64

higher in autpatitnts than in hospitalized patients whose proportion to outpatients tends to decrease.

Reading lisf I Ayd. F. 1. (1978) Lkpor ~u.ohena;ines: Twelve

Years’ &p&wce. Ayd Medic4 Cornmuni~% tions fnc.. Baitirmne

2 Ayd. J:. 1. (1980) In(. Urag The?, Neumt. IS. 5-6

3 Ban. 7’. A. and Ce&o~a. E. (1980) &y&o. P6a~,~~. Btdl. lb. b-13

4 Ekt. A. G. and Hess. S. M. t 1965) J. Phm- wuco~. E.tp. Ther. 148.~12421

5 Jergensen, A.. FredricsonOver0, K. und Hansen.

6 Julou. L. (1972) iuAcruatir4s Phdrmmvlo~iques fCheynrol. 1.. Roissier, 1. R, undL.cchet, P..edr 1. %I. 25. pp. 2349. Masson. Paris

7 Julnu. L.. Sounit, G., Ducmt. R.. Foumel. 1.. &nut. C. and MoUeI. F. (1973) 7Yt&apir, 28, 475499

8 Ki~~W~~. 1.. Vopt, A. H. and tX?mkqb ous, K. D. (113) Am. 1. &wkiutty, 119. 779-780

9 Lingjuerde. 0. (I973) Acra hychiarr. Stand. szqpl. 246,eu

10 Simon, P.. Rnnanien. 3.. Giue@.e% D.. Goujet. M..A. and IkmnMapnnn. P. (1978) Arch. Gen. _by-hi-. 35.893497

Narcotic analgesics and nigrostriatal dopamine~ic neurons

3 incrtww in rhe firing rate of the dopaminergic rreurons. Irhis article srtmmririzes recem dara which ore casting some light on :!zis probtem.

Cc% located in the substanda nigra pars compacta (SNC) can be antidromically activated by StimulaGon of the striarum. Spike ratr of the s~nra~us firing of such cells is Educed by i.v. injection of Y very small dose of the dopamine receptor agon- i%$t, apomorphine. It is believed that these ceHs an: the nigrostriatal do~amin~r~ic o:umns. which were fmt ch~racrerized by l3unncy. Walters, Roth, Guyenec and Aghajani~.

In order to estimate the activity of Ihe dopamine (DA) neurons. firing rate of the cells and turnover of the transmitter have kn uterine. An increased firing mte by a certaia treatment leads to an increased impulse ilcl Y to the nerve terminals. thus producing increases in transmitter release and levelaof DA metabofites. A decrease in the trammitter in the store site stimtdates Ihe lransniiaer ~ynrbesis.

T-ver r&e of DA and fir&g r&e of nig~=IDAneunms

It is known that adminisuation of either morphine or haloperidol causes an increase in the activity of DA neurons. Reviewing

the action% of opiates and antipsychotics on

the dopaminergic system. several interest- ing similarities and dissimilarities between the effects of these two classes of drugs are

found (Table I). Both drugs accelerale the turnover rate of DA in the bdn of the rat and mouse. especially in the striatum, nu- cleus accumbens, olfactory tub&e and hypothalamus, the areas where the lerrn- inals of dopaminergic neumns are highly concentrated. The increase in DA &mover elicited by opiates may be associated with incrraseq in release and synthesis of the tmnsmitter. However, this is not the case in rhe rdt, al~u~h the incntrrse in OIRIoVer seems lo be coupled with an increase in DA release in the mouse striatum. It is interesr- ing to note the DA metabolites, DOPAC and 3MT, in the animals treated with opiates. because it is believed that DOPAC and 3MT are intmneumnal and exnneumnal meta~li~es of DA. respectively. Adminis- tration of morphine causes a specitic increase in DOPAC level in the rat suiatum, while ir increases 3MTlevel in the mouse s~~a~rnl. This difference may explain the behavioral effects of opiates in these animals; opiates produce a catuleptic state in the rat whilst they enhance

TABLE 1. Cornprison of the actions of opiates and antips~zhoks

Fiing rare of DA neumns

DA synthesis aud levels of DA rnetel&es in fhe sbiannn andrmx&nbicarea

Ikplekm of DA after ~hibi~n of DA synrhzsis

DA-sensitive adenylate cyclilse activity after chmnk adminiswrion

Fiing rete of DA neurons

DA-ser&ive &nyfate cyclar4 activity

Aftkity of suiatal tymrine hydmlr ylase for ptcridine FofacMr

GABA release from sub.oamia nigla

Morphtrte Halqwidol

Both drugs - the king rate of DA neumns in SNC. whctherthcy are mnjec’ed systematically ordiirly in10 tk striatum Nt’ithcrdrug incn%~ it when& sni&nn is lesion&

Both drugs inueare

Both drugs eccelen~e

Bo!h drugs incrricse 3% ~~~i~u~ The ~o~i~~ increa9e is rendiiy incnese is dnly rever%d by DA pertially nversed hy agonists DA agonists Does nol change in vti Blnzr iw vhw

Doeslm!affccl IIn*%

Inhibits Does not change

locomomr activity in the moue. The behavioml change in the mouse may be due lo the stimulation of DA receptor by the micased amine. heeau.se the DA agonist apomorphine elicits the same behavioml excitation. Catalepsy seen in morphine tteated rrts might be pmduced by the block- ade of the striatal dopamittergic transmis sion due to reduced DA releaw, because opiate receptors have been demonstrated to exist on striatal ~min~r~ic nerve cttdittgs* and DA telease evoked by pouts sium depolarization in rdt striatal slices is inhibited hy opiates. The opiateinduced DA release inhibition is. however. not definite; &endorphin reportedly increaws sttiatal WPAC level hut fails to inhibit the DA release from the striataJ slices. Mar. phine also does not alter the DA level in the push-pull petfusate from the rat caudate nucleus (K. Iwatsubo, unpublished ohser. vations). Several studies have shown that the striatum is not the site ofopiafe action in producing catalepsy and have indicated the pet+qUeductal gay matter (Pen) and nu. cleus accumbens (Dill and Costa) instead. On the other hand. haloperidol seems to induce catalepsy hy blocking DA receptors in the sttiafum. since this behavior is reduced after iesion of this area (Costalt and Naylor).

While it is well known that antipsychotic phenothiazines and butyrophenones inhibit dopaminergic transmission by blocking DA receptors, opiate action at the receptor seems to be complicated. Antipsychotics added irt s&o inhibit the DA response of DA-sensitive adenylate cychtse which has been suggested as the ‘dopamine receptor’ by Kebabian, Petzold and Greengard; but opiates do not block the asponse of this enzyme to DA”. Administration of the DA receptor agonists. LDOPA and apomor- phine, antagonizes the morphine-induced catalepsy much more effectively than the catalepsy induced by chlorpromazine’. The DA agonists significantly reduce the firing rate of nigral DA neurons, whether mor- phine is present or (wt. while the agonists rever.se the haloperidobinduced increase in the tiring rate only! to the predtug levels. Moreover, opiate agonists reportedly do not inhibit the hinding of antipsychotics with DA receptors. Although these acute effects indicate that opiates may not inter- fere with the action of DA agonists at the receptor, studies on chronic adntintstration have demonstrated thrt ttrnphine as well us antipsychotics can change DA receptor ~nsitivity.

DA receptor supersensitivity has been suggested as responsible for enhanced behavioral responses and enhanced DA- sensitive adenylate cyclase activity of the striatum in animals treated chronically with

(Ai CONTROL (BJ CONmoL

NALOPERIC -it

MORPHINE

eidter opiates or antipsychotics3. Two pob sibilities arhe as to the difference between the results obtained from the acute and chronic experiments. First. only lonptctm binding of opiates with opiate receptors miglt stimulate the presynapiic terminals to inbi%t DA release. Second, only IonS-term presence of opiates might interfere with nonDA neurons which would then lrdd the ceils beating DA receptors to supersensitiv. ity.

btjection of either morphine or haloperidol also pnduces stgtitisant increases in the tiring mfe ofdopaminer~i~ neumns in SNC ranging from 50 to X0 and 30 to uw)‘S, above control levels. tebpx- tively. in unanrsthetized rat?.‘. It xemed that these eifects might be one of the came3 of the increased turnover mte of DA at the terminal site striatum. Nevertheless, such increases in the activity of dopaminergiz neurons are not ntxersariiy associated with the enhancement of dopaminrgic tram- mission. since opiates nducc the DA release (in rats) and haloperidol hlo& the post-synaptic D.4 rec~ptots. It was hypothesized that an incrrasc in D.A turn- over and tiring wte of the nigxl do~tniner~i~ neurons are a compcnattory reaction due IO the impaired dopaminer~ic tmnsmission through the strio-ni:rJl and!or striqallido-nigral toop~ However. thi\ hypothesis hrts not ~~n~en~r~ll~ a~xeptd.

Sites of action 0Popiates in niprcrrtriatal system

As to whether thee biochemical and etect~~phy~iololl_iual changes are a come- qurnce of the changes at the prerynaptic or post-synaptic sites. the following observa (ions are of interest. In mts, in which striata have been lesioncd by kainic acid (which

66

changes in the affinity for the cofactor and the impulse flow would be Ies 1 prob&k.

On the ofher hand, because a derrease in

Cal. love1 leads to an incn‘a*e in DA sp-

ithchis dnd acute administratwx of opiates reduces le cation content in the nerve end- ing fraction’, it is presumed that the opiate- induced lowering of Ca’. may produce

enhanced synthesis of DA and the excess ifmount of the intraneuronal catccholamine thus formed is passed directly to the catabolic site by a certain intr~neuronal di+ OI&X.

Demonstrations that micminjection of morphine and baloperidol directly into the \friafum is also effective in increa5ing the fir& rate of nigral DA neurons’ and that these two clas5es of drugs du> not enhance the firing mte when the striafwrn is L&t& indicate that the silti of their action in stimulating the nigral DA neurons is this &hue. Participation of nigml DA reccpton seems unlikely a\ it has been reported that there are no chdnges in the tiring Me of SNC’cells after iontophoretic application of apiatcs and antipychotics to these cells(see Ref. 6). It h;ls been shown that there are GABA and substance Pcontaining neurons in the rtrirrnigrai and strio-pallido-nigml pathways. When the effect of striaial ntimu- tation on the ~~fa~~~ firing of n&ml

DA neumns is recorded as a post- stimulus time hittogmm in rat. a certain period of firing jnhjbition i+, observed in mosr of the cells. GABA and glycine are nponedly involved in this inhibition. lnjec. lion of morphine or halopridol not only increases the firing rdte but dso reduces the period of the inhibition induced by the striatal rlimulation (Fig. I j An increase in GABA level which appear5 in push-pull prftwte from the rat SN is produced by the btimui.&on of the striatum and globus pal- lidUS@; adminiblration of morphine decreases such evoked release. but not ~l~~dol~‘. Local perfusion of SN with rno~h,~e also reduces the stimuIatio~ induced release of GABA. ligating that the site of opiate action to inhibit CABA rele;rsc is SN. Moreover, the tiring rate of cells located in the substantia (n&a) pars reticulata (SNR) is suppressed by mar- phine (Fimurty and Ghan). Because there ;Ln: many GABA-contaming neurons in SNR. it hay been hypothesized that a de- crease in the GABAegic inhibitory input from striatum IO nigral DA neurons via SNR may be one of the cauves of opiatL_ :nduced increase in the fiing rate.

Allergic asthma and rhinitis: the relationship between P;athobOolosv and

Asthma can be defined a a reversible increaw in ahways resistance associated with mechanical obstruction and hyper- reactivity to irritant stimuli. This definition avoids any suggestion that asthma is an allergic disease for in many cases it IS impossible to demonstrate the pence of an allergy that might trigger the response and even in allergic asthmatics stimuti such as exercise, cold air or inhafed inifants can start an attack. Nevettheless, in many sub. jects a&ma is due to immu~lo~c~ sen. sitivity to one or more airborne allergens. This is associated with the presence of IgE antibody for the sensitizing antigen on the surface of tissue mast cells and blood basophils and in the serum. Rhinifis can also be allergic or non-allergic and the pathobiology of allergic rhinitis is also based on IgE-dependent hypersensitivity to pollen (hayfever) or other air6ome altergens (allergic perenflial rhinitis).

We cannot yet explain why some indi- viduals become a&rgic and others do not. Any satisfactory tbemy must expIain why, when all of us make IgE and carry it on our mast cells, only about 30% of us have posi- tive skin reactions to defined allergens.

only IO-15% develop allergic rbinifis and probably less than YK suffer fmm asthma. Factors such as initial access of antigen, the genetic control of IgE synthesis and the effects of environmental conditions such as infection on the cellular conaol of IgE synthesis probably combine to determine overall s~ee~bility but discussion of these factor5 is beymld the scope of this review.

PhysIoIogy and pathoiffgy

The respiratory physiologist challenging an asthmatic with small amounts of antigen

observes an increase in resistance to air

flow, a decrease in compliance (elasticity) and an increase in residual volume. Increases in resistance are caused by teduo tion in the diameter of larger airways while

the changes in compliance and residual

volume are caused by the premature closing of stwall airway and tk trapping of air in the abeok. l‘,re ethologist ex~in~g the

iun~ofa~t~~nt~tmo~emw~~d~

in sfafus litmus observes, in addition to bm~~~~~ction, inR~at0~ oedema of the mucosa. hypzrsecretion of mucus and fk inliltration of eosinophils