khutla hape ka ho batla lithethefatsi empa eseng ho hlohlelletsa boroko.

Li-receptors tsa OX1 le tsona li kentse letsoho ho iphetola lits'ebetso tsa ho itlopa lijo ka mokhoa o qobelloang (Avena le Bocarsly, 2012), hape e hlalosoang e le "bokhoba ba lijo," boits'oaro bo bong bo qobelloang bo atile har'a batho ba batenya haholo (Volkow and Wise, 2005; Pedram et al., 2013). Le ha e ne e bontšoa qalong hore taolo e matla ea bohareng ea orexin-A e matlafatsa boitšoaro ba ho iphepa ka ho sebetsa ho li-circuits tse khethehileng tsa hypothalamic (Friederich et al., 2013), hypocretin / orexin-e kenyelletsang lijo ka bongata ho bonahala e susumetsoa ke lintlha tse ling tse 'maloa, ho kenyelletsa ho tsebahala ha lijo, tekanyo ea matla, boemo ba ho tsosa le boemo ba maikutlo (Yamanaka et al., 2003; Zheng et al., 2007; Choi et al., 2010; Tsujino le Sakurai, 2013). Sena se fana ka maikutlo a hore mokhoa oa hypocretin / orexin o ka kenya tšebetsong mekhoa e rarahaneng ea boitšoaro ho feta keketseho e le 'ngoe ea lijo (Mahler et al., 2012). Ho joalo, liphuputso tsa morao-rao li bonts'a ho kenyelletsoa ha ts'ebetso ea hypocretin / orexin ts'ebelisong e matla ea lijo tse matlafatsoang (Smith le Robbins, 2013).

Lijo tse qobelloang li ka hlahisoa ka litoeba ka ho fetoloa nako le nako ea ho fumana lijo ka linako tse itseng tsa thibelo ea lijo libeke tse 'maloa, boemo bo sithabetsang bo ka bakang likhathatso ha lijo tse ngata tse monate li ka hlaha ka tšohanyetso. Moetso o ne o netefalitsoe ka litlama litsoeng, o bonts'a phello e thibelang ea topiramate litlamong tse tlamang tsa lijo (Cifani et al., 2009) tse tšoanang le tse bonoang ho batho ba jang ho itlopa joala (McElroy et al., 2003). Leha data mabapi le ho kenyelletsoa ha tsela ea hypocretin / orexin ts'ebetsong ena ea liteko tsa ho itlopa lijo e sa fumanehe, re ithutile ka phello ea GSK1059865 e le sesebelisoa sa ho lekola bohlokoa ba li-receptor tsa OX1 (Piccoli et al., 2012). Ho khahlisang, GSK1059865, ka tekanyetso ea 10 le 30 mg / kg, e ne e sa khone ho thibela ts'ebeliso ea lijo tse matlafatsang haholo liphoofolong tse laoloang (e sa pepesoa le thibelo ea lijo tsa li-cyclic), e netefatsa phello e nyane ea OX1 receptor blockade ka moputso oa tlhaho ha e etsahala. tlasa maemo a mmele. Ho fapana le hoo, GSK1059865 e ile ea thibela mokhoa o qobelloang oa ho ja ho likhoto tse pepesitsoeng khatello ea maikutlo / thibelo ea lijo (Piccoli et al., 2012). Ho khahlisang, ho ja lijo khafetsa ho ne ho boetse ho thibetsoe ke mohanyetsi oa O1 SB-334867 ka liphatsa tsa lefutso tse nang le botenya empa eseng litekong tsa taolo (White et al., 2005). Liphumano tsena li netefalitse karolo ea phetiso e amohelang ea OX1 ho fihlelleng drive e fetelletseng e hlahisoang ke ho lakatsa ho amanang le mahlomola a neng a boetse a bonoa le lithethefatsi tse lemalloang.

Ho khahlisang ho ja ho boetse ho thibetsoe ke DORA SB-649868, empa eseng ka mokhethoa o khethiloeng oa OX2 receptor antagonist JNJ-10397049, o fana ka maikutlo a hore litlamorao tsa SB-649868 mohlomong li bakoa ke karolo ea OX1 mochine oa eona oa ts'ebetso (Piccoli et al. , 2012). Ka ho makatsang, ho haella ha phello ea almorexant ho liphoofolo tse senotsoeng feela ke khatello e matla ea maikutlo ho bontšitse hore ts'ebetso ea ho feto-fetoha ha linako tsa thibelo ea lijo e bohlokoa bakeng sa ts'ebetso ea ts'ebetso ea hypocretin / orexin ho khothaletsa ho ja ka mokhoa o phehellang oa lijo tse fumanehang habonolo (Funabashi et al., 2009; Pankevich et al., 2010). Tlhokomeliso ena e fana ka maikutlo a hore paradigm DORA ena le bahanyetsi ba OX1 ha ba sebetse haholo-holo ka ho thibela khatello ea maikutlo. Sena ha se makatse, ha ho fanoa ka karolo e rarahaneng ea hypocretin / orexin tlhokomelong ea tekano ea matla le kutloisiso ea methapo ea methapo ea kutlo (hypocretin / orexin neurons) ho arabela ka kotloloho liphetoho tsa maemo a phallo ea tsoekere le lipontšo tsa endocrine (Tsujino le Sakurai, 2013).

Ka kakaretso, liphetho tse fumanoeng le GSK1059865 li tiisa hore ho khetha ho hanyetsa ha OX1 ha ho ame ka kotloloho mekhoa ea moputso e amehang ho jeng hedonic, empa ho e-na le hoo tšehetsa karolo ea karolo e qobelloang ea ho ja lijo, tseo mohlomong li ikarabellang bakeng sa nts'etsopele le phehello ea ho ja ka tsela e sa tloaelehang. boits'oaro ho ba jang ho itlopa lijo mme ho ka etsahala hore ebe ho bakuli ba kulang. Ntle le moo, datha tsena li totobatsa tlhokeho ea ho lekola botjha setšoantšo sa antagonism se hlahisang, ho fihlela joale se thehiloe haholo ho SB-1 (Haynes et al., 2000), k'homphieutha eo ho eona ho buuoeng ka matla ka tekanyetso e phahameng le botsitso li seng li ntse li buisanoa (Hollander et al., 2012; McElhinny et al., 2012).

Ho fihla joale palo e lekantsoeng ea lithuto tsa biomarker ea batho e tšehetsa karolo ea hypocretin / orexin tsamaisong ea boitšoaro e bonahatsang ho lemalla, 'me ha ho le ea mong oa bona ea sebelisitseng li-pharmacologic. Liphetoho tsa litekanyetso tsa hypocretin / orexin maling li ile tsa bonoa ho lino tse tahang nakong ea ho khaotsa joala, ho bontša kamano e ntle le lintlha tsa khatello (von der Goltz et al., 2011), ha kamano e mpe e bonoe e na le litoro tse ngata ho ba tsubang ba sa tsubeng (von der Goltze et al., 2010). Polelo e ntseng e eketseha ea litekanyetso tsa hypocretin / orexin e ile ea fumanoa le maling a khubung ea batho ba tsubang ba tsubang le ba hlekefetsang bang bang (Rotter et al., 2012). Le ha ho ntse ho sa hlake hore na mokhoa oa ho hlalosa lintho tse fumanoeng ha o sa hlalosehe, lithuto tse anngoeng ke lefu la bohlanya li ile tsa ithutoa bakeng sa boikarabello ba tsona ba ho lemalla ka ts'epo ea ho fumana litholoana tse hlakileng. Ka hona, narcolepsy e amahanngoa le liphetoho hangata ho mofuta oa hypocretin / orexin (Peyron et al., 1998), e bakang khaello e kholo ea peptide, e ts'oanang le e fumanoang ho litoeba tsa hypocretin / orexin KO. Phapang e nyarosang ea ts'ebetso ea moputso le boits'oaro bo nkang kotsi e tlalehiloe lithutong tsa bongaka, empa ho ata ha ho tsuba koae ho bakuli bana ho ne ho sa fapana le ha baahi ba tloaelehileng (Bayard le Dauvilliers, 2013). Ho na le liphetho tse ka bonoang ka ho fapana le bopaki ba litlamorao tse fokolisitsoeng tsa lithethefatsi tse lemalloang ho litoeba tsa hypocretin / orexin KO (bakeng sa tlhahlobo ea bona Mahler et al., 2012; Boutrel et al., 2013). Ho khahlisang, lithuto tsa narcoleptic li phatlalalitse ka ho tsuba koae le likatse tsa nicotine e le mokhoa oa ho ikoetlisa ho fokotsa boroko le ho eketsa ho tsosa (Ebben le Krieger, 2012). Ka kakaretso, liphumano li bonts'a ho rarahana likamanong lipakeng tsa boits'oaro bo bobebe le ts'ebetso ea hypocretin / orexin bathong, e ts'ehetsang tlhoko ea lithuto tse eketsehileng tse fetoletsoeng haholoanyane.

Hypocretin / orexin le receptor ea OX1 ka matšoenyeho

Lingoloa tsa physiology li hlalosa libaka tse ka morao le tse phathing ea hypothalamus e le karolo ea potoloho ea maoto le maoto e laolang maikutlo a "ho loana kapa ho fofa" ha a araba ts'okelo e tlang (Hess le Akert, 1955). Joalokaha ho se ho boletsoe ka holimo, li-neuron tse hlahisang hypocretin / oirexin li sebakeng sa potoloho (Peyron et al., 1998) le morero ho bongata ba methapo ea boko e sebetsanang le tšabo, khatello ea maikutlo le matšoenyeho (Shin le Liberzon, 2009), ho fana ka maikutlo a karolo e ka bang teng ea hypocretin / orexin ho laoleng eseng feela ho tsosa le ho tsosa, empa hape le tšabo, matšoenyeho le likarabo tsa khatello ea maikutlo (Johnson et al., 2012a; Sears et al., 2013).

Khopolo-taba ena e ile ea phenyekolloa ho theosa le lilemo mme ea akaretsoa ka lihloohong le litlhahlobo tsa morao-rao (Bisetti et al., 2006; Mathew et al., 2008; Johnson et al., 2010, 2012a). Ka liphallelo tsena babali ba nang le thahasello ba ka fumana bopaki bo tšehetsang karolo ea hypocretin / orexin neurons ho hlophisa likarabo tsa boikemelo, phefumoloho, pelo le boits'oaro maikutlong le likhatellong tse susumetsang.

Hypothesis e sebetsang e bolela hore maikutlo a sithabetsang (kapa maqhubu a phahameng a lingaka tsa "choleiogenic") a ka eketsa ts'ebetso ho li-neurocretin / orexin neurons, tseo ka nako e 'ngoe li tla lokolla hypocretin / orexin libakeng tsa bona tsa terminal tse fumanehang libakeng tsa methapo ea methapo e laolang maikutlo le karabelo ea khatello. . Ebe hypocretin / orexin e tla be e fetolela boemo ba ts'ebetso ea ts'abo, khatello ea maikutlo le khatello ea maikutlo ho leba boemong bo phahameng ba ho tsosa, ho kenyelletsang limela tsa tlhaho, endocrine le boits'oaro bo tloaetseng ho tšoenyeha le maemo a tšabo. Ho phehella ka mokhoa o sa tloaelehang oa ho lokolloa ho feteletseng ha hypocretin / orexin ho ka bonoa e le sesosa se bohlokoa sa ho boloka lintho tse ngata tse tsosang takatso le matšoenyeho, hammoho le boikarabello ba ho khutlela mekhoeng ea tšabo ho batho ba reriloeng esale pele, ho fana ka maikutlo a karolo ea bohlokoa ea pathophysiological bakeng sa matšoenyeho.

Boitsebiso ho batho bo bontšitse tokollo e eketsehileng ea extracellular hypocretin / orexin e tsamaeang le maikutlo a susumetsang maikutlo ho amygdala ea lithuto tse nang le lefu la sethoathoa sa nakoana tse amanang le kalafo tse neng li kentsoe ka li-Microbalal phenes (Blouin et al., 2013). Thutong ena litekanyetso tsa hypocretin / orexin li ile tsa eketseha nakong ea ho tsoha 'me tsa fokotseha nakong ea boroko, empa litlhōrō tse phahameng ka ho fetesisa li ile tsa bonoa nakong ea ts'ebetso e matla ea maikutlo e matla ea tse mpe tse ntle le tse mpe. Amygdala e nkoa e le sebopeho sa senotlolo sa ho sebetsana le ho sesa le maikutlo a mabe, a amanang le matšoenyeho a pathologic. Ho litoeba microinjection ea hypocretin / orexin ho amygdala e eketsa boits'oaro bo ts'oanang le maikutlo (Avolio et al., 2011). Ho khahlisang, litekanyetso tse phahameng tsa "hypocretin / orexin" li fumanoe mokhatlong oa "cerebro-spinal fluid" (CSF) oa bakuli ba nang le Mathata a Ts'oaetso ea Panic, a fana ka maikutlo a hore na ho ka etsahala boemo ba hyperactivity (Johnson et al., 2010). Phuputsong e 'ngoe ho ile ha eketseha litekanyetso tsa hypocretin / orexin maling a potoloho ea lithuto tse nang le phepo e sa feleng e thibelang pulmonary disorder (COPD), boemo bo amanang le hypercapnia, acidosis le 10-fold e eketsehileng ea ho hlaseloa ke letsoalo (Zhu et al., 2011).

Liphumano tse fetolelang li fana ka maikutlo a hore thepa ea "hypocretin / orexin" e sebelisoang haholo-holo e kenella hare ke ho kenella ha li-receptors tsa OX1. Litlhotlong likarabo tsa likarabo tsa boitšoaro le boits'oaro ho khatello ea maikutlo li ile tsa fihleloa ke kalafo ea pele ho mahlale le bahanyetsi ba li-OeptNUMX receptor, joalo ka SB-1 (Johnson et al., 2010, 2012b), GSK 1034865 (Gozzi et al., 2011) le ACT-335827 (Steiner et al., 2013), kapa ka DORA, joalo ka almorexant (Steiner et al., 2012). Boitsebiso bo bohlokoa ba likarabo tse kang matšoenyeho bo ile ba bonoa kahar'a paradigms ho kenyelletsa boemo ba tšabo (Sears et al., 2013; Steiner et al., 2013), panicogenic lactate infusion (Johnson et al., 2010), hypercapnia (Li et al., 2010; Johnson et al., 2012b), Tsamaiso ea FG-7142 (Johnson et al., 2012a), leino le phahameng la nicotine (Plaza-Zabala et al., 2010), le yohimbine (Richards et al., 2008). Bopaki ba morao-rao bo sebelisang litoeba tsa OX1 le OX2 KO li bonts'itse karolo ea bohlokoa ea li-receptor tsa OX1 tse fumanehang sebakeng sa cousuleus ho itšunya-tšunya ho ithuta maemo a tšosang le ho theha memori ea tšohanyetso (Sears et al., 2013; Soya et al., 2013).

Bopaki ba hore li-neurocretin / orexin tse nang le li-neurons li fumana lipehelo tse tsoang ho li-neuron tse ling tse hlahisang factoriogenic peptide corticotropin releasing factor (CRF) le hore projeke ea hypocretin / orexin neurons libakeng tsa boko bo nang le CRF e hlahisitse monyetla oa hore lits'ebetso tsena tse peli tsa peptidergic li kenelletse taolong. ea karabelo ea khatello ea maikutlo (Ida et al., 2000; Pañeda et al., 2005). Leha ho le joalo, haeba tlhahiso-leseling ena e nepahetse, thepa ea ho tšoenyeha ea bahanyetsi ba CRF-1 (Zorrilla le Koob, 2004) le bahanyetsi ba OX1 ba ne ba tla feta, ba bonts'a profiles tse tšoanang. Ho khahlisang, phuputso ea morao-rao e sebelisang phMRI ho likhoto e bontša hore ho nka karolo ha CRF-1 le OX1 likarabo tsa khatello ea maikutlo ho ka aroloa ka tsela e sebetsang. Boitekong bona, 'mapa oa boko oa ts'ebetso oa phMRI o ile oa hlahisoa ho likhoto tse nang le yohimbine ho litekanyetso tse tsejoang ho hlahisa litlamorao tsa ho tšoenyeha. Litlhare tsa kalafo tsa nakong e fetileng ka CP-154,526, mohanyetsi ea khethiloeng oa CRF-1 (Seymour et al., 2003), kapa selekane sa OX1 se amohelang mohanyetsi GSK1059865 (Gozzi et al., 2011) li entsoe. 'Mapa oa boko oa ts'ebetso oa yohimbine o ile oa bonts'oa ke CP-154,526 ka koloing, oa hlohlelletsa, oa khutlisetsa morao, oa methapo ea mokokotlo, dorsal likarolo tsa Caudate-putamen le amygdala. Ka mokhoa o fapaneng, GSK1059865 e bonts'itse 'mapa oa ts'ebetso ea yohimbine bokong ba sethopo, septum, dorsal thalamus, amygdala, hralocampus ea ventral, orbitofrontal, pele, ka ho kenella, cingates retrosplenial, le piriform cortex (Gozzi et al., 2013). Ka kakaretso, mohanyetsi oa li-receptor oa OX1 o hlahisitse phello e eketsehileng ho tšabo, khatello ea maikutlo le khatello ea maikutlo ho feta mohanyetsi oa CRF1, a bona ts'ebetso ea libaka tsa dopaminergic mesolimbic system. Tumellanong le tlhokomeliso ea morao-rao, ho arohana ho fumanoe pakeng tsa litlamorao tsa bahanyetsi ba OX1 le CRF-1 ho sisteme ea mesopimbic dopamine tsamaisong ea khatello ea khatello ea khatello ea kelello (Wang et al., 2009) le nikotine e batlang (Plaza-Zabala et al., 2012).

Ho khahlisang ke hore lithutong tse ling bobeli ba maoala a OX1 bahanyetsi le DORA ha baa ka ba bonts'a litlamorao tse hohelang litekong tse ikhethang tsa boits'oaro (mohlala, li-maze tse phahameng le tse phahameng) (Steiner et al., 2012; Rodgers et al., 2013). Lintlha tsena li tsamaisana le khopolo ea hore hypocretin / orexin receptor antagonists ha e fetole maemo a ho tšoenyeha a basel ka litoeba, empa e fana ka thepa e tšoanang le ea ho tšoenyeha ha maemo a ho tšoenyeha a ntse a eketseha butle-butle ka lebaka la tšusumetso e matla joalo ka acidosis / hypercapnia.

Meeli le sephetho

Tlhahiso ea ho nka li-receptors tsa OX1 e le sepheo se ka khonehang maemong a kang Ho Tšoenyeha ho Thibelo ea Khatello ea Lithethefatsi, Keketso ea Lithethefatsi, le Binge Eating e ile ea hlahlojoa. Ho ipapisitsoe le tsebo ea hona joale mochineng oa ts'ebetso, bahanyetsi ba OX1 receptor ba lokela ho ba le likotsi tse fokolang tsa nts'etsopele ho feta li-DORA. Joalokaha ho totobalitsoe ke Scammell and Winrow (2011) le Boutrel et al. (2013) bakeng sa DORA, thibelo e sa fetoheng e tšoanang ea li-receptor tsa hypocretin / orexin ka mokhoa o ka bang teng: (1) ho kenya matšoao a kang a narcoleptic, ho kenyeletsa catalepsy; (2) ho etsa liqeto tse emisang sepheo; (3) fokotsa thabo e amanang le mesebetsi e khotsofatsang; (4) e susumetsa ho tsilatsila, ho robala boroko le ho sebetsana ka katleho le likarabo tlasa maemo a tšohanyetso kapa khatello ea maikutlo; (5) tšusumetso ho metabolism ea basal ka boima ba 'mele bo eketsehileng. Leha ho le joalo, ho fihlela joale boiphihlelo ba motho ka DORA suvorexant, SB-649868 le almorexant li khothatsa haholo, li bonts'a ho sa le teng ha liketsahalo tse boletsoeng ka holimo mme, haholoholo, ha ho ts'oaetso ea narcoleptic eoisode kapa ho senyeha ha ts'ebetso ea ho etsa liqeto ha ho lekoa kahare ho lethathamo la litekanyetso le khothalletsoang hajoale. Leha ho le joalo, tlhaiso-leseling e eketsehileng mabapi le palo e kholo ea baahi le tekanyetso e phahameng ea hlokahala ho fihlela sephetho sa ho qetela.

Ho khahlisang, kalafo e nang le bahanyetsi ba khethiloeng ba OX1 ha ea lebelloa ho arolelana le likotsi tse tšoanang le tsa DORA kaha ke feela li-receptor tsa OX2 li amahangoang haholo le narcolepsy e bonts'itsoeng bakeng sa lintja tse nang le phetoho ea liphatsa tsa lefutso ea "receptor" ena (Wu et al., 2011). Melemo e meng e ka ntlafatsang ea mohanyetsi oa OX1 e kenyelletsa: (1) Profilse ea boikhathollo ea prepinical e e khethollang ho li-benzodiazepines, li-serotonin-uptake inhibitors, le bahanyetsi ba CRF-1; (2) Matla a ho fokotsa maemo a amanang le hyper-arousal e amanang le liketsahalo tsa khatello ea maikutlo le tse matla tse nang le matšoao a loketseng a mmele, joalo ka tlhaselo ea letsoalo kapa ho tlohela lithethefatsi tse lemalloang; (3) Boitšoaro ba boits'oaro bo qobellang le bo pheta-phetoang bo amanang le maikutlo a ho hlasimolla, khatello ea maikutlo, kapa ho batla lithethefatsi; (4) Ho haella ha litakatso tsa meputso ea tlhaho, le (5) ho haella ha litlamorao tsa ho robala.

Lintlha tsena li ipapisitse le lethathamo la litheko tse fokolang tsa lithuto tsa pele, tse sa tsoa etsoa haufinyane le motsoako o mocha oa likhomphutha tse ikhethileng. Boithuto bo sa foleng ba dosing ha bo na, ka hona tlhaiso-leseling ea likotsi tsa nako e telele le melemo ha e fumanehe. Ntle le moo, ha ho bahanyetsi ba li-receptor ba amohelang ba OX1 ba kileng ba lekoa bathong ho fihlela joale mme tšitiso ea phetolelo e ntse e sa hlaka. Leha ho le joalo, menyetla e matlafatsang ea kalafo e ka fetolang maikutlo a ho tšoenyeha le boits'oaro bo khothalletsang e tsosa lipatlisiso tsa mantlha ebile e khothaletsa matsete a mafolofolo a lik'hamphani tsa meriana.

References