Mohanyetsi oa li-ghrelin (GHS-R1A) o hlokomoloha thepa e thabisang ea morphine mme o eketsa litekanyetso tsa peptide tsa opioid libakeng tsa moputso ho litoeba (2015)

Eur Neuropsychopharmacol. 2015 Oct 21. pii: S0924-977X (15) 00329-6. Doi: 10.1016 / j.euroneuro.2015.10.004.

Engel JA1, Nylander I2, Jerlhag E3.

inahaneloang

Lihormone tsa boko ba bo-gut joalo ka ghrelin haufinyane li khothalelitsoe ho ba le karolo ho taolo ea moputso. Ka tloaelo Ghrelin o ne a tsebahala ka mokhoa o laolang taolo ea lijo le boima ba 'mele homoeostasis. Ntle le moo, mosebetsi oa morao-rao o supile hore peptide ena e na le karolo ea ho etsa moputso o khothalletsoang ke lithethefatsi, ho kenyelletsa le keketseho ea morphine e bakang litekanyetso tsa extopacellular tsa dumbamine ea extumbal dopamine. Mona ke phello ea mohanyetsi oa ghrelin receptor (GHS-R1A), JMV2959, mabapi le ts'ebetso e khothalletsoang ea morphine ea sisteme ea mesolimbic dopamine e fumanoe liphuputsong. Ho feta moo, litlamorao tsa tsamaiso ea JMV2959 maemong a peptide ea opioid libakeng tse amanang le moputso li ile tsa hlahlojoa. Lenaneong la hajoale la liteko re bonts'itse hore tsamaiso ea JMV2959 ea pente, ka tekanyetso e sa sebetseng ka ho lekana, e bonts'a bokhoni ba morphine ho baka tšusumetso ea locomotor, ho eketsa maemo a kantle ho dopamine le ho beha maemo sebakeng sa litoeba. Tsamaiso ea JMV2959 e ntlafalitse haholo litekanyetso tsa lisele tsa Met-enkephalin-Arg6Phe7 sebakeng se ka hare sa ho kenella ka mpeng, dynorphin B sebakeng sa hippocampus le Leu-enkephalin-Arg6 ka striatum. Ka hona, re kholoa hore JMV2959 e thibela moputso o khothalletsoang ke morphine ka ho hlohlelletsa li-peptide tse sebetsang tsa li-preptor libakeng tsa striatum le li-ventral tegmental. Ntle le moo, li-peptide tsa hippocampal tse sebetsang tse amohelang kappa li ka ameha ho bokhoni ba JMV2959 to ea ho laola ho hlophisoa ha moputso. Ka lebaka la hore nts'etsopele ea bokhoba ba lithethefatsi e itšetleha, bonyane ka karolo e 'ngoe, litlamorao tsa lithethefatsi tse lemalloang ho sisteme ea mesolimbic datha e teng e fana ka maikutlo a hore bahanyetsi ba GHS-R1A ba lokeloa ke ho hlakisoa e le leano la kalafo la litheko tsa opioid.

 

 

 

 
   

inahaneloang

Lihormone tsa boko ba bo-gut joalo ka ghrelin haufinyane li khothalelitsoe ho ba le karolo ho taolo ea moputso. Ka tloaelo Ghrelin o ne a tsebahala ka mokhoa o laolang taolo ea lijo le boima ba 'mele homoeostasis. Ntle le moo, mosebetsi oa morao-rao o supile hore peptide ena e na le karolo ea ho etsa moputso o khothalletsoang ke lithethefatsi, ho kenyelletsa le keketseho ea morphine e bakang litekanyetso tsa extopacellular tsa dumbamine ea extumbal dopamine. Mona ke phello ea mohanyetsi oa ghrelin receptor (GHS-R1A), JMV2959, mabapi le ts'ebetso e khothalletsoang ea morphine ea sisteme ea mesolimbic dopamine e fumanoe liphuputsong. Ho feta moo, litlamorao tsa tsamaiso ea JMV2959 maemong a peptide ea opioid libakeng tse amanang le moputso li ile tsa hlahlojoa. Letotong la hona joale la liteko re bonts'itse hore tsamaiso ea JPV2959 ea peripheral, ka tekanyetso ha e na phello ka bobeli, e fana ka bokhoni ba morphine ho etsa hore tšusumetso ea maiketsetso e eketsehe, e eketse litekanyetso tsa extracellular tsa dopamine tsa extumbal le ho beha maemo a khethollo ea litoeba. Tsamaiso ea JMV2959 e ntlafalitse haholo litekanyetso tsa lisele tsa Met-enkephalin-Arg6Phe7 sebakeng se ka hare sa ho kenella ka mpeng, dynorphin B sebakeng sa hippocampus le Leu-enkephalin-Arg6 ka striatum. Ka hona, re nahana hore JMV2959 e thibela moputso o khothalletsoang ke morphine dessyecik ts'usumetso ea li-peptide tse sebetsang tsa "delta" receptor libakeng tsa striatum le tsa hareral. Ntle le moo, li-peptide tsa hippocampal tse sebetsang tse amohelang kappa li ka ameha ho bokhoni ba JMV2959 to ea ho laola ho hlophisoa ha moputso. Ka lebaka la hore nts'etsopele ea bokhoba ba lithethefatsi e itšetleha, bonyane ka karolo e 'ngoe, litlamorao tsa lithethefatsi tse lemalloang ho sisteme ea mesolimbic datha e teng e fana ka maikutlo a hore bahanyetsi ba GHS-R1A ba lokeloa ke ho hlakisoa e le leano la kalafo la litheko tsa opioid.

 

 

 

 

1. Selelekela

Ho pepeseha ka mokhoa o makatsang le tšibollo ea lithethefatsi tse tlatsetsang li susumetsa haholo sisteme ea mesolimbic dopamine, potoloho ea bohlokoa ea lits'ebetso tsa moputso oa boko (Nestler, 2005). Litlamorao tsena ho nahanoa hore li be ka tlase, bonyane ka karolo, nts'etsopele ea bokhoba ba lithethefatsi (Wise, 2004). Bokhoba ba lithethefatsi bo baka litlamorao tse ngata tse kotsi ho motho ka mong le sechabeng le ho kenella ka har'a meriana le ho ngola, ho phekola bothata bona bo boholo ba bophelo ba sechaba, ho lokiselitsoe (Koob le Le Moal, 2001). Ka ho hlakisa lits'ebetso tse tšoaeang tse lumellanang le bokhoni ba lithethefatsi tse lemalloang ho kenya tšebetsong tsamaiso ea mesolimbic dopamine, ho ka bonoa maano a ikhethileng a kalafo bakeng sa mathata a tšebeliso ea lithethefatsi.

Patlisiso e bonts'itse hore methapo e tloaelehileng ea methapo ea kutlo e laola ho ja le ho fumana moputso ka lithethefatsi tsa lijo le lithethefatsi (Morganstern et al., 2011), ho fana ka maikutlo a hore karolo ea karolo ea taolo ea lijo tsa "gut-brain peptides" joalo ka ghrelin e kenyelletsa phokotso ea moputso. Qalong, ho ile ha bontšoa hore ghrelin e baka ho lokolloa hoa li-hormone tsa kholo (Kojima et al., 1999) le ho tsosa ho ratoa ho litšoene (Tschop et al., 2000). Ho tla fihlela kajeno ho tsebahala hore ghrelin e eketsa takatso ea lijo, tlala le ho tsosa takatso ea lijo dessyecik lipotoloho tsa hypothalamic (bakeng sa tlhahlobo sheba Egecioglu et al. (2011)). Ntle le hypothalamus, li-ghrelin receptors (GHS-R1A) li hlahisoa libakeng tse amanang le moputso tse kang amygdala, striatum, prefrontal cortex, ventral tegmental area (VTA) le hippocampus (bakeng sa tlhahlobo bona Engel le Jerlhag (2014)) e bolelang hore Karolo ea mmele ea ghrelin e fetela ka nqane ho taolo ea matla ea homoeostasis. Ka 'nete, orexigenic peptide ghrelin e ile ea bontšoa e le seetsi sa mesolimbic dopamine system hammoho le taolo ea moputso, tšusumetso le ho noa joala, nicotine, amphetamine le cocaine ho litoeba (bakeng sa tlhahlobo sheba Engel le Jerlhag (2014)).

Li-opioids, joalo ka lithethefatsi tse ling tse lemalloang, li kenya tšebetsong sistamine ea mesolimbic dopamine e hlahisang ho lokolloa ha dopamine dessyecik ts'ebetso ea li-receptor tsa μ- le / kapa δ-opioid bokong ba li-nucleus accumbens (NAc) (Hirose et al., 2005, Murakawa et al., 2004, Yoshida et al., 1999) le ho VTA, mohlomong ka ho fokotsa GABA -Khabiso ea li-neurone tsa dopamine (Johnson le North, 1992). Ho feta moo, li-recumbal κ-opioid recumbal tse laolang tšebetso ea mesolimbic dopamine system (Chefer et al., 2005, Spanagel et al., 1992). Ho pepesetsoa khafetsa ka li-opioid ho hlahisa liphetoho tse feto-fetohang tsa li-neurotransmitters tse ngata, ho kenyelletsa le li-peptide tsa opioid, libakeng tsa moputso, tse tlatsetsang kholisong ea bokhoba ba tahi (De Vries le Shippenberg, 2002). Ka litekanyetso tsa khatello ea meriana ea rats ea GHS-R1A e bonts'a morphine-indued accumbal dopamine ho lokolloa le boits'oaro bo bobe ba boits'oaro (Sustkova-Fiserova et al., 2014). Morero oa karolo ea pele ea liteko tsa hona joale e ne e le ho etsa lipatlisiso tsa phello e matla ea mohanyetsi oa GHS-R1A, JMV2959, ka bokhoni ba morphine ho baka tšusumetso ea locomotor, ho lokolloa ha dopamine le ho beha sebaka se ratoang ke litoeba. Morero oa karolo ea bobeli ea thuto ena e ne e le ho lekola phello ea kalafo ea phetoho ea JMV2959 kapa ghrelin maemong a peptide (Met-enkephalin-Arg6Phe7 (MEAP), dynorphin B (DynB) le Leu-enkephalin-Arg6 (LeuArg)) libakeng tse amanang le moputso ho kenyelletsa amygdala, striatum, preortalal cortex, VTA le hippocampus.

 

 

2. Tsamaiso ea liteko

 

 

2.1. Liphoofolo

Ho ile ha sebelisoa li-moutu tsa banna ba baholo ba lilemo tsa post-pubertal tse tšoanang le li-NMRI tsa khale tsa 8-12 le boima ba 'mele oa 25-40 g; Charles River, Sulzfeld, Jeremane. Ka bokhutšoanyane, litoeba tsohle li ne li bolokiloe ka sehlopha 'me li bolokiloe mochineng oa khanya oa 12 / 12 h (/ mabone ka hora ea bosupa). Ho ile ha fanoa ka metsi a pompo le lijo (tloaelehileng chow; Harlan Teklad, Norfolk, England) ad libitum, ntle le nakong ea liteko. Ho ne ho sebelisoa litoeba tse ncha bakeng sa tlhahlobo e le 'ngoe ea boitšoaro hammoho le tlhahlobo ea peptide ea opioid. Liteko tsena li amohetsoe ke komiti ea Sweden ea Boitšoaro ea Lipatlisiso tsa Liphoofolo Gothenburg. Boiteko bohle bo entsoe ho fokotsa mahlomola a liphoofolo, le ho fokotsa palo ea liphoofolo tse sebelisitsoeng. Liphoofolo tsohle li ile tsa lumelloa ho eketsa bonyane beke pele beke ea liteko li qala.

 

 

2.2. Lithethefatsi

Morphine hydrochloride (Sepetlele sa Apoteksbolaget Sahlgrenska; Gothenburg, Sweden) e ile ea qhaloa ka koloing (tharollo ea sodium chloride ea 0.9%) 'me ea fuoa lipilisi ka 20 mg / kg 10 min pele ho qala ts'ebetso. Tekanyetso ena e ile ea khethoa ho tloha ha lethalinyana le tlase (10 mg / kg, ip) ha lea ka la baka tsusumetso ea locomotor litoeba tsa rona (ya data e sa bontsitsoeng). Tekanyetso e khethiloeng (6 mg / kg, ip) ea JMV2959 (e kopantsoe ho Institut des Biomolécules Max Mousseron (IBMM), UMR5247, CNRS, Montpellier 1 le 2 Univesithi e ne e le antagonist ebile e ne e kile ea e-ba antagonist. ha ho na ts'ebetso ea ts'ebetso ea locomotor, ho lokolloa ha dopamine ka mokhoa o ikhethileng le maemo a ratang maemo a litoeba (Jerlhag et al., 1). JMV2009 e ne e qhibilihile ka koloing (tharollo ea 2959% sodium chloride) mme e ne e lula e fuoa metsotso e mashome a mabeli pele ho pepesoa le morphine kapa decapitation bakeng sa tlhahlobo ea li-peptide tsa opioid. Tekanyetso e khethiloeng ea JMV0.9 ha ea ama boitšoaro bo bobe ba litoeba tlhahlobong efe kapa efe. Bakeng sa liteko tsa boits'oaro JMV2959 e ne e fanoa ka mokhoa o hlakileng ho tloha ha lithuto tsa rona li atoloha haholo ho bontša hore ente e le 'ngoe ea JMV2959 e fumana moputso oa lithethefatsi (bakeng sa tlhahlobo ea Engel le Jerlhag (2959). JMV2014 e sebelisitsoe nako e sa lekanyetsoang ka matsatsi a mahlano a latelang bakeng sa tlhahlobo ea peptide ea opioid ho eketsa monyetla oa ho bona phello e matla. Ntle le moo, ka ente e phetoang u qoba phello e mpefatsang ea khatello ea methapo ea methapo ea mali ka peptides. Acylated rat ghrelin (Bionuclear; Bromma, Sweden) e ne e ts'oeroe ka 2959% sodium chloride mme lethal dose le khethiloeng la ghrelin (0.9 mg / kg, ip) esale le bonts'oa ho baka moputso ho litoeba (Jerlhag, 0.33). Moralo o leka-lekaneng o ile oa sebelisoa bakeng sa mathata ohle a lithethefatsi.

 

 

2.3. Liteko tsa mosebetsi oa locomotor

Boithuto bo fetileng bo bontšitse hore morphine e baka tšusumetso ea locomotor ka litoeba (Wise and Bozarth, 1987). Ts'ebetso ea locomotor e ne e ngolisitsoe ka mabokoseng a robeli a kentsoeng molumo, a fepeloang le a enjineng (li-420 × 420 x 200 mm, Kungsbacka mät- och reglerteknik AB; Fjärås, Sweden). Methapo e mehlano ka mehele e mehlano ea libalaka tsa lifotokopi, botlaaseng ba lebokose, ho etsa tlhahlobo ea lifoto ho ile ha lumella sistimi e ipapisitseng le k'homphieutha ho ngolisa tšebetso ea litoeba. Ts'ebetso ea locomotor e hlalositsoe e le palo e bokelletsoeng ea libalaka tse ncha tsa fotokrate e sitisoa nakong ea 60-min. Litekong tsohle, litoeba li ile tsa lumelloa ho lula lebokoseng la tšebetso ea litsomi hora e le 'ngoe pele ho mathata a lithethefatsi. Ho ne ho se na phapang lipakeng tsa ho aha leha e le efe ho a mang a lihlopha tsa kalafo (data e sa bontšitsoeng).

Letotong la pele la liteko liteko tsa JMV2959 (6 mg / kg, ip) mabapi le tšusumetso ea morphine-ikiwa (20 mg / kg, ip) ho hlohlelletsa locomotor ho ile ha etsoa lipatlisiso. JMV2959 e ne e fanoe ka 20 min pele ho morphine mme ngoliso ea ts'ebetso e qalile metsotso e leshome ka mor'a ente ea ho qetela. Mouse e 'ngoe le e' ngoe e ile ea amohela motsoako o le mong oa kalafo (koloi / koloi, JMV2959 / koloi, morphine / koloi kapa JMV2959 / morphine; n= 8 ka motswako o mong oa kalafo) mme o ne a lekoa feela teko e le 'ngoe.

 

 

2.4. Sebaka se khethiloeng sa sebaka

Ho lekola litlamorao tsa JMV2959 mabapi le litlamorao tse atlehang tsa morphine ho litoeba tse ncha, liteko tsa maemo a sebaka se ikhethileng li entsoe ka litoeba joalo ka ha ho hlalositsoe pele (Jerlhag, 2008). Ka bokhutšoaane, lisebelisoa tsa CPP tse nang le likamore tse peli, tse nang le khanya ea 45 lx le mokhoa o ikhethang oa pono le tactile li ile tsa sebelisoa. Kamore e 'ngoe e ne e hlalosoa ke marako a metsu le a masoeu le mehala e lefifi ha e' ngoe e ne e e-na le mokato oa lehong le bosoeu le marako a betliloeng ka lehong. Ts'ebetso e ne e kenyelletsa maemo a pele ho letsatsi (1), boemo (matsatsi 2-5), le boemo ba morao-rao (letsatsi la 6). Ka nako ea boemo bo holimo, litoeba li ne li kentsoe liphutheloana ka koloi mme li kenngoe ka phapusing e nang le phihlello ea mahala likamoreng ka bobeli tsa 20 min ho fumana sebaka seo ba se ratang (kapa lehlakore) la bona. Boemo (20 min ka thupelo) e entsoe ka mokhoa o khetholloang moo morphine (20 mg / kg) e pentiloeng ka kamore e ratehang le koloi e nang le komporo e ratoang. Malinyane kaofela a ne a fuoa ente e le 'ngoe ea morphine hammoho le koloi letsatsi le leng le le leng' me liente li ne li fetoloa pakeng tsa hoseng le thapama ka moralo oa mekotla. Ha le qeta litoeba (n= 16) li ile tsa kenngoa ka JMV2959 (6 mg / kg, ip) kapa bophahamo bo lekanang ba tharollo ea koloi le 20 min hamorao e behiloeng bohareng pakeng tsa likhomphutha tse peli ka phihlello ea mahala likopanong ka bobeli tsa 20 min (ho theha lihlopha tse latelang tsa kalafo; Morph-Veh le Morph-JMV2959).

Khetho ea sebaka e ile ea balwa e le phapang ho% ea nako eohle e sebelisitsoeng ho joala joala ba lithethefatsi (ke hore. bonyane bo ratoang) komporo nakong ea boemo ba pele le boemo ba pele ho maemo.

2.5. Ka vivo litekanyetso tsa phatlalatso ea micodialysis le dopamine

Ka lebaka la hore JMV2959 e bonts'a morphine e kentsoeng-locomotor le maemo a khethiloeng a litoeba, litlamorao tsa JMV2959 (6 mg / kg, ip) ho lokolloe ha morphine-induction (20 mg / kg, ip) ho lokolloa ha dopamine ka dopamine ho sebelisitsoe lipatlisiso. Ka vivo Microbialysis ka litoeba tse tsamaeang ka bolokolohi. Bakeng sa litekanyo tsa litekanyetso tsa dopamine tsa extracellular dice, litoeba li ne li kengoe ka mokhoa o sa amaneng le lipatlisiso tsa microsalysis tse behiloeng ka har'a li-nucleus accumbens. Ka hona, litoeba li ne li sa anngoe ka isofluran (Isofluran Baxter; Univentor 400 Anesthesia Unit, Univentor Ldt., Zejtun, Malta), e behiloe ka har'a sethala sa litheko (David Kopf Instrsets; Tujunga, CA, USA) mme e bolokiloe e le mocheso oa mocheso ho thibela hypothermia. Xylocain adrenalin (5 μg / ml; Pfizer Inic; New York, USA) e ne e sebelisoa e le anesthetics ea lehae le carprofen (Rimadyl, 5 mg / kg ip) (Astra Zeneca; Gothenburg, Sweden) e ne e sebelisetsoa ho kokobetsa bohloko bofe kapa bofe bo ka ba teng. Lesapo la lehata le ile la pepesoa le lesoba le le leng bakeng sa phuputso eo 'me le leng la sekoti sa ankora la teba. Thupelo ena e ile ea fetoloa ka mokhoa o sa hlophiseheng hore e be lehlakoreng le letšehali la bokong. Lihokela tsa 1.5 mm anterior ho bregma, ± 0.7 lateral ho midline le 4.7 mm ka tlase ho bokaholimo ba bokong bo sebelisitsoe bakeng sa li-nucleus accumbens (Franklin le Paxinos, 1997). Ntlha e senotsoeng ea membrane ea dialysis (20,000 kDa e felisitsoe ka od / id ea 310 / 220 μm, HOSPAL, Gambro, Lund, Sweden) ea probe e ne e le 1 mm. Maqhubu ohle a ile a kenngoa ka mokhoa o kopaneng matsatsi a mabeli pele ho teko. Kamora ho buoa, litoeba li ile tsa bolokoa mekotleng e le 'ngoe ho fihlela ka letsatsi la liteko (Macrolon III).

Ka letsatsi la liteko probe e ne e hokahantsoe le pompo ea micoperfusion (U-864 Syringe Pump; AgnThós AB) mme e entsoe ka tharollo ea Ringer ka tekanyo ea 1.5 μl / min. Kamora hora e le 'ngoe ea ho lula sebakeng sa Microdialysis, lisampole tsa litlolo li ile tsa bokelloa metsotso e meng le e meng ea 20. Tekanyetso ea dopamine ea motheo e ne e hlalosoa e le kakaretso ea disampole tse tharo tse latellanang pele ho phephetso ea lithethefatsi / koloi ea pele, 'me keketseho ea "dopamine" e fumanehang ha e bapisoa le keketseho ea liperesente tse tsoang ho motheo. Kamora lisampole tsa motheo (−40 min ho fihlela 0 min), litoeba li ile tsa kenngoa ka JMV2959 kapa koloi (ka 0 min), e ileng ea lateloa ke morphine kapa ente ea koloi (ka 20 min). Kamora litsamaiso tsena tsa lithethefatsi ho ile ha bokelloa sampole tse robeli tsa 20 tsa metsotso. Ka kopanelo, lihlopha tse latelang tsa kalafon= 8 sehlopheng ka seng) e entsoe: koloi-koloi (Veh-Veh), koloi-morphine (Veh – Morph), JMV2959-koloi (JMV2959-Veh) le JMV2959-morphine (JMV2959-Morph).

Maemo a dopamine ka hara dialysates a ne a beoa ke HPLC ka bonoa ba electrochemical. Pompo (Gyncotec P580A; Kovalent AB; V. Frölunda, Sweden), phapanyetsano ea phapanyetsano ea ion (2.0 × 100 mm, Prodigy 3 μm SA; Skandinaviska GeneTec AB; Kungsbacka, Sweden) le detector (Antec Leoude; Zoecw Legew; Zoecw Leben); , The Netherlands) e sebelisitsoeng ka selefouno ea phallo ea phallo ea VT-03 (Antec Leyden) e ile ea sebelisoa. Karolo ea selefouno (pH 5.6), e nang le sulphonic acid 10 mM, citric acid 200 mM, sodium citrate 200 mM, 10% EDTA, 30% MeOH, e ne e hloekisoa e sebelisa filthara ea 0.2 μm membrane (GH Polypro; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman; PALL Gelman); Lund, Sweden). Mokhahlelo oa selefouno o ile oa hlahisoa ka lebelo la phallo ea 0.2 ml / min e fetisang draasser (Kovalent AB), mme mohlahlobi o ne a hlahisoa haholo ho + 0.4 V.

Kamora hore liteko tsa maiketsetso li phethe, litoeba li ile tsa emisoa, mme lipatlisiso li entsoe ka pontamine leholimo le leputse la 6BX ho tsamaisa tlhahlobo ea lehae. Mabili a ne a kentsoe sesebelisoa sa vibroslice (752 M Vibroslice; Campden Instruments Ltd., Loughborough, UK) mme a khaoloa ka likarolo tsa 50 μm. Tikoloho eo e ne e fumaneha hokae ka hore e shebe lintho tse ngata ho feta ka microscopy e bobebe. Boemo bo nepahetseng ba phuputso bo netefalitsoe (Franklin le Paxinos, 1997) mme ke litoeba feela tse nang le lipalo tse nepahetseng tse sebelisitsoeng tlhahlobisong ea lipalo.

 

 

2.6. Phekolo le ho arohana

Litlamorao kalafo ea JMV2959 maemong a MEAP, DynB le LeuArg libakeng tse amanang le moputso li ile tsa hlahlojoa. Litsuonyana li ne li kenngoa ka JMV2959 (6 mg / kg, ip, n= 8) kapa bophahamo ba koloi bo lekanang (ip, n= 8) ka matsatsi a mahlano a latelang. Metsotsoana ea 20 kamora ho ente ea ho qetela litoeba li ile tsa etsoa sehlabelo mme masale a tsoang litoeba tsena a bokelloa. Litoeba tse arohaneng li ne li kentsoe ke ghrelin (0.33 mg / kg, ip, n= 8) kapa bophahamo ba koloi bo lekanang (ip, n= 8) ka matsatsi a mahlano a latelang. Metsotso e mehlano ka mor'a ho tsoa ka ente ea ho qetela litoeba li ile tsa etsoa sehlabelo 'me bokelloa ba methapo ena bo bokelloa. The amygdala, striatum, preortal cortex, VTA le hippocampus li ile tsa qhaloa ka potlako 'me hang-hang tsa beoa leqhoeng le omileng mme tsa bolokoa ho −80 ° C ho fihlela ts'ebetso e tsoelang pele.

 

 

2.7. Ts'ebetso ea maemo a peptide ea opioid

Mekhoa ea ho tlosa homogenisation le peptide e ile ea latela mokhoa o tloaelehileng, o neng o hlalositsoe ka botlalo (Nylander et al., 1997). Ka bokhutšoanyane, ho ne ho kenyelitsoe asiti (95 ° C) acetic acid (1 M) ho disampole tse neng li le leqhoa. Mehlala eo e ne e futhumatsoa ka bateng ea metsi (95 ° C) bakeng sa 5 min, e kentsoe leqhoeng ebe e homogenised le Branson Sonifier (Danbury, CT, USA). Homogenate e ile ea nchafatsoa hape ho 95 ° C bakeng sa 5 min mme ea koaheloa ka leqhoa pele ho centrifugation bakeng sa 15 min ho 4 ° C le 12,074 ×g ho Beckman GS-15R centrifuge (Fullerton, CA, USA). Lintho tse qotsitsoeng li ile tsa hloekisoa le ho feta ho ea ka mokhoa o hlalositsoeng pele (Nylander et al., 1997). Likaroloana tse peli li ile tsa bokelloa: karolo ea III (Leu-Arg le MEAP) le karolo ea V (DynB). Mehlala ena e ne e omisitsoe ho vacuum centrifuge (Savant SpeedVac Plus SC210A; Thermo Science science Inc., Waltham, MA USA) mme e bolokiloe ka sehatsetsing (−20 ° C) ho fihlela tlhahlobo ea peptide.

Litekanyetso tsa immunoreactive (ir) tsa DynB, LeuArg le MEAP li ile tsa hlahlojoa ka li-radioimmunoassay le li-protocol li hlalositsoe ka botlalo libakeng tse ling (Nylander et al., 1997). Thupelong ea DynB, IgG e lwantshang lipōli (GARGG; Bachem, Bubendorf, Switzerland) e ne e sebelisoa ho arohanya peptide ea mahala le e thibelang motho. Dyn antiserum (113 +) e sebelisitsoe ka har'a lethala la ho qetela la 1: 600000. Ho etsa-sefapanano le Dyn e kholo e ne e le 100% mme le DynB (1-29) 1%. Ha ho ts'ebeliso ea sefapano le li-peptide tse ling tsa opioid tse ileng tsa bonoa. Bukeng ea LeuArg le MEAP, ho emisoa ha mashala ho ne ho sebelisoa ho arola peptide ea mahala le e thibelang motho. Bakeng sa antiserum ea LeuArg (91: 6D +, X -UMXD ea ho qetela): 1), ts'ebeliso ea lipalo e ne e le tlase ho 60000% bakeng sa Leu-enkephalin le MEAP, 0.01% bakeng sa DynB, 0.02% bakeng sa DynA, le 0.04% bakeng sa alpha-neoendorph. MeAP antiserum 0.08: 90D (II) e sebelisitsoe ka har'a lethala la ho qetela la 3: 1 160. Re-reaction re le Met-enkephalin, Met-enkephalin-Arg6, Met-enkephalin-Arg6Gly7Leu8, Leu-enkephalin le Leu-enkephalin-Arg6 e ne e le <0.1%

 

 

 

2.8. Tlhahlobo ea statistical

Lintlha tsa mosebetsi oa locomotor li ile tsa hlahlojoa ke ANO ea tsela e le 'ngoe e lateloang ke liteko tsa Bonferroni tsa post-hoc. Lintlha tsa maemo a khethollo ea maemo li hlahlobisitsoe ke ba sa lefelloang t-etona. Liteko tsa Microbalalysis li ile tsa hlahlojoa ke ANOVA ea mekhoa e 'meli e lateloang ke tlhahlobo ea Bonferroni kamora ho hoc ea lipapiso lipakeng tsa kalafo e fapaneng le ka kotloloho maemong a fanoeng. Mekhahlelo ea peptide e ile ea hlahlojoa le ea sa phuthoang t-etona. Lintlha li hlahisitsoe e le mokhoa oa ± SEM. Boleng ba monyetla oa P<0.05 e ne e nkuoa e le ea bohlokoa lipalo-palo.

 

 

 

3. Liphetho

 

 

3.1. Liphetho tsa JMV2959 ho morphine-inducing locomotor stimulation, accumbal dopamine ho lokolloa le sebaka se ratoang ke litoeba

Phello e akaretsang ea kalafo e fumanoe ts'ebetsong ea locomotor ho litoeba ho latela tsamaiso ea methapo ea morphine (20 mg / kg) le JMV2959 (6 mg / kg) (F (3,27) = 7.409, P= 0.0009; n= 8 ea Veh-Veh, JMV2959-Veh, JMV2959-Morph le n= 7 ea Veh-Morph). Joalokaha ho bontšitsoe Setšoantšo sa 1A, tlhahlobo ea posthoc e senotse hore kalafo ea pele ho nako ka ente e le 'ngoe ea JMV2959 (P<0.001) e fokolitse haholo ts'usumetso ea morphine e bakiloeng ke locomotor (P<0.01 Veh – Veh vs Veh – Morph). Tekanyetso e khethiloeng ea JMV2959 e ne e sena phello mesebetsing ea locomotor ha e bapisoa le kalafo ea koloi (P> 0.05). Ho ne ho se na phapang karabong ea tšebetso ea literene litoeba tse sebetsoang ke koloi le litoeba tse tšoaroang ke JMV2959-morhpine (P> 0.05).

Feiga. 1. E bula setšoantšo se seholo  

Setšoantšo sa 1

GHS-R1A antagonist JMV2959 e fana ka maikutlo a tšusumetso ea locomotor ea morphine, ho tsoa ha dopamine le boemo bo khetholloang ke litoeba. (A) Morphine-indedu (20 mg / kg ip) tsusumetso ea phenomotor e ile ea hlahisoa ka ente e le 'ngoe ea JMV2959 (6 mg / kg ip) (n= 7-8 sehlopheng ka seng; **P<0.01, ***P<0.001 tsela e le 'ngoe ANOVA e lateloang ke tlhahlobo ea Bonferroni post-hoc). (B) Boemo bo khethiloeng ke morphine (20 mg / kg ip) boemong ba maemo (CPP) bo ile ba fokotsoa ke ente e le 'ngoe e matla ea JMV2959 (6 mg / kg ip) ho litoeba (n= 8 sehlopheng ka seng, *P<0.05, tlhatlhobo ea unpaired). (C) Pele re bonts'itse phello e kholo ea morphine (20 mg / kg ip) ho eketsa tokollo ea dopamine ha e bapisoa le kalafo ea koloi (karohano ea nako 40-180 min (P<0.001), Veh-Veh vs Veh – Morph). Joalokaha ho bontšitsoe ho (C) kalafo ea pele ho JPVNNXX (2959 mg / kg ip) e bontsitse keketseho e tlisoang ke morphine ea ho lokolloa ha dopamine ha e bapisoa le kalafo ea pele ho koloi ka nako 6-40 le 100-140 min (##P<0.01, ###P <0.001, JMV2959-Morph ha e bapisoa le kalafo ea Veh-Morph). Tekanyo e khethiloeng ea JMV2959 e ne e se na tšusumetso e kholo tokollong ea accumbal dopamine ha e bapisoa le kalafo ea koloi nako efe kapa efe (P> 0.05, Veh-Veh vs JMV2959-Veh). JMV2959 e fokotsehile, empa ha ea ka ea thibela ka ho felletseng, morphine e ile ea susumetsa ho lokolloa ha dopamine ka nako ea karohano ea 60-140 (*P<0.05, **P<0.01, ***P <0.001, JMV2959-Morph ha e bapisoa le kalafo ea Veh-Morph). Metsu e emela lintlha tsa nako ea ente ea JMV2959, koloi le morphine. Boitsebiso bo hlahlojoang ka ANOVA ea litsela tse peli bo lateloang ke tlhahlobo ea Bonferroni post-hoc (n= 8 sehlopheng ka seng). Veh-veh (Sekwere), Veh-Morph (Rhomb), JMV2959-Veh (Triangle), JMV2959-Morph (sedikadikwe). Lits'oants'o tsohle li emela ± SEM.

Morphine-indedu (20 mg / kg) (Morph-Veh) sebaka se ratoang ka mokhoa o hlophisitsoeng se ile sa fihleloa haholo ka ente e le 'ngoe e mpe ea JMV2959 (6 mg / kg) (Morph-JMV2959) ka letsatsi la maemo a morao-rao (P= 0.025, n= 8 sehlopheng ka seng; Setšoantšo sa 1B).

Litekanyo tsa "scopal Micracalalysis" tsa dopamine ho litoeba li senotse phello ea mantlha ea kalafo (F(3,33) = 24.15, P<0.0001), nako F(11,308) = 7.05, P<0.0001) le kalafo × tšebelisano ea nako (F(11,308) = 8.63, P<0.0001) (Setšoantšo sa 1C; n= 8 sehlopheng ka seng). Morphine e ile ea eketsa amanang le dopamine e lokolloang ea dopamine e amanang le kalafo ea makoloi ka nako ea karohano ea 40-180 min (P<0.001). Joalokaha ho bontšitsoe ho Setšoantšo sa 1C phello ena e fokotsoe ke kalafo ea pele ho JMV2959 ka nako 40-80 (P<0.01), 100 (P<0.001), 140 (P<0.01) le 160-180 min (P<0.001). JMV2959 e fokotsehile, empa ha ea ka ea thibela ka ho felletseng, morphine e bakile accumbal dopamine ho lokolloa kaha ho bile le phapang lipakeng tsa kalafo ea koloi le kalafo ea JMV2959-morphine ka nako ea nako 60-80 (P<0.01), 100 (P<0.001), 140 (P<0.01) le 160 min (P<0.05). Tekanyo e khethiloeng ea JMV2959 e ne e se na tšusumetso e kholo tokollong ea accumbal dopamine ha e bapisoa le kalafo ea koloi nako efe kapa efe (P> 0.05).

 

 

 

3.2. Litlamorao tsa kalafo e sa foleng ea JMV2959 kapa kalafo ea ghrelin maemong a peptide ea opioid

Tekanyo ea "irun" (ir) ea li-peptide tse tharo libakeng tsa boko tse lekantsoeng li ka fumanoa ho Lethathamo 1, Lethathamo 2. Phekolo ea Sub-chronic JMV2959 e ile ea eketsa haholo maemo a MEAP ho VTA, DynB ho hippocampus le LeuArg ho striatum (Lethathamo 1). Ho ne ho se na liphapang libakeng tse ling tse ileng tsa fuputsoa e leng amygdala le preortal cortex. Phekolo ea nakoana ea ghrelin ha ea ka ea fetola haholo maemo a MEAP, DynB kapa LeuArg (Lethathamo 2).

Phekolo ea 1Sub-chronic JMV2959 kalafo e ile ea eketsa haholo boemo ba Met5-enkephalin-Arg6Phe7 (MEAP) sebakeng sa ventral tegmental (VTA), maemo a ir DDororphin B (DynB) ho hippocampus (HC) hammoho le maemo a ir le Leu-enkephalin-Arg6 (LeuArg) ho striatum (STR) bapisoa le kalafo ea makoloi. Ho ne ho se na liphapang libakeng tse ling tse batlisisitsoeng. Lits'oants'o tsohle li emela ± SEM. (amygdala (AMY), le preortal cortex (PFC).
 JMV2959Koloip-Value
 Maemo a Ir MEAP
AMY14.52 ± 3.9115.61 ± 4.370.838
STR43.47 ± 5.5447.60 ± 7.940.754
PFC3.61 ± 0.902.94 ± 0.410.450
VTA8.69 ± 0.754.63 ± 0.420.003
HC4.52 ± 0.802.56 ± 0.230.170
 Maemo a Ir DynB
AMY2.56 ± 0.411.90 ± 0.250.759
STR8.69 ± 0.8910.17 ± 0.910.547
PFC2.24 ± 0.361.60 ± 0.200.169
VTA8.89 ± 0.555.98 ± 0.210.079
HC3.70 ± 0.412.36 ± 0.190.042
 Maemo a Ir LeuArg
AMY13.46 ± 1.6911.07 ± 1.450.270
STR14.50 ± 0.8912.12 ± 0.930.046
PFC11.21 ± 1.3210.80 ± 1.440.776
VTA12.96 ± 1.6310.96 ± 1.390.245
HC5.29 ± 0.755.67 ± 0.720.663
 
Phekolo ea 2Sub-Chronic ghrelin e sa fetoleng ha e fetole maemo a ir5-enkephalin-Arg6Phe7 (MEAP), dynorphin B (DynB) kapa Leu-enkephalin-Arg6 (LeuArg) sebakeng se seng le se seng sa moputso se amanang le moputso, ke hore. sebaka sa ventral tegmental (VTA), amygdala (AMY), striatum (STR), preortalal cortex (PFC) le hippocampus (HC). Lits'oants'o tsohle li emela ± SEM.
 GhrelinKoloip-Value
 Maemo a Ir MEAP
AMY12.00 ± 3.9115.46 ± 3.020.517
STR43.59 ± 7.2461.15 ± 12.460.176
PFC3.75 ± 0.463.17 ± 0.640.550
VTA11.96 ± 1.0310.60 ± 0.910.249
HC6.75 ± 1.885.20 ± 1.010.314
 Maemo a Ir DynB
AMY3.97 ± 1.095.42 ± 2.270.488
STR11.15 ± 0.8913.03 ± 2.410.434
PFC3.23 ± 0.502.38 ± 0.180.072
VTA5.11 ± 0.158.25 ± 1.590.070
HC4.32 ± 0.873.19 ± 0.290.095
 Maemo a Ir LeuArg
AMY9.67 ± 1.539.47 ± 1.290.928
STR8.69 ± 0.878.87 ± 0.440.875
PFC4.61 ± 0.474.47 ± 0.390.921
VTA8.35 ± 1.046.99 ± 0.420.407
HC4.97 ± 0.503.47 ± 0.410.086
 

 

 

 

4. Puisano

Boithuto ba hona joale bo boetse bo tšehetsa khopolo-taba ea hore karolo ea 'mele ea orexigenic peptide e kenyelletsa taelo ea moputso. Ho joalo, re bonts'itse hore tsamaiso e poteletseng ea mohanyetsi oa GHS-R1A e bonts'a bokhoni ba morphine ho baka tšusumetso ea locomotor, ho eketsa maemo a dopamine ho NAc le ho etsa hore sebaka se ratehe sa litoeba. Re fumane hape hore sub-chronic JMV2959, empa eseng ghrelin, kalafo e ile ea eketsa maemo a ir tis a MEAP ho VTA, DynB ka hippocampus le LeuArg ka striatum, e fana ka bopaki ba pele ba hore bokhoni ba ho bua ka ghrelin ho saena ho matlafatsa bo ka kenyeletsa li-peptide tsa opioid .

Lintlha tse hlahisitsoeng mona li bontša hore khanyetsano ea GHS-R1A e ama bokhoni ba morphine ho kenya ts'ebetso ea mesolimbic dopamine system ho litoeba. Ho latela liphuputso tse bonts'ang hore JMV2959 e thibela bokhoni ba morphine ho eketsa maemo a kantle ho lisele tsa accumbal dopamine le ho baka boits'oaro bo totobetseng ho likhoto (Sustkova-Fiserova et al., 2014). Ka ts'ehetso, tsamaiso e bohareng ea ghrelin e eketsa pherekano, empa eseng palo ea likhatiso tse mafolofolo tsa lever, lenaneong le matlafatsang la karolelano ho likhoto tse itaolang, (Maric et al., 2012). Khang ea hore ghrelin e tšoaeang bokhoba ba lithethefatsi e ts'ehetsoa hape ke liphuputso tse bonts'ang hore JMV2959 e fokotsa ho noa le tšusumetso ea ho noa joala likhoto le hore amphetamine, cocaine le nicotine e bakiloeng ke moputso o koetsoe ke lehloeo la GHS-R1A ka litoeba ( bakeng sa tlhahlobo sheba Engel le Jerlhag (2014)) le hore liphatsa tsa lefutso liphatseng tsa lefutso tse amanang le ghrelin li amahanngoa le ho noa joala, ho tsuba le amphetamine (bakeng sa tlhahlobo bona Engel le Jerlhag (2014)).

Liphumano tsa hona joale tse nang le litekanyetso tse eketsehang tsa li-peptide tsa opioid ho striatum, VTA le hippocampus kamora kalafo ea JMV2959 ea kalafo e sa foleng li fana ka maikutlo a hore ho be le tšebelisano ea pele lipakeng tsa li-peptide tsa opioid le li-ghrelin. Li-opioid tsa endo native li kenyellelitsoe liphellong tse khotsofatsang, eseng feela tse susumetsoang ke opioids empa le lithethefatsi tse ling tsa tlhekefetso le meputso ea tlhaho, le lits'ebetsong tse feto-fetohang tse boneng kamora ho pepesetsoa hoa lithethefatsi khafetsa (Trigo et al., 2010, Van Ree et al., 2000). Ka sebele ts'ebetso ea sisteme ea mesolimbic dopamine e laoloa ke li-opioid tsa endo native maemong ka bobeli a VTA le NAc (Hirose et al., 2005, Spanagel et al., 1992) le liketso li bontšitsoe e le tse tobileng kapa tse sa tobang ka ho feto-fetoha ha li-transmitters tse ling (Charbogne et al., 2014).

Re fumane mona hore kalafo ea sub-chronic JMV2959 e ile ea eketsa maemo a MEAP ho VTA. MEAP e tsoa ho proenkephalin feela 'me e ne e sebelisoa e le lets'oao la li-peptide tsa proenkephalin tse sebetsang haholo ka li-receptor tsa δ-opioid. Re kholoa maikutlo a hore maemo a eketsehang a endo native MEAP ho VTA e latelang kalafo ea JMV2959 a ka thibela bokhoni ba morphine ba ho fokotsa GABA-inhibition ea mesoaccumbal dopamine neurons (Johnson le North, 1992), tse ka bakang litlamorao tse fokotsehileng tsa morphine tse hlahisitsoeng ka mor'a JMV2959. Ka tšehetso, GHS-R1A e fumaneha ka li-interneuron tsa GABAergic ho VTA (Abizaid et al., 2006). Ho feta moo, lithuto tsa pejana li bontšitse hore infra-VTA infra ea JMV2959, dessyecik Mechine e sa tsejoeng, moputso o hlahisoang ke moputso o hlahisoang ke ghrelin-ikiwa (Jerlhag et al., 2011) hammoho le tšebeliso ea lijo tsa ghrelin-mediated sucrose ka litoeba (Skibicka et al., 2011), li fana ka maikutlo a hore likarolo tsa likarolo tsa GHS-R1A li bohlokoa bakeng sa taolo ea moputso. Ho ts'ehetsa khang e joalo ke lintho tse fumanoeng tse bonts'a hore tlala e 'ngoe e laolang li-peptide, joalo ka galanin le orexin, li loants'oa thepa e khahlisang ea morphine dessyecik mekhoa ea lehae kahare ho VTA (Narita et al., 2006, Richardson le Aston-Jones, 2012).

Boemong ba striatum, re fumane hore sub-chronic JMV2959 e eketse litekanyetso tsa LeuArg, e fana ka maikutlo a hore bokhoni ba JMV2959 ba ho fumana boiketlo ba sebaka sa morphine, boithuto ba dopamine le ho ts'oaroa ha locomotor ho latela, bonyane ka karolo, ho ntlafatseng accumbal δ- ts'ebetso ea opioid receptor. Ho eketseha ha litekanyetso tsa LeuArg ho ka bakoa ke ho fetoha ha enzymatic peptides ea dynorphin ho isa enkephalin kapa ho tsoa ho nts'etsopele e ntlafalitsoeng ea Dyn ho NAc e le karabelo ho dopamine e eketsehileng, e lateloang ke tlholeho ho LeuArg. Liphuputso tse fetileng tsa albeit li bontšitse hore ts'ebetso ea mesolimbic dopamine system e laoloa dessyecik Li-receptor tsa κ-opioid ho NAc (Spanagel et al., 1992) le li-endogenous κ-opioid receptors li fana ka thibelo ea tonic ho tsebiso e thibelang dopamine neurotransuction le ho fumana cocaine e hlahisitsoeng ea dopamine ho NAc (Chefer et al., 2005), ha rea ​​ka ra etsa joalo. bonts'a hore JMV2959 e fetola maemo a ir DynB ho striatum. Ka hona, lithuto tse ling li ntlafalitsoe ho li-peptide tsa prodynorphin ho hlakisa tšebelisano lipakeng tsa GHS-R1A antagonism le dynorphin.

Thutong ea hona joale re boetse re bonts'itse hore kalafo ea JMV2959 e eketsa haholo maemo a hippocampal DynB. Ghrelin e eketsa kopanyo ea mohopolo le moralo oa mokokotlo oa dendritic, e hlahisa bokhoni ba nako e telele mme e etsa hore ho be bonolo ho hopola dessyecik hippocampal GHS-R1A ka litoeba (Carlini et al., 2010, Diano et al., 2006). Ntle le moo, litoeba tsa GHS-R1A tse tsoang lefatšeng ka bophara li bonts'a mohopolo o ntlafalitsoeng oa tlhahlobo litlhahlobisong tsa metsi a Morris le mohopolo o ferekaneng oa kelello maemong a tšabo ha a bapisoa le litoeba tsa mofuta oa hlaha (Albarran-Zeckler et al., 2012). Li-peptide tsa Dynorphin, ho kenyelletsa DynB, li na le li-hippocampus tse ngata 'me li tseba ho sebelisa nako e telele (Chavkin et al., 1985, Wagner et al., 1993) hammoho le ho sitisa ho ithuta ka sepakapaka ho litoeba (Sandin et al., 1998). Ka hona, re nahana ka maikutlo a hore mohanyetsi oa GHR-R1A a ka boloka mohopolo oa moputso ka ho thibela monyetla oa nako e telele oa hippocampal dessyecik ts'ebetso ea DynB. Ka kopanelo, lintlha tsena li fana ka mochine o ka sebelisang mohopolo oo JMV2959 ka eona dessyecik li-peptide tsa opioid li ka fetola matlafatso. Leha ho le joalo, li-receptor tsa opioid li ajoa ka bongata bokong, li fana ka maikutlo a hore libaka tse ling, tse sa kenyelelitsoeng thutong ea hona joale, li ka ba le karolo ho GHS-R1A moputso o laoloang ke morphine-ikiwa. Mohlala, tšebeliso ea lijo tse tlisoang ke moea oa ghrelin le khatello ea lever bakeng sa sucrose e fokotsoa ke tsamaiso ea bohareng kapa ea methapo ea methapo ea methapo ea kutlo (qo-opioid receptor antagonist (Romero-Pico et al., 2013). Leha ho le joalo, karolo ea li-peptide tsa opioid libakeng tse ling e hloka ho hlakisoa lithutong tse tlang.

Li-ligands tsa endo native μ-receptor ligands, endomorphin le beta-endorphin, ha lia ka tsa hlahlojoa mona hore re ka se khone ho hlahisa sephetho sa JMV2959 ho li-peptide tsena. Ehlile thepa ea moputso ea morphine e kenyelletsa li-receptor tsa μ-opioid ho VTA hammoho le NAc (Hirose et al., 2005, Johnson le North, 1992, Murakawa et al., 2004, Yoshida et al., 1999). Leha ho le joalo, mohanyetsi oa μ-receptor antagonist ha a fumane lijo tse kenang ka sejo sa ghrelin (Naleid et al., 2005) kapa tšusumetso ea tšusumetso ea ghrelin le tšusumetso ea dumbamine ea dumbamine (Jerlhag et al., 2011), e fana ka maikutlo a hore bokhoni ba GHSR- Mohanyetsi oa 1A ho laola matlafatso ha a kenyeletse li-μ-receptors. Ka lehlakoreng le leng, JMV2959 e amme peptides ea opioid e nkiloeng ho proenkephalin le prodynorphin e bonts'a hore ba kanna ba kenya letsoho litlamorao tse hlahisitsoeng ke bahanyetsi ba GHSR-1A.

Le ha lithuto tsa pejana li bonts'itse hore tsamaiso ea li-ghrelin systemic e baka moputso (Jerlhag, 2008) hammoho le ho ntlafatsa thepa e khotsofatsang ea lithethefatsi tse lemalloang (bakeng sa tlhahlobo ea bona Engel le Jerlhag (2014), mona re bonts'a hore kalafo ea boemo bo tlase ea ghrelin ha ea ka ea fetoha litekanyetso tsa ir tis tsa li-peptide tsa opioid ho efe kapa efe ea libaka tse ithutoang tsa moputso. Tsamaiso ea systemic ghrelin accine expression ea c-fos libakeng tsa hypothalamic, empa eseng libakeng tsa mesolimbic le hippocampal (Pirnik et al., 2011) le ho tlangoa ha ghrelin e ngotsoeng ka fluorescently e lekanyelitsoe ho li-neurons tse laolang lijo tsa hypothalamus (Schaeffer et al., 2013 ). Ho kopantsoe hammoho le liphumano tse bonts'ang hore ghrelin, ntle le ho latela palo ea li-hypothalamus, e ke ke ea bonoa libakeng tse tebileng tsa boko tse latelang tsamaiso ea sepakapakeng sa ghrelin (Furness et al., 2011, Grouselle et al., 2008, Sakata et al., 2009 ), e hlahisa monyetla oa hore systemic ghrelin e qobelle mokhoa oa moputso dessyecik mekhoa e sa sebetseng e ikemetseng ea li-opioid tsa mehleng ea khale. Ka ts'ehetso, ho lokolloa ha moea oa ghrelin-instipal dumbamine ho hloka ho phahamisa orexigenic hypothalamic signaling (Cone et al., 2014), tsamaiso ea sepakapaka sa sepakapaka ha e fetole tšebeliso ea lino tse tahang ho litoeba (Lyons et al., 2008) le hore ho se lekane hoa ghrelin e potolohang ha e hlahise joala. - Moputso o fumanoeng litoeba kapa lino tse tahang litekong (Jerlhag et al., ka khatiso). Monyetla oa hore tsamaiso e ka tlase e sa feleng ea ghrelin e eketsa maemo a ir tis tsa li-peptide tsa opioids li lokela ho tsotelloa leha ho le joalo sena se hloka ho fuputsoa ka botlalo lithutong tse tlang.

Bokhoni ba lithethefatsi tse lemalloang ho baka tšusumetso, ho lokolloa ha dopamine le ho etsa hore sebaka se ratoang sebakeng se ratoe li amana haufi le thepa ea matla ea litlhare tse tlatsetsang mme litekanyetso tsena li nkuoa e le karolo ea ts'ebetso ea bokhoba ba tahi (Wise, 2004). Ka lebaka la hore mona re fumane hore JMV2959 e lumellana le litekanyetso tsena tsa meputso ho litoeba re nahana hore GHS-R1A e ka bapala karolo ea bohlokoa lits'ebetsong tsa bokhoba, le hore li-opioids tsa endo native li kenya letsoho lits'ebetsong tsena. Ka kopanelo lintlha tsena li bonts'a hore bahanyetsi ba GHS-R1A ba lokela ho hlakisoa e le kalafo ea ts'ebeliso ea lithethefatsi.

Karolo ea mohloli oa lichelete

JE le EJ ba ts'ehelitsoe ka lithuso tse tsoang ho Lekhotla la Lipatlisiso la Sweden (Grant no. 2011-4646, 2009-2782 le 2011-4819), motheo oa boko ba Sweden, LUA / ALF (Grant no. 148251) ba tsoang Sepetlele sa Sahlgrenska University, Alcohol Lekhotla la lipatlisiso la Sweden le rekisang joala ba litloholo le metheo ea Adlerbertska, Fredrik le Ingrid Thuring, Tore Nilsson, Längmanska, Torsten le Ragnar Söderberg, Wilhelm le Martina Lundgren, NovoNordisk, Knut le Alice Wallenberg, Magnus Bergvall, Anons. , Mokhatlo oa Sweden oa Bongaka, Mokhatlo oa Sweden oa Phuputso ea Bongaka le Gothenburg Psychiatry Research Foundation. Lekhotla la lipatlisiso tsa joala la Sweden Alcohol Retailing Monopoly le Lekhotla la Lipatlisiso la Sweden (K2012-61X-22090-01-3) li tšehelitsoe ka IN. Mehloli ea lichelete e ne e se na karolo moqopolong oa thuto, ho bokelleng, ho hlahlobisisa le ho toloka data, ha ho ngoloa tlaleho, le ha ho etsoa qeto ea ho phatlalatsa tlhaiso-leseling.

 

 

 

phehisa

JAE e qapile thuto mme e ngola mongolo. O ILE a ngola karolo e ngotsoeng ka letsoho, mosebetsing. EJ o qapile thuto, a ngola protocol, a khona ho batla lingoliloeng, ho sekaseka le ho etsa tlhahlobo ea lipalo mme a ngola moralo oa pele oa buka e ngotsoeng ka letsoho. Bangoli bohle ba kentse letsoho ho tšehetsa buka e ngotsoeng ea ho qetela.

 

 

 

 

Khohlano ea thahasello

EJ e fumane tšehetso ea lichelete ho tsoa ho Novo Nordisk Foundation. Sena ha se fetole lingoloa tsa lingoli mabapi le ho arolelana lintlha le lisebelisoa. Bangoli ba setseng ha ba phatlalatse hore ha ho likhohlano tsa phaello.

 

 

Liteboho

Britt-Mari Larsson, Kenn Johannessen, Qin Zhou le Lova Greekström ba ananeloa ka teboho bakeng sa setsebi le thuso ea bohlokoa ea tekheniki. GHS-R1A antagonist JMV2959 e fanoe ke Æterna Zentaris. Moprofesa Jean Martinez le Dr. Jean-Alain Fehrentz ba amoheloa ka tlhahiso ea JMV2959

 

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