Mokhoa oa Opioid le Tšebetso ea Lijo: Mekhoa ea Homeostatic le Hedonic (2012)

Linnete tsa Obes 2012; 5: 196-207MOTHE: 10.1159 / 000338163

Nogueiras R. · Romero-Picó A. · Vazquez MJ · Novelle MG · López M. · Diéguez C.

Lefapha la Boikoetliso, Sekolo sa Bongaka, Univesithi ea Santiago de Compostela - Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

 

inahaneloang

Li-opioids li bohlokoa lits'ebetsong tsa moputso tse lebisang liketsong tsa ho lemalla joalo ka ho itaola li-opioid le lithethefatsi tse ling tsa tlhekefetso ho kenyeletsa nikotine le joala. Li-opioids li boetse li kenella khokahanong e pharalletseng ea neural e laolang boitšoaro ba ho ja, e amang mekhoa ea homeostatic le hedonic. Ka kutloisiso ena, li-opioid li bohlokoa haholo ho fetoleng lijo tse fumanehang habonolo, 'me bahanyetsi ba opioid ba thabela ho ja lithethefatsi le ho lakatsa lijo tse fumanehang habonolo. Kahoo, ho lakatsa lijo tse matlafatsoang ho ka nkoa e le mofuta oa bokhoba bo amanang le opioid. Ho na le malapa a mararo a mantlha a li-opioid receptors (µ, ĸ, le δ) tseo li-receptors li amehang haholo moputsong. Tsamaiso ea "li-agonist" tse ikhethileng ho NAcc ea litoeba e etsa hore ho fepa le ho liphoofolo tse nang le tlala, ha Tsamaiso ea "antagonists" e fokotsa tšebeliso ea lijo. Boithuto ba pharmacological bo boetse bo supa karolo ea li-receptors tsa ĸ- le δ-opioid. Lintlha tsa pele ho mehlala ea li-transgenic knockout li fana ka maikutlo a hore litoeba tse haellang tse ling tsa li-receptor tsena li loantšana le botenya bo matla bo bakiloeng ke botenya.


Selelekela

Li-opioids li sebelisitsoe e le li-analgesics ka makholo a lilemo, mme ts'ebeliso ea opium e le moemeli oa tranquilizer e na le nalane ea lilemo tsa 5,000. Ka li-1970s, ho ile ha fumaneha hore liphoofolo li entse li-opioids tsa endo native [1]. Li-peptides tse tsoang ka ntle tsa tlhaho li kenyelletsa li-endorphin, enkephalin, dynorphin le endomorphin hape li sebetsa ka li-receptor tse tharo tse fapaneng, µ-, δ- le ĸ-opioid receptor (MOR, DOR le KOR), bao e leng litho tsa lelapa le phahameng la protheine ea G e kopantsoeng. li-receptors. β-Endorphin e hlahisoa ka liseleng tse bokellaneng ba "hypothalamus" le bokong ba methapo ea kelello. E sebetsa ka MOR mme e susumetsa takatso ea takatso hammoho le boitšoaro ba thobalano. Enkephalin e hasoa hohle bokong 'me e sebetsa ka MOR le DOR. Dynorphin e sebetsa ka KOR mme e fumanoa mokokotlong oa mokokotlo le likarolong tse ngata tsa boko, ho kenyelletsa hypothalamus [1].

Ho ja ha se mokhoa o bonolo, o litšila. E hloka sete ea mesebetsi e lokelang ho etsoa ke methapo ea methapo e bohareng le e potelletseng ho hokahanya ho qalisoa ha sejo sa lijo, ho fumana lijo, tšebeliso ea lijo tse rekiloeng, le ho felisoa ha lijo [2]. Boholo ba mesebetsi ena ke boits'oaro bo ithutoang kamora ho khoesoa. Ka hona, hona joale ho na le tlhokomeliso ea bokahohle hore CNS ka kakaretso, ho fapana le setsi se ikhethileng, ke hore, hypothalamus, e kenang taolong ea boitšoaro ba ho ja. Har'a palo e kholo ea ts'ebetso ea bioloji, sistimi ea opioid e amohetse e bapala karolo ea bohlokoa lits'ebetsong tsa moputso oa neural tse lebisang ho boits'oaro bo kenyelletsang joalo ka ho itaola ha li-agonists tsa opioid ka kotloloho le lithethefatsi tse ling tsa tlhekefetso tse joalo ka nicotine le joala. Mefuta e mengata ea neural e kenyelletsang ts'ebetsong ea bokhoba le eona e kenyelletsa moputso oa lijo. Batho ba hanyetsanang le opioid receptor ba rata ho sebelisa lithethefatsi tse lemalloang ebile ba lakatsa lijo tse fumanehang habonolo. Lintlha tse fumanoeng lilemong tsa morao tjena li bonts'itse hore bahanyetsi ba opioid, joalo ka naloxone kapa naltrexone, ba fokotsa ho ja lijo tse matlafatsoang, athe li-agonists tsa opioid receptor, tse kang morphine kapa syntephumin analogues, li eketsa ts'ebeliso ea lijo. Ts'ebetso e matla ea morphine le lithethefatsi tse ling tsa oponid agonist ka kakaretso li eketsa tekanyo ea lijo le phaello ea boima ba 'mele ka tsela e fetohang. Ho fapana le moo, kalafo ea morphine e sa foleng e theola takatso ea lijo le boima ba 'mele. Haholo-holo, tsamaiso ea morphine e sa foleng e lebisitse kemisong ea phepo e sa sebetseng, ha ente ea tse ling tsa li-agonists tsena ka har'a li-nucleus bokellase e lebisitse keketseho e kholo ho fepa lijo tse nang le mafura a mangata ha li bapisoa le lijo tse nang le mafura a fokolang kapa lijo tse nang le mafura a nang le lik'habohaedreite. Polelo ea MOR le ligand preproenkephalin li ile tsa eketseha ka har'a li-bokellase tsa nucleus, preortalal cortex, le hypothalamus ea litoeba tse tsoang ho matamo tse jang lijo tse nang le mafura a mangata. Ha re e kopanya, lintlha tsena li bolela kamano e matla pakeng tsa litsela tse tsamaeang le 'mele, homeostasis ea boima ba' mele, le ho ja lijo tse matlafatsang, haholoholo tse fanang ka moputso [3]. Ho kopana hona ho lebisitse mohopolong oa hore ho se sebetse hantle ha boko ba opioidergic ho ka ba le karolo ho pathophysiology ea botena le linaha tse ling tsa mafu tse amanang le boima ba 'mele bo fetotsoeng.

Tlhahlobo ena e tla shebana le karolo ea bophelo ea meriana le maiketsetso a li-opioid receptors tekong ea matla le mochine o arolang liketso tsa bona. 1). Ho feta moo, re tla akaretsa lithuto tsa morao-rao tsa teko ea bongaka tse bonts'itseng liphetho tse ntle tsa bakuli ba batenya haholo. Ho utloisisa karolo e nepahetseng le mekhoa ea li-receptor tsa opioid ho ka lebisa ho khethollo ea lipheo tse ncha tse lebisitsoeng tseleng e khethehileng ea hedonic ka litoeba le batho.

Setšoantšo sa 1

Liphetho tsa sistimi ea opioid ho matla a lekantsoeng. Li-receptor tsa opioid li fumanoe ho hypothalamus (li-modulating signostatic signals) le libakeng tse ling tse eketsehileng tsa hypothalamic tse kang mesolimbic dopaminergic system (e laolang li-signals tsa hedonic) [66]. Litlamorao tsa sistimi ea opioid ho homeostatic le hedonic taolo ea lijo li thehiloe hantle [67]. Litlaleho tsa morao-rao li boetse li fana ka maikutlo a karolo ea bohlokoa ea endoros MOR [59] le KOR [62] Li-opioid receptors taolong ea tšebeliso ea matla le karohanyo ea limatlafatsi.

http://www.karger.com/WebMaterial/ShowPic/202951

 

Li-Opioid Receptors le Feeding Behafire: Lits'ebetso tsa Homeostatic le Hedonic

Li-receptor tsa opioid li ajoa ka bongata hohle ho ts'ebetso ea methapo e bohareng, mme li fumaneha libakeng tse 'maloa tsa boko tse amanang le taolo ea matla homeostasis. Karolo ea li-receptor tsa opioid ho tekano ea matla e bontšitsoe lilemo tse mashome a 'maloa tse fetileng (e hlahlojoa ho [1,4]). Tlaleho ea pele e bonts'ang hore blockade ea li-receptor tsa opioid e fokotsa tšebeliso ea lijo tse sebelisitsoeng naloxone, mohanyetsi oa kakaretso oa opioid receptor [5]. Ho tloha ka nako eo, liphuputso tse ngata li fumane hore tsamaiso le litloaelo tse akaretsang tsa bahanyetsi ba opioid receptor hangata li theola takatso ea lijo le boima ba 'mele mefuteng ea phepelo, ho kenyelletsa le Zucker ea liphatsa tsa lefutso le likhoto tse matlafatsang tsa lijo.6,7,8,9,10]. Ka lebaka leo, litsebi tsa kelello tsa li-receptor tsa opioid li eketsa tšebeliso ea lijo [11]. Ntle le moo, the MOR gene, haholo-holo genotypes ea rs1799971 ho exon 1 le rs514980 le rs7773995 ho intron 1, li ne li amana hantle le BMI le botenya [12].

Le ha mokhoa o nepahetseng oa molek'hule oa "opioid" o fokotsang takatso ea lijo o sa utloisisoe hantle, lits'ebetso tsa opioid le melanocortin ka kotloloho lia sebelisana. Melanocortins ke lelapa la liprotheine tse fokotsang takatso ea lijo, 'me moetapele oa tsona, ea bitsoang pro-opiomelanocortin (POMC), o kenyelletsa li-hormone tse matlafatsang tsa alpha-melanocyte tse fokotsang takatso ea lijo le beta-endorphin e nang le tšusumetso, har'a lintho tse ling, maikutlo le takatso ea lijo.. Ho khahlisang, li-neurons tsa POMC li hlahisa li-postynaptic MOR tse arabelang ho li-agonist tse khethang li-neurons tsa POMC le tse sitisang ketso ho thunya. Ntle le moo, ts'ebetso ea li-subtypes tse tharo tsa opioid receptor, tse fumanehang litsing tsa GABAergic, e thibela li-neurons tsa POMC tsa Presynaptic. Tsena tsa morao-rao le li-presynaptic tsa li-agioists tsa opioid, hammoho le taba ea hore li-neurons tsa POMC li kopanya le ho lokolla opioid ea nako e telele, li etsa mohlala ka kamano e bohlokoa lipakeng tsa litsamaiso tsena ka bobeli, 'me ea lebisa tekong ea mofuta oa tšebelisano ena [13]. Ho fokotsa tšebeliso ea lijo, melanocortins e sebetsa haholo ka li-receptor tse peli, e leng melanocortin receptor 3 le 4 (MC3R le MC4R). Ho tsosa takatso ea lijo e hlahisoang ke li-peptide tse amanang le agouti (AgRP), mohanyetsi oa nako ea morao oa MC3R le MC4R o fokotsoa ke kalafo ka naloxone [14,15]. Li-receptor tsa opioid tse ikarabellang ts'ebetsong ena li bonahala e le MOR le KOR, kaha ho koaloa ha li-receptor ka bobeli ho hatelletse lijo tsa AgRP tse kenyellelitsoeng ho ja [16]. Leha ho le joalo, blockade ea opioid receptor ka 'ngoe ka thoko ha ea ka ea fetola ketso ea orexigenic ea AgRP [16]. Tšebelisano e haufi pakeng tsa sistimi ea opioid le melanocortin e ile ea ntlafatsoa le ho feta ke ho shebella ha phello ea orexigenic ea beta-endorphin (MOR ligand) e ts'oaroa ke agonist ea MC3R le MC4R [17]. Ka lebaka leo, kalafo e nang le mohanyetsi ea khethiloeng oa MOR e hatelletse ketso ea orexigenic ea molateli oa MD3R / MC4R [17].

Mokena-lipakeng o mong oa bohareng oa boitšoaro ba ho fepa le ho leka-lekanya matla ke neuropeptide Y (NPY). NPY le AgRP li lutse ka har'a hypothalamic arcuate nucleus, 'me li-neuropeptide ka bobeli ke lintlha tse matla tsa orexigenic. Ho na le litlaleho tse 'maloa tse bonts'ang hore phello ea orexigenic ea NPY e itšetlehile ka sistimi ea opioid. Mohlala, tsamaiso e bohareng le e poteletseng ea naloxone e fokotsa boitšoaro bo fetisang ba ho fepa ba NPY [18,19,20,21]. Li-receptor tsa bohlokoa ka ho fetisisa tsa opioid tse buellang liketso tsa NPY ke MOR le KOR, joalo ka ha ho bontšoa ke 'nete ea hore NorBIN (KOR antagonist) le β-FNA (MOR antagonist) ba ne ba sebetsa hantle ho ferekanya phepelo ea NPY e hlahisitsoeng, athe naltrindole (DOR antagonist) e entse se fetole litlamorao tsa NPY [18].

Orexin A ke mofuta o mong oa neuropeptide orexigenic o fumanehang ho hypothalamus ea morao. Litlaleho tse fapaneng li bontšitse hore boitsoaro bo tlisoang ke orexin bo fetoloa ke li-opioids. Hypothalamic ente ea orexin e ekelitse polelo ea mofuta oa enkephalin sebakeng sa "ventral tegmental", "nucleusular" le "nucleus" e ka hare ea "amregdale" e fanang ka maikutlo a ho kenya letsoho phello ea eona ea orexigenic [22]. Ho latela sena, naltrexone e ile ea tšoaea ketso ea orexigenic ea orexin A [23]. Ho khahlisang, naltrexone e boetse e thibetse litlamorao tsa orexin A ha e ne e tsamaisoa ka kotlolloho ka har'a li-nucleus accumbens, e bonts'a hore orexin e hloka ho nka khato ka libaka tse amanang le thepa ea moputso ea moputso ho khothaletsa boitšoaro ba ho fepa [23]. Ka mokhoa o fapaneng, li-opioids ha li tsamaisane le litlamorao tsa qoqotho e shebaneng le melanin, e leng neuropeptide e 'ngoe e fumanehang hamorao ho hypothalamus [24]. Phello e 'ngoe ea bohlokoa e ne e le hore ts'usumetso ea mafura a mangata a hlohlellelitsoeng ke tsamaiso ea DAMGO, setsebi sa kelello sa MOR, ka har'a li-bokono tsa nucleus se hloka ho supa ha orexin e sa bonahaleng sebakeng sa ho kenella ka hare ho setsi [25], ho fana ka maikutlo a hore tšebelisano pakeng tsa sistimi ea opioid le orexin e tsamaisana le litsela tsa homeostatic le hedonic.

Ntle le taolo ea phepelo ea lijo ka lipontšo tsa homeostatic, li-opioids li bapala karolo ea bohlokoa ho likarolo tsa hedonic tsa ho ja le mekhoa ea meputso, ho feto-fetoha le botsitso ba tharollo e nang le litholoana le lijo [26,27,28]. Ho fumaneha ha phepo ea hedonic ho kenyelletsa ts'ebetso ea mesolimbic dopamine tsela, dopaminergic projeke ho tloha sebakeng sa ventral tegmental ho ea ho li-nucleus accumbens, tseo mohlomong e leng mokena-lipakeng oa bohlokoa ka ho fetesisa oa moputso oa lijo. Li-opioid tsa ka ntle li laola tsela ea mesolimbic dopamine maemong ka bobeli a sebaka sa ho kenella ka mokokotlong le li-nucleus accumbens [29]. Kahoo, boholo ba lithuto li entsoe ka ho enta opioid receptor agonists / antagonists libakeng tsena tse peli tsa mesolimbic dopamine tsela. Litlaleho tse ling li fana ka maikutlo a hore litlamorao tsa li-opioid ho thepa e ruisang ea lijo li na le tšusumetso ho feta litlamorao ho taolo ea matšoao a homeostatic. Mabapi le sena, naloxone e hatella tšebeliso ea tharollo ea sucrose ka mokhoa o hlakileng ho feta ts'ebetso ea metsi [30] le ho thibela khetho ea tharollo ea saccharin [31]. Ho fokotseha ho tšoanang ha khetho ea sucrose ho ile ha boela ha bonoa kamora kalafo ka naltrexone [32]. Ka lehlakoreng le leng, tsamaiso ea DAMGO, agonist ea MOR, bokong ba nyutlelie e eketsa ho kenella ha saccharin [33], le ente ea DAMGO sebakeng se khubung ea ventral e boetse e phahamisa karabelo ea ho fepa liphoofolong tse satiated ka botlalo [34]. Li-opioids li boetse li fetola mokhoa oa ho khetha lijo tse itseng ha li bapisoa le lijo, joalo ka ha ho bontšoa ke 'nete hore kalafo ea litoeba tse nang le naltrexone hantle e fokotsa tšebeliso ea lijo tsa sucrose [35]. Leha ho le joalo, li-laboratori tse ling li sitiloe ho bonts'a tšebelisano lipakeng tsa li-opioids le khetho ea lijo [36,37] kapa ho fumaneha ha khetho ea sebaka se amanang le sucrose [38]. Ntle le moo, optidx antepton antagonist naltrexone ha ea ka ea fetola phepelo e tsoang ho ghrelin e kentsoeng tseleng ea moputso oa mesolimbic [39]. Ghrelin, e leng motsoako oa "peptidic" o tsoang ka mpeng o eketsang takatso ea lijo, o sebetsa ka sejo sa ghrelin mme o hlahisoa haholo ka har'a hypothalamus, empa le libakeng tse fapaneng tsa sisteme ea mesolimbic dopamine. Kahoo, ghrelin e hlohlelletsa boitšoaro ba ho fepa ha e kenngoe sebakeng sa moea o kenang kapa se bitsoang li-nucleus accumbens [39,40]. Leha ho le joalo, boitšisinyo bo nang le naltrexone bohareng ba sebaka se kenellang ka mokokotlong kapa li-nucleus accumbens ha boa ka ba nyatsa ketso ea orexigenic ea ghrelin [39]. Tka hona, liphuputso tsena li fana ka maikutlo a hore sistimi ea opioid ha e bohlokoa bakeng sa liketso tsa ghrelin mabapi le thepa ea moputso ea lijo, leha lithuto tsa nako e tlang tsa tlhahlobo ea "haspic" hotspots 'bokong li hlokahala pele liqeto tse tiileng li ka fihlella.

Taba ea bohlokoa e lokelang ho rarolloa ke hore boholo ba bahanyetsi ba opioid ba tlalehiloe hore ba fokotse takatso ea lijo ea nakoana, empa ba fokolang ba bonahala ba fokotsa ho ja nako e telele. Leha ho le joalo, mosebetsi o tsepamisitse maikutlo ho bahanyetsi ba bang ba maiketsetso ba maiketsetso, 3,4-dimethyl-4-phenylpiperidines, e bontšitse katleho ea nako e telele. Haholo-holo, LY255582, eo vivo e sebetsang joaloka mohanyetsi oa MOR le KOR, e fokotse takatso ea lijo le boima ba 'mele ka nako ea matsatsi a 7 ha e ente intraventricularly hang ka letsatsi [41]. K'homphieutha ena e boetse e fokotse tšebeliso ea lijo le boima ba 'mele ha li fanoa ka mokhoa o sa ts'oaneng oa ho monya likhoto tsa Zucker nakong ea phekolo ea matsatsi a 30 [8]. Ka mokhoa o ts'oanang, tlaleho e 'ngoe e fumane hore likhoto tse feptjoang ke lijo tse nang le mafura a mangata li fumana kalafo e sa foleng ea molomo le LY255582 bakeng sa matsatsi a 14 li fokotse mafura a' mele ka ho fokotsa ho ja haholo le tšebeliso ea ts'ebetso ea lipid [9]. Ho feta moo, LY255582 e boetse e thibetse tšebeliso ea phepo e ntle haholo ka mor'a kalafo ea matsatsi a 4 mme e thibetse ho kenella ha mesolimbic dopamine neurons ka har'a li-nucleus tse hlahisitsoeng ke phepo e phahameng e fuoang [10]. Kahoo, LY255582 e bonahala e le lithethefatsi tse matla tse sebelisang nako e telele ho sebetsa.

Opioids le mathata a ho ja

Boitsebiso bo bokelletsoeng morao tjena bo bonts'itse phetoho ho polelo ea methapo e fapaneng ea li-neuropeptide le li-neurotransmitter maemong a neuropsychiatric a amanang le tlhekefetso ea boits'oaro bo joalo ka anorexia amanosa (AN) le bulimia manthaosa (BN). Haholo-holo boholo ba bakuli ba nang le AN le BN ba bonts'itse li-antibodies khahlanong le alpha-melanocyte-e tsosang li-hormone (α-MSH), peptide ea melanocortin e fokotsang takatso ea lijo ebile e le tlasa taolo ea li-peptide tsa endioid tse sebetsang ka nako ea pele le ea pele. receptors tsa postynaptic [42]. Ho latela sena, datha e fumanoeng mefuteng ea teko e ts'ehetsa maikutlo a hore li-opioids, ntle le ho ba orexigenic ka se (haholo-holo bakeng sa lijo tse fumanehang habonolo) kapa ho khona ho fetolela lijo tsa "intrinsic" tsa hedonic tsa lijo, le tsona li kenyelletsa takatso ea lijo e amanang le tsona. Lits'ebetso tse etsang hore kamohelo ea lijo le khetho e kholo [43].

Ho bile le tlhahiso ea hore AN e hlaha e le sephetho sa ts'ebetso ea ts'ebetso ea motsoako oa opioid oa mehleng ea khale ho sebetsana le khaello ea lijo e sa lebelloang e kenyelletsang ho kenyelletsa phetisetso ea phetoho e lekantsoeng ea matla a nakoana kapa phokotso ea maikutlo a mabe a amanang le khaello ea lijo. Tlhahiso ena e ka matahanngoa le karolo e ka bang teng ea li-opioid ka har'a lijo tse tlisoang ke khatello ea maikutlo, empa ho rarahana le ho se lumellane ha lingoliloeng mabapi le tšitiso ea meriana le tsamaiso ea opioid ho anorexia ho etsa hore ho be thata ho lekola mofuta ona ka botlalo. Ntle le moo, bathong, ho tlalehiloe hore ho fokotsoe ho tlama MOR ka sethaleng sa insula ho bakuli ba batho ba nang le bulimia, mme sena se ne se amana haholo le boitšoaro bo potlakileng. Hore na sena se bakoa ke taolo e tlase e amanang le 'muso ea li-receptors kamora ho itima lijo kapa e bonts'a boemo ba ho lakatsa bo ntse bo sa hlaka. Hape ha ho hlake phello ea bahanyetsi ba opioid kalafo ea bakuli ba bulimic moo liteko li hlahisitseng litholoana tse bohloko.

Le ha nyeoe ea karolo ea li-opioid ho AN e sa ntse e sa hlaka, taba ea ho ja lijo, e hlalosoa e le mokhoa o fosahetseng oa ho fepa ka lijo tse monate, tse nang le lijo tse ngata tse nang le liswiti, mafura kapa ka bobeli ka nako e lekanyelitsoeng. ea nako, e ea qobella. Sena se bohlokoa haholo ho tloha ha 6.6% ea baahi ba tloaelehileng e itloaetsa ho ja. Ho feta moo, ho itlopa lijo ho boetse ke karolo ea bohlokoa ea botona. Ebile, botenya bo bonahala ho 65% ea bakuli ba nang le bothata ba ho ja ho tlōla ba nang le tsoelo-pele e eketsehileng ka nako le ho tsoela pele ho ja. Ho tšoana lipakeng tsa boitšoaro bo bobe ba ho ja le ho hlekefetsa lithethefatsi ho ile ha totobatsoa ke Waller le basebetsi-'moho [44], ea hatelletseng hore likarolo tsa ho ja ho tlatsana li ka kopana le tlhahlobo ea DSMIII ea tlhekefetso ea lithethefatsi mme ea buisanang le monyetla oa hore ho hloka ts'ebetso ea opioid ho ka etsa hore ho itlopa joala ho tlose. Lintlha tse fumanoeng mefuteng ea liphoofolo li bonts'itse hore moferekanyi oa MOR le KOR, nalmefene ha se feela mokhoa oa ho itlopa lijo mme o boetse o eketse lijo tse ngata tsa lijo tse sa rateheng. Litla-morao tsena li kanna tsa kopanngoa le ho thibela li-MOR sebakeng sa karohano ea mokokotlo, e lebisang ho disinhibition ea li-interneurons tsa GABAergic 'me hamorao tsa fokotsa phallo ea dopamine ho li-nucleus accumbens.

Boithuto ho bakuli ba bulimic ba tšoaroang ke bahanyetsi ba opioid receptor antagonists ba bontšitse phokotso ea boholo le maqhubu a ho loana ha ho latela taolo ea naltrexone, le lintlafatso litsing tse amanang le bakuli tse ngata. Sena se ne se kenyelletsa palo ea likotlo le lipompo le kabo ea lijo tse tloaelehileng [45]. Liphephetso tsena li boetse li atlehile ho fokotsa nako ea ho itlopa joala ho bakuli ba batšo le ba jang batenya ho feta tekano, leha ho tlalehiloe tse ling tsa lintho tse bohloko. Le ha mabaka a phapang ena a lula a sa hlaka, ho lokela ho hlokomeloa hore phuputso ea morao tjena e tlaleha makhetlo a mangata a ho 'fumana ts'ebetso' G-allele oa A118G single nucleotide polymorphism ea MOR ho bakuli ba batenya ho feta tekano. Bakuli bana ba boetse ba tlaleha lintlha tse kholo haholo tekanyetsong ea ho itlaleha ea ho ja hedonic [46]. Lithuto tsa nako e tlang tse nang le sebopeho sa roboto le mofuta oa genotype lia hlokahala e le ho hlalosa hantle le ho senola bakuli ba tla rua molemo kalafong ka lithethefatsi tse lebileng tsamaisong ea opioid

Li-opioids le lijo tse fumanehang bathong

Boithuto ba pharmacological ba karolo ea li-opioid tse laolang boits'oaro ba phepo ho batho bo fokotsoe feela ho bahanyetsi ba kakaretso ba opioid receptor ba joalo ka naloxone (kahare), naltrexone le nalmefene (ka molomo) (e lekantsoe ho [4,47]). Lithuto tsena kaofela li ile tsa etsoa ka palo e tlase ea bakuli ba boima ba tloaelehileng, empa boholo ba bona ba fumane ho fokotseha ha lijo tsa nako e khuts'oane, ha ho sa be le litlamorao tse kholo tsa tlala [4]. Ho fokotseha ha takatso ea lijo ho ne ho ts'oana, ebile ho na le 11-29%, ho fana ka maikutlo a karolo e hlakileng ea li-opioid receptors ka boits'oaro ba phepo ea batho. Leha ho le joalo, mohoanto oa bohlokoa o hlahisitsoe ke taba ea hore ba bang [48,49,] empa eseng kaofela [50,] li bontšitse hore naltrexone e bakile ho nyekeloa hoa pelo. Mabapi le 19% ea lithuto li tlalehiloe nausea kamora ts'ebetso ea naltrexone, ha e bapisoa le 9% e amohelang placebo [49,51]. Leha lithuto tsena li sa atleha ho fumana kamano lipakeng tsa phokotso ea lijo le ho nyekeloa hoa pelo, lithuto tse ling li tla hlokahala ho hlakisa hantle haeba litla-morao tsena li ka kenya letsoho ho hatelleng lijo tsa naltrexone. Ketso ea naloxone le naltrexone mabapi le boitšoaro ba ho fepa hape li ithutile ho bakuli ba batenya. Bahanyetsi ka bobeli ba opioid receptor ba khonne ho hatella phepelo ea lijo, mme tse ling tsa lithuto tseo tse batenya li tlalehile le ho fokotseha ha tlala. Leha ho le joalo, ho nyekeloa hoa pelo le hona ho ile ha bonoa ho bakuli ba 'maloa ka mor'a taolo ea lithethefatsi [4,52].

Le ha litlamorao tsa naltrexone litekanyetsong tsa lijo tsa nakoana li hlakile, e hloleha ho hlahisa boima ba 'mele bo ts'oanang, leha e le ka litekanyetso tse phahameng (ke hore 300 mg / day) [53,54,55]. Leha ho le joalo, phekolo ea ho kopanya le naltrexone le bupropion (antidepressant e khethang ka mokhoa o ikhethileng ho transporter ea dopamine) e bonahala e sebetsa haholo mme ha joale e le tlasa teko ea karolo ea III. Nama e kopaneng ea naltrexone / bupropion e hlahisa keketseho e kopanetsoeng ea ho thunya ha neurone ea POMC, phokotso ea synergistic ea ho ja lijo ka litoeba, le ho theola boima ba 'mele lithutong tsa batho ba batenya haholo [56]. Lithuto tse 'maloa tse ikemetseng tsa kliniki li lekile motsoako ona lilemong tsa ho qetela. Ho e 'ngoe ea litlaleho tsena, bakuli ba 419 ba nang le botenya bo sa rarahanang ba ile ba phekoloa ka placebo kapa litekanyetso tse tharo tsa naltrexone ea ho lokolla hang-hang e kopantsoeng le 400 mg / letsatsi le tsitsitseng la ho lokolla bupropion bakeng sa libeke tsa 48. Thutong ena ea II lithutong tse batenya haholo, phekolo e kopaneng e hlahisitse tahlehelo e kholo ea mmele ho feta placebo, naltrexone monotherapy, kapa bupropion monotherapy [56]. Phuputso e 'ngoe ea morao-rao ea tleliniki e entse 56-beke, teko e laoloang ka mokhoa o hlophisitsoeng oa placebo e ileng ea lekola ho sebetsa le polokeho ea naltrexone hammoho le bupropion e le papatso ea tšebeliso e matla ea boitšoaro (BMOD). Barupeluoa ba 793 ba batenya ba ile ba tšoaroa ka mofuta oa placebo hammoho le BMOD, kapa naltrexone (32 mg / letsatsi) e kopantsoeng-hammoho le kopropion (360 mg / letsatsi) hammoho le BMOD. Kamora libeke tsa 56, kalafo e kopaneng ea naltrexone / bupropion e bontšitse phokotso e phahameng ea boima ba 'mele le ntlafatso ea matšoao a kotsi ea lefu la pelo le methapo [57]. Leha ho le joalo, kalafo ka lithethefatsi tsena e ne e amahanngoa le litlaleho tse ngata tsa ho nyekeloa hoa pelo ho fapana le placebo. Ho fihla joale, tlaleho ea bongaka e nang le boholo bo boholo ba baahi e ne e le thuto ea Contrave Obesity Research I (COR-I), e ileng ea lekola phello ea kalafo ea naltrexone / bupropion ka boima ba 'mele ho ba nang le karolo e feteletseng ea 1,74258]. Bakuli bana ba ne ba phatlalalitsoe ka teko e sa sebetseng, e sa boneng mahlo hape e tsamaeang le sebaka sa III e entsoeng libakeng tsa 34 tsa USA. Barupeluoa ba ile ba abeloa ka mokhoa o sa sebetseng ka 1: 1: tekanyo ea 1 ho fumana naltrexone e tsoetseng pele (32 mg / letsatsi) hammoho le bupropion e tsoetseng pele (360 mg / letsatsi), tlhahiso-le-naltrexone e tsoetseng pele (16 mg / letsatsi) hammoho le tokiso e tsitsitseng. bupropion (360 mg / letsatsi), kapa placebo e tsamaeang habeli ka letsatsi, e fanoe ka molomo bakeng sa libeke tsa 56. Ka mokhoa o ts'oanang le lithutong tse fetileng, bakuli ba ileng ba phekoloa ka ho kopana ha naltrexone / bupropion ba bontšitse phokotso e phahameng ea boima ba 'mele [58]. Leha ho le joalo, hape, liperesente tse ngata tsa lithuto tse tšoaroang (tse haufi le 28%) li tlalehiloe ho nyekeloa hoa pelo, ha ho bapisoa le 5% ea batho ba tšoaroang ke placebo. Ho opeloa ke hlooho, ho qhekelloa, ho tsekela, ho hlatsa, le molomo o omileng ho ne ho boetse ho etsahala khafetsa lihlopheng tsa naltrexone hammoho le bupropion ho feta sehlopheng sa placebo [58]. Ha li kopantsoe hammoho, lintlha tsena li bonts'a tlhokeho ea nts'etsopele le tlhahlobo ea sistimi ea opioid e le sepheo sa lithethefatsi ho hlola mathata a moralo oa ho ithuta ho kenyelletsa: tšebeliso ea bohanyetsi ba opioid, ho se kenyele sehlopha se laoloang ke placebo, ts'ebeliso ea palo e fokolang ea lithuto le / kapa ho se kenyeletse bakuli ba hlonephileng joaloka bakuli ba batenya haholo.

Mefuta ea Mananeo a Laoloang Bakeng sa Tlhahlobo ea Metabolic ea Opioid System

Liphetho tsa pharmacological li matlafalitsoe ka litoeba tsa tlhaho. Haholo-holo, liphetoho tse entsoeng ka metabolic ho litoeba tse fokolang ho MOR le KOR li ithutile li sebelisa lijo tse fapaneng. Tlaleho ea pele e ithutang litlamorao tsa khaello ea MOR matsatsing a ho leka-lekana ha matla ho tloha 2005 mme ea fumana hore MOR e ne e se bohlokoa bakeng sa taolo ea tekanyetso ea matla ha litoeu li feptjoa lijong tse tloaelehileng [59]. Leha ho le joalo, litoeba tse haelloang ke MOR li ne li loantšana le botenya bo khothalletsoang ke ho ja ka lebaka la polelo e phahameng ea CPT-1 mesifa ea marapo, li fana ka maikutlo a khothaletso ea mafura a acid ha a bapisoa le litoeba tsa mofuta oa hlaha [59]. Ntle le phello ena e molemo boima ba 'mele, ho haella ha MOR ho boetse ho ntlafalitse mamello ea tsoekere ka mor'a lijo tse mafura a mangata [59]. Habohlokoa, litlamorao tsena kaofela li ne li sa ikemisetse ho jella lijo hobane litoeba tse haelloang ke MOR ha li bonts'e liphetoho lipakeng tsa boits'oaro. Ka mokhoa o ts'oanang, sehlopha se ikemetseng se bonts'itse hore litoeba tse haelloang ke MOR tse pepesetsoeng lijo tse matlafatsang tsa caloric li fumane boima bo tlase le mafura a bapisoa le litoeba tsa mofuta o hlaha [60]. Ho feta moo, ho haella ha MOR ho ntlafalitse mamello ea li-glucose ha litoeba li ne li feptjoa lijong tsena. Tumellanong le thuto e fetileng, liketso tsena kaofela li ne li sa ikemisetsa ho ja lijo. Leha ho le joalo, mosebetsi ona o bonts'itse hore litoeba tse haelloang ke MOR ka lijo tse tloaelehileng li eketsa boima ba 'mele le ho hlonepha ha li ntse li ja chow [60]. Kamora nako, tlaleho e 'ngoe e ithutile phello ea khaello ea MOR mehloling ea tlhollo ea lijo le ts'ebetsong ea hedonic ea ho fepa boits'oaro [61]. Bangoli bana ba fumane hore tlasa kemiso e itseng ea matlafatso ea litoeba tsa MOR e haellang e bontšitse tšusumetso e fokotsehileng ea ho ja lijo tse tloaelehileng le li-pellets tsa sucrose [61]. Leha ho le joalo, litoeba tse haellang tsa MOR li bonts'itse bokhoni ba kelello bo sa bonahaleng, ho bonts'a hore tsela ea MOR ea sebaka sa mahareng e khothaletsa tšusumetso ea ho ja empa ha e bohlokoa bakeng sa thepa ea hedonic ea lijo [61].

Ka lehlakoreng le leng, haufinyane ho bonts'itsoe hore liphatsa tsa lefutso tsa KOR li fetohile limatlafatsi, tsoekere le lipid metabolism ha li arabela lijong tse nang le mafura a mangata. LIPHOOFOLO tse haelloang ke KOR li ne li sa khone ho fumana boima ba 'mele esita le kamora ho qeta nako e telele lijong tsa mafura a mangata,' me sena se ne se tsamaisoa ke tlhokomelo ea litšenyehelo tsa matla le maemo a tšebetso a locomotor [62]. Ho feta moo, litoeba tse haellang KOR ebile li fepa lijo tse nang le mafura a mangata li ne li fokolitse polokelo ea mafura a hepatic ka lebaka la phokotseho ea sebopeho sa triglyceride le keketseho ea mafura a acid β-oxidation ka har'a sebete [62]. Ka kakaretso, ho ka fihleloa qeto ea hore liphetoho tse kholo tsa boima ba 'mele ha li eo ho litoeba tse sa lekaneng tsa KOR hape le litoeba tse kopaneng tsa haelloang ke litoeba tse tharo tsa opioid, MOR, DOR le KOR, ha li feptjoa lijo tse tloaelehileng tse mafura a fokolang. Leha ho le joalo, maemong a tšebeliso e telele ea lijo tse nang le mafura a mangata, bahanyetsi ba li-opioid receptor bahanyetsi ba ka ba molemo ho fokotseng tšenyo ea metabolic e bakiloeng ke botenya bo khothalletsoang ke ho ja.

Ntle le litlamorao tsa ho haella ha KOR, liphetoho tse entsoeng ka lebaka la khaello ea dynorphin, ligand ea endoria ea KOR, le tsona li se li nahannoe. Ho fapana le litoeba tse haelloang ke KOR, litoeba tse nang le liphatsa tsa lefutso tsa dynorphin ha lia ka tsa bontša phetoho ho boima ba 'mele ha li feptjoa lijong tse nang le mafura a mangata [63]. Leha ho le joalo, litekanyetso tsa serum tsa mafura a mahala li ne li fokotsehile ho litoeba tse haelloang ke dynorphin tse fepeloang ka lijo tse nang le mafura a mangata, ho bonts'a phallo ea mafura a acid e fokotsehileng ho potoloha kapa ho eketseha ha oxidation ea mafura.63]. Le ha li-tiske moo liphetoho tsa oxidation ea mafura li ka fetoloang li sa ka tsa ithutoa, ka kakaretso, ho ka tšeptjoa hore tsela ea endo native dynorphin-KOR e phetha karolo ea bohlokoa phetolelong ea metabolism ea mafura. Liphumano tse loketseng ka ho fetisisa ho litoeba tse nang le tšitiso ea dynorphin li ile tsa bonoa nakong ea ho itima lijo. Ha e le hantle, ho haella ha dynorphin ho fokotsa boima ba mafura le boima ba 'mele nakong ea hora ea 24 ka potlako [63]. Litlamorao tsena li ne li sa bakoe ke phetoho ts'ebelisong ea matla kapa ts'ebetsong ea methapo, empa ke ts'ebetso e eketsehang ea tsamaiso ea methapo ea kutloelo-bohloko. Ntle le moo, ho ile ha fumaneha hore banna, empa eseng basali, ba haelloang ke dynorphin ba na le karolelano ea phefumoloho e fokotsoang, e bonts'ang naha eo ho eona ho khothalletsoang lipid ho khothaletsoa [63]. Ho bohlokoa ho hlokomela hore ha ho na lithuto tse fumanehang mangolong mabapi le karabelo ea litoeba tse sa lekaneng tsa KOR ho itima lijo, empa ho nahanela hore bahanyetsi ba KOR ba fokotsa hyperphagia e potlakileng ea litheko [64] le hore litoeba tsa KOR mutant li bonts'a phetoho ho metabolism ea mafura, ho bonahala ho utloahala ho nahana hore litoeba tse se nang KOR li ka arabela ka mokhoa o ts'oanang le litoeba tse haelloang ke dynorphin.

Litlhaloso tse qetellang

Bohlokoa ba kemiso ea tšebetso ea li-opioid system le li-parameter tse ling tse bohlokoa bakeng sa taolo ea matla li bontšitsoe ka litlaleho tse ngata tsa preclinical le tsa kliniki (tse akaretsoang mofuteng oa feiga. 1). Leha ho le joalo, ho sa na le likheo tsa bohlokoa tsebong ea rona tse mabapi le mathata a 'maloa a amanang le opioid. Mohlala, ho bonahala ho hlakile hore khaello e felletseng ea MOR le KOR e baka liphetoho tse ngata lekaleng ea matla, haholo ha litoeba li fepuoa lijo tse matlafalitsoeng. Leha ho le joalo, karolo e ka bang teng ea khaello ea DOR ha e so ithutoe, 'me ho latela datha ea pharmacological, ho ka etsahala hore u fumane liphetoho tse bohlokoa tsa metabolic kamora ho senyeha ha DOR. Ho tlameha ho hlakisoa hape hore, leha ho na le palo e kholo ea datha e bokelletsoeng lilemong tse 'maloa tse fetileng mabapi le ho kenya letsoho ha li-opioid receptors e le libapali tsa bohlokoa meputsong ea lijo / joala, ho na le lipelaelo tse matla mabapi le moo sephetho sa lithuto se nang le opiate bahanyetsi ba ka hlalosoa e le bopaki bakeng sa karolo e tobileng ea li-opioids kapa hore na ke litlamorao tsa litla-morao tse amanang le tsamaiso ea litlhare tsena. Leha bopaki bo leka-lekaneng bo bontša hore litla-morao tsa bohanyetsi ba opioid li bontšitsoe ka mokhoa o ikemetseng oa litla-morao, lithuto tse tsoelang pele ka liphatsa tsa lefutso tse khethehileng tsa li-receptor tse fapaneng tsa li-opioid lihlopheng tse ikhethang tsa methapo ea kutlo li lokela ho etsoa liphoofolong tsa liphoofolo ha li bapisoa le meriana e tloaelehileng mekhoa ea ho netefatsa hore datha tse hlahisitsoeng li ka hlalosoa hantle. Mabaka a ikhethang ke sebaka sa li-opioid receptors libakeng tse 'maloa tsa sisteme ea mesolimbic dopamine joalo ka sebaka sa likarolo sa ventral le likarolo tsa nucleus. E tla ba ho khahlisang haholo ho hlahisa le ho tšoaea litoeba tse sa hlokeng MOR, KOR kapa DOR libakeng tsena tse ikhethang tsa boko ho utloisisa hantle mohato ona o fetisang liketso tsa sistimi ea opioid maemong a lijo tsa hedonic. Hape, taba ea bong e lokela ho tsotelloa kaha ho tsejoa hore bahanyetsi ba KOR ba banna ba atlehile haholo ho hatella phepelo ea lijo ho feta ho basali. Ka mokhoa o ts'oanang, ho batho li-ligor tsa KOR / MOR li fumanoe li hlahisa li-analgesia tse kholo ho basali ho feta banna. Ho fapana le hoo, ho liphoofolo, ho fumanoe hore li-agonists tsa KOR li hlahisa litlatsetso tse matla ho feta litšehali ho feta tsa basali. Ka kopanelo, liphuputso li bonts'a ho ba teng hoa liphapang tsa bong le mefuta-kholo ea li-opioid receptor mediated biological effects [65].

Kamora nako, tlhaiso-leseling ea kliniki e tiisa sephetho se fumanoeng liphoofolong tsa liphoofolo, e leng se bonts'ang hore thibelo ea li-opioid receptors e fokotsa ho ja haholo ho bakuli ba mafube le ba motenya. Habohlokoa le ho feta, lipatlisiso tsa morao-rao li bonts'itse hore motsoako oa naltrexone le bupropion o na le bokhoni ba ho susumetsa boima ba 'mele ho bakuli ba batenya haholo. Mokhoa ona, o seng o ntse o le tekong ea karolo ea III, o hlahisitse tšepo e ncha bakeng sa kalafo ea botena. Ho joalo, bothata bo boholo bo boletsoeng esale pele bo amana le litlamorao tse fumanoang liperesente tsa bakuli ba tlalehileng ho nyekeloa hoa pelo le litsotsi tse ling tse sa rateheng. Sena se totobatsa tlhokeho ea nts'etsopele ea metsoako e mecha, mohlala, li-agonists tse fapaneng, tse khonang ho fihlella katleho ea kalafo libakeng tse amohelang batho ba maemong a tlase, tse lokelang ho lebisa polokelong e ntle le maemong a ho mamella. Le ha ho hlokahala lithuto tse eketsehileng ho hlakisa bohlokoa ba litlamorao tsena tse sa rateheng nakong ea ntlafatso ea kalafo, ho ka ba bohlokoa ho sekaseka hore na kalafo ena e lokela ho eletsoa feela ho bakuli ba bang ba batenya, empa eseng ho ba bang ba nang le nalane e itseng ea kliniki.

 

 

Liteboho

Mosebetsi ona o tšehelitsoe ke lithuso tse tsoang Ministerio de Educacion y Ciencia (CD: BFU2008; RN: RYC-2008-02219 le SAF2009-07049; ML: RyC-2007-00211), Xunta de Galicia (CD: PGIDUM06NXXNXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX / 208063), Fondo Investigaciones Sanitarias (ML: PI2010), le Lenaneo la Sesebelisoa sa Sesebelisoa sa bosupa sa Europe (FP14 / 061700-7) tlasa litumellano tsa tumello n ° 2007 (CD: 'Neurofast'). CIBER de Fisiopatología de la Obesidad y Nutrición ke bohato ba ISCIII, Madrid, Spain.

 

 

Tlhaloso ea Phatlalatso

Bangoli ba phatlalatsa hore ha ho na likhohlano tsa thahasello.


 

 

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