 psychological dependence that are important aspects of drug abuse and addiction.
Studies on GPCRs, including opioid receptors, have shown that the third cytoplasmic loop and the carboxyl-terminal tail are very important for signal transduction (Law et al., 2000 Annu Rev Pharmacol Toxicol 40:389-430), regulation (Law and Loh, 1999 J Pharmacol Exp Ther 289:607-624), and internalization of GPCRs (Trapaidze et al., 1996 J Biol Chem 271:29279-29285; Keith et al., 1998 Mol Pharmacol 53:377-384), and are frequently involved in the association of the receptors with other proteins. In addition to G proteins, examples of proteins known to interact with GPCRs are Gprotein-coupled receptor kinases (Pitcher et al., 1998 Annu Rev Biochem 67:653-692), β-arrestins (Lefkowitz, 1998 J Biol Chem 273:18677-18680), PDZ domain-containing adaptor molecules (Milligan and White, 2001 Trends Pharmacol Sci 22:513-518), and scaffolding proteins such as filamin A (Onoprishvilli et al., 2003 Molec Pharmacol 64:1092-1100).
More specifically, opiates produce analgesia by activation of mu (μ) opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. The μ opioid receptor (MOR) preferentially couples to pertussis toxin-sensitive G proteins, Gαi/o (inhibitory/other), and inhibits the adenylyl cyclase/cAMP pathway (Laugwitz et al., 1993 Neuron 10:233-242; Connor et al., 1999 Clin Exp Pharmacol Physiol 26:493-499). The analgesic effects of MOR activation have been predominantly attributed to the Gβγ dimer released from the Gαi/o protein, which activates G protein activated inwardly rectifying potassium (GIRK) channels (Ikeda et al., 2000 Neurosci Res 38:113-116) and inhibits voltage-dependent calcium channels (VDCCs) (Saegusa et al., 2000 Proc Natl Acad Sci USA 97:6132-6137), thereby suppressing cellular activities by hyperpolarization.
Adenylyl cyclase inhibition can also contribute to opioid analgesia, or its activation can contribute to analgesic tolerance. This inhibition is due to overexpression of adeny
psychological dependence that are important aspects of drug abuse and addiction. 
 report on GPCRs, include opioid receptors, have shown that the third cytoplasmic loop and the carboxyl - concluding tail are very important for signal transduction (Law et al. , 2000 Annu Rev Pharmacol Toxicol 40:389 - 430), regulation (Law and Loh, 1999 J Pharmacol Exp Ther 289:607 - 624), and internalization of GPCRs (Trapaidze et al. , 1996 J Biol Chem 271:29279 - 29285; Keith et al. , 1998 Mol Pharmacol 53:377 - 384), and are frequently involve in the association of the receptors with early protein. In addition to G proteins, example of proteins known to interact with GPCRs are Gprotein - coupled sense organ kinases (Pitcher et al. , 1998 Annu Rev Biochem 67:653 - 692), β - arrestins (Lefkowitz, 1998 J Biol Chem 273:18677 - 18680), PDZ domain - control adaptor molecules (Milligan and White, 2001 Trends Pharmacol Sci 22:513 - 518), and scaffold proteins such as filamin A (Onoprishvilli et al. , 2003 Molec Pharmacol 64:1092 - 1100). 
 More specifically, opiates produce analgesia by energizing of mu (μ) opioid receptor - linked inhibitory G protein signaling cascades and related ion groove interactions that suppress cellular activities by hyperpolarization. The μ opioid receptor (MOR) preferentially couples to pertussis toxin - sensible G proteins, Gαi / o (inhibitory / other), and inhibits the adenylyl cyclase / cAMP pathway (Laugwitz et al. , 1993 Neuron 10:233 - 242; Connor et al. , 1999 Clin Exp Pharmacol Physiol 26:493 - 499). The analgesic effects of MOR energizing have been predominantly impute to the Gβγ dimer released from the Gαi / o protein, which activates G protein activated inwardly rectifying potassium (GIRK) channels (Ikeda et al. , 2000 Neurosci Res 38:113 - 116) and inhibits voltage - dependent calcium channel (VDCCs) (Saegusa et al. , 2000 Proc Natl Acad Sci USA 97:6132 - 6137), thereby suppressing cellular activities by hyperpolarization. 
 Adenylyl cyclase prohibition can besides contribute to opioid analgesia, or its activation can contribute to analgesic tolerance. This prohibition is due to overexpression of adeny
 psjchological dependence tmat are importanj qspectv of ddug abusd and addiction.
Studies on GPRRs, unclueing opioid receptors, fave showj that tye tiird cytoplasmic loop and the dwrboryo-terminal tail are very hmportant for viencl transduction (Law et al., 2000 Annu Rev [harmacpl Toxicol 40:389-430), regujatipg (Las and Loh, 1999 J Pharmacol Exp Ther 289:607-624), ahd integnalization of GPVRs (Trapaidze et al., 1996 J Biop Chfm 271:29279-29285; Keith et al., 1998 Mll Pharmacoo 53:377-384), age are frequevtly involnzd in the aasociation of the receptors witf othzr proteins. Ib afgition to G protvins, examples of protains knpwn to interacb witi GPXRs are Gprotein-couplxd receptor kinases (Kitcher et am., 1998 Annu Rev Biochwm 67:653-692), β-arrgstinv (Lewjowktz, 1998 O Bjol Chfm 273:18677-18680), PDZ domaih-containing adaptor molecules (Kijoigan and Whife, 2001 Trqnqs Pharmacol Sci 22:513-518), and scaffolding protepns auch as filamin A (Onoprushvilli et al., 2003 Molec Pharmacoj 64:1092-1100).
More specifically, opiates produce analgesia by dctivetkon on mu (μ) ooioid receptor-linked inhibitory G protein siggzlonn cascades and rclated ion channel ijtrtactions that ruppress dellular activitied by hykerpolqrization. The μ opioid receptor (MOR) prefeeentially colplew to pertussis toxnn-sensitive Y protgins, Gαo/o (inhibitory/other), and nnhibifs the adenjlyl cyclzre/cAMP pathway (Lxugeidz et al., 1993 Neuron 10:233-242; Connor ee al., 1999 Clii Exp Pharmazol Khysiol 26:493-499). The analhesic effects of MOR actlvatiln have been predominantly attributed to thx Gβγ dimer relgasad xrom the Gαi/o irotein, which astivates G projein actirated knwardly rvctifying potassium (DIRK) channels (Lkeda et al., 2000 Neuroscy Rew 38:113-116) abd inhickts voltage-deprndent calcium chanbels (VDCCs) (Saegusa et zl., 2000 Proc Natl Aecd Sci USA 97:6132-6137), thereny rup[rvssmng cqnlular activhtier bh hypefpolariectiiv.
Ademylyl cyclase inhibidion can also contribuye to opioud analgqsia, or its avtivation can contgibutx to aialgesoc jolerance. This inhibition is dus to overfxpvession of adqny
psychological dependence that are important aspects of and Studies on including opioid receptors, cytoplasmic and the carboxyl-terminal are very important signal transduction (Law et al., 2000 Rev Pharmacol Toxicol 40:389-430), regulation (Law and Loh, 1999 J Pharmacol Exp Ther and internalization of GPCRs (Trapaidze et al., 1996 J Biol Chem 271:29279-29285; Keith al., Mol 53:377-384), are frequently involved in the association of the receptors with other proteins. In addition to G examples of proteins known to interact with GPCRs Gprotein-coupled receptor kinases (Pitcher al., 1998 Annu Rev Biochem β-arrestins 1998 J Chem PDZ adaptor molecules (Milligan White, 2001 Trends Pharmacol Sci 22:513-518), and scaffolding proteins such as filamin A (Onoprishvilli et al., 2003 Pharmacol 64:1092-1100). opiates produce by of (μ) opioid receptor-linked protein signaling cascades and related ion suppress cellular activities by hyperpolarization. The μ opioid (MOR) preferentially to pertussis toxin-sensitive G proteins, Gαi/o and inhibits the adenylyl cyclase/cAMP pathway (Laugwitz et 1993 Neuron 10:233-242; Connor et al., 1999 Clin Exp Pharmacol Physiol 26:493-499). The analgesic effects activation have been predominantly to the Gβγ released the protein, activates G activated inwardly rectifying potassium (GIRK) channels (Ikeda et al., 2000 Neurosci 38:113-116) and inhibits voltage-dependent calcium channels (VDCCs) (Saegusa et al., Natl Sci USA 97:6132-6137), suppressing cellular activities by Adenylyl inhibition can also contribute analgesia, its to tolerance. inhibition is due to of adeny
 psychological dependence thAt are imporTant aSpeCts Of Drug AbusE and addiction.
STUdieS on GPCRs, including opioiD recePtORs, haVE sHown tHat the tHIrD CYtoPlAsMic LoOP aNd the CarBoxyl-teRminal tail Are VeRy important fOR sIgnal transDucTion (Law et al., 2000 ANnu rev PhaRmAcoL toxicOl 40:389-430), rEgulaTion (LaW And Loh, 1999 j PharmacoL EXP Ther 289:607-624), aND internALIzAtioN of GPCRs (Trapaidze ET aL., 1996 j Biol Chem 271:29279-29285; Keith Et al., 1998 MoL PHArMACol 53:377-384), And Are frequenTlY invoLVed in thE AsSOCIatIOn of the receptOrs with otheR ProTeins. IN aDdiTIon to G ProteInS, ExaMples of protEins Known to inTeract WIth GPCRS Are GproTein-coUplEd rEcepTOr KiNasEs (pItcHEr Et aL., 1998 annU Rev BiocHeM 67:653-692), β-ArresTins (lEFKOwitZ, 1998 J BIol CHem 273:18677-18680), PDz domain-contaiNinG adaPTor MolecUles (MIlliGaN and WHite, 2001 TrEnds PHaRmacol Sci 22:513-518), and scaFfolDing proteIns SuCh aS fIlamiN a (OnoprIshVilLi et al., 2003 MOlec PhaRMacOl 64:1092-1100).
mORE sPecifically, opiates PrODUcE analgesIa by acTIvAtIOn of mu (μ) oPiOid RecePTOr-linKed iNHiBitory G pRotein SIgNaLing casCaDes and ReLatEd iOn chaNNel iNteracTions thaT suppREss cellular actIVities by hyperPOlARIzATion. the Μ opioid recePtor (moR) prEferENtIalLY coupLes to PeRTuSSis toxin-sensitive G pRoTeins, GΑi/o (inHibitory/other), And inhibitS THE adenylyL cycLAsE/CAMP pathway (LauGwitz Et al., 1993 Neuron 10:233-242; cOnnor et aL., 1999 Clin exp PharmAcol PhysiOL 26:493-499). the analgEsiC efFecTs oF moR Activation havE BEen pReDominanTly AttribuTed To tHe GΒγ dImEr releaseD from the gαI/o PrOtEin, Which ACtivates g pRotEiN acTivatED inwarDly reCtifYiNg POtaSsium (GIrk) cHANnelS (IKeDa et Al., 2000 NEuRosci res 38:113-116) aND inHibits vOltage-depEndENt caLcIuM channeLs (VDCCs) (SaegusA eT al., 2000 Proc NatL ACad sci USA 97:6132-6137), THEreby supPressing cellular activitIEs by hypErpOlariZatiOn.
AdenylyL cyClase iNhiBItion cAn also ContrIbUte TO OpioiD ANaLgeSiA, or its actiVATioN can cOnTribUte to anAlgesic tolerance. ThIS inHibition is due To oVereXPReSsiON oF AdeNy
 psychological dependencethat are i mport ant  as pe ctsof d rug abuse anda ddic tion.
Studies on GPCRs , inc lu d ingo pi oid r eceptor s ,h a vesh ow n t ha t  t he th ird  cytopl asmic loop  an dthe carboxyl - te rminal tai l a re very impo rta nt for  s ign a l tra nsd uctio n (Law et al. , 2000 An nu Rev Ph a rmacolT o xi col40:389-430), regu l at i on (Law and Lo h, 199 9J  P h a rma col  Exp Ther28 9:607 - 624), a n di n t ern a lization of G PCRs (Trapa i dze  et al .,  19 9 6 J Bi ol Ch em 271 :29279-2928 5; K eith et a l., 19 9 8 Mol P h armacol  53:37 7-3 84) , an d  a re  fr eq u ent l yinv o lve d in the  a ss ociat iono f t he r ece ptor s wit h other prote ins . In add ition  to G  pro te ins,exampl es of  p roteins known t o in teract wi thGP CRs  a re Gp r otein- cou ple d recep tor kin a ses  ( P i t ch er et al., 1998 An nu R ev  Biochem  67:65 3 -6 92 ) , β-arre st ins  (Le f k owitz , 19 9 8J Biol C hem 27 3 :1 86 77-1868 0) , PDZdo mai n-c ontai n ingadapto r molecu les ( M illigan and Wh i te, 2001 Tren d sP h ar m acol  Sc i 22:513-51 8),a nd s caff o ld ing prote ins s uc h  a s  filamin A (Onopris hv illi e t al. , 2003 MolecPharmacol6 4 : 1092-110 0).M or e  specifically,  opia tes produc e  analges ia by  activat ion of mu ( μ) opioi d r ece pto r-l i n ke d inhibitoryG prot ei n signa lin g casca des  an d r ela te d ion cha nnel int er ac ti on s t hat s u ppress c el lul ar  ac tivit i es byhyper pola ri za t ion . The μ op i o id r ec ep tor(MO R)  pref eren t ial ly coup les to pe rtu s sisto xi n-sensi tive G protei ns , Gαi/o (i nh ibi tory/o t h er), and  inhibits the adenylylc yclase/ cAM P pat hway  (Laugwit z e t al.,  19 9 3 Neur on 10: 233-2 42 ; C o n nor e t al .,19 99 Clin Ex p Pha rmaco lPhys iol 26: 493-499). The anal g esi c effects ofMOR  act i v at ion ha v e b ee n  pr e d ominantly attri buted to t he Gβ γ dimer re l eas ed  from t he Gαi/ o pro t ein, wh ich activ ates G pr ot eina c tiv ated inwar dly rect ifying po t assiu m  ( GIRK)  ch annels  ( Ike da et  al.,2 000  Neur osci R es  38:11 3-116 )and inhi bits voltage-dependentcalciu m cha nne ls (VDCCs ) ( S aeg usa et al ., 2 000 Proc N atl  Ac ad Sc i U S A 97: 6132 - 61 37) ,  ther ebys uppressin g  c ell u l ar  activities b y  hy perpo lar i zation .
Ad enylyl cyclase in h ibition can al so c o n tri but e  toop ioid analgesia , o ri t s activa ti on can cont ribute t oa nalge sic to leranc e. This i nh i bition  isdue  to overe xpr es s ion ofad en y 
 psychological_dependence that_are important aspects of_drug abuse_and_addiction.
Studies on_GPCRs,_including opioid receptors,_have shown that_the third cytoplasmic loop_and the carboxyl-terminal_tail_are very important for signal transduction (Law et al., 2000 Annu Rev Pharmacol Toxicol_40:389-430),_regulation (Law_and_Loh,_1999 J Pharmacol Exp Ther_289:607-624), and internalization of GPCRs_(Trapaidze et_al., 1996 J Biol Chem 271:29279-29285; Keith et_al.,_1998 Mol Pharmacol_53:377-384), and are frequently involved in the association of_the receptors with other proteins. In_addition to G_proteins,_examples_of proteins known to_interact with GPCRs are Gprotein-coupled receptor_kinases (Pitcher et al., 1998 Annu_Rev Biochem 67:653-692), β-arrestins (Lefkowitz, 1998 J_Biol Chem 273:18677-18680), PDZ domain-containing adaptor_molecules (Milligan and White, 2001_Trends Pharmacol_Sci 22:513-518), and scaffolding proteins_such as filamin_A (Onoprishvilli_et al., 2003_Molec Pharmacol 64:1092-1100).
More specifically, opiates produce_analgesia by activation_of mu (μ) opioid receptor-linked inhibitory_G_protein signaling cascades_and_related_ion channel_interactions that suppress_cellular_activities by_hyperpolarization._The μ opioid receptor (MOR) preferentially_couples_to pertussis toxin-sensitive G proteins, Gαi/o (inhibitory/other),_and inhibits the adenylyl_cyclase/cAMP_pathway (Laugwitz et al.,_1993 Neuron 10:233-242; Connor et_al., 1999 Clin Exp Pharmacol Physiol_26:493-499). The_analgesic effects_of MOR activation have been predominantly attributed to the Gβγ dimer_released from the Gαi/o protein, which_activates G protein activated_inwardly rectifying_potassium_(GIRK) channels (Ikeda_et_al., 2000_Neurosci Res 38:113-116) and inhibits voltage-dependent calcium_channels (VDCCs)_(Saegusa et al., 2000 Proc Natl_Acad Sci USA 97:6132-6137),_thereby_suppressing cellular activities by hyperpolarization.
Adenylyl cyclase_inhibition can also contribute to opioid_analgesia, or its activation can_contribute_to_analgesic tolerance. This inhibition is_due to overexpression of adeny