Naloxone e thibela ho kenngoa ka takatso ea likhoho (2007)

. Sengoloa se ngotsoeng; e fumaneha ho PMC 2010 Jun 5.

E hatisitsoe ka mokhoa o qetelle o hlophisitsoeng e le:

PMCID: PMC2881196

NIHMSID: NIHMS205439

inahaneloang

Tlhaloso

Takatso e bakoang ke takatso ea mantlha ea mantlha pele ho ts'oaetso ea lithethefatsi hape e baka mathata a ho ja. Bahanyetsi ba Opiate ba bontšitsoe ba sebetsa hantle ho fokotsa litakatso tsa lithethefatsi le lijo. Ho lakatsa, joalo ka ha ho hlalosoa e le ho arabela ts'usumetso e neng e amana le moputso, ea eketseha kapa e kenella, ka ho qobelloa ka thobalano mohlaleng oa phoofolo oa ho khutla.

maikemisetso

Pampiri ena e ikemiselitse ho khetholla litlamorao tsa mohanyetsi oa opiate, naloxone, ho ho kenella ha takatso ea sucrose.

mekhoa

Batho ba tummeng ba 106 ba litoeba tsa likhoto ba hatelloa ka tharollo ea 10% sucrose 2 h / letsatsi matsatsi a 10. Ka letsatsi le leng la 1 kapa la 30 la thibelo e qobelloang, likhoto li ile tsa arabela ka ho felisoa ka 6 h mme ea ntan'o kenngoa (ip) ka saline kapa naloxone (0.001, 0.01, 0.1, 1, kapa 10 mg / kg). Joale likhoto li ile tsa arabela bakeng sa 1 h bakeng sa tlhahiso ea leseli + leseling le neng le hlahisitsoe pele le nehelano e 'ngoe le e' ngoe ea nakong ea boits'oaro.

Results

Likhoto li ile tsa arabela haholoanyane ho timelleng le ho latela saline ka letsatsi la 30 vs ka letsatsi la 1 (ho kenella ka takatso ea takatso). Ntle le tloaelo ea phokotso ea ho araba ka ho latela 10 mg / kg ka letsatsi la 1, naloxone e ne e sebetsa hantle haholo ka letsatsi la 30. Ka letsatsi la 30, naloxone e fokotsehile haholo ho arabela litekanyetso tsohle ntle le bakeng sa 0.1 mg / kg.

Nahanisisa

Keketseho e itšetlehileng ka nako ea kutlo ea mohanyetsi oa opiate e lumellana le liphetoho tse itšetlehileng ka nako tsamaisong ea opiate kamora ho qobelloa ho tlosoa ke sucrose. Liphetoho tsena li ka etsa hore karolo ea nakoana ea takatso ea boitšoaro ba sucrose e etsoe. Ntle le moo, liphumano tsena li ka sebelisoa ho ts'ehetsa ts'ebeliso ea naloxone e le moriana o thibelang mathata ho itšilafatsang.

Keywords: Tlatsetso, ho ja, Naltrexone, botenya, Opiate, matlafatso, bocha

Selelekela

Ho lemalla lithethefatsi le litloaelo tse lemalloang tsa lijo li atile.; ; ). Ho nona haholo maemong a mangata ho bakoang ke ho ja ho feta tekano, ke koluoa ​​e fokolang haholo ea bophelo bo botle hobane litheko ho USA li imenne habeli lilemong tse 20 tse fetileng (CDC). Ho fokotsa mathata a joalo a amanang le bokhoba, ka hona ho bohlokoa ho utloisisa mekhoa e tlatsetsang ho ferekaneng ha lithethefatsi le lijo.

Meputso ea lijo le lithethefatsi e tsamaisoa ke "neural circry" e tšoanang.). Leha litlamorao tsa nako e telele tsa tlhekefetso ea lithethefatsi li kanna tsa fapana le litloaelo tse mpe tsa lijo mabapi le liphetoho tsa boko ba (), li-adaptation tsa neural tse thusang ho ithuta ka meputso ea lihlopha tse fapaneng (mohlala, lijo le lithethefatsi) li kanna tsa tšoana (). Liphetoho tse joalo, le liphetoho tsa boits'oaro (ho ithuta) tseo ba tsamaisanang le tsona, hangata li ithutoa ho sebelisoa mehlala ea liphoofolo ea bokhoba ba taolo ().

Ho khutlisetsoa morao hoa takatso ea ho batla moputso ke mohlala o le mong o faneng ka leseli la neurobiology ea ho batla lithethefatsi () le temohisiso ea morao-rao mabapi le ho batla lijo (, ; ). Mohlaleng ona oa phoofolo, likhoto li arabela bakeng sa tlhahiso ea tšusumetso (molumo + leseling) eo pele e neng e amahanngoa le ho ipusa ka moputso. Boholo ba karabelo bo nkuoa e le mohopolo oa ho batla moputso 'me o sebetsa e le mohopolo oa "ho lakatsa". Re sebelisa mohlala ona, rona le ba bang re hlokometse le ho tšoaea keketseho e itšetlehileng ka nako ea ho arabela bakeng sa litekanyetso tsa lithethefatsi le lijo nakong ea ho itšunya-tšunya ho itaola (; bakeng sa litlhahlobo). Ntle le ho fumana hore "poloko" ea ho lakatsa sucrose e hanela mananeo a etselitsoeng ho e fokotsa (mohlala, ho satiation le sucrose; ), re fumane hore likhoto ha li amehe habonolo ka litlamorao tse hlahisang koae ka khoeli e le 'ngoe ea koae e qobelloang khahlanong le 1 letsatsi (). Phumano ena e fana ka maikutlo a liphetoho tse itšetlehileng ka nako ho sensitivity ea li-system tsa moputso oa boko mme e re lebisitse ho nahana hore na lits'ebetso tse joalo tsa phetisetso li kanna tsa angoa ke, kapa tsa kenya letsoho, ho kenyeng takatso ea sucrose.

Opiates ke sistimi e le 'ngoe ea mokhethoa. Boholo ba lingaka tsa Opiate (hangata naloxone kapa naltrexone) li fumanoe li fokotsa takatso ea lijo le lijo tse batloang ke lijo le / kapa batho ba batenya haholo (; ). Ba boetse ba fokotsa takatso ea koae le joala (; ). Lithutong le likhoto, naltrexone e fokotseha ho araba likatse tsa cocaine (), joala ka mor'a ho pepesetsoa joala), le ho araba ho na le tšusumetso ea khethollo e entsoe ka joala (). Ntle le moo, ho likhoto tse koetlisitsoeng ka koae, o fumane hore heroin e bile le litlamorao tse ngata kamora nako ea ho se ts'oaroe ke ts'ebeliso ea ts'ebeliso ea kelello ea koae - maikutlo a fanang ka maikutlo a hore tsamaiso ea DA kapa opiate (kapa bobeli ba tsona) e fetotsoe ka lebaka la ho lakatsa. Ho lokolloa ha DA ka har'a nucleus accumbens (NAcc) ho eketsoa / ho fokotsehile ka microinjection ea opiate agonist / antagonist sebakeng sa "ventral tegmental tegmental" (VTA; ; ) le li-opoates tsa mehleng ea khale li ja lijo tse jeoang ka likhoto () ho kenyelletsa tšusumetso ea ho ja lijo (). Ka hona, joalo ka ha re hlokometse phello ea ho ithiba ka matla ho maikutlo a DA a amanang le ho arabela bakeng sa setšoantšo se otlolohileng ka sefahleho (), re iqapetse hore re tla boela re bone phello ea nako e thehiloeng ho thetso ho ama sistimi ea opiate ha e arabela setšoantšo sa sucrose-paired.

Thutong ea hona joale, re ile ra lekola litlamorao tsa opiate antagonist naloxone mabapi le ho kenella litakatsong tsa sucrose. Ha litlamorao tsa ho ts'oenyeha ka lebaka la moputso o amohetsoeng, re se re sa re letho ka ho batla phallo, re se re khethile lethathamo la lithuto tsa rona. Bafuputsi ba nakong e fetileng (; ; ; ; ; ; ; ba hlalositse litlamorao tse amanang le boitšoaro tsa naloxone le naltrexone e tšoanang ho ultralow (ho fihlela 1 pg / kg), e tlase haholo (30 ng / kg), le tekano (1-5-20 mg / kg) ho isa tekanyetso e phahameng ea lethal dose (holimo ho isa ho XNUMX mg / kg). Re khethile litekanyetso ka tekanyetso e tlase ho isa ho litekanyetso tse tlase haholo / li-ultralow li ka nyarosoa ke mekhoa e sa thibeleng (e sa amohelang).).

Lisebelisoa le mekhoa

Animals

Lingoloa e ne e le litoeba tse tona tse telele tsa batho ba bolelele ba Evans tse 106 (350-450 g) Lefapheng la Western Washington University Psychology vivarium. Likhoto li ne li imeloa Mantaha o mong le o mong, Laboraro le Labohlano bakeng sa nako ea tlhahlobo. Likhoto li ile tsa bolokoa ho Mazuri Rodent Pellets, mme metsi a ile a fuoa lib libas ntle le ha ho boletsoe lits'ebetsong tse akaretsang. Li-pellets le metsi li ne li fumaneha hape ka lipapatso ka likamoreng tsa ho ipusa ntle le ha ho boletsoe lits'ebetsong tse akaretsang. Likhoto tsohle li ile tsa lula ka tlung e khabisitsoeng ka har'a vivarium ntle le nakong ea koetliso le liteko tsa letsatsi le letsatsi ha li tlisoa ka phapusing ea boithatelo. Likhoto li ile tsa bolokoa mokolokotoane o khutliselitsoeng molemong oa khanya ea motlakase ka khanya ea hora ea bohlano ka hora ea 12 hoseng Ts'ebetso tsohle tse etsoang ho likhoto li latela litataiso tsa NIH bakeng sa tlhokomelo ea liphoofolo mme li amohetsoe ke Komiti ea Tlhokomelo ea liphoofolo le tšebeliso ea Washington University University.

didirisiwa

Likamore tsa boithati, tse laoloang ke tsamaiso ea Med Associates (Georgia, VT), li ne li e-na le levers tse peli, empa lever e le 'ngoe (lever e sebetsang le e ke keng ea hlakoloa) e ileng ea kenya pampiri ea infusion. Mechine ea khatiso ho lever e ngoe (ea sa sebetseng, ea litheko) le eona e tlalehiloe. Tharollo ea 10% ea sucrose e ile ea kenngoa ka pokothong ea mokelikeli oa metsi bakeng sa ts'ebeliso ea molomo (Med Associates). Likamore tsena li ne li e-na le li-emter le li-diagnostis tse 'ne (li-Associates) tse kopantsoeng ka mokhoa oa tic-tac-toe (maballo a ka pele lisentimetara tse 10.5 ho tloha leboteng; maballo a lehlakoreng le leng le le leng la 6 cm ho tloha leboteng) kahare ho phaposi ea boiketlo mokatong oa mabota a tšepe. Li-emitters / tse sibolotseng li ne li khokahantsoe le mohala oa lemati kapa leboteng le ka morao kapa lipaketeng tse khabisitseng maboteng a lehlakoreng. Libalaka li ile tsa beoa bakeng sa ho bala palo ea likhefu tse phethahetseng. Sistimi ea mesebetsi ea locomotor e ne e kopantsoe le sistimi ea pokello ea data ea Med Associates.

Tsamaiso e akaretsang

Likhoto li ile tsa amohuoa metsi ka malapeng a tsona 17 h pele ho thupelo ea pele. Metsi a ne a sa fumanehe likamoreng tsa boipheliso qalong, empa a khutlisetsoa likamoreng tsa boipheliso ha likhoto li ithuta ho arabela ka ts'epahalo bakeng sa sucrose (> 20 sucrose deliveries / day), kapa kamora matsatsi a 3 a koetliso ea boitaolo bakeng sa likhoto tse ba lieha ho ithuta ho tobetsa sucrose. Metsi a ile a khutlisetsoa malapeng ka mor'a 48 h ea bohloki. Teko e kenyelelitse mekhahlelo e meraro: koetliso, ho ithiba le liteko. Joalokaha ho hlalositsoe ho Selelekela, ho arabela mokhahlelong oa liteko (maemo a ho khutlisetsoa) ho nkuoa e le lethathamo la takatso. Likhatiso tsa Lever nakong ea liteko ha ho mohla li kileng tsa matlafatsoa ka sucrose. Koetliso le liteko li qalile ka 8:30 AM

Karolo ea boikoetliso

Likhoto li ne li koetliselitsoe ho itaola (0.2ml) ho kenngoa ka sekontiri se metsi. Koetliso e ile ea etsoa ka linako tse 10 tsa letsatsi le letsatsi tsa 2-h tlasa kemiso e tsoelang pele ea matlafatso (mochini o mong le o mong oa khatiso o ile oa matlafatsoa) ka nako ea 40-s kamora moputso o mong le o mong o fumanoeng. Mechini ea khatiso ea lever e ne e baloa nakong ea nako empa ha e na litholoana. Seboka se seng le se seng se ne se qala ka ho kenngoa ha serethe se sebetsang le khanya ea ntlo e khubelu e neng e lutse thutong eohle. Molumo oa li-5-s (2,900 Hz, 20 dB kaholimo ho morao) + khanya (7.5 W leseli le lesoeu ka holimo ho lever e sebetsang) sedikhete sa konkreite se tsamaeang le moputso o mong le o mong. Qetellong ea karolo ka 'ngoe, boemo ba ntlo bo ne bo felisoa' me lehamali le sebetsang le ne le khutlisoa. Ha ho na moeli palong ea meputso e fumanoeng.

Mokhahlelo o qobelloang

Qetellong ea mohato oa thupelo, likhoto (n= 8- rats / sehlopha) li ne li abetsoe ka mokhoa o sa reroang ho e 'ngoe ea linako tse qobelloang tsa ho itima lijo (matsatsi a 11 kapa a 1). Boitšoaro ba boikoetliso (mokhoa oa ho ja ka mokhoa o lekanang, ho sebetsa ka mafolofolo le ho se sebetse) bo ile ba bapisoa pakeng tsa lihlopha ho netefatsa hore lihlopha ha li fapane haholo nakong ea thupelo. Likhoto li ile tsa lula vivarium nako eohle ea ho khaotsa ho tsuba. Saline e ne e fanoa ka har'a mp'a motšehare oa matsatsi a mabeli pele a etsa liteko tsa ho fihlisa liphoofolo ka liente.

Karolo ea liteko: Karabelo ea ho atoloha

Ka letsatsi la liteko, likhoto tsohle li ile tsa fuoa linako tse 6, 1-h tsa ho fela tse neng li arotsoe ke metsotso e 5 ho fihlela ba fihla tekong ea ho se arabe ka likarabo tse ka tlase ho 15/1 h ho motho ea neng a sebetsa pele. Molumo oa leseli + le bobebe oa discrete o ne o le sieo nakong ea mananeo ana. Seboka se seng le se seng sa 1-h se qalile ka ho kenyelletsa leise e sebetsang le khanya ea ntlo. Qetellong ea karolo ka 'ngoe, boemo ba ntlo bo ne bo emisoa,' me setei se sebetsang se ne se khutlisoa. Likhoto tse peli li ile tsa fuoa seboka se eketsehileng sa 1-h ho fihlela sepheo sa 15-likarabo / 1 h.

Karolo ea tlhahlobo: Ho araba cue

Seboka sena se qalile metsotso e 5 kamora ho fela ha seboka sa ho qetela sa 1-h. Intraperitoneal ente ea saline kapa naloxone (0.001, 0.01, 0.1, 1, kapa 10 mg / kg) e hlahile hanghang pele ho karolo ena. Teko ea ho lakatsa ho ts'oaroa ha cue e susumetsoang ke ccr-e ne e na le seboka sa 1-h moo likarabo ho lever e neng e sebetsa pele li lebisitse ho hlahisoeng ha molumo oa lentsoe + leseling lenaneong le tsoelang pele la ho matlafatsa le nako ea 40-s.

Karolo ea liteko: Ketsahalo ea locomotor

Ts'ebetso ea locomotor e ile ea bokelloa karolong eohle ea liteko.

Tlhahlobo ea data

Karolo ea boikoetliso

Ho hlahisa litlatsetso tsa letsatsi le letsatsi (infusions), likarabo tsa lever tse sebetsang, le likarabo tse sa sebetseng tsa lever li ile tsa hlahlojoa ka mehato e arohaneng e phetoang ea ANOVA (RM ANOVA) ba sebelisa Nako (matsatsi a 1 ho ea ho boithuto) le lintlha tse ling tsa mahareng tsa sehlopha (10 kapa 1) le Dose (saline, 30, 0.001, 0.01, 0.1, kapa 1 mg / kg naloxone) ho netefatsa hore likhoto li lekoa ka nako tse fapaneng le ka litekanyetso tse fapaneng tsa naloxone e fumane koetliso e lekanang.

Karolo ea liteko

Lintlha tse tsoang mananeong a ho timela (Karabelo ea phetisetso) le liteko tsa ho batla tsa cue-induction sucrose (Karabelo ea cue) li ile tsa hlahlojoa ka thoko bakeng sa likarabo tse felletseng tse sa netefatsoang ho molemi ea neng a sa sebetse le likarabo ho mofani ea sa sebetseng. Lintlha tsena li ile tsa hlahlojoa ho sebelisoa ANOVA le lintlha tse lipakeng tsa sehlopha sa Letsatsi (1 kapa 30) le Dose (saline, 0.001, 0.01, 0.1, 1, kapa 10 mg / kg naloxone). RM ANOVA e ileng ea latela e ile ea etsoa ho extinction e arabang lever e arabelang ho netefatsa hore lihlopha tse lokelang ho hlahlojoa ka saline kapa naloxone li ne li sa fapana pele ho thetso ea lithethefatsi. ANOVA ena, Nako e ne e le likarolo tsa 6, 1 h ho fela. Kakaretso ea lipalo tsa locomotor e tsoang ho Karabelo ea Karabelo le Karabelo bakeng sa linako tsa cue le tsona li ile tsa hlahlojoa le li-ANOVA tse arohaneng tse sebelisang lintlha tsa Letsatsi le Tekanyetso. Mehlala ea lipara t Liteko li entsoe lipakeng tsa karabo ea mafolofolo ka hora ea botšelela ea ho timela le Karabelo ea seboka sa cue bakeng sa lihlopha tse tšoaroang ke letsoai ho netefatsa hore ts'ebetso ea ho khutlisetsoa e hlahisitse karabelo e matla ea kenyelletso libakeng tse bobeli tse qobelloang tsa ho ila. Mehlala e ikemetseng t Teko e entsoe ka ho arabela ka mokhoa o ikhethileng ho arabeloa Karabelo ea moqoqo oa cue pakeng tsa sehlopha sa 1 se tšoaroang letsoai le sehlopha sa 30 se tšoaroang saline ho netefatsa ho kenella ka takatso ea sucrose.

Lipapiso tsohle tsa lipalo li entsoe ka mofuta oa SPSS 12.0. Lipapiso tsa hoc tsa hoc tse latelang ANOVA li entsoe ka liteko tsa LSD. Lintlha tsa sehlopha li hlahisoa e le moelelo ± SEM temaneng le lipalo.

Results

Karolo ea boikoetliso

Likhoto tse hlano tse ileng tsa sitoa ho bonts'a boitšoaro bo ikemetseng ba taolo (infusions e akaretsang mabapi le koetliso li ne li le kholo ho feta litekanyetso tse 2 tse tlase tlasa moelelo) li tlositsoe thutong. Ho bao ba ithutileng boitaolo (N= 106), palo ea mananeo a koetliso ea sucrose a eketsehile ka linako tse leshome tsa koetliso ea letsatsi le letsatsi [phello ea Nako, F (9, 846) = 22.9, p<0.001]. Ntle le moo, ho arabela ka lever e sebetsang ho eketsehile nakong ea thupelo [phello ea Nako, F (9, 846) = 8.4, p<0.001] ha a ntse a araba ka lever e sa sebetseng e fokotsehile [phello ea Nako, F (9, 846) = 56.8, p<0.001] e bonts'a khethollo e matla lipakeng tsa libapali. Likhoto li hatelletse karolelano ea makhetlo a 167 ± 11.4 ho lever e sebetsang le makhetlo a 3.4 ± 0.5 ho lever e sa sebetseng ka letsatsi la ho qetela la thupelo. Ho ne ho se na litlamorao tse kholo kapa litšebelisano tsa Letsatsi kapa Dose bakeng sa mehato efe kapa efe e bontšang hore lihlopha tsohle li ne li lekana pele ho ts'ebeliso ea letsatsi le letsatsi.

Karolo ea liteko: Karabelo ea ho atoloha

Likhoto tse ileng tsa lekoa hore li tla timela ka letsatsi la 30 la ho qobelloa ho tlosoa ka marapo li ile tsa arabela ho lever e mafolofolo ho feta likhoto tse lekiloeng ka letsatsi la 1 [phello ea Letsatsi, F (1, 94) = 47.1, p<0.001], e bonts'a ho ts'oaroa ha takatso ea sucrose. Lever e sebetsang e arabela ka letsatsi 1 karolelano ea likarabo tsa 63.3 ± 5.2 ho feta 6 h ha e bapisoa le 135 ± 8.9 likarabo ho feta 6 h ka letsatsi la 30. Joalokaha ho bontšitsoe ho Lisebelisoa le mekhoa, RM ANOVA e latelang ea lever ea arabang ka hora ea 6 ea Extinction e arabela ( 6, 1-h sessions) e netefalitse keketseho e itšetlehileng ka nako ho karabelo ka kakaretso ka tšusumetso e kholo ea Letsatsi, F (1, 94) = 47.1, p<0.001 le ts'ebetso ea Letsatsi la bohlokoa ka Nako, F (5, 470) = 10.1, p<0.001. Tšebelisano ena hammoho le tšusumetso e kholo ea Nako, F (5, 470) = 157.6, p<0.001 e netefalitse phokotso e kholo ea karabelo ho feta 6 h ea Extinction araba. Ho ne ho se na litlamorao tse kholo tsa Dose, kapa litšebelisano tse bohlokoa ntle le ts'ebelisano ea Letsatsi le Nako, e bonts'ang hore lihlopha tsa letsatsi la 1 kapa la 30 li entiloe ka letsoai kapa naloxone li ne li ts'oana le lipalo pele ho ts'ebeliso ea lithethefatsi. Matsatsing ao ka bobeli, nako ea karabelo ea 6-h Extinction e ne e le phokotso e makatsang ea sekhahla sa ho arabela ka ho arabela hora ea 1 (36.6 ± 3.5 vs 64.6 ± 4.9 likarabo, letsatsi 1 le letsatsi 30) e kholo ho feta hora ea 6 ( Likarabo tsa 3.0 ± 0.4 vs 7.8 ± 1.1, letsatsi la 1 le letsatsi la 30).

Karabo e sa sebetseng ea lever e ne e boetse e phahame haholo ka letsatsi la 30 ka karolelano ea likarabo tsa 7.4 ± 1.8 vs 20.2 ± 1.7 likarabo tse fetang 6 h, matsatsi a 1 le a 30, ka ho latellana, F (1, 94) = 26.6, p<0.001. Ho bile le likheo tse ngata tsa "photobeam" nakong ea tlhahlobo ea Extinction ea ho arabela ka letsatsi la 30 vs day 1 ka karolelano ea 3,154.4 ± 113.1 vs 3,932.8 ± 111.4 photobeam break ho feta 6 h, matsatsi a 1 le 30, ka ho latellana, F (1, 94) = 24.1, p<0.001. Ho ne ho se na litlamorao tsa bohlokoa tsa DOSE mme ho ne ho se litšebelisano tse bohlokoa bakeng sa karabelo ea lever e sa sebetseng kapa boitšoaro ba locomotor (p boleng bo tlohang ho 0.2 ho isa ho 0.8) bo bonts'a ka ho eketsehileng hore lihlopha tsa kalafo li ne li sa fapana pele ho kenoa ka letsoai kapa naloxone.

Karolo ea tlhahlobo: Ho araba cue

Bakeng sa lihlopha tse tšoaroang ke letsoai, ho arabela ka mokhoa o hlakileng ho ne ho le boholo ho Karabelo ea thuto ea cue vs hora ea botšelela ea ho felisoa ka matsatsi a mabeli le a 1 a ho qobelloa ho qobelloa. The t mekhoa e ne e t (10) = - 2.6, p<0.05 ea letsatsi la 1 le t (6) = −5.8, p<0.001 ea letsatsi la 30 (data ha e bontšoe). Ka hona, likhoto tse maemong a letsoai li ne li arabela ka ts'epahalo bakeng sa leqheka le kopaneng la sucrose. ANOVA ea lever e mafolofolo e arabelang nakong ea ho araba likarolo tsa cue e senotse phello ea bohlokoa ea Letsatsi, F (1, 94) = 86.1, p<0.001, Tekanyo, F (5, 94) = 4.6, p<0.01, le tšebelisano ea Letsatsi le Dose, F (5, 94) = 3.8, p<0.01. Sena, hammoho le ho khetholla phapang e kholo lipakeng tsa letsatsi la letsoai la 1 le letsatsi la saline la 30 le arabang, t (16) = - 6.1, p<0.001, le tlhahlobo ea data (Feie. 1) e bonts'itse ts'ebetso ea takatso ea takatso ea setšoantšo se katiloeng ka sefahleho. Joalokaha ho bontšitsoe ho Lisebelisoa le mekhoa, ena e le 'ngoe t Teko e entsoe joalo ka tlhahlobo ea netefatso e netefatsang hore ho kenella ha takatso ea takatso ho bonoe litlamong tse tšoeroeng ke letsoai. Ka nako eo ho ne ho hlokahala hore o tlose litlamorao tsa ho incubation ho hlahloba litlamorao tsa naloxone ka nako e ngoe le e ngoe. Re entse sena re sebelisa mekhoa e 'meli. Taba ea mantlha, re ne re hlahloba feela tlhaiso-leseling ka matsatsi a 1 le a 30 ka boikemelo. ANOVA ea lever e sebetsang e arabang ka letsatsi la 1 ha ea senola phello e kholo ea naloxone, F (5, 46) = 1.6, p= 0.2. Leha ho le joalo, papiso pakeng tsa sehlopha sa letsoai le sehlopha sa 10 mg / kg se bonts'itse mokhoa o lebisang ho lekhoxone le amohelang karabelo (p= 0.06). ANOVA ea lever e sebetsang e arabang ka letsatsi la 30 e senotse phello e kholo ea naloxone, F (5, 48) = 4.7, p<0.01. Liphapang tsa bohlokoa tsa poso li bonts'itsoe ho Feie. 1. Taba ea bobeli, ho leka ho bapisa ka ho hlaka katleho ea naloxone ka letsatsi la 1 ho isa ho la 30, re ile ra tlosa litlamorao tsa ho kenella ka ho fetolela datha ho liperesente tsa karabelo e tloaelehileng ea letsoai (letsatsi la 1 le arabela e le liperesente tsa letsatsi la 1 saline le la 30 le arabela joalo ka liperesente tse 30 tsa letsoai la 1). ANOVA e ile ea etsoa ka lintlha tsena tse fetotsoeng ho sebelisoa lintlha tse lipakeng tsa Letsatsi (30 kapa 0.001) le Dose (0.01, 0.1, 1, 10, kapa XNUMX mg / kg naloxone). ANOVA e hlahisitse phello e kholo ea Letsatsi, F (1, 78) = 4.7, p<0.05, Tekanyo, F (4, 78) = 2.6, p<0.05, le letsatsi le batlang le le bohlokoa ka ho sebelisana ha Dose, F (4, 78) = 2.4, p= 0.05. Joalo kaha ona e ne e le moralo oa lithuto tse mahareng, mokhoa ona ha o fane ka matla a lipalo joalo ka ha a bapisa boitšoaro bo anngoeng ke lithethefatsi le motheo oa ona (kahare ho lithuto); leha ho le joalo, e fana ka mokhoa oa lipalo ho bapisa litlamorao tsa lithethefatsi ka lihlopha tse seng li ntse li fapana ka lebaka la litlamorao tsa phetoho e ngoe. Joalokaha ho bontšitsoe Feie. 2, naloxone e ne e sebetsa haholoanyane ka letsatsi la 30 le letsatsi la 1 ho litekanyetso tse 2 tse tlase tse lekiloeng (0.001 le 0.01 mg / kg). Setšoantšo sa 2 e hlahisa liperesente tsa data ea saline e tlositsoe ho 100 ho fana ka katleho ea naloxone ho fihlella Karabelo bakeng sa karabelo e sebetsang ea lekhonono (100% e tla ba ho felisoa ka botlalo ha ho arabeloa).

Feie. 1 

Litlamorao tsa naloxone mabapi le Karabo ea cue-paired e ts'oeroang ka letsatsi la 1 ka letsatsi la 30. Ho buuoa ka mekhoa ea ± SEM bakeng sa karabelo e sebetsang. Asterisk e bontša phapang ea bohlokoa ho tloha ka letsatsi la 1 (e bonts'itsoe feela bakeng sa lihlopha tsa saline ho totobatsa ho kenella ...
Feie. 2 

Ts'ebetso ea naloxone ho Araba bakeng sa Cue e tsokotsoang ka marang-rang ka letsatsi la 1 ho isa ho la 30 matsatsi. Mets ± SEM e bonts'oa liperesente tse 100 tsa letsoai le arabang (liperesente tsa Saline tse baloang bakeng sa sehlopha ka seng e le Karabelo ea cue e arotsoeng ke letsoai le arabang) ...

Karabo e sa sebetseng ea lever e ne e phahame ka letsatsi la 30 le 1, F (1, 94) = 8.8, p<0.01, empa ho ne ho se na phello ea Dose, 'me ho ne ho se na tšebelisano e kholo. "Incubation" ea karabelo e sa sebetseng ea lever e ne e hlile e le nyane haholo, ka karolelano ea likarabo tsa 0.8 ± 0.4 ka letsatsi la 1 le 2.4 ± 0.4 likarabo ka letsatsi la 30.

Ts'ebetso ea locomotor nakong ea Karabo ea cue, joalo ka ha motho ea lever ea arabelang a sa sebetse, e ne e phahame ka letsatsi la 30 ka letsatsi la 1, F (1, 94) = 4.4, p<0.05. Ka mokhoa o ts'oanang, ho ne ho se na phello ea DOSE mme ho ne ho se na tšebelisano e bohlokoa. Ketsahalo ea locomotor e bile le karohano ea li-photobeam tse 516 ± 53.3 ka letsatsi la 1 vs 672 ± 52.5 likhefu tsa photobeam ka letsatsi la 30.

Puisano

Phuputso e teng hona joale e hlahlobile katleho ea mohanyetsi oa opiate, naloxone, ha a amohela ho araba sets'oants'o se nang le sefahleho sa khale le nakong e tlang ea ho qobelloa ka thipa. Naloxone o ile a fumanoa a fupere ho arabela ka mokhoa o ikhethileng khoeli e le 'ngoe le e' ngoe ka letsatsi le le leng la ho qobella ho tsuba (Feie. 1). Ntle le moo, kamano ea litlamorao e ile ea bonoa ka letsatsi la 30 moo naloxone e kengoang e arabela tekanyetso e tlase (0.001 le 0.01 mg / kg) le tekanyetso e phahameng (1 le 10 mg / kg), empa eseng ka tekanyo e mahareng (0.1 mg /kg; Feie. 1). Liphetho tsena li ts'ehetsa monahano oa rona oa hore naloxone e ka sebetsa hantle ho fokotsa ho arabela ha cue e entsoe ka lijo. Sena se boetse se re lebisa ho nka hore ho na le phetoho e nkang nako e itseng ntlheng e itseng ea sistimi ea opiate libekeng tse 'maloa tsa ho se qobelloe ho itaola ka boipuso tse tšoanang le ho kenella hoa takatso ea boithati. Ka kakaretso, kaha likhoto li ne li amehile haholo ka litekanyetso tse tlase tsa naloxone ka letsatsi la 30 (Feie. 2), re fihlela qeto ea hore karolo e itseng ea sistimi ea opiate e ba hlokolosi haholoanyane ho feta khoeli e le 'ngoe ea ho qobelloa ho se itaole.

Ho fokotseha ha litakatso tsa hauxone mohlaleng ona oa litekanyetso tsa ho khutla ho tšoanang ho hlalositse litlamorao tsa ts'ebeliso ea naloxone ha e pepesetsoa koae, joala le likatse tsa lijo ho batho (; ; ; ). Ha e le hantle, mofuta oa phoofolo o netefalitsoe. Leha ho le joalo, lipatlisiso tsa morao-rao mabapi le phello ea lethal e le 'ngoe la naltrexone mabapi le ho araba boteng ba tšusumetso ea khethollo, eo pele e neng e bonts'a ho fumaneha ha sucrose, ha ea ka ea fumana phello ea naltrexone mabapi le karabelo e fanoang (). Ho se lumellane hona ho kanna ha bakoa ke lintlha tse 'maloa tsa mokhoa. Taba ea mantlha ke hore re ntse re ithuta ho khutlela bothateng ba rona ka lebaka la tlhahiso ea khang ea konkreite e neng e entsoe ka pente ka sefahleho, ha e ntse e tsoela pele. a lekola litlamorao tsa tšusumetso ea khethollo. Ts'ebetso ea mefuta ena e fapaneng ea likhoele ho bonahala e hloka likarolo tse fapaneng tsa neural (; ). Taba ea bobeli, re hlokometse litlamorao tse ts'epahalang ka ho fetisisa tsa naloxone ka letsatsi la 30 la ho itima lijo ka likhoka ha e ile ea lekoa ka mor'a ho felisoa ka matsatsi a ka bang 15. Ho boetse ho na le ho nahanoa ka liphapang tsa ho sebetsa hantle ho hlalosa phapang pakeng tsa naloxone le naltrexone; le ha ho le joalo, sena ha se na monyetla oa hore lethal e le naltrexone (2.5 mg / kg) le lona le ne le tšoana le litekanyetso tsa rona tse phahameng. Ntle le bophelo bo bolelele ba haltrexone, litekanyetso tsa naloxone le naltrexone li tšoana le tse ling ().

Ha re lumele hore litlamorao tsa naloxone thutong ea hona joale e ne e le ka lebaka la khatello ea boits'oaro ka ho fana ka matšoao a ho khaotsa ka boomo. Likhoto tsa rona ha lia ka tsa bonts'a matšoao a hlakileng a ts'epo ea opiate ebang ke ka pele kapa ka mor'a taolo ea naloxone. Leha re sa ka ra hlahlojoa ka mokhoa o hlophisehileng, ha re a ka ra sheba ho tlosoa ka mokokotlo oa mokokotlo (piloerection, lets'ollo, ho bua ka meno kapa ho sisinyeha kapa ho sisinyeha) ebang nakong ea ho qobelloa kapa ka matsatsi a liteko. Ntle le moo, boima ba 'mele bo ile ba eketseha ka lebaka la ho ikoalla ka thata le ts'ebetso ea locomotor ha ea ka ea angoa ke naloxone (ya data e sa bonts'ang). Matšoao a joalo a ikhethileng a ho tlohela ka mokhoa o ikemiselitseng ka mokhoa o hlakileng a hlalositsoe ka mor'a mokhoa o tloaelehileng oa ho ja tsoekere (). Leha ho le joalo, regimen eo (12 h 25% glucose e kopantseng le 12 h e qobelloang ho itima lijo letsatsi le letsatsi bakeng sa matsatsi a 8) e ne e fapane haholo le thuto ea hona joale ka maemo a tsoekere le maemo a tlisoang ke lijo (likhoto tsa rona li ile tsa fumana tsoekere e fokolang 'me ho ne ho se mohla li jang lijo nyotsoe). Holim'a moo, o sebelisitse lethaliti la naloxone le leholo ka makhetlo a mabeli, 20 mg / kg, e le lethal dose la rona le phahameng ka ho fetisisa.

Tekanyetso e 'ngoe ea thuto ea hona joale bakeng sa ho toloka litlamorao tse itšetlehileng ka nako ea naloxone e bile karabelo e tlase haholo bakeng sa sets'oants'o se entsoeng ka sefahleho ka letsatsi la 1. Ha sena se totobatsa ho kenella ha takatso ea takatso ha ho bapisoa le letsatsi la 30, ho bula monyetla oa hore khaello e akaretsang ea naloxone ka letsatsi la ho araba la 1 e bile ka lebaka la ts'ebeliso e matla ea naloxone ka sekhahla sa ho araba le / kapa "sephetho sa fatše." Maikutlo ana a mabeli a etsa hore re ele hloko tlhalohanyo ea rona ea katleho ea naloxone thutong ea hona joale; leha ho le joalo, liphuputso mabapi le ho itšetleha ka sekhahla li ts'ehetsa kakaretso hore litheko tse tlase tsa ho arabela li lokela ho ba kotsing ea ho sitisoa (; ). Ntle le moo, le ha e se ea bohlokoa ka lipalo, ho ne ho na le tšekamelo ea tekanyetso e phahameng ea naloxone ho fokotsa Karabelo bakeng sa cue ka letsatsi la 1 (p= 0.06, 10 mg / kg vs saline, kakaretso ea ANOVA; bona Feie. 1). Sena se supa ho haella ha sebopeho sa fatše.

Mokokotlo oa phello ea lethalone bakeng sa naloxone mabapi le ho Arabela bakeng sa koluoa ​​ka la 30 e ne e ikhethile. Taba ea hore moriana o ne o sebetsa hantle ka tekanyetso e tlase haholo le litekanyetso tse holimo, empa eseng tekong e bohareng, e ka supa mekhoa e mengata ea ho amohela karabelo bakeng sa setšoantšo se tsamaeang ka maoto.

Mochine oa sephetho sa biphasic e ka ba katleho ea lebatooa ho mohanyetsi holim'a litekanyetso tseo re li lekileng. Mohlala, ho na le li-receptor tse eketsehileng tsa opiate ho NAcc vs the VTA (; ) le lithuto tsa microinjection tse tataisang li-agonists tsa opiate (; ) ho NAcc le VTA li hlokometse sesebelisoa se ikhethang sa opiate receptor subtype le phapang e akaretsang ea tšebeliso ea litekanyetso. E ka ba litekanyetso tse tlase tsa naloxone li sebetsa hantle ho e 'ngoe ea libaka tsena, athe litekanyetso tse peli tse phahameng li amehile haholo. Tekanyetso e bohareng e ka hlahisa "ho hloka tekano" ho thibelo e akaretsang ea sistimi ea DA e hokahanyang likarolo tsena tsa bokong. Ha e le hantle, sena se ka hlahisa keketseho ea phapang ea karabelo e susumetsoang. Sena ke seo re se boneng se latela tekanyetso ea 0.1 mg / kg. Tlhahlobo ea lintlha tsa karabo e senotsoe, ho tsoa ho likhoto tse leshome sehlopheng, likhoto tse tharo sehlopheng sa 0.1 mg / kg li entse likarabo tse 70 kapa ho feta (70, 70, 72) ha likhoto tse tharo li entse likarabo tse tlase ho 25 (15, 18, 24) . Likhoto tse setseng sehlopheng seo li arabile makhetlo a 29-41 (29, 32, 38, 41), athe moelelo oa saline e ne e le 46.4. Ka kakaretso, mokhoa o tsoang tlhahlobisong ea data ho likhoto tse ikhethang o ne o le bakeng sa ho fokotseha ha karabelo ho latela saline e latelang 0.1 mg / kg ha likhoto tse ling li hlile li bonts'a monyetla oa ho arabela.

Khabareng, le ha naloxone e khethile ka mokhoa o khethiloeng ho arabela ka cue-e kentsoe ka letsatsi la 30, ha ea ka ea fokotseha ka letsatsi la 30 ho arabela maemong a letsatsi la 1 (Feie. 1). Ka hona, re kanna ra ba ra bona feela karolo e nyane ea neuroadaptations e felletseng e tlatsitsoeng ke takatso ea boithati ea sucrose. Litsamaiso tse ling tsa transmitter e le li-modulators tsa ho kenella ha takatso ea takatso ke batho ba batlang thuto e tsoelang pele. Glutamate ke khetho e kanna ea ba sa tsoa fumana hore thibelo ea ho tlosoa ha glutamate le glutamate autoreceptor agonist LY379268 e bonts'itse ts'ebetso ea takatso ea sucrose ha e tsamaisoa ka mokhoa o hlophisitsoeng kapa e lebisitsoe ho khubu ea bohareng ba amygdala (). GABA ke sepheo se seng se ka khonehang kaha VTA GABA neurons e ka 'na ea thibela mesolimbic DA neurons (; ); ka hona, li-receptors tsa GABA e tla ba sepheo sa ho ama boits'oaro bo susumetsang. Kamora nako, DA ka boeona e tla ba moemeli ea hloahloa, haholoholo ha re hlokometse ho fokotseha ho itšetlehileng ka nako ho latela litlamorao tsa karabelo e entsoeng ke koae bakeng sa cueine e tsamaeang ka sefahleho ().

Nahanisisa

Joalokaha naloxone e ile ea sebetsa haholo kamora nako ea ho qobella ho tila, e kanna ea ba mokhoa o lakatsehang oa kalafo bakeng sa ho fokotsa litakatso tsa lijo. Mohlala, batho ba fetang 90% ba jang lijo ba hloloa ho fihlela sepheo sa ho theola boima ba 'mele (). Liphetho tsa hona joale li boetse li tlatselletsa lithuto tsa tliliniki tse sebelisang naloxone le naltrexone ho fokotsa ho khutlela ho takatso ea lijo le bulimia, tšebeliso ea joala le ho tsuba koae (; ; ; ). Liphumano tsena li tšehetsa karolo e akaretsang ea opiate system ho khutla, ho kenyelletsa le litakatso tsa boits'oaro, tse amanang le lihlopha tse fapaneng tsa moputso.

lumela hore baa fokola

Patlisiso ena e ne e tšehelitsoe ke NIDA / NIH e fang DA016285-01 le moputso oa tlatsetso e nyane ea baithuti ba nyane (DA016285-01-S2).

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