ewer
Neutrotrainsnuitters in Palin Control Norman Trieger, D.M.D., M.D.
(Author's Note: Muich of the following report was originally wcritten for presentation at the Third Jorgensen Memorial Lecture in March 1978. This subject matter has beco me one of the "hottest" areas of cturrent research. In the past year a cascade of original research publications appeared in Science and other leading scientific journals. My paper has been updated to include newer information through January 1979. This expanded version was then presented at the American Dental Society of Anesthesiology's Annuial Scientific Meeting in Chicago.) THIRD ANNUAL JORGENSEN MEMORIAL LECTURE March 5, 1978 Loma Linda University School of Dentistry, California
Niels Jorgensen was my friend. I had the privilege of learning and exchanging ideas with him over a period of almost 20 years. He was not an eloquent lecturer nor a prolific writer, yet he perservered and developed newer knowledge which had universal application. His studies and publications on anatomy related to local anesthesia have withstood well the test of time. His concept of pain control in dentistry was ahead of its time. It has only recently been more widely emulated and is being taught in several dental schools and graduate hospital programs. JOSEPH P. OSTERLOH MEMORIAL LEC(TURE February 18, 1979 Chicago, Illinois Joe Osterloh would have enjoyed being here today. He used to say that a conviction differed from an opinion or a belief in that while you held the belief, a conviction held you. One ofJoe Osterloh's strong convictions was that the American Dental Society ofAnesthesiology was destined to do important things for dentistry and anesthesiology. He knew that this would take time and he helped lay the groundwork for its future. Some of these goals have come into being. The Society now has a growing membership and recognizes a special category of Fellows in General Anesthesia, those dentists who have had extended, advanced education and training. This Fellowship took almost 20 years to develop. It was Joe Osterloh's offspring. He also insisted on high standards of anesthesia office practice and ever better training programs. He was an engaging, determined and witty gentleman - who told some awful jokes. Buit if you didn't like that onehe had another for youi. To those who knew him, only a few recollections will ignite a warm glow; for those who never knew Joe Osterloh, you will appreciate some measuire of the man. He had a flair for art. He wore 66
special detachable collars; he was a connoisseur offine wines and an epicure; he was a collector of religious musical chants from around the world. He served the ADSA for many years as treasurer, editor, vicepresident and president. Joe died January 3, 1972 at the age of 57. In 1970, when I visited him in his office in San Francisco, I was initially disappointed by the obvious faded elegance of the suite. In my mind's eye I had envisioned this big man practicing in the most attractive of offices. It did not take long to appreciate that he was not to be judged by his surroundings but rather by the deft and knowledgeable way he managed his patients. I am very pleased to have been invited to present this Joseph P. Osterloh Memorial Lecture. He would have understood the need for a long-range view. He would have appreciated my effort to try to decrease the gap of time by enhancing the disseminating of newer information. The lag in time - from that point when never information is developed and introduced, until it gains widespread acceptance is, we are advised by social scientists, an average of 20 years in length! One may want to challenge this assertion or at least seek to find out why thereis such a protracted delay, particularly in an age when communications have advance.d by quantum leaps. Almost every major innovation has had a similar experience. This century saw the development of a variety of new means of communication. Radio and television have greatly expanded our exposure to newer knowledge. The motion picture camera, developed early in this century, became an important means for disseminating information. Indeed, Dr. Niels Jorgensen used movies to describe and demonstrate his techniques of local anesthesia to a vast audience of dentists. Notwithstanding these and many other methods of communication available today, it seems to take too long for pertinent new knowledge to reach acceptance. The field of anesthesiology and pain control is certainly no exception. I find it very frustrating to accept such delay and try by a number of techniques not only to keep up with new developments but to spread this information to my students and colleagues. Publishing in the Journal ofthe American Dental Society of Anesthesiology, Anesthesia Progress or other periodicals offers one of the many outlets for such dissemination. Lectures and electronic audio and video tapes provide additional means to reduce this level of frustration and try to shorten the time lag. With this aim in mind I should like to serve as reporter of some very exciting new information which has not yet appeared in textbooks published as late as 1976 and 1977. Much of it is so new that it has not yet ANESTHESIA PROGRESS
appeared in ouir cturrent professional periodicals. It is beginning to show uip on national and international programs of research presentations and will asstume growing importance to all of uis in the fututre. This material concerns the very basic biologic considerations of excitability - withouit which life does not exist. While we have long been concemed with nerve excitability and the means to modify it, basic science has lagged badly in this field and left the practicing clinician to fouinder in a sea of relative ignorance. We have been tauight abouit the presence of an extensive network of peripheral nerves, of a central spinal cord where impuilses are collected and disseminated and also abouit the master compuiter anid switchboard in the head. In dentistry we have learned throuigh the efforts of men stuch as Jorgensen and others to influience neuiral conductivity by local anesthetic techniquies as well as influiencing more centrally derived responses by psychologic and pharmacologic methods. Whichever way we effect change, it must work at the most basic level as molecular chemical alterations. My interest and excitement with some of the latest reports relate to these basic mechanisms of neuirotransmission. Reflect for a moment how far-reaching this can be. All neuirological activity involves these molecuilar changes. The hallmark of life itself is excitability of cells. When these processes cease there is death. When these processes falter there is disease. When they fuinction normally all celluilar activities are coordinated and integrated into growth, development, creativity and achievement. Barchas et al (1978) in a recent article writes of "behavioral neuirochemistry". They offer a nuimber of examples to show how neuroreguilators act to adapt to environmental influiences. All techniques we uise to modify excitability whether they be local or general anesthesia, hypnosis or behavior modification, placebo or compassion, all requiire neuirochemical change. Freuid, the father of Psychiatry, always maintained that uiltimately we wouild find a physical basis for neuiroses and psychoses and indeed for all huiman thouight and behavior. My euiphoria and expectations are obviously quiite prematuire. We are not on the doorstep entering the house of infinite knowledge buit perhaps we are fuirther on the path to that doorway. I shall discuiss some of this current work on neuirotransmitters and then try to relate its significance to some ofouir own daily work and practice. Hopefuilly, I will also reach some young, bright sttudent who will be stimuilated to research fuirther and make a greater contribuition to this area. Let us begin by a brief historical look at neurotransmission. (Collins) (Fig. 1). Epinephrine was first isolated in 1898 by John Abel of Johns Hopkins University. J.N. Langley uising an extract from the adrenal gland, stimtulated various organs innervated by sympathetic nerves. On this basis he distingtuished sympathetic, parasympathetic and somatic nervous systems in 1901. It was recognized that the autonomic MAY-JUNE, 1979
systems consisted of postganglionic adrenergic sym-
pathetic fibers.
In 1902, T.R. Elliot suggested that
epinephrine
was released from nerves when stimuilated - he enunciated the concept of "neuiral commuinication by means
of chemical transmitters." In 1907 Dixon stuggested that the Vagiis nerve liberated a mtuscarine-like substance and in 1914 Sir Henry Dale after reinvestigating the properties of acetylcholine introduiced the term "parasympathomimetic." He posttulated that its extremely brief action was dtue to rapid destruiction by an esterase in the tissuies. He contrasted this witlh the relatively longer action of the neuirotransmitter suibstance associated with the sympathetic system. HISTORY OF NEUROTRANSMISSION
1898 Johni Abel 1901 J.N. Langley
1902 T.R. Elliot 1907 Dixoni
TTRIEGER
Epinephrine isolated
SvmIpathetic! Parasymopathetic + Somatic Ne-xoiis Sx stemrs Neuri al collmllmtnllicattion l)b clhemrical transmnittels"
Vagus lilberated NItiscariie-
1914 Sir Henry! Diale
like sull)stance "Paraulsv pthlolinetic" +
1921 Otto LOe\\wi
Esterase Acetycholine prodllced
Neuri-al Responses
Figure 1
Otto Loewi, in 1921, finally proved that chemical transmission in auitonomic nerves by acetylcholine prodtuced neuiral responses. Althouigh acetylcholine has been known for over 50 years, its isolation and stuidy has been extremely difficuilt becauise of its rapid hydrolysis by acetylcholinosterase which is also present in high concentration wherever ACH exists. Earlier stuidies indicated that anesthetics generally depress central cholinergic activity in mammals. (Hanin). Recently, in 1978, a study (Ngai and others) has shown that different anesthetics e.g. Halothane, Enfluirane and Ketamine affect different specific brain areas and produice a change in the turnover rate of ACH. More importantly, a cauisal relationship was demonstrated between the change in neuirochemical transmitter (ACH) at the specific brain site induiced by the anesthetic and electrophysiologic effects as monitored from the brain. Now back to the Epinephrine story. (Fig. 2.) Duiiing the 1930's Walter Cannon and others reported "Sym1930 NN'alter- Cailoni
"SsyrDpathine E
+
Syrmpuathini I"
1946 Coti0 EtileD Nore-iLevohrioneas tl callsiiiittei1950 Klinie Re.seipiiie bulocks 1950 Lelii-naii
Noreopinlephiinae
Chlorpi-om-azine (Thor-azine) and the Dopamine Systemi
1960 Cotziiis
Dopalminle-Levodlopa fior Par-kinisoni's Disease
Figure 2
67
pathlin
capable of increasing blood presstire and heart rate. They later described ain excitatory stubstaince "Sympathin E" and an inhibitory suibstance "Sympathiin I In 1946 Von Euiler proposed norepiniephrine as the chemical transinitter for the sympathetic system and indicated that sympathetic nerve stimnuilatioin may also liberate small (itiaitities of epiniephrine itself. For many yearsi these 3 agents were believed to be the only neuirotransmitters. Then the substance Dopamine, known to be involved in the formnation of norepiinephlinne and epinephrine was thouiglht not only to be an inteirnediaiv but also to serve as a specific neuirotransmitteI in its owIn right. Considered one of the greatest discoveries in the treatInent of neuirologic disease, Cotzias in 1960, treated patients with Parkinson's Disease, who slhow a deficiency of Dopamine in their basal gainglia, witlh levodopa. Levodopa produices dramatic restilts by cointrolling the tremnoI aind cogwlheel rigidity in Parkiinson's. Prior to this, the introduiction of Reser-pine and Chlorpromazinie (or Thorazine) were slhowIn to tran(luilize by iniflhieinciing this dopamiine tr-ainsimitter system. The phairmacologic managemenit of sei-iouis psychiatric disease over the past 20 years has been predicted on the uise of druigs to modify dopaminergic transmission. It is drcamiiatic to see a schizophr-enic patient wh1o has discon tinuted his daily Thorazine medicationi begiin to redevelop his frightening halluicinations after a week to 10 days. Reinstituiting the druig controls this threatening symnptomi. This type of pharmacologic approach has greatly changed the need for long-term hospitalization of many psyclhotic patients. Other advances in psychiatric diseases are awaiting better tunderstanding of neuirotransmitter stubstances. The Benzodiazepine aire a grouip of' agents witl w ide tler-apeuitic application as tranq(lilizers, aniticonvulsants, hyvpnotics aind muiscle i-elaxanits. The main representative of this grouip of druigs is diazepam (Valitim). Very recenitlv (Mohler & Okada) specific benzodiazepinie receptor sites have l)een identified in the central nervous system. These sites arie located primarily in the syniaptic membrcanie firaction onl the cell stirfaice aind not withinl the cell. The greatest concentratioll of these stereo-specific rece)tors was fouind in the cerebral cortex, followed bv the hypotialamutis, and co()tiinues at decreasinig concentr'ationis cauidally in the brain aindl spinlal cord. A similair denisity distribution exists for receptors to the nieurlotrauismnitter GABA(Gamma a mino butyric acid), suipporting the importance of this nieti-roitrcansmitter in the action of benzodiazepinies. The GABA receptor, however, does not appear to be the dciazepatm specific binding site. Tricyclic acnticlepressanits, the major agents uised in treating psychiiatric depression todaiy, form major groplls: OCne grouip serves to contiol psyclhomnotor- agitation anid h1as a higlh incidenice of sedation this group works by inhaibiting .scrotonin uiptake. The seconid gr-ouip tenids to overcome rietairded depressive states by prodtucinig psychlomolotor activation -this group works by inhibiting the uiptake of norepinephrine. Alpha nor-adrenergic r-eceptor sites are readily 68
idenltified in the brain. Sedative aind hypnlotic druligs act
b)y l)locking these receptor sites. The tricvclics show a close coirrelation between riedticing psychomotor agitation andl tleir affinity for alpha adrenergic binding sites in l)rain menrl)ranes. (VI'Prichard et al). (deMontigniy and Agihajanian). WVe now7 come to one of the more fascinating sections of the ciuirrent neuiirotiransmitter story. (Guiillemaan). (Fig. 3). In 1969, Reynlolds reported findinig a grouip of cells in the brain, in the periventricular and peria(liiedtictal gray areas, wlhicih whieni stiiniulated electrically, prodticed profotiiud analgesia equtial to lairge doses of morphinie. This airea was subsequently idenitified as the site of actioIn by irnoiophinle. In verV short order Goldstein at Stamnford, SiminoIn at N.Y. University and Pert atnd Snyder of Johlns Hopkins demonistriated these opiate receptors and tlheorized the presenice of nattiurally occiurring endogenotis opiates to explain the presence of suclh highly specific reeeptor.s in miaimiails. Huiglhes aind Kosterlitz in 1974 at the Unixersitv of Aberdeen isolated opiate-like fLictors whicil thev called enkephalins. Tereniuits at the University of
Uppsala independently identified morphinle-like fac-
tor-s in brain extriacts. Other workers seairched for alternate fuinctions. Kastin in New Orleanis V.A. Hospi-
tal suiggested that methioniine or metenkephialini may facilitate lear-ninig. Frank et al shiowed that seizuire activity or "wet-dog shiakes", cauised by injectioni of metenikephialinie or leuicine enkephialinis were distinct firomar-eas of analgesic effects. 1964 Li
Beta-lipotropin Beta Endorphin Opioid receptors
1969 Reynolds 1974 hlu1ghies &
Enkephalins
Koster litz 1974 Peirt & Snxder Goldstein, Simnon
Enidorphiin.s
Figure 3
A decade before the enkephalinis were identified, Li from the University of Califor-nia at Sani Franicisco, isolated the pituiitar y beta-lipotropin- a 91 amino acid poly-peptide chain. The amino acid sequtenice of the mutclh smaller peptide, metenkephalin matclhes a segmenit of the beta-lipotropin. Li imported a large number of camel pittuitaries - the camel is knowni to be a paini insensitive animal - and he then extracted a 31 aminillo acid segment of beta-lipotropin. The resuiltinig compotind was namined beta-endorphlini aiid was founiid to be 48 times more potent thani morphinle when injected into the brain of experiInental animals and 3 timese more potent when injected intravenously.
Simoni at N.Y.U. is credited with the termn "endorphin" for "morplhin within". Other workers isolated endorphins fiom other animals - mainily from the pittuitary's pars intermnedia. They identified alpha, beta, gaimma and delta endorphinis which slhowed varying effects: For exaimple, alpha-endorphin injected in riats piroduiced 15-30 minuttes of analgesia chiefly of the head and neck regionl, reduiced body temperaturle and tranquiilized the ANESTHESIA PROGRESS
animal for 30-60 miiiiutes. B-endorphinls prodticed profolln1d analgesia for several hours, lowered body temper-attuie aind, depending on the dose, cautsed a catatoniic state. Gaminma-endorphin did not produice anilgesia, raised body temperiatiure aind maide rats agitated aind violent. Delta-enidorphlinl hals beeni shown to have ain ainilgesic effect. Beta-endorphin accouints for virtually all of the opiate-like activity of the pittuitary glaiind whiichi is ailmost devoid of enkephalin. ACTH and beta-endorphin aire probably derived from the sacme lairger precuri-sor molectule and both acre released into the circtlationi at times of stress. (Snyder). Becautse of the wide varietv of effects showni in the r elationslhip of beta-endorphins to behavior, an initenlse inlterest in psychliiatric r-esearch hais been generated. The intravenous injectioni of beta-endorphin into a smiiall number of psyclhotic patients in an uinconitrolled sttudy by Kline & Lehmann (who by the way, developed Reser-pine and Chlorpromazine, respectively, in the 1950's), yielded inconcltusive restults. Laski of Einsteiin Medical College in New York was himself injected with beta-endorphin and reported "a spacedout, floating feeling" and a sensation of "perplexity". His mouitlh becaime dry, he became sleepy fouir lhouirs after inftusioin anld hlis blood pressuire fell to 80/40 foir a nunmber of hours. Watson et al showed that naloxone r edtuced autditory hallutcinatioins in schizophrenics, in a double blind stuidy. Pomerantz at the University of Toronto stuggested that the ancalgesic actioni of actuptunctulre is duie to the stimuntlation and release of endorphins. He hals shown that acuipulnctutre tisatily slhows the firing of briain cells involved with pain perception buit not in the absence of pituiitary gland or in an intact animal given naloxone to block the binding of endorphins to opiate receptors. Cturrent research with acuipuinctuire seems to indicate that painfuil needling is requiired for a period of 15-20 minuiites before the onset of analgesia. This has been slhowin in lx)th hlumatin and animal stuidies. (Havei). The muiltiplicity aind location of the needles does not seem to be critical to the produiction of analgesia. Endorphins may play a significant role in ntarcotic atldiction. It is theorized that exogenouis opiates suippress endogeniouis opiate syntlhesis. Stopping the narcotic abruptly in the face of decreased endorphinl leads to withdr-awal symptomns. Mairgulies et al have showIn that beta-endorphin is associated witlh overeating in geenetically obese mice acnd rats. The overeating is blocked by naloxone. Receptor-s for endorphin have also been fouind in the gut (ileiim). Mairgulles suggests that overteating for obese individuals is similar to opiate dependenice with its dysplhor-ia on witlhdrawal and tendency toward relapse. Relief of intractable paini lhas been produiced in huliminan patients iy stimulationi of electrodes perman e ntlv implanited in the periventricular aind per-iac(luedtictall griay areas. This relief was blocked by naloxone aind also showed chalr-acteristic development of toleraince with repetitive stimullation. (Hosobuchi, Akil et al and Hosobtuchi et al). Opiate receptor-s have been located in a numiber of areas suelh as in the spinal MAY-JUNE, 1979
cord (laminae I & II); in the substantia gelatinosaspinial tract of the V cranial nerve: in the nuiclei of the solitary tract, commissuiralis and amliglius which serve vagal responses, respiration, conigh snippressioni orthostatic hvpotenision, natnsea and voomiting and inhibition of gastric secretion as well as otlher areas coIntrolling euiphoria, miosis, etc., etc. (Synder; Neale et
al).
Another fascinating finding was by Palmouir at the University of California Berkeley. She reported that schizophrienic patients innder-going renal dialysis showed improvement in their mental statuis. Slhe fotinid
enkephalin with an tinnustnal leuicine riather than methioniine-enkeplhalini configuri-ation in the dialysate fluiid. Dr. Palmour s! uiggests that this may represent a genetically determined variation which uinderlies schizophrenics. Ervin at U. C. L.A. injected this dialysate fluiid containing leuicine-enkephalin into animals and produiced patterns of suistained limbic seizuire, but
naloxone reversible. Udenfried of the Roche Instittute of Molectilar Biology has discovered that the original 91 peptide B-lipotropini described by Li is preceeded by a mulch longer peptide molecuile. (Fig. 4). This has been confirmed by otheis and is being called pro-opiocortinl becauise it is also a prectursor to ACTH. This htige compouind (which is 10 times that of B-endorphiin) is released from the pittuitary at times of stress. It divides into segments which affect a variety of neurlohu-moral not
mechanisms.
1976 Udenfiied 1977 Spector 1978 Elbrenipreis &
"Pro-opiocortin"
"Moripliine-like Comixpo)uid" (M LC) Balgot D-Phenivlalaniine proloongs
Enikephlalini effect
Figure 4
Spector at the Roche Instittute of Molecuilar Biology discovered a non-peptide morphine-like compouind (MLC) in brain extracts, urine and huimnan cerebriospinal fluiid. This suibstance is 100 times more potent than morphine. It produiced catatonic states wlhen minuite amouints were injected into rats. However, the reaction was not preventable or reversible with nialoxoine as it is with morphine or the endorphins. (Gintler et al). This, morplhine-like compouind (M LC) may constituite yet another neuirotransmitter dealing with paiin perception. More recently Jacquiet described two types of opiate receptor-s based on their response to the different dextro and levo forms of morphiine. The first tvpe is higlhly steieo-specific. They are blocked bv nailoxonie and mediate morphine analgesia. He suiggests that their natuiral ligands aire the endogenou s endoiphinls. Receptors of the second type possessinig a low degree of stei-eo-specificity and not being blocked by ncaloxone, mediate the synidromiie of hyper-excitability and explosive motor behavior seen after direct micIoinjection of morphinle into certaiii CNS sites. This latter effect is similair to abstinence svndIrome and suiggests a relationshlii) in opiate
dependience.
69
The cuirienit high interest in the netiiophysiology of painilhas led to yet acnotlher impoirtant recent discovery. A derivative of the niatuirallv occuirring nuicleotidecyclic GM P - (guianosine 3', 5' inonophosphalte) when administered directly into the CNS produices a high level of analgesia witlhouit ind uciiig sedation, depressing respir-ation or altering either awareniess or locomotor activity. (Cohn). The analgesic properties aire neitlher prevented nor reversed by ncaloxone. Cyclic GMP is ubiquitously presenit in all maimmnals with higher concenltrcation fouind in brain and certain orgatns. It has been linked to a role as a neurotransmitter in munscariinic cholinergic activity in the CNS and in the suiperior cervical ganglion. While it apparently plays a role in paiin perception, cyclic GMP's mechainism of action is decidedly different from the opiates and remarkablv fiee of their depressant effects. Ehlenpreis at Chicago Medical School recently repor-ted on the effect of administering the amino acid D-phenyvlalainle to mice. It appairently cauised inhibition of carboxypeptidase A - aIn enzyme known to degrade enkeplhalin. These mice showed increase toleraiice to palin aiid incr-eased enkephalin levels. D-plheInylalaninie was tried in 11 chi-onic pain patients by Balgot, also of Chicago Medical School, who showed 9 of the 11 to become either completely pain free or markedly improved. A long term douible-blind stuidy is tunderway. XVhat does all this menan?? Albert Einstein is often (ltioted as sayinlg, "God is subtle buit not maliciouis." It is most likely that the endorphinis will be shown to be signiificanit neurotransmitters for many neuiroendocrinie fuinctions. The enkephalins are identified with mediation of paiin. Is it possible that they provide for enhanced survival of the species by allowing most other-wise painfiul experience to be accommodated? Do they serve to datmpen the pain after a while mutch like other netur al mechaniismns show accommodation and increasin-ig toler-anice? Do they serve as a euiphor'iant or pleasuire souiice or as a reward mIechanism?
It hoas been noted that long distance ruinner-s experienlce a kind of riaptuire after significant exertion of 3-4 miles or 15-20 minuttes. They become euiphoric and feel as if they couild go on forever. They r isk confronting traffic and other hlazards with a sense of invincibilitv. Many runners speak of feeling "high" for a long period aftei the rutin is over. Indeed if this constituites a lack-up survival system taking over after the early adren aline responise is exhiauisted and lactic acid rises to painfuil levels, it couild ser-ve to blunt the pain aind enable the animnal to continuie his flight or fight. Enkephalinls have also been slhowin to inhibit the rielease of substanice "P" fi-om afferent neturon termincals and thereby decriease nlociceptioIn. (FredericksoIn et al). Macdoniald and Nelson have showni that the opioids
70
produice a presyniaptic effect, blocking transmitter release, rather tlhani post-synaptic responsiveness. Undeistandinig the expanded iole of the newer neuirotransmitters will help to resolve many quiestions
related to normal and abnormal behavior. At this early stage most of IsI can only expiess a sense of awe and look forward to learning more as newer knowledge accuimu tlates at a fast pace. We may one day sooi, come to uinderstanid h1ow anestlhesia really works. Recently it was demonstr-ated in mice that nitrouis oxide at 55%, significantly reduiced the painfiul response to phenylquiinone - a very irritating druig. (Berkowitz) This effect was blocked by naloxone. This analgesic effect was attribuited to N20 cauising the release of endogenouis endorphins. I have been uinimpressed witlh ouir own limited attempts to demonstrate this relationship in huimans. Using an electric puilp tester, threshold pain levels went ulnclhanged despite 55% N20 for more thani 45 minuttes. Utisuially the stubjective effects of N20 are noted within a minuite after beginning inhalation. This is incompatible with the slower onset we recognize for endorphin release. Several recent reports (Smith, et al; Har-per, et al), suibstantiate that naloxone does not antagonize
nitrouis oxide anesthesia oI other general anesthetics and therefore is not mediated by the endorphinlenkephalin system. Even the remarkable placebo effect has been attribuited to endorphin release. Levine at the University of California in San Francisco coInduicted a stuidy of 50 patients following removal of wisdom teeth. The response to naloxone (10 mgm) was compared to a placebo. Patients who were identified as placebo responders based on prior experience, dev'eloped more pain wheni naloxone was given. Inter-estingly, at a lower dose of naloxone (4 mgm) analgesia was enhanced in a laboratory cold-pressor test while with 10 mgm prodtuced a greater incidence of pain. Stuidies
by Grevert and Goldstein showed that naloxone failed to alter experimental paiin or mood in hutmans. They concluided that these laboratorv proceduries did not activate endorplhins. If the rate of neuirophysiologic resear-clh contin ties, we shouild not be too stirpr-ised to see newer, more specific methods to eliminate pain and suifferinig develop within the next twenty or so years. XVe have travelled from the discovery of local anesthesia in 1904 to its incorporationi into general practice in the late 20's and 30's. We salw the introduiction of preinedicationi anld intIravenouis sedatioIn foI dentistiry in the 1930's anid its appearance in teaching and clinical tuse bv the 1950 and 60's. If the social scienitists are correct anid we mlake haste slowly, we shouild realize clinical applicationis of the newer informationi being presenited today before the yeai 2000. May we live to enjoy the firuiits of these
labors.
ANESTHESIA PROGRESS
REFERENCES Akil H Mayer D J Liebeskind J C 1976. Antagonism of stimulation Stereospecific and nonstereospecific effects of (plus) and (minus) -produced analgesia by naloxone, a narcotic antagonist. Science morphine: evidence for a new class of receptors. Science 198:842845. 191:961-962. Akil H Richardson D E Hughes J Barchas J D 1978. EnkephalinJacquet Y F & Marks N 1976. The C-fragment of Betalike material elevated in ventricular cerebrospinal fluid in pain palipotropin: an endogenous neuroleptic or antipsychotogen? Science tients after analgetic focal stimulation. Science 201:463-465. 194:632-634. Barchas J D Akil H Elliot G R Holman R B Watson S J 1978. Jacquet Y F 1978. Opiate effects after adrenocorticotropin or Behavioral neurochemistry: neuiroregtulators and behavioral states. (Beta) - endorphin injection in the periaqueductal gray matter of Science 200:964-973. rats. Science 201:1032-1034. Berkowitz B A Ngai S H Finch A D 1976. Nitrous oxide "analLeff D N 1978. Doctors debate brain. Med World News 86-96. gesia": resemblance to opiate action. Science 194:967-968. Medical World News 1978. Placebos may kill pain by triggering Biggio G Casu M Corda M G DiBello C Gessa G L 1978. Stimulaendorphin release. 16-17, Sept. 18. tion of dopamine synthesis in caudate nucleus by intrastriatal enMacdonald R L & Nelson P G 1978. Specific opiate-induced kephalins and antagonism by naloxone. Science 200:552-554. depression of transmitter release from dorsal root ganglion cells in Bloom F Segal D Ling N Guilleman R 1976. Endorphins: proculture. Science 199:1449-1450. found behavioral effects in rats suggest new etiological factors in Marx J L 1978. Opiate receptors: implications and applications. mental illness. Science 194:630-632. Science 189:708-710. Bonica J J Proceedings: Considerations in management of acute Margules D L Moisset B Lewis M J Shibuya H Pert C B 1978. pain. Hosp Prac January 1977. (Beta) - endorphin is associated with overeating in genetically obese mice (ob/ob) and rats (fa/fa). Science 202:988-991. Cohn M L Cohn M and Taylor F H 1978. Guanosine 3', 5' monophosphate: a central nervous system regulator of analgesia. Medical World News 1978. Once-a-month drug stops pain in Science 199:319-322. preliminary trials. MWN Sept. 4, 10. Collins V J Principles of Anesthesiology 2nd Ed. Lea & Febiger, M D 1978. The intriguing endorphins. Medical News Mag 22:1, Phila 1976. 47-49. Mohler H, Okada T 1977. Benzodiazepines receptor: demonstradeMontigny C & Aghajanian G K 1978. Tricyclic antidepressants: long term treatment increases responsivity of rat forebrain post tion in the central nervous system. Science 198:849. synaptic neurons to serotonin. Science 202:1303-1305. Neale J N, Barker J L Uhl G R & Snyder S H 1978. EnkephalinEditorial - 1978. Enkephalins, opiate receptors and general containing neurons visualized in spinal cord cell cultures. Science anesthesia. Anesthes 49:1, 1-2. 201:467-469. Frank H, McCarty B C & Liebeskind J C 1978. Different brain Nusynowitz M L 1978. Endocrinology J Am Med Assoc 239:6, areas mediate analgesic and epileptic properties of enkephalin. Sci527. Ross D H, Medina M A, Cardenas H L 1974. Morphine and ence 200:335-336. Frederickson R C A Burges V Edwards J D 1977. Hyperalgesia ethanol: selective depletion of regional brain calcium. Science induced by naloxone follows diurnal rhythm in responsivity to pain186:63-65. ftil stimuli. Science 198:756-758. Smith R A Wilson M Miller K W 1978. Naloxone has no effect on Frederickson R C A Burgis V Harrell C E & Edwards J D 1978. nitrous oxide anesthesia. Anesthes 49:6-8. Dual actions of substance P on nociception: possible role of enSnyder S H, Banerjec S P, Yamamura H I, Greenberg D 1974. dogenouis opiods. Science 199:1359-1361. Drugs, neurotransmitters and schizophrenia. Science 184:1243Gintzler A R, Gershon, M D, Spector S 1978. A non-peptide 1253. morphine-like compouind: immunocytochemical localization in the Snyder S H 1977. Opiate receptors in the brain in physiology in mouse brain. Science 199:447-448. medicine. N E J Med 296:5, 266-271. Grevert P Goldstein A 1978. Endorphins: naloxone fails to alter Snyder S H 1978. The opiate receptor and morphine-like peptides in the brain. The Am J of Psychiatry 135:6, 645-652. experimental pain or mood in humans. Science 199:1093-1095. Guillemin R 1978. Peptides in the brain: the new endocrinology Tamminga C A, Schaffer M H, Smith R C, Davis J M 1978. of the neuron. Science 202:390-402. Schizophrenic symptoms improve with apomorphine. Science Guillemin R 1978 (At Salk Institute). Beta-lipotropin and endor200:567-568. phins: implications of cturrent knowledge. Hosp Prac Trieger N 1974. Pain Control. Quintessence Publishing Co., Hanin 1 1978. Anesthetics and central cholenergic function - a Chicago, Berlin. perspective. Editorial. Anesthes 48:1, 1-3. U'Prichard D Greenberg D A Sheehan P P Snyder S H 1978. Harper M H Winter P M Johnson B H Eger E I 1978. Naloxone Tricyclic antidepressants: therapeutic properties and affinity for does not antagonize general anesthesia in the rat. Anesthes 39:3-11. alpha noradrenergic receptor binding sites in the brain. Science Hosobuchi Y Adams J E Linchitz R 1977. Pain relief by electrical 199:197. stimulation of the central gray matter in humans and its reversal by Van Allen M W 1978. Neurology. J Am Med Assoc 239:06, 531. naloxone. Science 197:183-186. Watson S J Berger P A Akil H Mills M J Barchas J D 1978. Effects Hosobuchi Y Rossier J Bloom F E Guillemin R 1979. Stimulation of naloxone on schizophrenia: reduction in hallucinations in a subof human periaqueductal gray matter for pain relief increases impopulation of subjects. Science 201:73-75. munoreactive B-endorphin in ventricular fluid. Science 203:279Yaksh T L 1978. Opiate receptors for behavioral analgesia resem281. ble those related to the depression of spinal nociceptive neurons. Jacquet Y F Klee W A Rice K R Dijima I Minimikawa J 1977. Science 199:1231-1232.
MAY-JUNE, 1979
71
Neutrotrainsnuitters in Palin Control Norman Trieger, D.M.D., M.D.
(Author's Note: Muich of the following report was originally wcritten for presentation at the Third Jorgensen Memorial Lecture in March 1978. This subject matter has beco me one of the "hottest" areas of cturrent research. In the past year a cascade of original research publications appeared in Science and other leading scientific journals. My paper has been updated to include newer information through January 1979. This expanded version was then presented at the American Dental Society of Anesthesiology's Annuial Scientific Meeting in Chicago.) THIRD ANNUAL JORGENSEN MEMORIAL LECTURE March 5, 1978 Loma Linda University School of Dentistry, California
Niels Jorgensen was my friend. I had the privilege of learning and exchanging ideas with him over a period of almost 20 years. He was not an eloquent lecturer nor a prolific writer, yet he perservered and developed newer knowledge which had universal application. His studies and publications on anatomy related to local anesthesia have withstood well the test of time. His concept of pain control in dentistry was ahead of its time. It has only recently been more widely emulated and is being taught in several dental schools and graduate hospital programs. JOSEPH P. OSTERLOH MEMORIAL LEC(TURE February 18, 1979 Chicago, Illinois Joe Osterloh would have enjoyed being here today. He used to say that a conviction differed from an opinion or a belief in that while you held the belief, a conviction held you. One ofJoe Osterloh's strong convictions was that the American Dental Society ofAnesthesiology was destined to do important things for dentistry and anesthesiology. He knew that this would take time and he helped lay the groundwork for its future. Some of these goals have come into being. The Society now has a growing membership and recognizes a special category of Fellows in General Anesthesia, those dentists who have had extended, advanced education and training. This Fellowship took almost 20 years to develop. It was Joe Osterloh's offspring. He also insisted on high standards of anesthesia office practice and ever better training programs. He was an engaging, determined and witty gentleman - who told some awful jokes. Buit if you didn't like that onehe had another for youi. To those who knew him, only a few recollections will ignite a warm glow; for those who never knew Joe Osterloh, you will appreciate some measuire of the man. He had a flair for art. He wore 66
special detachable collars; he was a connoisseur offine wines and an epicure; he was a collector of religious musical chants from around the world. He served the ADSA for many years as treasurer, editor, vicepresident and president. Joe died January 3, 1972 at the age of 57. In 1970, when I visited him in his office in San Francisco, I was initially disappointed by the obvious faded elegance of the suite. In my mind's eye I had envisioned this big man practicing in the most attractive of offices. It did not take long to appreciate that he was not to be judged by his surroundings but rather by the deft and knowledgeable way he managed his patients. I am very pleased to have been invited to present this Joseph P. Osterloh Memorial Lecture. He would have understood the need for a long-range view. He would have appreciated my effort to try to decrease the gap of time by enhancing the disseminating of newer information. The lag in time - from that point when never information is developed and introduced, until it gains widespread acceptance is, we are advised by social scientists, an average of 20 years in length! One may want to challenge this assertion or at least seek to find out why thereis such a protracted delay, particularly in an age when communications have advance.d by quantum leaps. Almost every major innovation has had a similar experience. This century saw the development of a variety of new means of communication. Radio and television have greatly expanded our exposure to newer knowledge. The motion picture camera, developed early in this century, became an important means for disseminating information. Indeed, Dr. Niels Jorgensen used movies to describe and demonstrate his techniques of local anesthesia to a vast audience of dentists. Notwithstanding these and many other methods of communication available today, it seems to take too long for pertinent new knowledge to reach acceptance. The field of anesthesiology and pain control is certainly no exception. I find it very frustrating to accept such delay and try by a number of techniques not only to keep up with new developments but to spread this information to my students and colleagues. Publishing in the Journal ofthe American Dental Society of Anesthesiology, Anesthesia Progress or other periodicals offers one of the many outlets for such dissemination. Lectures and electronic audio and video tapes provide additional means to reduce this level of frustration and try to shorten the time lag. With this aim in mind I should like to serve as reporter of some very exciting new information which has not yet appeared in textbooks published as late as 1976 and 1977. Much of it is so new that it has not yet ANESTHESIA PROGRESS
appeared in ouir cturrent professional periodicals. It is beginning to show uip on national and international programs of research presentations and will asstume growing importance to all of uis in the fututre. This material concerns the very basic biologic considerations of excitability - withouit which life does not exist. While we have long been concemed with nerve excitability and the means to modify it, basic science has lagged badly in this field and left the practicing clinician to fouinder in a sea of relative ignorance. We have been tauight abouit the presence of an extensive network of peripheral nerves, of a central spinal cord where impuilses are collected and disseminated and also abouit the master compuiter anid switchboard in the head. In dentistry we have learned throuigh the efforts of men stuch as Jorgensen and others to influience neuiral conductivity by local anesthetic techniquies as well as influiencing more centrally derived responses by psychologic and pharmacologic methods. Whichever way we effect change, it must work at the most basic level as molecular chemical alterations. My interest and excitement with some of the latest reports relate to these basic mechanisms of neuirotransmission. Reflect for a moment how far-reaching this can be. All neuirological activity involves these molecuilar changes. The hallmark of life itself is excitability of cells. When these processes cease there is death. When these processes falter there is disease. When they fuinction normally all celluilar activities are coordinated and integrated into growth, development, creativity and achievement. Barchas et al (1978) in a recent article writes of "behavioral neuirochemistry". They offer a nuimber of examples to show how neuroreguilators act to adapt to environmental influiences. All techniques we uise to modify excitability whether they be local or general anesthesia, hypnosis or behavior modification, placebo or compassion, all requiire neuirochemical change. Freuid, the father of Psychiatry, always maintained that uiltimately we wouild find a physical basis for neuiroses and psychoses and indeed for all huiman thouight and behavior. My euiphoria and expectations are obviously quiite prematuire. We are not on the doorstep entering the house of infinite knowledge buit perhaps we are fuirther on the path to that doorway. I shall discuiss some of this current work on neuirotransmitters and then try to relate its significance to some ofouir own daily work and practice. Hopefuilly, I will also reach some young, bright sttudent who will be stimuilated to research fuirther and make a greater contribuition to this area. Let us begin by a brief historical look at neurotransmission. (Collins) (Fig. 1). Epinephrine was first isolated in 1898 by John Abel of Johns Hopkins University. J.N. Langley uising an extract from the adrenal gland, stimtulated various organs innervated by sympathetic nerves. On this basis he distingtuished sympathetic, parasympathetic and somatic nervous systems in 1901. It was recognized that the autonomic MAY-JUNE, 1979
systems consisted of postganglionic adrenergic sym-
pathetic fibers.
In 1902, T.R. Elliot suggested that
epinephrine
was released from nerves when stimuilated - he enunciated the concept of "neuiral commuinication by means
of chemical transmitters." In 1907 Dixon stuggested that the Vagiis nerve liberated a mtuscarine-like substance and in 1914 Sir Henry Dale after reinvestigating the properties of acetylcholine introduiced the term "parasympathomimetic." He posttulated that its extremely brief action was dtue to rapid destruiction by an esterase in the tissuies. He contrasted this witlh the relatively longer action of the neuirotransmitter suibstance associated with the sympathetic system. HISTORY OF NEUROTRANSMISSION
1898 Johni Abel 1901 J.N. Langley
1902 T.R. Elliot 1907 Dixoni
TTRIEGER
Epinephrine isolated
SvmIpathetic! Parasymopathetic + Somatic Ne-xoiis Sx stemrs Neuri al collmllmtnllicattion l)b clhemrical transmnittels"
Vagus lilberated NItiscariie-
1914 Sir Henry! Diale
like sull)stance "Paraulsv pthlolinetic" +
1921 Otto LOe\\wi
Esterase Acetycholine prodllced
Neuri-al Responses
Figure 1
Otto Loewi, in 1921, finally proved that chemical transmission in auitonomic nerves by acetylcholine prodtuced neuiral responses. Althouigh acetylcholine has been known for over 50 years, its isolation and stuidy has been extremely difficuilt becauise of its rapid hydrolysis by acetylcholinosterase which is also present in high concentration wherever ACH exists. Earlier stuidies indicated that anesthetics generally depress central cholinergic activity in mammals. (Hanin). Recently, in 1978, a study (Ngai and others) has shown that different anesthetics e.g. Halothane, Enfluirane and Ketamine affect different specific brain areas and produice a change in the turnover rate of ACH. More importantly, a cauisal relationship was demonstrated between the change in neuirochemical transmitter (ACH) at the specific brain site induiced by the anesthetic and electrophysiologic effects as monitored from the brain. Now back to the Epinephrine story. (Fig. 2.) Duiiing the 1930's Walter Cannon and others reported "Sym1930 NN'alter- Cailoni
"SsyrDpathine E
+
Syrmpuathini I"
1946 Coti0 EtileD Nore-iLevohrioneas tl callsiiiittei1950 Klinie Re.seipiiie bulocks 1950 Lelii-naii
Noreopinlephiinae
Chlorpi-om-azine (Thor-azine) and the Dopamine Systemi
1960 Cotziiis
Dopalminle-Levodlopa fior Par-kinisoni's Disease
Figure 2
67
pathlin
capable of increasing blood presstire and heart rate. They later described ain excitatory stubstaince "Sympathin E" and an inhibitory suibstance "Sympathiin I In 1946 Von Euiler proposed norepiniephrine as the chemical transinitter for the sympathetic system and indicated that sympathetic nerve stimnuilatioin may also liberate small (itiaitities of epiniephrine itself. For many yearsi these 3 agents were believed to be the only neuirotransmitters. Then the substance Dopamine, known to be involved in the formnation of norepiinephlinne and epinephrine was thouiglht not only to be an inteirnediaiv but also to serve as a specific neuirotransmitteI in its owIn right. Considered one of the greatest discoveries in the treatInent of neuirologic disease, Cotzias in 1960, treated patients with Parkinson's Disease, who slhow a deficiency of Dopamine in their basal gainglia, witlh levodopa. Levodopa produices dramatic restilts by cointrolling the tremnoI aind cogwlheel rigidity in Parkiinson's. Prior to this, the introduiction of Reser-pine and Chlorpromazinie (or Thorazine) were slhowIn to tran(luilize by iniflhieinciing this dopamiine tr-ainsimitter system. The phairmacologic managemenit of sei-iouis psychiatric disease over the past 20 years has been predicted on the uise of druigs to modify dopaminergic transmission. It is drcamiiatic to see a schizophr-enic patient wh1o has discon tinuted his daily Thorazine medicationi begiin to redevelop his frightening halluicinations after a week to 10 days. Reinstituiting the druig controls this threatening symnptomi. This type of pharmacologic approach has greatly changed the need for long-term hospitalization of many psyclhotic patients. Other advances in psychiatric diseases are awaiting better tunderstanding of neuirotransmitter stubstances. The Benzodiazepine aire a grouip of' agents witl w ide tler-apeuitic application as tranq(lilizers, aniticonvulsants, hyvpnotics aind muiscle i-elaxanits. The main representative of this grouip of druigs is diazepam (Valitim). Very recenitlv (Mohler & Okada) specific benzodiazepinie receptor sites have l)een identified in the central nervous system. These sites arie located primarily in the syniaptic membrcanie firaction onl the cell stirfaice aind not withinl the cell. The greatest concentratioll of these stereo-specific rece)tors was fouind in the cerebral cortex, followed bv the hypotialamutis, and co()tiinues at decreasinig concentr'ationis cauidally in the brain aindl spinlal cord. A similair denisity distribution exists for receptors to the nieurlotrauismnitter GABA(Gamma a mino butyric acid), suipporting the importance of this nieti-roitrcansmitter in the action of benzodiazepinies. The GABA receptor, however, does not appear to be the dciazepatm specific binding site. Tricyclic acnticlepressanits, the major agents uised in treating psychiiatric depression todaiy, form major groplls: OCne grouip serves to contiol psyclhomnotor- agitation anid h1as a higlh incidenice of sedation this group works by inhaibiting .scrotonin uiptake. The seconid gr-ouip tenids to overcome rietairded depressive states by prodtucinig psychlomolotor activation -this group works by inhibiting the uiptake of norepinephrine. Alpha nor-adrenergic r-eceptor sites are readily 68
idenltified in the brain. Sedative aind hypnlotic druligs act
b)y l)locking these receptor sites. The tricvclics show a close coirrelation between riedticing psychomotor agitation andl tleir affinity for alpha adrenergic binding sites in l)rain menrl)ranes. (VI'Prichard et al). (deMontigniy and Agihajanian). WVe now7 come to one of the more fascinating sections of the ciuirrent neuiirotiransmitter story. (Guiillemaan). (Fig. 3). In 1969, Reynlolds reported findinig a grouip of cells in the brain, in the periventricular and peria(liiedtictal gray areas, wlhicih whieni stiiniulated electrically, prodticed profotiiud analgesia equtial to lairge doses of morphinie. This airea was subsequently idenitified as the site of actioIn by irnoiophinle. In verV short order Goldstein at Stamnford, SiminoIn at N.Y. University and Pert atnd Snyder of Johlns Hopkins demonistriated these opiate receptors and tlheorized the presenice of nattiurally occiurring endogenotis opiates to explain the presence of suclh highly specific reeeptor.s in miaimiails. Huiglhes aind Kosterlitz in 1974 at the Unixersitv of Aberdeen isolated opiate-like fLictors whicil thev called enkephalins. Tereniuits at the University of
Uppsala independently identified morphinle-like fac-
tor-s in brain extriacts. Other workers seairched for alternate fuinctions. Kastin in New Orleanis V.A. Hospi-
tal suiggested that methioniine or metenkephialini may facilitate lear-ninig. Frank et al shiowed that seizuire activity or "wet-dog shiakes", cauised by injectioni of metenikephialinie or leuicine enkephialinis were distinct firomar-eas of analgesic effects. 1964 Li
Beta-lipotropin Beta Endorphin Opioid receptors
1969 Reynolds 1974 hlu1ghies &
Enkephalins
Koster litz 1974 Peirt & Snxder Goldstein, Simnon
Enidorphiin.s
Figure 3
A decade before the enkephalinis were identified, Li from the University of Califor-nia at Sani Franicisco, isolated the pituiitar y beta-lipotropin- a 91 amino acid poly-peptide chain. The amino acid sequtenice of the mutclh smaller peptide, metenkephalin matclhes a segmenit of the beta-lipotropin. Li imported a large number of camel pittuitaries - the camel is knowni to be a paini insensitive animal - and he then extracted a 31 aminillo acid segment of beta-lipotropin. The resuiltinig compotind was namined beta-endorphlini aiid was founiid to be 48 times more potent thani morphinle when injected into the brain of experiInental animals and 3 timese more potent when injected intravenously.
Simoni at N.Y.U. is credited with the termn "endorphin" for "morplhin within". Other workers isolated endorphins fiom other animals - mainily from the pittuitary's pars intermnedia. They identified alpha, beta, gaimma and delta endorphinis which slhowed varying effects: For exaimple, alpha-endorphin injected in riats piroduiced 15-30 minuttes of analgesia chiefly of the head and neck regionl, reduiced body temperaturle and tranquiilized the ANESTHESIA PROGRESS
animal for 30-60 miiiiutes. B-endorphinls prodticed profolln1d analgesia for several hours, lowered body temper-attuie aind, depending on the dose, cautsed a catatoniic state. Gaminma-endorphin did not produice anilgesia, raised body temperiatiure aind maide rats agitated aind violent. Delta-enidorphlinl hals beeni shown to have ain ainilgesic effect. Beta-endorphin accouints for virtually all of the opiate-like activity of the pittuitary glaiind whiichi is ailmost devoid of enkephalin. ACTH and beta-endorphin aire probably derived from the sacme lairger precuri-sor molectule and both acre released into the circtlationi at times of stress. (Snyder). Becautse of the wide varietv of effects showni in the r elationslhip of beta-endorphins to behavior, an initenlse inlterest in psychliiatric r-esearch hais been generated. The intravenous injectioni of beta-endorphin into a smiiall number of psyclhotic patients in an uinconitrolled sttudy by Kline & Lehmann (who by the way, developed Reser-pine and Chlorpromazine, respectively, in the 1950's), yielded inconcltusive restults. Laski of Einsteiin Medical College in New York was himself injected with beta-endorphin and reported "a spacedout, floating feeling" and a sensation of "perplexity". His mouitlh becaime dry, he became sleepy fouir lhouirs after inftusioin anld hlis blood pressuire fell to 80/40 foir a nunmber of hours. Watson et al showed that naloxone r edtuced autditory hallutcinatioins in schizophrenics, in a double blind stuidy. Pomerantz at the University of Toronto stuggested that the ancalgesic actioni of actuptunctulre is duie to the stimuntlation and release of endorphins. He hals shown that acuipulnctutre tisatily slhows the firing of briain cells involved with pain perception buit not in the absence of pituiitary gland or in an intact animal given naloxone to block the binding of endorphins to opiate receptors. Cturrent research with acuipuinctuire seems to indicate that painfuil needling is requiired for a period of 15-20 minuiites before the onset of analgesia. This has been slhowin in lx)th hlumatin and animal stuidies. (Havei). The muiltiplicity aind location of the needles does not seem to be critical to the produiction of analgesia. Endorphins may play a significant role in ntarcotic atldiction. It is theorized that exogenouis opiates suippress endogeniouis opiate syntlhesis. Stopping the narcotic abruptly in the face of decreased endorphinl leads to withdr-awal symptomns. Mairgulies et al have showIn that beta-endorphin is associated witlh overeating in geenetically obese mice acnd rats. The overeating is blocked by naloxone. Receptor-s for endorphin have also been fouind in the gut (ileiim). Mairgulles suggests that overteating for obese individuals is similar to opiate dependenice with its dysplhor-ia on witlhdrawal and tendency toward relapse. Relief of intractable paini lhas been produiced in huliminan patients iy stimulationi of electrodes perman e ntlv implanited in the periventricular aind per-iac(luedtictall griay areas. This relief was blocked by naloxone aind also showed chalr-acteristic development of toleraince with repetitive stimullation. (Hosobuchi, Akil et al and Hosobtuchi et al). Opiate receptor-s have been located in a numiber of areas suelh as in the spinal MAY-JUNE, 1979
cord (laminae I & II); in the substantia gelatinosaspinial tract of the V cranial nerve: in the nuiclei of the solitary tract, commissuiralis and amliglius which serve vagal responses, respiration, conigh snippressioni orthostatic hvpotenision, natnsea and voomiting and inhibition of gastric secretion as well as otlher areas coIntrolling euiphoria, miosis, etc., etc. (Synder; Neale et
al).
Another fascinating finding was by Palmouir at the University of California Berkeley. She reported that schizophrienic patients innder-going renal dialysis showed improvement in their mental statuis. Slhe fotinid
enkephalin with an tinnustnal leuicine riather than methioniine-enkeplhalini configuri-ation in the dialysate fluiid. Dr. Palmour s! uiggests that this may represent a genetically determined variation which uinderlies schizophrenics. Ervin at U. C. L.A. injected this dialysate fluiid containing leuicine-enkephalin into animals and produiced patterns of suistained limbic seizuire, but
naloxone reversible. Udenfried of the Roche Instittute of Molectilar Biology has discovered that the original 91 peptide B-lipotropini described by Li is preceeded by a mulch longer peptide molecuile. (Fig. 4). This has been confirmed by otheis and is being called pro-opiocortinl becauise it is also a prectursor to ACTH. This htige compouind (which is 10 times that of B-endorphiin) is released from the pittuitary at times of stress. It divides into segments which affect a variety of neurlohu-moral not
mechanisms.
1976 Udenfiied 1977 Spector 1978 Elbrenipreis &
"Pro-opiocortin"
"Moripliine-like Comixpo)uid" (M LC) Balgot D-Phenivlalaniine proloongs
Enikephlalini effect
Figure 4
Spector at the Roche Instittute of Molecuilar Biology discovered a non-peptide morphine-like compouind (MLC) in brain extracts, urine and huimnan cerebriospinal fluiid. This suibstance is 100 times more potent than morphine. It produiced catatonic states wlhen minuite amouints were injected into rats. However, the reaction was not preventable or reversible with nialoxoine as it is with morphine or the endorphins. (Gintler et al). This, morplhine-like compouind (M LC) may constituite yet another neuirotransmitter dealing with paiin perception. More recently Jacquiet described two types of opiate receptor-s based on their response to the different dextro and levo forms of morphiine. The first tvpe is higlhly steieo-specific. They are blocked bv nailoxonie and mediate morphine analgesia. He suiggests that their natuiral ligands aire the endogenou s endoiphinls. Receptors of the second type possessinig a low degree of stei-eo-specificity and not being blocked by ncaloxone, mediate the synidromiie of hyper-excitability and explosive motor behavior seen after direct micIoinjection of morphinle into certaiii CNS sites. This latter effect is similair to abstinence svndIrome and suiggests a relationshlii) in opiate
dependience.
69
The cuirienit high interest in the netiiophysiology of painilhas led to yet acnotlher impoirtant recent discovery. A derivative of the niatuirallv occuirring nuicleotidecyclic GM P - (guianosine 3', 5' inonophosphalte) when administered directly into the CNS produices a high level of analgesia witlhouit ind uciiig sedation, depressing respir-ation or altering either awareniess or locomotor activity. (Cohn). The analgesic properties aire neitlher prevented nor reversed by ncaloxone. Cyclic GMP is ubiquitously presenit in all maimmnals with higher concenltrcation fouind in brain and certain orgatns. It has been linked to a role as a neurotransmitter in munscariinic cholinergic activity in the CNS and in the suiperior cervical ganglion. While it apparently plays a role in paiin perception, cyclic GMP's mechainism of action is decidedly different from the opiates and remarkablv fiee of their depressant effects. Ehlenpreis at Chicago Medical School recently repor-ted on the effect of administering the amino acid D-phenyvlalainle to mice. It appairently cauised inhibition of carboxypeptidase A - aIn enzyme known to degrade enkeplhalin. These mice showed increase toleraiice to palin aiid incr-eased enkephalin levels. D-plheInylalaninie was tried in 11 chi-onic pain patients by Balgot, also of Chicago Medical School, who showed 9 of the 11 to become either completely pain free or markedly improved. A long term douible-blind stuidy is tunderway. XVhat does all this menan?? Albert Einstein is often (ltioted as sayinlg, "God is subtle buit not maliciouis." It is most likely that the endorphinis will be shown to be signiificanit neurotransmitters for many neuiroendocrinie fuinctions. The enkephalins are identified with mediation of paiin. Is it possible that they provide for enhanced survival of the species by allowing most other-wise painfiul experience to be accommodated? Do they serve to datmpen the pain after a while mutch like other netur al mechaniismns show accommodation and increasin-ig toler-anice? Do they serve as a euiphor'iant or pleasuire souiice or as a reward mIechanism?
It hoas been noted that long distance ruinner-s experienlce a kind of riaptuire after significant exertion of 3-4 miles or 15-20 minuttes. They become euiphoric and feel as if they couild go on forever. They r isk confronting traffic and other hlazards with a sense of invincibilitv. Many runners speak of feeling "high" for a long period aftei the rutin is over. Indeed if this constituites a lack-up survival system taking over after the early adren aline responise is exhiauisted and lactic acid rises to painfuil levels, it couild ser-ve to blunt the pain aind enable the animnal to continuie his flight or fight. Enkephalinls have also been slhowin to inhibit the rielease of substanice "P" fi-om afferent neturon termincals and thereby decriease nlociceptioIn. (FredericksoIn et al). Macdoniald and Nelson have showni that the opioids
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produice a presyniaptic effect, blocking transmitter release, rather tlhani post-synaptic responsiveness. Undeistandinig the expanded iole of the newer neuirotransmitters will help to resolve many quiestions
related to normal and abnormal behavior. At this early stage most of IsI can only expiess a sense of awe and look forward to learning more as newer knowledge accuimu tlates at a fast pace. We may one day sooi, come to uinderstanid h1ow anestlhesia really works. Recently it was demonstr-ated in mice that nitrouis oxide at 55%, significantly reduiced the painfiul response to phenylquiinone - a very irritating druig. (Berkowitz) This effect was blocked by naloxone. This analgesic effect was attribuited to N20 cauising the release of endogenouis endorphins. I have been uinimpressed witlh ouir own limited attempts to demonstrate this relationship in huimans. Using an electric puilp tester, threshold pain levels went ulnclhanged despite 55% N20 for more thani 45 minuttes. Utisuially the stubjective effects of N20 are noted within a minuite after beginning inhalation. This is incompatible with the slower onset we recognize for endorphin release. Several recent reports (Smith, et al; Har-per, et al), suibstantiate that naloxone does not antagonize
nitrouis oxide anesthesia oI other general anesthetics and therefore is not mediated by the endorphinlenkephalin system. Even the remarkable placebo effect has been attribuited to endorphin release. Levine at the University of California in San Francisco coInduicted a stuidy of 50 patients following removal of wisdom teeth. The response to naloxone (10 mgm) was compared to a placebo. Patients who were identified as placebo responders based on prior experience, dev'eloped more pain wheni naloxone was given. Inter-estingly, at a lower dose of naloxone (4 mgm) analgesia was enhanced in a laboratory cold-pressor test while with 10 mgm prodtuced a greater incidence of pain. Stuidies
by Grevert and Goldstein showed that naloxone failed to alter experimental paiin or mood in hutmans. They concluided that these laboratorv proceduries did not activate endorplhins. If the rate of neuirophysiologic resear-clh contin ties, we shouild not be too stirpr-ised to see newer, more specific methods to eliminate pain and suifferinig develop within the next twenty or so years. XVe have travelled from the discovery of local anesthesia in 1904 to its incorporationi into general practice in the late 20's and 30's. We salw the introduiction of preinedicationi anld intIravenouis sedatioIn foI dentistiry in the 1930's anid its appearance in teaching and clinical tuse bv the 1950 and 60's. If the social scienitists are correct anid we mlake haste slowly, we shouild realize clinical applicationis of the newer informationi being presenited today before the yeai 2000. May we live to enjoy the firuiits of these
labors.
ANESTHESIA PROGRESS
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