main neurophysiologicalfunctionsofmorphineinmanarediscussed. Per Key words: abnormal alleles.Earlypreclinicaldiagnosedpatientsshouldbemanaged firstphysiologicallyandnutritionally should beestimatedinbloodplasma,targetingparkinsonianprone populations(depressedpersons),andcorrelatedwith stages ofmorphinebiosynthesisinparkinsonians.Thelevels centralnervoussystem(CNS)producedmorphine secondary metabolitesofdopamineorsimilarsubstances.Metabolic testsshouldbedesignedtoestablishthefaulty hypothetically proposethedamageofsubstantianigraneurons by endogenousneurotoxinsresultingfromabnormal W Summary Per Palabras clave: de lossignoslaenfermedad. tratamiento. Serecomiendaunmanejofisiológicoydietéticodeestaspersonas(pre-parkinsonianos)anteslaaparición proveniente delsistemanerviosocentralenlasangredepersonasnormalesyparkinsonianosantescualquier para undiagnósticopreclínicodelaenfermedadParkinsonidiopáticoesnecesariocompararlosnivelesmorfina metabolitos enlaspoblacionesdealtoriesgogenéticoycorrelacionarlosconlosalelospresentesellas.Seconcluyeque desencadena laenfermedaddeParkinsonidiopática.Debendiseñarsepruebasfuncionalesquepermitanidentificardichos endógenas, metabolitosanormalesporcantidadocalidad,resultantesdelmetabolismosecundariodeladopaminalocual parkinsonianos. Seadmitequeeldañodelasneuronasmelánicaslasustancianegraseproduceporneurotoxinas el serhumanoydelaimportanciaaclararsubiosíntesisparaestablecerlasetapasdefectuosasenlosenfermos Papaver somniferum Se presentaunapanorámicatabuladaygráficadelosconocimientosactualessobrelabiosíntesismorfinatantoen Resumen Y CONTROVERSIAS OPINIONES, DEBA Recibido:03/12/07/ e sketchpresentknowledgeonthemorphinebiosyntheticpathway in ea-Sasiaín J. ea-Sasiaín J. Parkinsondisease,earlydiagnosis,biosynthesis,. Biosíntesisdelamorfina:suimportanciaenenfermedadParkinson. enfermedaddeParkinson,diagnósticoprecoz,biosíntesis,morfina. Biosynthesisofmorphine:itsimportance inParkinson´sdisease. comoenlosanimales.Hacemosunanálisisgeneraldedosfuncionesprincipaleslamorfina ITS IMPORT Biosíntesis delamorfina:suimportanciaenenfermedadParkinson BIOSYNTHESIS OFMORPHINE: Enviado ap ANCE INP ares: 1 TES ARKINSON´S DISEASE 1/12/07/ T Papaver somnifer o explainidiopathicParkinson´sdiseasewe Aceptado publicación: 29/04/08/ Rev .Fac.Med. Rev um .Fac.Med. L 2008;56:161-189. andinanimals. 2008;56:161-189. . T wo 161 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 162 Rev case ofHazum(3).Lactucarium,thedriedlatexwildlettuces,mainly without indicationbytheinvolvedresearchersofhorticulturalvarietiesanalized,ifanyin proposed foritsprecursorcodeinebyGulandandRobinson Morphine hasaverycomplexpentacyclicstructurewithfiveassymetriccarbons(Figure1),first families withfewalkaloidproducinggenera. as graminealcomponentsofhay used asamildhypnoticuptotheXIXthcentury discovery ofthousandstheminplantswhichthey areconsidereda fifties assummarizedbyHolmes(5,6).Itisthefirstalkaloidisolated(1)andopenedgatefor morphine inducedcatalepsy Mavrojanis (49)postulated morphinesynthesisbyrats,asanexplanationofhis observationsof Animal morphineendogenoussynthesis(AMES) by Gates(46),Ginsburg(47)andBeyerman(48)with theircoworkers. century manyeffortsweremadetowardsthechemical synthesisofmorphinewhichwasachieved and hisresearchgroup(12-15)asshowndiagrammatically infigures2-5(16-45).DuringtheXXth Bruneton (9),Poeaknapo(10)andKream(1 Crucial stepsofitsbiosyntheticpathwaywerefoundby Battersby(7)andBarton(8),depictedby nates fromasequentialacetylation-deacetylationofsalutaridinol. B ringarisesfromR-reticulineandthefinalclosureofEorigi- animals fromdopamineresultinglevodopadecarboxylation.The dihydroxyphenyl-L-alanine). RingsCandDcomebothinplants tyr and bothtohim botanistJoséLuisFernández 1. Figure 1.

Special thanksto ProfessorRyanJ.Huxtableforhis timelyadviceontheextentofGuland andRobinsonoriginalpaper osine butinanimalsitcomesfr .Fac.Med. 2008V H H O O

Morphine. O 5 4

6 3 E IntheopiumpoppyringAderivesstraightfrom A 2 7 C 12 13 ol. 56No.2 15 H . In1970 11 B 14 1 8 om levodopa(L-DOP , alsocasuallysupposedtobeasourceofmorphine(3),arebotanical D 16 9 10 V ir H ginia E.Davisspeculatedon thismattertyingtheaddiction Alonso forclarifying tomethetaxonomicalbinomial oftheopiumpoppy NCH 1) andfullyclarified,mainlythroughtheworkofZenk , mostlyforchildren.Howevercompositae,aswell A = 3 â

3,4 1 Early intheXIX Introduction which hasseveralcultivars mically asasubspeciesofthelatter Papaver somniferum in natureasthewildprecursorof Papaver setigerum to synthesizemorphine(2)is non cultivatedplantspeciesreported over threethousandyears.Theonly Papaver somniferum dried latexoftheopiumpoppy isolated morphinefromopium(1),the cows (3)hasbeendisproved(4) morphine inmilkfromwomenand L) beingasourceofexogenous of cultivatedlettuce( experimental data,onthepossibility cursory proposal,withnosupporting , andfinallyprovedinthenineteen “ secondary metabolism Lactuca vir th centurySertürner DC, considered , cultivatedfor Lactuca sativa L, buttaxono- osa L,was 1 . The ” , . . Figure 2. presence inopiumwassubstantiated(14). and itscongeners(10),wasfirstisolatedfr the biosynthesisof>2500isoquinolinealkaloidsinplantkingdom includingmorphine

H H

O O HO HO HO HO

H H 3 3 CO CO HO HO (13, 14) (13, L -DO PA (S)-

Papaver reticulinebiosynthesis. NH N

2 NH NCH H C O 2 (12)

OH 3

O

H H H

O O

H

3'OH-N-methylcoclaurine HO HO HO 3 HO HO HO CO Norcoclaurine N om (S)-Reticulinebeingthecentralintermediateof Annona reticulata

O H H H N NCH

3

HO

4-Hydroxyphenylacetaldehyde L

L-tyrosine H (13).Soonther

H

H O 3 3 NH H H C HO HO CO O O O C O 2 Coclaurine N-methylcoclaurine O H O H eafter its H N H N C H 3 163 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 164 Rev .Fac.Med. 2008V and/or atcarbon3´(20,21).Subsequent intermediatesuptoS-reticulinehavenotbeenestablished. established (10).Thefirst nine asamethylgroupdonortoyield (S)-reticuline;Thesequenceofmethylationreactionsremains tobe though thelatterisnotadequatefor thebainebiosynthesis.MethylationreactionsinvolveS-adenosylmethio- cor product toclosetheisoquinolinering,butthisdoesnotexplain thepresenceof1-carboxylicacid assymetr reactants becausecarbon1oftheresultingbenzylisoquinolineis assymetrical(S).Inordertoexplainthe Coscia (17)tooccurevenspontaneously sation wouldnotexplaintheformationof1-carboxylicacidsassuggested byBrossi(16),andshown Figur oxidase tofurnishnorlaudanosolineasincor Boettcher states(10)thatonemoleculeofL-DOP proved thattheyareonlymethylatedatthe7positionnotsuitable forthebiosynthesisofmorphine. P most likelybytransamination,andsubsequentlydecarboxylatedto 3,4-dihydroxyphenylacetaldehyde(DO- AL) butdispellstheassumptionthatonemoleculeofdopamineistransformed toDOP r esponding toTHP e 3. y ofcarbon1Kr Animal reticulinebiosynthesis. ol. 56No.2 , andits3´methylderivativedemonstrated inL-DOP eam (1 in vivo 1) pr

methylation ofTHPoccurspreferentially butnotexclusivelyatcarbon6 oposes anenzymaticallydir , substitutedphenylpyr Br r ect forthe ossi (16)isolatedthis,andsimilar A maybetransformedto3,4-dihydr in vivo situation. Thepr ected r uvic acidsar eduction oftheSchiffcondensation A tr e themostlikelycarbonyl oposal ofDOP eated parkinsonians(16) , carboxylicacidsand oxyphenylpyr AL byamonoamine AL conden- uvate, H H 3 3 C C H H Figure 4. Barton (8),almostsimultaneouslywithitsisolationfrom Papaver liver pigandinhumanneuroblastomacellstakesplacebiochemicallyexactlythesamewayasprovenfor neuroblastoma cells (2).OnlytheS-enantiomerofTHP(norlaudanosoline)isafeededasprecursormorphineinhuman the Ering,completingmorphineringsystem.10 O 3 3 O CO CO HO HO O (S)-Reticuline plant(23).Anenzymaticsystemlabelledsynthaseyieldssalutaridine, lookedforandsynthesizedby Thebaine biosyntheticpathway. (30,31) (22) H NCH NCH H 3

3 in vitro

(23) (29) (10).EpimerizationofS-toR-reticulineisdonebyacytochromeP450enzymefrom H H 3 3 Dehydroreticulinium IonDehydroreticulinium CO HO HO CO

Salutaridinol 7-O-acetate H H 3 3 C H C Intheplantkingdomonlygenus O O O O NCH C O 3 (24) C H 3 Papaver H N Croton salutaris (25) C H (29) 3 H H speciesbelongingto5differentsectionsmake 3 3 (R)-Reticuline CO C HO H O O CoA

(29) byBarnes(8). (25)

CoASAc

H N C Papaver H 3 (26) hasbeenshowntoclose H H

3 3 C C H Salutaridinol O O O H H

H 3 3 CO CO HO O Salutaridine H O H (8,11,27) N C (28)

H H NCH 3 3 165 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 166 Rev .Fac.Med. 2008V Figure 5 in other animalspecies(36,37).Demethylation ofthebainetoyieldoripavine(38)hasbeenshownoccur both phenolic methyletherareactionthathasbeenknownforoverfifty yearstobecarriedoutbyman(35)and two additionalassymetriccarbonsatpositions6and14,finally morphinebydemethylationofthe DC) removestheO-methylgroupsofthebainetoyield,throughneopinone andcodeinone,,thathas In mammalsmorphinone isacataboliteofthebaine (41),codeine(42)andmorphine (43-45). Janssen (38)foundthisalternative andproposedamorphinone,substancenotreportedinopium, stage. liver andkidneywereabletotransform thebainetooripavine,codeineandmorphine(34).Brochman- caca mulatta) Papaver somniferum . Morphine biosynthesis. (41)andman( ol. 56No.2 L andintestedanimals:laboratory rat( Homo sapiens Inthe Papaver )malignanttumorcells genusonly Papaversomniferum Rattus rattus in vitro (10).Microsomesfromratbrain, ) (40),rhesusmonkey L(sin. Papaver setigerum (Mac- T Blood Brain amygdala,5samples Brain cortex Brain Central NervousSystem Urine Kidney Skin Adrenal pheochromocytomaPC-12 Adrenals Intestine Pancreas Submandibular gland Lung Heart Thymus Blood plasma Spinal cord,lumbar Spinal cord Medulla oblongata Pons-medulla Cerebellum Midbrain Hypothalamus Cerebral cortex Liver Spleen able 1.

(A-B)

Laborator y r odents r (A) Ratlaborator epor 0.233 +/-0.031pmol/day 0.07 +/-0.015pmol/g 0.07 +/-0.015pmol/g ted tomakemorphine 0.25+/- 0.09pgmol/g 0.26 +/-0.07pmol/g 0.12 +/-0.05pmol/g 1.64 +/-0.49pmol/g 0.59 +/-0.10pmol/g 0.67 +/-0.18pmol/g 0.63 +/-0.28pmol/g 0.93 +/-0.36pmol/g 0.43 +/-0.09pmol/g 0.62 +/-0.32pmol/g 4.21 +/-0.09pmol/g 0.37 +/-0.07pmol/g 1905 +/-632fmol/g 1209 +/-364fmol/g 0.52 +/0.07pmol/g 6.30 +/-1.9pmol/g 0.70 +/-0.2pmol/g 551 +/-221fmol/g 381 +/-100fmol/g 0.23+/-0.01ng/g 57 +/-34fmol/ml 329 +/-93fmol/g 10zeptomol/cell 12.7 +/-5.4ng/g 61 +-16fmol/g 26 +/-2fmol/g 7.0 +/-3.2ng/g 16 +/-5fmol/g 17 +/-6fmol/g 11 +/-2fmol/g 2+/-1fmol/g 0.346 pmol/g 1.474 pmol/g 0.27 pmol/g 0.13 pmol/g 3.10 pmol/g 7.22 pmol/g 105.31 ng/g AMOUNT y 1.0 pmol/g not stated , Rattus norvegicus Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Donnerer 2(64) Poeaknapo (10) Meijerink (66) Meijerink (66) Meijerink (66) Meijerink (66) Meijerink (66) Donnerer (60) Donnerer (60) Donnerer (60) Donnerer (60) Donnerer (60) Goumon (63) Goumon (63) Gintzler (59) Molina (62) Guarna (61) Molina (62) Molina (62) Molina (62) Munjal (67) Molina (62) Molina (62) Molina (62) AUTHOR Zhu (66) Oka (68) Lee (65) Lee (65) Lee (65) Lee (65) Lee (65) Lee (65) 167 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 168 other fourhuman malignanttumorscell lines(4).Inhumanblood plasma significantamounts of “ proclivity ofalcoholtothatmorphine(50-52).Seeverswronglyrefutedherontheground Rev Human bloodgranulocytesmakemorphineboth samples (90,91)suggestingexcretionofbothendogenous andexogenousmorphine. zona (T with normalcontrols,socialandabstemiousalcoholdrinkers andpatientswithseverepaindueto reported byKazuoMatsubara(89)inparkinsonianpatients treatedwithlevodopa,whencompared tissues, heartatriaandtumors.Increasedurinaryexcretion ofmorphineandtwo a guenon(T a lagomorph,thirdrodent,fourartiodactyls(threeherbivores andoneomnivore),twoprimates: characterized asmorphine(60).Itwasalsofoundinafish,anamphibian,twodomesticcarnivores, lines butnotinfourhuman lung cancercelllines novo SH-SY5Y humanneuroblastoma cellsprovideamodelforthecompletedemonstration ofthe in bloodmononuclearandred cells(84)mostprobablyastheresultofcodeinedemethylation (84). been summarizedbyKreamandS reviewed byBenyhe(55),Meijerink(56)andHosztafi(57)themorerecentadvanceshave noraporphine isomers.OverthelastquarterofXXthcentury misinterpreting thepossiblemetabolicroute.Sourkes(54)insistedinalternativerouteleadingto urine (73)andwascautiouslylabelledbyGintzler was firstdetectedbyradioimmunoassaysinlaboratoryratsandmice(T (4,58), nowadaysBöttcher(10),dispelledallpossiblediscussionontheexistenceof unless hypotheses…areconsonant…withknownfactstheycanhavenovalidity .Fac.Med. 2008V Par circadian rhythminthelevelofendogenousmorphinehasalsobeenencountered”. was foundinrats(69).Reticulinehasbeenratbrain(22).QuotingHorak(72),Benyhe(55)wrote:“A Bar Harbor the balb-cmousearealbino.ThelatterahighlyinbredlineoriginatedinRoscoeB.Jacksonlaboratory T synthesis ofmorphine(4)also detectedinfournormallungcell(67)andhuman cancer able 1. Heart 9-10morning Brain 4-5afternoon Brain Spleen 4-5afternoon Spleen Small intestine4-5afternoon Small intestine9-10morning Heart 4-5afternoon Brain 9-10morning Central NervousSystem,3regs. able 4);subsequentstudiesshowwidevariationinmorphine urineexcretionin24hour ticular inter able 2)andman(T

(A-B) , canbeconsider est mustbegiventothefactthatlaborator Laborator ol. 56No.2 y r ed geneticallyasidenticalsiblings. odents r able 3).Inhumansmorphinehasbeendetectedincells, fluids, tefano (1 epor (B) Mouse,laborator ted tomakemorphine 0.29 +/-0.02ng/g 1). Three magnificentreportsbyChotimaPoeaknapo 2.63 pmol/g 1.16 pmol/g 1.42 pmol/g 0.60 pmol/g 0.34 pmol/g 12.8 pmol/g 0.39 pmol/g AMOUNT in vitr invivo IRA MLC 12 pmol/g “ morphine likecompound o y rat,inmanycasestheso-calledW (67)withoutadditionofprecursors, norin and y, After 18monthsdrinkingethanolcoclaurine

Mus musculus in-vitr AMES wassoundlyprovedas o (83,84) anditisalsopresent able 1)aswellinhuman Gintzler (70) Guarna (71) Horak (72) Horak (72) Horak (72) Horak (72) Horak (72) Horak (72) Horak (72) Horak (72) AUTHOR ” : MLC(59),later AMES. Morphine precursors was istar rat,and ” (53) de and theyfully characterizeditasmorphine (93)andoverthelastdecade theyhavefounditin an George B.Stefanoandhis teamreportedinitiallythepresenceofMLCininvertebrates (92) ( 80,81). presence incerebrospinalfluid wasdetectedbothinnormalpersonsandseverely sickpatients morphine havebeenfoundbysensitive(67)andhighly sensitiveanalyticalprocedures(79),andits possibly becausetheminimallevelofdetectionmethodused wasnotaslowwiththemostrecentones(79). * Only onesetofnegativeresultonendogenousmorphineinheart,skeletal muscleandspleenofcalfwasreported(77), Sheep Rabbit Cat T Guenon Dog Cattle Guinea Pig T Species Pig Eel oad able 2. V Oryctolagus cuniculus er Cercopithecus aetiops tebrates speciesr Anguilla rostrata Scientific name Canis familiaris Cavia porcellus Bufo marinus Bos taurus Felis catus Ovis aries Sus scrofa epor ted tomakeendogenousmorphine Central NervousSystem Central NervousSystem Central NervousSystem Calf brainbasalganglia Medulla oblongata Milk, lyophilized Pons andmedulla Chromaffin cells Hypothalamus Hypothalamus Hypothalamus Cerebral cortex Hypothalamus Cerebral cortex Adrenal glands Adrenal glands Hippocampus Hippocampus Cerebellum Cerebellum Spinal cord Cerebellum Cerebellum Mid brain Mid brain Location Caudate Caudate Cortex Cortex Brain Urine Brain Lung Skin Skin 0.233 +/-0.031pmol/day 0.29+/-0.04pmol/mg 0.13+/-0.02pmol/mg 0.05+/-0.01pmol/mg 0.10+/-0.09pmol/g 3.01 +/-1.48pmol/g 0.25-4.9pmol/g notstatedMLC notstatedMLC 1.5+/-0.7ng/g not statedMLC 0.09pmol/mg 2.7+/-1ng/g 33 +/-10ng/g 0.134pmol/g 0.388pmol/g 0.15pmol/g 0.22pmol/g 0.16pmol/g 4+/-1ng/g 2+/-1ng/g 8+/-3ng/g 5+/-2ng/g 4+/-1ng/g 12 +/-3ng/g 14 +/-4ng/g 14 +/-4ng/g 12 +/-6ng/g 0.3-5ng/g 24 +/-7ng/g notstated 0.11 ng/g Amount excreted 14ng/g Traces Donnerer 2(64) Goldstein (76) Goldstein (76) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Gintzler (59) Kodaira (75) Killian (77) Molina (62) Molina (62) Molina (62) Molina (62) Molina (62) Munjal (67) Hazum (5) Epple (74) Neri (78) Oka (68) Oka (68) Oka (68) Oka (68) Oka (68) Author * 169 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 170 morphine endogenous synthesis.Kosterlitz (109,1 During thelast30yearsit hasbeenprovedbeyondanyreasonabledoubtthat animals carryon Implications of morphine productionbyleukocytesandtheediblemussel, the increasedreleasebynicotine,cocaineandethanol (107,108)havebeenreportedtoincrease Numerous assaysbythisgroupprovidingprecursorslike levodopaandreticuline(106),aswell increasing numberofmollusks,crustacea,annelida, nematodesandplatyhelminths(T Rev ting tocheckthemorphinelevelsatsinoauricular(Keith-Flack)nodeinrightatrium.T *CSF samplesincludedseveralfrompatientswithmalignanttumorsintheirCNS.**Itwouldhavebeenmostinteres- THP and reticulinewerebothdetectedinhumanpancreaticcarcinomaDAN-Gcellstheformerbrain(19).S- “liquid” dietandtheexcr that alargepartofitdependsondiet.Hofmann(91)reportstheresults ofavoluntarywhowassubmittedtospecial cohort ofvoluntarieswasselected,study(90)urineexcretionshows awidevariationofmorphineexcretionindicating T Cerebro SpínalFluid* Urine Milk Urine restrictedliquiddiet Glioma Pancreatic carcinomaDAN-G Choriocarcinoma JEG-3 Hepatocellular carcinomaHepG2 Keratinocyte lineHaCaTinvitro Neuroblastoma SH-SY5Yinvitro 4 Lungcelllinesin-vitro Blood plasmatobaccosmokers Blood plasmaafterexercise Blood plasma Red bloodcells Blood mononucleatedcells Blood granulocytes Heart atria** able 3. .Fac.Med. 2008V , butnotitsRisomer Morphineandpr AMES , isincorporatedbyhumanneur etion ofmorphinedecr ol. 56No.2 ecursors inman 0.179 +/-0.006pmol/g 3.45 +/-0.08zmol/cell 0.05 +/-0.005pmol/g 106.3 +/-61.53ng/g Amount morphine 11.2 +/-4.21ag/cell 0.82 +/-0.56ng/ml 154-741 pmol/day 10.4 +/-1.6ag/cell 81.3 +/-7.9pg/ml 41-115 pmol/day 1.96 -24.6pg/ml 8.5 +/-1.0ag/cell 15 zeptomol/cell 117 +/-31pg/ml 0.005-7.6 ng/ml 16-318 fmol/ml 80 +/-39pg/ml 1 zeptomol/cell 2 zeptomol/cell 4 zeptomol/cell 80 +/-32pg/ml eased sharply 110-139 pg/ml 0.2 -0.4ng/ml 3.7 -58.8ng/g Not Detected 0.05 ng/ml oblastoma cells(10).InMikus,whodoesnotr MLC . 10) askedconsistently forthephysiological Other substances THPReticuline Mytilus edulis THPCodeine . etrahydr Poeaknapo (10) Poeaknapo (10) Poeaknapo (10) Poeaknapo (10) Poeaknapo (10) Matsubara (89) Boettcher (84) Boettcher (84) Boettcher (84) Cardinale (81) Hofmann (91) Hofmann (91) Y Munjal (67) Munjal (67) Munjal (67) Mikus (90) Blume (73) oshida (86) Shorr(80) Hazum (3) Olsen (88) Cadet (87) Zhu (82) Brix (85) Zhu (83) opapaver epor Liu (79) Liu (79) Author t howthe able 5). oline

Normal controls Normal

Cerebral embolus Cerebral

Herpes zoster Herpes

Parkinsonians on levodopa on Parkinsonians Social drinkers (20-60 g/day) (20-60 drinkers Social

* Pig´s roundworm Medina´s filaria Leech Snails Species this sporozoonare available. parasite reported(104)asamodifier ofthehostorganismonaccountopioids,butnodatamorphine productionby Mussels Nematode Bilharzia be reviewedtakingintoconsideration endogenousmorphine´sactions.Thecoccidium

Lobster Trichina T Abstinent alcoholics Abstinent URINE FROM URINE

T

or the hour of collection of the sample as well as its volume were not stated, nor the diet of the voluntaries. Some groups wer (89) and the rates at which these subjects transformed intermediates suggest a very high (fifty to one) morphine/codeine conversion rate when compared with levodopa overloaded parkinsonians. Alcoholics, either social or abstemious, have a slightly increased excretion. Effects of able 5.

able 4.

e small in number Inver

Morphine and pr Schistosomamansoni tebrates speciesr Ascaris suum Dracunculus medinensis Theromyzon thessulatum Lymnaea stagnali Scientific name Mytilus galloprovincialis Mytilus edulis Nippostrongylus brasiliensis Schistosoma mansoni Ascaris suummale Ascaris suumfemale V Planorbarius corneus Modiolus deminissus Homarus americanus T richinella spiralis ivipar

. The patients who complained of sever us ater

ecursors in human urine, consolidaton of Kazuo Matsubara´s analyses (89). The extent and/

11

12

#

8

4

4 9 epor

(103) ontheimmunesystemoftheir experimentalhostsattributedtoendorphinsmust

31.04+/-15.69

THP pg/ml THP

10.03+/-4.67

11.05+/-3.77 3.19+/- 0.68 3.19+/-

ted tomakeendogenousmorphine

6.70+/-1.13 9.98+/-3.36 *

Ganglia Location Whole worm hemolymph Ganglia Ganglia muscle muscle Foot tissue CNS Ganglia Ganglia Nerve cord Hemolymph

16

18

16

29

#

4

4 62.22+/-17.54

Amount IRA 2.67+/- 0.44ng/ga 12.1+/-3.4 pmol/ml 45+/-10.2 pmol/g 180+/-23.47ng/g 252 +/-32.68ng/g 0.30+/- 0.03pmol/g 6.20+/-2 pmol/g 2.41 ng/ganglion 3.36 pg/mg 718pg/ml

gm pg/ml pg/ml CODEINE

e pain due to herpes zoster excr

4.16+/- 0.91 4.16+/-

3.02+/- 0.52 3.02+/-

.1/05 2.93+/-0.23 2.01+/-0.53

.7/12 3.94+/-0.23 3.97+/-1.22

.5/02 1.96+/-0.24 1.35+/-0.22

MORPHINE

24.60+/-9.70

10.25+/-4.82 3.54+/-1.16 neurotransmitter and/or immune suppresorhost Function adscribed immune suppresorhost signal molecule neuromodulator neurotransmitter hormonal Eimeriavermiformis

eted a high level of morphine”

THP

CODEINE

MOLAR RA MOLAR

,8 1,527 0,288

,9 0,893 0,398

,6 8,546 0,262

,8 1,041 0,382

,0 1,523 0,406

1,92 TIOS

Sonetti (94) Sonetti (94) Author Goumon (101) Zhu (100) Pryor (98) Leung (99) Pryor (98) Zhu (93) Stefano (92) Stefano (92) Sonetti (96) Zhu (100) Sonetti (96) Pryor (102) Pryor (102) Sonetti (96) Sonetti (96) Goumon (95) Casares (97) Casares (97) Pryor (98)

CODEINE

MORPHINE 0,173 isalsoa 171 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 172 available. Max(1 excretion ofexogenousmorphineinmilkanditsactiononsucklingrats(1 endogenous morphinecouldberecoveredfromthemedlinedatabase,wheresomereportsof of endorphinswithphysiologicalsleephasbeenreviewed(1 SLEEP its endogenoussynthesisdisruptedbymassiveamountsofexogenousmorphine. mechanisms andthewithdrawalor“abstinence”syndromeinaddictswarnsclearlyonfrailtyof toxicological effectsduetoabuseclearlyshowitsimportanceinindividualmoodandpleasure (1 The knowledgeaccumulatedoverthelasttwocenturiesonpharmacologicaleffectsofmorphine Physiological actionsofendogenousmorphine invertebrates (T hosts. Severalphysiologicalandneuropathologicalactionshavebeencorrelatedwith level, whileconsideringtheprotectiveactionforparasitesandinfectingagentsagainsttheir at Old Society (1 last yearsmostlybytheworkofStefano´sgroupthathaveincorporatedMorphineResearch astonishingly scarceanddevotedmostlytodemonstrateitsreality with diverseaspectsofendorphinshavebeenextremelynumerouswhilethoseon painful herpes zoster(zona)asshownby theirratesofexcretion(89). (121). Matsubarademonstrated ahighrateofconversioncodeineintomorphine inpersonswith thermononiception inmice (121),aswellaneurotransmitterinthecentralnervous system(CNS) perception” (1 (1 though notdevoidofrisks,“painkiller”.Theneurochemical basisforpainhavebeendescribed quintessence wassoughtforthatmainreason(1)and morphineis,indeed,themosteffective, P persons. AMES wouldexplainthedecreaseinhoursofsleep aswellitslowerqualityinmostageing both thedecreaseoftyrosinehydroxylase(TH)activity (1 by puberty)couldbedeterminedhigh of infancy(decreasingwithagefrommorethan16hours adayduringthefirstyeartoeighthours a habitastheadultaddict´sneedle”(1 that “perhapsfortheinfant,periodicexposuretofeeding-acquiredcasomorphinsbecomesasmuch milk inducesbothasoothingeffectandsleepintheirsucklinginfantswithoutrecoursetopropose and cueingsatiationinducedsleep”,butitismoretemptingtosuggestthatmorphineinwomen´s provide arewardtotheinfant,reinforcingsearchforfood,increasingmother-infantbonding, peptides indigestedmilk:“absorptionofopioidgeneratedbypepticdigestionmilkmay relevance of Rev AIN. 12) indicatetwomainneurophysiologicalactionsinman,sleepandpainmodulation,whileits 18) andthe“activation”of morphinemadebyleukocytes“maycontributeto peripheral pain .Fac.Med. 2008V W Opiumanditscompositepreparationswereused sinceantiquityforpainrelief.Its . Narcosisisoneofthemainef estbury hasbeenfocusedonendogenousmorphineactionatthemolecularandcellular 1 1). AMES butadvancednosuggestionsonitsrole.However 19). Guarna(120)hasshown theimportanceof W able 5). ork overthelastfifteenyearsatNeuroscienceResearchInstituteofSUNY 16) speculatedonaseriesofef ol. 56No.2 16). Moreoverthelongperiodsofdeepsleepcharacteristic fects ofexogenousmorphineinhumans(1 AMES earlyinlifewithadecreaseage.Inadults fects ofendorphinsandcasomorphins,active 17), aswellahypotheticalloweringof 13) whilenoreportsonitsrelationto AMES inthemodulationof acute . This situationchangedinthe , publishedpapersdealing 14) andinfants(1 12).The relation AMES were AMES in 15) are extremely reduced bothinnumberandfunctional activity ganglia, mainlyinthepars compacta ofthesubstantianigra(SN),wheremelanized neuronsare facts haveaccumulatedthat locatethemaindisturbanceformotorproblems atbrain´sbasal the sourceofthisinfluence”; “thismaybetheresultofinjuriesmedullaitself…”. Sincethen disease dependsonsomeirregularity inthedirectionofnervousinfluence…the injuryisratherin disease waslocatedattheupperspinalcord:“Bynature ofthesymptomswearetaught,that Parkinson (122)deducedfromtheknowledgeathistime thatthesupposedproximatecauseof Etiology specific neuralcenters. tremulous typebeforerigidityappearscorrelateswith lesssevereneuronallesionsandatwhat simplified conceptofamotordisorder(126).Itisnot statedifthelessmalignantcourseof presence ofanumberadditionalproblemsleads him toconsiderthatPDismorethanthe clinical motorgroupsofparkinsonians:tremordominanttypeandrigidity-bradikynetictype,butthe pace” (122)sothatfallingcanoccurevenbyretropulsion.Poewe(125)distinguishestwomain aggravated by“apropensitytobendthetrunkforwards,andpassfromawalkingrunning tumble andfallduetolackofadequateresponseobstacleswhilewalkingorslipping,acondition problems inthecourseofhisdisease;amongstthemmosttroublingdisorderisatendencyto malfunctions giveanindividualpatternaccordingtoeachpatientandparkinsonianhasadditional to completetheclassicalcaseof“idiopathic”Parkinson´sdisease(PD). years. Theothercomponentsofthemotortriad:bradikynesiaandrigiditybecomeapparentstepwise even furthertopartsoftheotherlimbs.ThisstageI(124)Parkinson´sdescriptioncanlastfor the wellknownmovementof“countingcoins”,whichmightextendtoarmsamesideand insidious, “highlyafflictive”(122),conditionbeginsusuallywithaunilateraltremorofthefingers, examination, theonlysurefoundationforpathologicalknowledge”(122).Theclinicalcourseofthis that mereconjecturetakestheplaceofexperiment;and,analogyissubstitutionforanatomical conciliatory explanationshouldbeofferedforthepresentpublication:inwhich,itisacknowledged, sciences whichmoreparticularlybelongtothehealingart.Itthereforeisnecessary with whichhypotheticalstatementsareadmitted,innoinstancemoreobviousthanthose back theconclusionsofthisoverview:“Theadvantagesthathavebeenderivedfromcaution “tremor” and“paralysis”terms(123).Thefirstparagraphofthemonographyisherebyquotedto known asatriadandCharcotproposedtonameitParkinson´sdisease,whilediscussingboth palsy” sixmenwithaverydiscapacitatingandprotractedsyndromecharacterizedbywhatwas One hundredandninetyyearsagoJamesParkinson(122)describedassufferingfrom“shaking Relevance fortheunderstandingofParkinson´sdisease study sincemammaryglandsexcretemorphine(5). might beapotentialindicatorofmalignancy human malignanttumorsdependsonmorphineproductionandmonitoringbloodlevels malignant tumorlines(10,67)opensanewfieldofresearchtolookifabsencepaininmost The demonstrationofmorphineinsevengliomas(88)andfourout12differenthuman . Mammaryadenocarcinomasisaparticulargroupto . Dopaminevery lowlevelsareresponsible A numberofadditional , thatsome 173 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 174 Evenmore ifmethylationsarenotperformedatthecorrectpositionsofTHP( Accumulation ofmethylatedderivativesTHPmightbenoxioustomelanizedneurons(138,139). (136,137) emphasizetheimportanceofmethylationtoproduceparkinsonisminlaboratoryanimals. levodopa treatment(135).SeveralreportsontheinducingeffectofS-adenosylmethionineinmice Pearce reportedaggravationofsignsPDbyloadingmethioninetothedietparkinsonianson with thelowerincidenceofPDinalcoholconsumingpeople(134). Parkinson inducingeffectsoftetrahydroisoquinolinesarisingafterethanolicingestion(132,133)contrast and goingtosleep,givesan“atypicalParkinson”thatrevertsonthetimelywithdrawalofinfusions. to toxinspresentinleavesofthesoursoptree, neurotoxins inlaboratoryanimals(127,128);humansveryinterestingreports(129-131)arerelated the primarycauseofmelanizedneuronsdeath:1-benzyltetrahydroisoquinolineshavebeenreportedas but recently for themostincapacitatingsigns:rigidityandbradikynesia.MostauthorsfeelthatPDcauseis“unkown” Rev after withdrawingthesemedications,but10 number ofneurotropicdrugscauseiatrogenic“parkinsonisms” mostly“tremulous”,andreversible carboxytetrahydroisoquinolines (16)atcarbon methylation atastepunsuitableforbuildingthemorphinaneringsystem,like1-benzyl,1- understood” andthat“manyminorspotswereobserved…theynotfurtherinvestigated”.Even concluded: “thesignificanceofthoseabnormallylargeamountsurinaryp-tyramineisnotyet percent with deaminatedaromaticaminoacids(140).Barbeaureported(141)thepresenceinurineof80 on analogswithlessphenolicgroups(formedbyreactionofdopamine,tyramineand/orphenylethylamine morphine metabolicsystem either conclusions fromthoseexperiments orfromthoseperformedbyoverloadingintermediates ofthe with cellsareusedtostudy theactionofnumerousagentsinrelationtoPD(151). Drawingfinal drugs thatwould“cure”PDorprovideneuroprotection. Inasimilarattempt their actiononmelanizedneurons,theyprovideways thathavebeenextensivelyusedtolookfor irreversible (150). to studycellbiologic processesinreallife. NeurochemicallyPDcan beconsideredfarmorethan “a them tosuchacomplexorganism asthehumanbeing.Banati(152)statesneed ofnewmethods hydroxydopamine (147),rotenone(148)andparaquat (149),haveshownasimilaraction. responsible ofanextremelysevereformparkinsonism inyoungadults.Otherchemicals, have dealtwithpreneurotoxinMPTPuncoveredbyDavis (145)andLangston(146)astheagent A substantialnumberofreportsontheimportanceexotoxins inthegenesisofParkinson´sdisease reticuline mustalsobeconsideredandruledout. that coulddamagethemelanizedneurons. a culprit:welackknowledgeoftheexactintermediatesinvolvedorsimilarcondensationproducts has beenpointedasaprobablealteredreaction(144),yetitisnotpossibleatthismomenttopinpoint Methylation hasalreadybeenpostulatedasthebasisofautointoxicationinPD(143).N-methylation before institutinganypharmacologicaltherapyand/orintheCNSofdeaduntreatedparkinsonians. it isworthinvestigatingtheirpresenceinearlyparkinsoniansbythemostadequatemethodsofanalysis, .Fac.Med. 2008V ofhisparkinsoniansthe“pinkspot”thatBoultondemostratedtobetyramine(142)and , however T oxic parkinsonismsandtheirexperimentalmodelsarenot identicaltoPD,yet,by , alar ol. 56No.2 ge numberoffactspointtoendotoxinsandmostlikelymethylatedonesas in vivo andmoreso A percent failureinepimerizationfromtheStoRformof seven Annona muricata , wouldleadtoabnormalmetabolicproductsand in vitr ofakineticdruginducedparkinsonismsare o isunsoundandevenmoreextrapolating L,which,usedasateatosedate in vitr Figure o 3),oraredone studies mostly A lar six ge daytime sleepiness (EDS)canpredateclinical PDandfourreportsof REMsleepbehaviordisorder last from3-5yearsupto10-14 yearsorlonger period microscopy oftheSNneurons, issubstantial,estimatedat60-70percent(170)and thatalatency It isgenerallyacceptedthat beforeclinicalsignsappearthedamage,asobserved byphotonic Preclinical period:latency Nosography may modifyPD.Itappearsthatparkinsonians,unaware oftheirgeneticalbasis,shapeinfirmity risk factorslikemidlifeadiposity(168)aswellhighmilk andcalciumintakeinmidlife(169)which physical exercisecorrelatesalsowithlowerrisk(167). Statistically designedstudiesprovidecluesto individuals lesspronetousethistypeofstimulation has beenpostulated(166).Theinfluenceof correspond withlowerincidenceofPD(163-165).Thepossibilityabasicbehaviorthatmakes Coffee consumption,alcoholicbeveragesdrinkingandtobaccocigarettesmokinghavebeenfoundto the roleofgeneticpolymorphisminpathogenesisPD. PD” asksforestablishingtherelevantpathophysiologicmechanismsaswellfurtherexplorationon Parkinson. DanielKam late-onset Parkinson´sdiseaseinwhitenorthamericans,buttherearefivegenesyoungonset in PDdatasuggesttoFung(161)thatthereisnocommongeneticvariantexertsalargeriskfor mitochondrial pathwaysandtwowithintracellularproteininclusions(160).Genome-widegenotyping populations andin“familialparkinsonism”(FP): molecular andgeneticunderpinnings”.Severalabnormalalleleshavebeenfoundinparkinsonian Forman (159)geneticsshouldprovide“arationalnosologyforparkinsoniandisorderslinkedtotheir Genetical basesforPDarewidelyacceptedandthisareaisreceivingcloseattention. of valproicacidandhepaticcoma. liver andotherpossiblereactionsareinefficientasclinicallyprovedbytheammoniainducedtoxicity (157,158), isunlikely:nervoustissuedoesnotperformtheKrebs-Henseleitureacycleasdoneby lost bytransamination(15)sinceammonia,“adeadlyneurotoxin”(156),producingoxidativedeamination neurons ofthesubstantianigraparscompactarat”(155).InCNSlevodopaaminogroupis SN neurons. radicals resultingfrom“oxidative”deaminationhavebeenrepeatedlysuggestedasafactordamaging that becomedefectiveortheylackedgeneticallytheabilitytoperformcertainfunctions.Oxygenfree pigmented duetodecreaseofneuromelanin.Damagemitochondriahasbeenestablished(154) nigra duetodeatheitherbyapoptosis(153)orotherreasons(152).Theremainingneuronsareless At thecellularlevelinPDthereisanextremelossofneuronsatparscompactasubstantia its secondarymetabolismhasnotbeenconsideredyetasamostimportantrouteinman. dif TH deficiencysyndromeofthestriatum.maybeinvolvedinpathogenesisPDatseveral ferent levels”(1 from thetimethatneuropathological lesionscanbeseentotheovertdevelopmentof signscan Arai wasunabletodetect“dopamine-degradingactivityofmonoamineoxidaseinthe 17): theresultingextremelylowproductionofdopamineiscertainlyresponsible,but Y in Chan(162)basedon“theassociationbetweenslowacetylatorstatusand . Abbott (171)quotesthesuggestion thatexcessive Abeliovich correlatesthreemutatedgeneswith According to . 175 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 176 (184) founda 38 protracted course,diemostly bypulmonaryinfectionand/orrespiratoryterminal failure.Hely IV found ameanof7yearsto reachHY The lastHYstagesarehard tosustainbothforparkinsoniansandtheircaregivers. Hely(184) Prognosis to EDSinpatientswithPD”butFabbrini(183)feelsthat EDSisnotpresentinuntreatedPDpatients. patients, accordingtoliteraturequotedbyGjerstad(182) whostates:“…thediseaseitselfcontributes sudden sleepepisodes”(181).EDSprevalenceratesin PDvaryfromoneinsixuptotwo Ferreira pointstoexcessivedaytimesleepiness(EDS)aswell as,“inappropriate,irresistible,unpredictable have manywelldocumentedproblemsbothatbedtimeand duringtheday Another nonmotorproblemtowhichmuchattentionhas beengivenrecentlyissleep.Parkinsonians SCOP have beenrecentlyreviewed(177)andtheimpactonpersonalactivitiesarepresentlyratedby clinical course:UPDRSanditsmostrecentupdateMDS-UPDRS(176).Depressionratingscales psychologically and/orsocially several numericalgradingsystemsforPDhavebeenproposedinordertoevaluate,eitherphysically Hoehn and pinpointed byShiba(175). developíng alongitsmotormalfunctionsortheresultoftreatment. in theirdetailedanalysismostacceptthatdepressionisamainfeatureofPD,eitherprecedingit, that controlmoodshouldoccurinpatientswhosufferfromPDanddepression”.Thoughauthorsvary characteristic linkbetweenthecatecholaminergicneuronsthatcontrolmovementsand two conditionsasfollows:“IfacommoncausativemechanismisproposedforPDanddepression, HY I (HY),fouradditionalones:HYIIandIIIfornottoodisabledpatientsthemoreseverestages have particularpersonalitytraits(173)andveryfrequentlydepression(174).Charlton(13 spirituous liquors”openingthestudyoflifestyleinrelationtoPD.Itisadmittedthatparkinsonians the consequenceofconsiderableirregularitiesinhismodelivingandparticularlyindulgence for severaldaysonemploymentofconsiderableexertionthatlimb”andcaseII“thedisease…being a lifeofremarkabletemperanceandsobriety…wasdisposedtoattributehishavingbeenengaged Parkinson´s originalessay(122)describestwoofhiscasesasfollows:caseI“…agardener Clinical picture or accumulationofweakPD-causingsubstances. with levodopa.OnaccountoftheslowdevelopmentPD, parkinsonians andcouldbeabscribedtofaultylocalmorphinesynthesisbothbeforeduringtreatment predating anaverageof10to12yearsovertsigns.Sleepdisturbancesareextremelycommonin Rev and10-14yearstostage IV .Fac.Med. 2008V A and system(178-180). Y V , inthelatterpatientbeing“confinedtobedorwheelchairunlessaided”.Inaddition ahr (124)classifiedthedegreeofseveritymotorproblemsandnumberedafterstage percent ol. 56No.2 mortalityrate duringthefirst10years. V . As allhumanlifemustcome toanend,parkinsonians,afteralong , diseaseprogressionandtocomparetheef stagesIV -V . Poewe(185)gives7.5-9 years toreachstage Abe (172)postulatesalong-termexposure Anxiety asamainfeaturehasbeen , relatedornottomedication. fect oftherapiesonits 8 ) tiedthis , leading , Belladona ( Pharmacological T initial yearsoftherapy Y of thisreplacementtherapydiminishingresponseisapparentandthecoursediseasecontinues. and decreasesthebradikynesiaofparkinsonians,thoughtremordoesnotdisappear (188) andBarbeau(189)almostsimultaneouslyfoundthatlevodopareleavesdramaticallytherigidity and severalanticholinergicagentsweretried:biperidenisstillinuse(186).Degkwitz(187),Birkmayer effort todetermine ifusingitasafirstmedication woulddelaytheneed ofusinglevodopaasthe The factthatselegilineprevented thetoxicactionofMPTPinmonkeys(200)led toacooperative Prevention digestion anddefecation.Improvementofbreathingmechanics iscertainlyvital. parkinsonians. Dietisafundamentalissuetofilleach individualneedsandfacilitateswallowing, advanced stagesofthedisease. strongly recommended(199).Theyaremostimportant inthedailylifeofpatients,particularly Before theuseoflevodopasupportingmeasuresmainly ofnursingcareandphysicaltherapywere Non pharmacological dopamine agonists,asanalternativeortocomplement levodopa therapy transferase (COMT),likeropirinoleandtolcapone. its catabolism:inhibitorsofaminooxidaseB,likeselegiline,orthecatecholortho-methyl rate oflife. that medicationdoesnotseemtostoptheprogressionofdiseaseitself,norprolongaverage PD bylevodopaadministrationtopreviouslyuntreatedparkinsonians(198).Poewe(126)considers (197). Brefel-Courbonandhiscoworkershavedemonstratedanincreaseofthelowpainthresholdin more seriouspsychiatricproblemsinparkinsoniansaresubsequenttopharmacologicaltreatment believe thatalldopamineagonistshavesedativeeffectsleadtohypersomnolence(196).The Cases oftreatedparkinsoniansfallingsleepwhiledrivingcarshavebeenreportedandsomeauthors Diskynesias duetolevodopatreatmentpoorlymanagedhavebeensuppressedbymorphine(194,195). therapy (190)andhedoesnotrecommendstartinghighdosagelevodopaatthetimeofdiagnosis. levodopa-induced dyskinesiasandfluctuationsprimaryreasonsfordelayingtheinitiationoflevodopa selegiline evaluationasprotectivetreatment(192)wasdisputed(193).Fahn,mostwisely symptoms (191).Settingthemomentwhentreatmentwithlevodopaisimperativeasend-pointfor old alcoholicparkinsonianmaledidnotkillthepatientbutproducedasuperbmixtureofsignsand Levodopa isnotconsideredtoxic(190)andeveningestionofover80gramslevodopabya61years association lowerssystemicundesiredeffectsandpermitstheuseoflowerdosageslevodopa. the so-calledbloodbrainbarrier(BBB),andactasperipheralinhibitorsofdopadecarboxylase.This reatment et thelifespanifnotprolonged(184)ismorebearabletotreatedpatientsparticularlyduring Additional medicamentshavebeendevelopedthatprolongdopamineactionbyinterfering Atr opa belladona . Levodopaisadministeredwithbenserazideorcarbidopa,whichdonottr L) preparationswereusedtoreducethetremor All facilitiesshouldbeadaptedtothelimitedmotor controlof Another approachusesdopaminer . , withconflictingresults . After alonguse , considers gic drugs, a most verse 177 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 178 shown inhuman urineexcretiondepending ondiet,alcoholingestion, andcigarettesmoking. Standarization ofsamplecollection isoftheutmostimportancesincedefinitechanges havebeen Collection ofbloodsamples as astartingpoint. blood, takingintoaccounttheclaimbySUNY selecting themostsensitive,reliableandreproducible wayofdeterminingmorphinelevelin review onanalyticalmethodsformorphinehasbeen published(217)andcanbethebasisfor signs appear belated. Morerecentlyseveralauthorsaskforanearlypre-clinicaldiagnosis,i.e.beforeclassical appears theneuronaldamageatsubstantianigraishighandneuroprotectionmighthavebeen trial inthatsensehasbeendisappointing(204,205)butitmustbekeptmindwhentremor the damagetoneuronesimpairedinPDisofutmostimportance.Themostrecentclinical its intake(203)sinceaminoacidscompetewithlevodopa´sabsorption.Itisclearthatpreventing patients (201).DietsforPDhavebeencenteredinloweringproteinintake(202)andredistributing (190) butFactorfoundthatvitaminEmadelessseverethecourseofdiseaseinfourteen no finalconclusionswerereachedonaccountofthebasicconceptdelayinglevodopatreatment simultaneously andvitaminEwasalsotestedtryingtodecreasetheactionofoxygenfreeradicals: effective, thoughnotdevoidofrisk,therapyforPD(189).Theideaneuroprotectionevolved Rev Subsequently endogenousdepressedpersonswould beanothergroupforstudy Pharmacologically untreatedparkinsoniansisthe firstgroupthatmustbeinvestigated. been presentinamountsbelowthelevelofdetection oftheiranalyticalprocedures. understand that“absent”and“detected”mightmean thatthesubstancelookedforcouldhave (PD) patients”(215),“…inserumofpatientsPD nomorphinewasdetected”(216);we are reported. No dataonmorphinelevelsinbloodplasmaofuntreated,so-calledlevodopa-naïve,parkinsonians between thelevelsofisoquinolinederivativesandoccurrencedisease”(214). derivatives inuntreatedPDsubjectscomparedwithnormalindividualstodeterminethecorrelation pointed toinMcNaught´sassertion:“Itisthereforenecessarydeterminethelevelofisoquinolines etiology be startedinthedrug”isadubiouspropositioninasmuchas,accordingtopresentedhypothetical at theearlieststage(orevenbeforesymptomsarepresent)shouldbedeveloped”,though“should degeneration beforetheappearanceofclinicalsymptoms”andstated:“methodsdiagnosingPD Marsden (213)suggestedtheexistenceof:“alongperiod(perhaps30yearsormore)ofnigral Morphine determination fundamental importancemustbefurtherandintensivelyinvestigated. (210) and“eatinghealthy”(21 from earlyyouthcansignificantlypreventthecentralneurondamagebydifferenttoxicsubstances” individual shoulddecreasetheseverityofinfirmitiesheisproneto,since“keepingproperdiet .Fac.Med. 2008V , levodopaispartlymetabolizedtoneurotoxinsbyparkinsonians. , asameantohelpparkinsonians(167,206-209). Y et theindiangroupatKeralareports:“morphinewasabsentinserumofthese ol. 56No.2 1) isacornerstoneof“wellnessmedicine”(212)inwhich InstituteforNeuroscienceatOld The correctnutritionforeach This directionhasbeen . W An extensive estbury (85) AMES and ofpeoplebearingallelesclearlylinkedtoPD, selected groupsofendogenousdepression,whichconstitutesamostimportantgroupPDpatients In additiontotheuntreatedparkinsonians,abovesketchedstudiesshouldbeconductedin (219-221) shouldbecarriedon. of abnormalones(142).Correlationtheresultsobtainedwiththosefromadvancedtechniques with adecarboxylaseinhibitorwouldpermittostudytheleakingofthosemetabolitesorpresence the methylatedmetabolitesleadingfromTHPtoS-reticuline.Thereafterlevodopaadministration Sophisticated analyticalproceduresusinglabelledprecursorsshouldbedesignedaimingtoclarify after astandardiseddoseoflevodopa. before thetest,atacorrecttimeaftergivingthemperipheraldopadecarboxylaseinhibitorand peripheral decarboxylaseinhibitorsandcheckinglevelofmorphineinbloodplasmaatthreemoments: necessary todeterminetheamountofbloodmorphinedueCNSproductioninhumans,byloading In additiontonervoustissuemorphineissynthesizedbymanyor Development ofmetabolictests for asufficientperiodoftimepriortobloodsamplingdetectitslevelsinplasma. ingested, thelargenumberofpotentialanimalsourcesmorphineshouldexcludetheiringestion Although thereportsofMikusandHofmann(90,91)donotdetailkindfoodtheirvolunteers late risers)inaccordancewiththepostulatedimportanceofmorphinephysiologicalsleep. blood levelsinhumans,keepingmindthecircadianrhythmofeachindividual(earlyrisersvs variation ofmorphinelevelsindiversemouseorgans(72)studiesondaily Fasting inrats(65)andmussels(218)increasetheirmorphinesynthesis.Consideringthedaily and methionine,inspiteofBao attractively presenteddietbarelycoveringthebasicrequirements ofessentialaromaticaminoacids promote asmuchoptimismfeasiblerestoringtheir “joiedevivre”whilefeedingthemamost uncertainty etc. Theadvantageofgroupmanagementforparkinsonians, beforetheybecomeastatistical muscular relaxation,walkingdynamics,bilateralmovements,strengtheningofspinalextensormuscles, should beinstitutedaimingfundamentallytowardsanextremeimprovementofvoluntarycontrol neurochemical damageseemshighlyprobable,wefeelthatphysicalcorrectiveactivetraining can bediagnosedassuchbeforeovertmotorsignsappear design ofphysical therapyandMs.María Pombo forhiswiseguidanceof thelevodopatreatment,ProfessorHector her clinicalParkinson´sdisease. Pardo andGabrielOsornoMesa whocarriedhispre-parkinsonianmothertotheoldageinwhich shedeveloped professional helpofhiscolleagues The analyticalcompilerofthishypotheticallydirectedreview recognizeswithdeep,everlastinggratitude,the Acknowledgments , shouldbewiselypracticedinordertofulfill(oreven increase)theirsocialneedsand As alreadystated(223)weowe similarfeelingstoProfessorPabloLorenzana Armando CarvajalPuyana,Gonzalo MartínezSanmartín,FranciscoMontoya T ing Zhu´ssuggestions(222). T eresa Acosta forcarrying iton. YOP , FP andsimilardiseases.Ifparkinsonians , orwhenevertheexistenceoffuture gans oftherat(T A. The authorgives awelldeserved T ejada Hernández(R.I.P able 1)anditis .) forhis 179 OPINIONES DEBA TES Y CONTROVERSIAS OPINIONES DEBA TES Y CONTROVERSIAS 180 Edgard PrietoSuárezfortheirpatienceandunderstanding,toProfessors well astheMedicalScienceMonitorandotherfreeaccessserials. liberal policyforrecoveryofdocumentsbytheProceedingsNational throng forBiologicalInformation,NLM,NIH,USPHS,inBethesda(Md),thePubMeddatabaseandmost This workcouldnothavebeenachievedwithouttheopenandfreeaccessprovidedbyNationalCenter of thispaper Ezpeleta MerchánforsettingtheExceltablesandbothherMs.RuthMolinaLizcanofinal W for readingandcommentingthemanuscript. Arciniegas Álvarez,MariaE.KaneandHernando Aaron BunsenLernerandRichardEvansSchultesfortheirlifelonginfluence,tomyclassmatesEduardo recognition isduetotheeditorsofourRevistasProfessorsCarlos recognition tohisclinicalprofessors(224)whoimbuedhimwithahumaneattitudetowardspatients.My Rev 4. 5. this review the UniversidadComplutenseFacultaddeFarmaciaLibraryandallotherpersonswhocontributedtodocument Angeles LangaoftheInstitutoCajal,Madrid.SoledadMonteroCorrederaandMartaSilvaIglesias María CabarcasoftheUniversidadJaverianaLibrary the librariansMaríaElviraRamírezCastillaandMarthaMuñoz,ofCentralLibraryourUniversity 2. 3. 1. References e thankIngridHerrera, .Fac.Med. 2008V Poeaknapo C. 17. Holmes HL. Pr 91. Academic Press.1986:1-98. Hazum E,SabatkaJJ,Chang KJ,FindlayJW Huxtable RJ,Schwar dietary morphineconstitutealigand forspecificmorphine( eininger . . V.

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