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Nociceptin/Orphanin FQ and Opioid Receptor-Like Receptor Mrna

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Nociceptin/Orphanin FQ and Opioid Receptor-Like Receptor Mrna THEJOURNALOFCOMPARATIVENEUROLOGY444:358–368(2002) Nociceptin/OrphaninFQandOpioid Receptor-LikeReceptormRNA ExpressioninDopamineSystems CAMILLES.NORTON,1* CHARLESR.NEAL,1,2 SUNEELKUMAR,1 HUDAAKIL,1,3 ANDSTANLEYJ.WATSON1,3 1MentalHealthResearchInstitute,UniversityofMichiganMedicalCenter, AnnArbor,Michigan48109-0720 2DepartmentofPediatrics,UniversityofMichiganMedicalCenter, AnnArbor,Michigan48109-0720 3DepartmentofPsychiatry,UniversityofMichiganMedicalCenter, AnnArbor,Michigan48109-0720 ABSTRACT Althoughnociceptin/orphaninFQ(N/OFQ)influencesdopamine(DA)neuronalactivity, itisnotknownwhetherN/OFQactsdirectlyonDAneurons,indirectlybymeansoflocal circuitry,orboth.Weusedtwoparallelapproaches,dualinsituhybridization(ISH)and neurotoxiclesionsofDAneuronsbyusing6-hydroxydopamine(6-OHDA),toascertain whetherN/OFQandtheN/OFQreceptor(NOP)mRNAareexpressedinDAneuronsinthe ventraltegmentalarea(VTA)andsubstantianigracompacta(SNc).IntheVTAandSNc, smallpopulations(ϳ6–10%)ofN/OFQ-containingneuronscoexpressedmRNAfortyrosine hydroxylase(TH),therate-limitingenzymeforDAsynthesis.Similarly,veryfew(1–2%) TH-positiveneuronscontainedN/OFQmRNAsignal.AmajorityofNOP-positiveneurons (ϳ75%)expressedTHmRNAandroughlyhalfoftheTH-containingneuronsexpressedNOP mRNA.ManyN/OFQneurons(ϳ50–60%)expressedglutamicaciddecarboxylase65and67 mRNAs,markersfor␥-aminobutyricacid(GABA)neurons.Inthe6-OHDAlesionstudies, NOPmRNAlevelswerenearly80and85%lowerintheVTAandSNc,respectively,onthe lesionedside.Theselesionsappeartoleadtocompensatorychanges,withN/OFQmRNA levelsapproximately60%and300%higherintheVTAandSNc,respectively,after6-OHDA lesions.Finally,N/OFQ-stimulated[35S]guanylyl-5Ј-O-(␥-thio)-triphosphatelevelswerede- creasedintheVTAandSNcbutnottheprefrontalcortexafter6-OHDAlesions.Accordingly, itappearsthatN/OFQmRNAwasfoundlargelyonnondopaminergic(i.e.,GABA)neurons, whereasNOPmRNAwaslocatedonDAneurons.N/OFQisinapositiontoinfluenceDA neuronalactivitybymeansoftheNOPlocatedonDAneurons.J.Comp.Neurol.444: 358–368,2002. ©2002Wiley-Liss,Inc. Indexingterms:orphaninFQ;ORL1;substantianigracompacta;ventraltegmentalarea;tyrosine hydroxylase;6-hydroxydopamine Threeopioidreceptorsknownas␮,␬,and␦havebeen withinthemembrane-spanningregionoftheNOPare cloned(Evansetal.,1992;Kiefferetal.,1992;Chenetal., similarto␮,␬,and␦opioidreceptors(Mollereauetal., 1993;Mengetal.,1993;Thompsonetal.,1993;Wanget al.,1993;Yasudaetal.,1993;Fukudaetal.,1994).With polymerasechainreactionamplificationandlowstrin- gencyhybridizationtechniques,severallaboratoriesde- Grantsponsor:NIH;Grantnumber:5RO1DA08920. tectedhuman,mouse(Mollereauetal.,1994),andrat *Correspondenceto:CamilleS.Norton,UniversityofMichigan,Mental HealthResearchInstitute,205ZinaPitcherPlace,AnnArbor,MI48109- (Bunzowetal.,1994;Chenetal.,1994;Fukudaetal., 0720.E-mail:[email protected] 1994;Wangetal.,1994;Wicketal.,1994)cDNAsencod- Received26March2001;Revised13November2001;Accepted10De- inganovelreceptor,whichwillbereferredtoasNOP(also cember2001 knownasORL1).Approximately65%oftheresidues PublishedonlinetheweekofFebruary11,2002 ©2002WILEY-LISS,INC. DOI10.1002/cne.10154 N/OFQ AND NOP mRNA EXPRESSION IN VTA AND SNc 359 1994; Lachowicz et al., 1995). Despite this similarity, clas- To better understand the anatomic relationships be- sic opioid ligands do not specifically bind to the NOP with tween the orphanin and DA systems, two parallel ap- any significant affinity (Fukuda et al., 1994; Mollereau et proaches were used to ascertain whether N/OFQ and NOP al., 1994; Wang et al., 1994). mRNA are expressed within DA-containing neurons in the A 17 amino acid peptide termed orphanin FQ or noci- VTA and SNc. In one series of experiments, we used dual ceptin (N/OFQ) was discovered to be the high-affinity en- in situ hybridization (ISH) techniques to examine poten- dogenous ligand for the NOP (Meunier et al., 1995; Rein- tial coexpression of mRNA for tyrosine hydroxylase (TH), scheid et al., 1995). There is a significant amino acid the rate-limiting enzyme for DA synthesis, with N/OFQ sequence similarity between N/OFQ and the endogenous and NOP mRNA in tegmental and nigral neurons. Addi- opioid peptides. This resemblance is particularly striking tionally, we determined whether N/OFQ mRNA was colo- in the case of dynorphin A(1-17). Orphanin FQ and dynor- calized with mRNAs for glutamic acid decarboxylase 65 phin A have the same amino acid length, a similar amino and 67 (GAD), markers for ␥-aminobutyric acid (GABA) acid motif (“Phe-Gly-Gly-Phe” in N/OFQ and “Tyr-Gly- neurons. In another set of studies, N/OFQ and NOP Gly-Phe” in the opioid peptides) at the amino terminal and mRNA expression levels were measured in the SNc and similar groups of positive charges in the midportion and VTA after destruction of DA neurons with the neurotoxin C-terminal end (Meunier et al., 1995; Reinscheid et al., 6-hydroxydopamine (6-OHDA). To determine whether the 2ϩ 1995). Like other opioid ligands, N/OFQ modulates Ca density, functional activity, or both, of this G-protein– channels (Knoflach et al., 1996; Connor and Christie, ϩ coupled receptor (i.e., NOP) population was altered after 1999), activates inward rectifying K channels (Connor et 6-OHDA lesions, our final set of studies measured al., 1996; Vaughan and Christie, 1996) and inhibits cAMP N/OFQ-stimulated [35S]guanylyl-5Ј-O-(␥-thio)-triphosphate production (Meunier et al., 1995; Reinscheid et al., 1995). ([35S]GTP␥S) binding VTA, SNc, and PFC. Opioid ligands exhibit varying degrees of affinity for each of the opioid receptors (Mansour et al., 1995). Despite the aforementioned similarities between opioid and the opioid-like orphanin system, N/OFQ does not bind with MATERIALS AND METHODS any appreciable affinity to the classic opioid receptors Adult male Sprague-Dawley rats (275–300 g, Charles (Reinscheid et al., 1995). Accordingly, the orphanin sys- River, Wilmington, MA) were maintained and handled tem, although resembling the opioid system in many according to NIH guidelines. All protocols used in the ways, has evolved into a distinct and independent system present study were approved by the university unit for lab (Meng et al., 1996; Reinscheid et al., 1996; Danielson and animal medicine at the University of Michigan. The rats Dores, 1999). were housed three per cage, maintained on a 12/12 hour The widespread anatomic distribution of the orphanin light/dark schedule (lights on at 6 AM, off at 6 PM), and system (Bunzow et al., 1994; Fukuda et al., 1994; Molle- provided food and water ad libitum. reau et al., 1994; Wick et al., 1994; Lachowicz et al., 1995; Neal et al., 1999a, b) suggests involvement in a broad 6-OHDA lesions array of neurologic functions. For example, N/OFQ admin- The rats were deprived of food 24 hours before surgery. istration (i.c.v.) decreases nociceptive threshold in the ro- On the day of surgery, each rat was first injected with dent tail flick test (Meunier et al., 1995; Reinscheid et al., atropine methyl nitrate (0.05 mg/kg, i.p., in 0.9% saline) 1995; Rossi et al., 1996), increases feeding (Pomonis et al., 1996; Stratford et al., 1997), activates neuroendocrine re- followed by an injection of desmethylimipramine (15 mg/ sponse to stress (Devine et al., 2001), decreases anxiety in kg, i.p., in distilled water) and sodium pentobarbital behavioral tests (Jenck et al., 1997; Griebel et al., 1999), (30–60 mg/kg, i.p.). Each rat was then placed in a stereo- impairs motor coordination (Devine et al., 1996b), alters taxic frame, and by using neurosurgical techniques, a ␮ locomotion (Reinscheid et al., 1995; Devine et al., 1996b; small hole was drilled through the skull. A 10- l Hamilton Florin et al., 1996, 1997b), and influences learning and syringe was lowered into the brain parenchyma and either memory processes (Sandin et al., 1997; Manabe et al., 6-OHDA (2 mg/ml in 0.1 mg/ml ascorbic acid) or vehicle 1998; Hiramatsu and Inoue, 1999). (0.1 mg/ml ascorbic acid) was injected into the right me- ␮ Orphanin FQ and NOP are moderately to heavily ex- dial forebrain bundle at a rate of 0.5 l/min over an pressed in dopamine (DA) -rich areas such as the ventral 8.25-minute period. The injection coordinates were 3.0 tegmental area (VTA), substantia nigra compacta (SNc), mm anterior to bregma, 1.8 mm right of the midline, and and prefrontal cortex (PFC; Florin et al., 1997a; Neal et 8.3 mm ventral with respect to the surface of the skull al., 1999a, b). The orphanin system is, therefore, in a (Paxinos and Watson, 1986). Injections of 6-OHDA at position to influence DA neuronal activity and several these coordinates were used to lesion both nigral and studies have shown a functional interaction between these tegmental dopamine neurons (Berridge and Robinson, two systems. Local N/OFQ application into the striatum 1998). After the 6-OHDA or vehicle injection, the microsy- increases DA levels as well as locomotor activity (Konya et ringe was left in place for an additional 2 minutes and al., 1998). Additionally, N/OFQ administration into the then removed slowly. After surgical closure, each rat was VTA or lateral ventricle decreases accumbal DA levels as injected with warm 0.9% saline (3–6 cc, s.c.) and placed in measured with microdialysis (Murphy et al., 1996; Mur- an incubator until it became ambulatory, after which it phy and Maidment, 1999). Alterations in DA release are was returned to an individual cage with food and water typically associated with motivational states; however, supplied ad libitum. Fourteen days after the lesions, each N/OFQ administration (i.c.v.) fails to produce conditioned rat was decapitated; the brain rapidly
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