I-Biol Psychiatry. Umbhalo-ngqangi wombhali; ifumaneka kwi-PMC Jun 1, 2009.
Ishicilelwe kwifomu yokugqibela ehleliweyo njenge:
PMCID: PMC2666333
I-NIHMSID: I-NIHMS51419
Kudala kurhanelwa ukuba i-brain norepinephrine (NE) idlala indima ebalulekileyo kumlutha, kodwa le mbono iye yagqunywa kakhulu kwiminyaka yakutshanje ngokuqwalaselwa okubalulekileyo kwezinye iinkqubo zobuchopho ezibandakanyekayo kwiziyobisi ezifana ne-dopamine kunye ne-glutamate, kwaye kutshanje, i-orexin (1, 2). Nangona kunjalo, izifundo ezitsha sele ziqalisile ukubuyisela umva lo mkhwa ngokubonelela ngobungqina obubambekayo bokubaluleka kwe-NE kumlutha, njengoko kubonisiwe ngamanqaku e-2 kumcimbi wangoku (Schank et al., Zachariou et al.).
Izifundo zakwangoko ze-NE kunye nokulutha zigxile kwi-opiates kunye nokurhoxa kwe-opiate. Ii-opiates zithintela ngamandla umsebenzi we-NE locus coeruleus (LC) neurons, kunye nokuhoxiswa kwe-opiate kusebenze ngamandla ezi seli, okukhokelela kumbono wokuba i-LC idlala indima ebalulekileyo kukuxhatshazwa kwe-opiate. Nangona kunjalo, izilonda ze-LC okanye iingqikelelo zayo azinampembelelo kwimpawu zomzimba okanye eziphazamisayo zokurhoxiswa kwe-opiate (3, 4). Ngokuqinisekileyo, umsebenzi ophakamileyo we-LC neurons ngexesha lokurhoxa uneziphumo zokuziphatha, kodwa ezo ziphumo zihlala zingacacanga.
Uphononongo lwakutsha nje lubonise ukuba i-NE neurons ngaphandle kwe-LC ibalulekile kuxhatshazo lwe-opiate. Ngaloo ndlela, i-beta adrenoceptor stimulation kwi-nucleus yebhedi ye-stria terminalis (BNST) ibaluleke kakhulu kwi-aversiveness yokuhoxiswa kwe-opiate; le NE isuka kwi-medullary A1 kunye ne-A2 NE iiseli, hayi iLC (4). Le ngeniso efanayo ye-NE kunye ne-receptor kwi-BNST ifunyenwe ibaluleke kakhulu kuxinzelelo olubangelwa uxinzelelo (5), ecebisa ukuba ukuchaswa kokurhoxa kwe-opiate kunokunxulumana nokuxhalaba okubangelwa kukurhoxa (bona Umfanekiso we1 ebonisa igalelo leNE kwi-BNST).
Amaphononongo ambalwa avavanye ukubandakanyeka kwe-NE kwengqondo kuxhatshazo oluvuselelayo. Inqaku elinye kulo mba wangoku landisa uhlalutyo lwe-NE kunye nokuba likhoboka lokuxhatshazwa ngokwengqondo, kwaye eminye imixholo efanayo ibonakala ngathi yokuxhatshazwa kwe-opiate. Ngaphandle kweziphumo zayo ezaziwayo zokuvuza / zokuqinisa, icocaine ebukhali ikwasebenza njengearhente enamandla yexhala (6). Schank et al. (pg * yalo mbandela) isebenzisa ubuhle, obusanda kuphuhliswa i-dopamine-beta-hydroxylase (DBH) yokunkqonkqoza ngaphandle kwempuku ukubonisa ukuba umbindi we-NE uyimfuneko kuxinzelelo olunjalo lwe-cocaine. Le modeli yezilwanyana ayinayo i-enzyme ye-DBH, eyimfuneko ekwenzeni i-NE kwi-dopamine. Besebenzisa uvavanyo oluqhelekileyo lokuxhalaba (olunyusiweyo kunye ne-maze), abaphandi bafumanise ukuba ukunkqonkqozwa kwe-DBH akubonisi mpendulo yoloyiko kwinaliti ye-cocaine ebukhali, ngelixa iimpuku zohlobo lwasendle zenza. Okubalulekileyo, ukuxhalaba koku kunkqonkqozwa kwe-DBH kunokuhlangulwa ngolawulo lwe-DOPS, ikhompawundi enokuguqulwa ibe yi-NE ngaphandle kwesidingo se-DBH kwaye ngaphandle kokutshintsha amanqanaba e-dopamine. Kwinyathelo elingaqhelekanga kodwa elinamandla kwisifundo sokunkqonkqoza, abaphandi baqinisekisa iziphumo ezingasentla kunye nokusetyenziswa kwe-pharmacological kwiigundane zohlobo lwasendle, ebonisa ukuba i-DBH inhibitor disulfiram, okanye i-beta adrenoceptor antagonist propranolol, kodwa i-alpha1 okanye i-alpha2 i-adrenoceptor antagonists, ivelise isiphumo sokuziphatha esifanayo. Ke, olu phando lubonisa ukuba iziphumo ezixhalabisayo ze-cocaine zibangelwa, ubuncinci ngokuyinxenye, kwi-NE esebenza kwi-beta adrenoceptors. Ezi ziphumo ziyahambelana neziphumo ezininzi zangaphambili ezidibanisa ubuchopho obuphezulu be-NE kunye nexhala. Okubalulekileyo, ezi ziphumo zikwafana neziphumo zokuba unxunguphalo oluphakamileyo ngexesha lokurhoxa kwi-opiate okanye i-cocaine ixhomekeke kuvuselelo lwe-beta receptor (7). Njengoko ababhali babonisa, oku kuxhalaba okubangelwa kukuhoxiswa kunokuba yindawo apho iziphumo zabo zibaluleke kakhulu kunyango lweklinikhi. Ngenxa yokuba ukuphepha iimpendulo zokurhoxa kungumba wokuqhubela phambili ekubuyeleni kwakhona ngexesha lokuzila, unyango oluthintela ukuxhalaba okunxulunyaniswa ne-NE lunokwandisa ixesha lokuzila kwaye lunciphise ukuphinda ubuyele. Esi sigqibo siyahambelana neziphumo zangaphambili zokuba ukubuyiselwa okubangelwa uxinzelelo-okuvuselela ukufuna i-cocaine kukwavalwe lunyango lwe-beta adrenoceptor antagonist (8).
Olu dlelwane phakathi kwexhala le-cocaine ebukhali kunye nokurhoxa kwe-cocaine kuyaxaka ekuqaleni - kutheni i-cocaine ebukhali inokuvelisa impendulo efana nempendulo yokurhoxiswa kwe-cocaine? Ukumisela ii-substrates zeselula kwezi mpendulo zexhala le-noradrenergically-mediated iya kuba ngumsebenzi obalulekileyo kwixesha elizayo. Nokuba yeyiphi na indlela yeselula ephantsi kwezi mpendulo zonxunguphalo, zibalulekile kuba zibonisa omnye umcimbi odidayo onokunika ulwazi malunga nemiba ebalulekileyo yokusetyenziswa kakubi kwecocaine. Oko kukuthi, ukongeza kwi-hedonic kunye nezenzo zokuqinisa, i-cocaine ebukhali ivelisa ixhala, oko kukuthi, impendulo efana nokuhoxiswa. Umnqweno wokunqanda ukuxhalaba okunxulumene nokurhoxa kunokukhokelela ekunqweneleni kwe-cocaine kunye nokutya, ukuvelisa ixhala elongezelelweyo kunye nokunqwenela okuhambelanayo kwakhona. Ke ngoko, amaxhala afanayo aveliswa yi-cocaine ebukhali kunye nokurhoxa kwe-cocaine kunokuvelisa umjikelo wengxelo oqinisekileyo onokuthi ube phantsi kweminye imiba efihlakeleyo kunye nebaluleke kakhulu ekliniki yokusetyenziswa kakubi kwe-cocaine. Oku kuphakamisa ukuba ukunyanga ixhala eliqhutywa yi-NE elinxulunyaniswa ne-cocaine ebukhali kunye nokurhoxa kwe-cocaine kunokuba luncedo ekliniki.
Omnye umbuzo obalaseleyo kolu phononongo kulapho i-NE isebenza khona ukuqhuba ixhala- okanye iimpendulo ezinxulumene noxinzelelo kwicocaine. Umsebenzi wangaphambili ubonisa ukuba i-amygdala eyandisiweyo yinto enokwenzeka, ngakumbi i-BNST. UDelfs et al (4) ibonise ukuba i-beta adrenocceptor stimulation kwi-BNST ibalulekile kwi-aversiveness of acute opiate withdrawal, kunye nomthombo ohambelanayo we-NE yi-medullary A1 kunye ne-A2 neurons. Izifundo ezilandelayo zibonise ukuba le ndlela inye iyimfuneko ekubuyiseleni uxinzelelo lwe-cocaine- okanye ukufuna i-opiate (9). Njengoko kuphawuliwe ngasentla, le ndlela ifanayo inxulumene kakhulu neempendulo zokuxhalaba okubangelwa uxinzelelo (5). Ke ngoko, uqikelelo lwe-medullary NE kwi-amygdala eyandisiweyo ibandakanyeka ngokubalulekileyo kwezi mpendulo zoxinzelelo / zoxinzelelo ezinxulumene nokubuyela kweziyobisi. Olunye ulwandiso olubalulekileyo lwesifundo se-Schank et al iya kuba kukufumanisa ukuba le ndlela iyabandakanyeka na kwiziphumo ezixhalabisayo ze-cocaine ebukhali; Ukufunyaniswa okunjalo kuya kuseka ngakumbi unxibelelwano phakathi koxinzelelo olunxulunyaniswa ne-cocaine ebukhali kunye nokurhoxa, kwaye kugxilwe kuphando ekucaciseni ngakumbi iindlela kunye nonyango kwezi mpendulo zoxinzelelo.
Njengoko kuphawuliwe ngasentla, umba omnye obalulekileyo obalaseleyo yindlela icocaine kunye ne-opioids ezivelisa ngayo utshintsho kwi-NE neurons ukuguqula iimpendulo ezinxulumene nokuziphatha kuxinzelelo kunye noxinzelelo. Uxinzelelo kunye noxinzelelo lunonxibelelwano oluchazwe kakuhle kunye nolubanzi kunye nokukhotyokiswa ziziyobisi, ukusukela ekubuyiseleni umva ukuya ekubeni yinto esichengeni ekuphuhliseni umlutha. Ke ngoko, ukuqonda ulungelelwaniso lwemolekyuli oluveliswa ngamachiza amluthayo kwi-NE neurons lunakho ukuveza iithagethi zemolekyuli zokuphuhlisa unyango lokulawula umlutha. Kulo mqulu, iphepha likaZachariou et al (*) lithatha inyathelo elibalulekileyo kule ndlela. Ngokusekwe phezu kobudlelwane obusekwe kakuhle phakathi kweenguqu kumsebenzi we-adenylyl cyclase (AC), umsebenzi we-NE neuronal kunye ne-chronic morphine-induced withdrawal syndrome, aba babhali baqeshe iimpuku ngokususwa kofuzo kwii-isoforms ezimbini ze-AC eziye zasebenza nge-calcium / i-calmodulin, I-AC1 kunye ne-AC8. Ukongeza, imouse egcina ukucinywa kabini kwe-AC1 kunye ne-AC8 yavavanywa. Nangona ukufunyaniswa kwe-AC1 + AC8 kunkqonkqoza iigundane (KO) kubonakala kudidekile ngokuyinxalenye yotshintsho lwembuyekezo, ukucinywa okukodwa kwe-isozyme nganye kuvelise i-phenotype engaguqukiyo eyayichasene nemiphumo ye-morphine engapheliyo, kubandakanywa ukuhoxiswa kokuziphatha kwe-naloxone kunye nokunciphisa amandla okuziphatha. ye-basal firing rates kunye ne-forskolin-induced firing ye-LC NE neurons. Ngaphaya koko, uphuhliso lonyamezelo kwi-LC neurons kwi-inhibition yi-mu opioids yancitshiswa kwiimpuku ze-AC1 kunye ne-AC8 KO. Okubalulekileyo, i-acute analgesic effect ye-morphine kunye nokuphuhliswa kokunyamezela kwi-morphine-induced analgesia yayichanekile kuzo zonke ezintathu ze-KO genotypes. Ezi datha ziqinisekisa kakuhle indima ye-AC ekulawuleni i-morphine-induced withdrawal syndrome, kunye nobudlelwane phakathi komsebenzi we-AC kunye nokuhoxiswa kwe-morphine.
Mhlawumbi eyona nto ibalulekileyo yeZachariou et al. kukwenza umzamo wokuqala wokuhlola iipateni zokubonakaliswa kofuzo kwi-LC ukwenzela unxulumano olunokubakho lokurhoxiswa kwemorphine. Lo ngumsebenzi onzima ngenxa yezizathu ezininzi, kubandakanywa izicubu kunye nokungafani kokuziphatha komntu ngamnye. Nangona kunjalo, ukuthelekisa iprofayili ye-morphine ebangele utshintsho kwi-gene expression phakathi kwe-genotypes ebonisa iimpendulo ezahlukeneyo ze-phenotypic zokuziphatha kunye ne-electrophysiological kwi-morphine engapheliyo inokuvumela ukuchongwa kweenguqu ezibangelwa yi-morphine ezinxulumene nokurhoxa. Ngelishwa, ngelixa eli linge lokuqala elinesibindi kwiprofayili ebanzi yemfuza ye-LC neurons yafumanisa umahluko onomdla phakathi kwe-genotypes, uninzi lwazo lwaluhambelana nolindelo olusekwe kwizifundo zangaphambili, alizange libonise inani elincinci labaviwa abacacileyo abaza kujolisa kwixa elizayo. izifundo. Xa sibuyela emva, mhlawumbi kunethemba eligqithiseleyo ukulindela ukuba i-database ekhangayo eyenziwe kule ngxelo iqulethe ulwazi olwaneleyo lokuchonga izinto eziqhelekileyo eziqhelekileyo ezilawula ukuziphatha okuntsonkothileyo njengokuhoxiswa kwe-opiate; ingakumbi xa kujongwe ukuba imodeli yofuzo esetyenzisiweyo yayikukucinywa kofuzo lwe-encoding ye-AC isozyme nokuba ukucinywa bekukuyo yonke ingqondo kwaye kungangqalanga kwi-LC. Isisombululo ngokuqinisekileyo kukuba le ngxelo ibe yinyathelo lokuqala elibalulekileyo kwizifundo ezizayo usebenzisa iindlela ezongezelelweyo zofuzo ukuqhubela phambili ukuhlukanisa kunye nokuvavanya amacandelo e-genome anokulawula ngamandla ukuhoxiswa kwe-phenotype eyenziwa yi-opioids engapheliyo.
Imihlathi
Iphepha elichazayo ukuba awusenanto oyifunayo: Le fayili yeFayile yombhalo wesandla ongabhalwanga owamkelwe ukushicilelwa. Njengenkonzo kumakhasimende ethu sinika le ngcaciso yokuqala kwincwadi yesandla. Umbhalo wesandla uza kufumana ukukopishwa, ukufakela, nokuphonononga ubungqina obunokubakho ngaphambi kokuba kukhutshwe kwifomu yayo yokugqibela. Nceda uqaphele ukuba ngexesha lokuveliswa kweeprogram ezinokuthi zifumaneke ezinokuthi ziphazamise umxholo, kunye nazo zonke izisemthethweni ezichasayo ezisetyenziswa kwiphephancwadi.
I-Financial Disclosures - Bobabini ababhali baxela ukuba akukho mdla wemali we-biomedical okanye ungquzulwano olunokubakho lomdla.
Ucaphulo
;