Peripheral opiate receptor mechanisms

TIPS - January 1981 21

i i i i

Peripheral opiate receptor mechanisms John Hughes Imperml ( "olleg¢ o f Scwnce and Technology, Department o f Bt, ,e, emistr~,, Imperial Insttn+te Road. London.~ I.I,':" 2AZ. U.K.

Introduction

The discovery of endogenous opioid peptides in the pituitary and brain owed much to the exploitat ion of k~owledge gained about the actions of opiates in peripheral o rgans such as the guinea-pig ileum and mouse vas deferens. It s eems therefore aplx~site that studies on the endorphins and enkephal ins have given new insights into the nature and role of opiate receptor mechan i sms in peripheral tissues. It was perhaps not surprising but it was certainly exciting when. having studied the distribution o fenkepha l ins in the brain,

Terry Smith. i l ans Kosterlitz and myselP mere also able to demons t ra te significanl quant i t ies o f enkephal in- l ike peptides in the gastro-intestinal tract, autonomic nervous structures and o ther tissues. A series of immunohist t~:hemical studies confirmed and ex tended these obser- vations t s and it is now clear that enkephalin-l ike and l i-endorphin-like immunoreactivi ty is m iddy distributed in the periphery. Consequen t upon these dim- co~eries are various reports suggesting the much a i d e r distribution o f opiate receptor.+ than was hitherto suspected, it is prema-

TABLE 1. Inhibition of neurotransmitler release by opioids at ~arious peripheral sites

Site Neurotransmmer Predt~minant opiate receptor

Acctylcholine

Noradrcnalinc

Guinea-pig ileum* I Rabbit ileum * Mouse ileum Rabbit atria Sympathetic ganglia* Cat nictitating membrane* 1 Mouse ~as deferens" Rat v~s deferens Rabbit vas deferens Rabbit ear alter), Splenic nerve*

m u

(delta) (delta) (mul

Idelta) delta delta i m u

[mu) (delta) (deltal

? (iuinea+pig taenia caecum Unidentified inhibitoD + transm~ncr Rat colon

Note that neurotransmitter release has only been determined directl~ al those sites marked*. In onl~ a te~ ca~s has sufficient pharmacological characterisation t~en c:lrrtcd out to determine the pretk~minant receptor t}lX': those designations in brackets are based on incomplete data or refer to receptors that do nt~ fit 1he mu/dcha cla~- s,fication completely.

TABLE 1 I. Peripheral etlccls of opiates or opioid peptides

Site Opiate medmted effect

Rat stomach Rat jejunum

Dog exocrine pancreas

Dog endocrille pancreas

Adrenal tvartex Adrenal medulla Fat cells

Kidney Neuroblastoma/glioma cells

Inhibit somatostatin release Inhibit PGEt stimulated aden}l cycla~, acti',il}

and mater Itanslcr Inhibit bicarbonate, x~,ater and ent'~mc ~'crct~on

evoked by secretion or duodenal acidification Inhibit somatostatin release mith subwqucnt ~ncrca~'

in insulin and glucagon se;:reuon lot "cases corticoslerone i-roduction Inhibit catecholamine release Increases phosphofructokinase activity Decreases phosphobexoseisome rose activiu, Increases lipolysis (not blocked b.v naloxonc) Decreases omithine decarboxylase activity Inhibit adenyl cyclase Decreases AMP-dependent prote:n kinases Decrea~s ornithine deearlmxylase activity Decreases s.vnthesis of gangliosides and membrane

glycoproteins.

tart" I l l dr~.l~,~, al l} COllCJuMi)n~ tt~nc~.'rflill~, the ph~io logscal tunclit,n~ t~l l~.'riphcral op iate receptor system,, hut lhts ~..'ems an appropr iate tittle" in v,hich Io at tempt to correlate the a~ ailab]e ~acls ,s, d h.~, r~these~.

Peripheral opiate receptors Opiate receptors can |~: ident i l icd ,,nd

located ei ther b} classical ph;:rmacological techniques inxoh ins ~.lgOfltSl modulat ion o! ph'~,itdngical c,.enls lind the u,~: ol slereoselccti~,e antagonish, o i b} receph~r b inding technique., ulil i,qne JadioJabclled Iigands. The lat ler method ha,, on l ) been successful at re la t i te l ) k '~ per ip l , - ra l ~tle,. such am the guinea-pig and r~hh t i leum. mou.~ vas dcferens and adrenal :ncdul la ~hereas pharmacological a,~sa}s ,ugge,I a much ~ idcr d is t r ibut ,m I Tables l and l l~ Ho~e~er at the present lime the classifica- lion and indeed the definition of opiate receptors is in ~)me disarra}. It is quite clear from numerous receptor bi rding and parallel bioassa} qudics thai mu!l pie t.vpcs of opiate receptors exist. There -ceeptors ha~e been gi~cn a ~ariet~ ol G r t c k letter prefixes, the d~:finition and attribution ol the letters ~arying from laboratorx to laborator}, depending t,n the particular techniques ernplo}ed. At the pre,.cm time mu- and delta-receptors are the most widel} accepted subchissifications (Table 111| since the e~idence include,, a distinct agonist potent", series at each reccpt,w tn bioassay and ligand receptor displacemcnl assays, different pA2 ~alues lor naloxone against putative mu- and delta-receptor agonists in dd ta -mcep to r "enriched" prep- arat ions and more recenth e~idenze from cross-proteclitm and tolerance ~tttdics. Rob.~on and Kosterlitz + xxerc able to sh tm that phenox)benzamine irrexersibl.~ in- hibits the reteptor binding of [+H]dih}dromorphine and of I+H]ID-Alaa-D+Lcu+) + enkephalin. Prior incubation with cold enkcphal in protected the enkcphalin binding siles bUl not the dihydromorphine binding sites whereas cold d ih}dromorphinc protected the dih}dromorphine tmu- receptor) bmdmg sites but not the enkephal in (della-receptor) sitc+, Sitnilarlx Albert t lerz + and hi', collc'agttes havc shoxvn that chronic t reatment of mice +~ ith sufentanyl (mu-agonist) rendered the mouse xas delerens insensitixe to o ther mu-agonists , hut had little effect on the delta agonist (D-Alaa-D-Leu~+-enkephalin. The reverse occurring v,hvn the animals were chronically treated with the delta agonist. This latter type of analysis has been used aim+ to support the idea that dynorphin receptors in the mouse x as defe-

(+ 15h.¢+ ~t,r N o a h Holland Blllnlc Jlk'al P;C,s 103 I

22 T I P S - J a n u a r y ! 081

Mu DELTA

t MORPHINE

I NALOXONE

/]-ENDORPHIN

I--- MET-ENKEPHALIN

t LEU-ENKEPHALIN

DYNORPHtN7

l-Tg. I. Jipectrum of o/,iate receptor activities.

tens and fl-endorphin receptors in the rat vas dcfcrens are distinct from other mu- and delta-receptors. However this type of analysis does not define a receptor type and caution should be exerci~d in interpreta- tion. For example it is not clear whether the 'desensitization" is primarily a receptor or post-receptor directed effect and the results are only likely to be clear cut where there are enormous potency differences between ligands as there are in the mouse and rat vas deferens.

The evidence for a third opiate (k~:ppa) receptor is less conclusive although kappa agonists such as ethylketocyclazocine are poorly antagonised by opiate antagnnists in the guinea-pig ileum and mouse vas deferens. However binding studies indicate that mu-receptor ligands compete well for [~H]cthylketocyclazocine (EKC) high affimty binding sites and vice versa s. At present the proposed kappa receptor can only be defined a.~ being somewhat less sensaive to naloxone and to interact with liga[~ds that do not appear to substitute for mu-agonists in morphine dependent animals. There is a low affinity binding site for EKC that is insensitivc to mu- and delta- ligands but the relevance of this is yet to b¢ determined.

There are also examples of peripheral receptors that do not fit the above classifi- cations. In the rabbit ear artery, the enkephalin mediated inhibition of the noradrenergic contraction cannot be mimicked by mu-agonists. In the rat and rabbit vas defcrens g-endorphin is many limes more potent than other mu- or deha-agonists and yet ~0-endorphin is read- ily antagonised by naloxone albeit at some ten times the concentration required for other mu- receptor sites. These may be examples of extreme tissue/receptor selec- tivity since a similar separation of mu- and delta-,'eceptors occurs in the vasa from different strains of mice. There are also responses which are not blocked by naloxone; thus a lipolydc effect of/~-endorphin,

and to a much lesser extent other opioids, has been demonstrated in rabbit adipo- cyles and this effect is mimicked by nalox- o n e '~.

At present we are left with the opiate receptor defined in terms of that moiety which mediates a pharmacological response which can be stereoselectively anlagonised by naloxone. Thu,,~ mu- and delta-receptors are opiate by definition, although this may be misleading since morphine and many of its cogeners are not della-agonists. The differentiation between these receptors may be somewhat anatagous to alpha~ and alpha= adrenocep- tars. If, as in Fig. 1, we repre~nt the opiate receptors as a continuum, although they might be quite separate macromolecules,

then we can represent the ligand specificity as shown. Thus extremes of activity or tissue ~lectivity may be found in which our present antagonists are ineffective and cannot be classified as opiate, Further definition of the receptor types will be only determined unequivocally by the development of more specific antagonists.

The apparent plurality of receptors is matched by a proliferation of putative cndogenous ligands (Table IV). However that is not to say that this throws any further light on the classification of receptor types. At the present time it is imposs- ible to assign a particular physiological function on the basis of iigand affinity for a specific receptor. A comparison with the cateeholamines is instructive in this

u 4 ' ' ?

l'r~ I /

t J , ;,, _ + \,~, ~ ./f;~ f. I , ! - - ~ D , ~ ]

. . .

)--

Fig. 2. D~trlbalian o f peripheral opioid peptides. Enkephalin.like immanoreactive (ELI) neurones ( . . . . ) appar- en@ arise in the spinal cord and innervate ganglion cells and adrenal medulla via the ventral rootL E LI.neurone,~ are also prezem in tire vagu~ nerve (V). It is not ceffain whether the EL1 is presenl in cholinerglc or separate neurones. V~riom patterns o f ELI (~ ~) art seen in ganglia varying from patches to dense innervation. ELI in the gut is mainly con~ned to neurones ~w~ich probably arise from intrinsic ganglia (not shown). EL1 cell bodies and chromaffin granule~ ( ~ ) are also seen in sympathetic ganglia and adrenal medulla where in each cnse there is co- storage with noradrtnaline. A number o f SIF-cells (e) have also been reported to contain ELI. ~-endorphin-like immanoreactivity ( ~ ) is seen in cells o f the itdermediate lobe o f the pituitary and to a much lex~er extent in the anterior loire; other immanortactive cells are seen in the pancreas ¢P) and gastrointestinal tract. Dynorphin ( 1-13pimmunortactivity (~ ". ° ) is present in the posterior lobe o f the pituitary. SC. C, IM - sympathetic ganglia, A D -adrenal medulla, C B -carotid body. Note that these distributions probably vary markedly with species and can only been reg4rded as approximations" at present.

TIPS- January 1981 23

respect, for ex3ml~le the relative ix~tency of adrenaline to ~oradrenaline gkes no indi- cation of the respective roles of these amines in any particular physiological situ- ation. In this particular case the generally less potent notadrenaline subserves a neurotransmitter function whilst adrenaline has a hormonal role. Taking this comparison further ! would consider it extremely unlikely that one receptor type interacts specifically with one ligand. Thus at some mu-receptor specific sites /~-endorphin may act normally as a mediator whilst at o ther mu-sites methionine-enkephalin may be the natural mediator.

Peripheral endogenous opioid peptides The available evidence suggests that the

peripheral opioid peptides could act as endocrine (from pituitary and adrenal glands), apocrine (in stomach and pancreas) or neuronal hormones (sympathetic ganglia and ne~ 'ous plexi o f gut). Fig. 2 illustrates the postulated distribution of /3-endorphin-. dynorphin- and enkephalin-like peptides in various peripheral tissues. Complete chemical characterisation is lacking for the pept~des at most o f these sites. In the pituitary it has been est imated that less than 10% of the endorphin immunoreactivity is due to authentic .8-endorphin (other known forms include LPHm-.~. N-acetyl-fl-endorphin and N-aeetyI-LPH~-.O, whilst less than 5% of the adrenal enkephalin-like peptides are authentic enkephalin. Same of these unde- termined structures may just be precursors or storage depots for the opioid peptides but is is possible that multiple types of opioid peptide are released together and either have a concerted or dispersed mode of acti,m,

Physiological roles of peripheral opioids Inspection of tables I and I 1 gives an idea

of the possible tissues and physiological processes which may act as targets for peripherally released opioid peptides. In general these phenomena have been little investigated with respect to their physiological significance. It is not neces- sarily true that the presence of opiate receptors indicates a physiological role for the receptor or an endogenous opioid ligand. However it is interesting to specu- late on possible physiological function:; of the various systems.

Cineulalin~ opioid peptides Opioid peptides released from the

pituitary may modulate biochemical events at such d ive r~ sites as the adrenal cortex,

fAt=d.! - III Opmle receptor cla',',dicat=on

[)¢Mgllall l+)rl P~.llerl+.,'~ ~a2rles NJl ,+~.onv l~.C "a+dturll "q~lll"

mu B[: • MOR MI ' I F l ~ nM 21~- tIHI delta II~ XlI: -lit: • M{)R 241 .Ills%| ~ 20 kappa umk'fincd' ~. 12 nM ;. ,~igma uml¢lim:d ~ - ":,

N o t e tha! although ~l -¢ndorphln ( [ t t : ) P, a ~,e~ l~.~tt.nl mt ,- , tgon! . l it teqt , lre~ 1411~mc~ mt~,c n,=h,xtm~ h , et: ~c t ~

il~, aclioD in the m o u ~ ,. as defe ren ' , th i ln morl~hlnt: ( M( )R } XI,,~ lhc ix~lcnl tlctLJ agom~l mt'lh=~ m~i'Ic cr~kcl,h.dm

( M E ) an d l eu¢ ine -enkepha l in ( [ . l : ) bcha*.c m, typlc,d mu-,~gomq'~ in lht ' eumca -p tg i l eum ,~ ~th renpt 'cl | l , n , l h~ 4)11/: ilnl;igOlll~*m.

T h e ~ l d i u m '*hill IN il mea~.urc o t lht." decrca',,e In r ¢ c e p l . r h , q d m g Ihat t It-Clll • '~ hen m¢,~ur¢+| in . o d i u m c~,n

|alniFig m e d i a c o m p a r e d io MldlIIITI t1"¢12 ~Ka l~a d~¢~111~|• ;~rt r tp l t - • t -n tcd I.,, the. ~.12tllt~C|il/lll. lnL ILION k¢'fll I~)lllld'*. IThl2 ,a~-callcd sigma ligarld~ ~uch ~n SKI 10. 4L17 and nalorphmc all h ~ c m,mc dt'ert'c ..I .Inl: i~.,f l l ,I 11¢1i~. I I } a'* ~¢11 a, I~ lng h,tlhl¢inogem¢

kidne), pancreas, sex organ,, and lat cells. The available e q d e n c e snggests that /J-cndorphin or like peptidcs may Ix. involved in a homeostatic response to stress since l ipotropin-endorphin peptides are released under such conditions in parallel with adrenocorticotropin. There arc several reports that naloxone treatment can exacerbate stress r e s p o a ~ s thus pro- viding additional support for an ameliora- tive role fl~r opioid peptides in stressful conditions. For example naloxone en- hances oedema formation (elicited b~ car- rageenin) and markedly increases gastric erosions in cold stressed rats". "There are also reports that the normalls low ,B-endorphin levels in blood ;,re markedl.~ elevated during birth in bc, th mother and child. Dynorphin ~, which h~s yet to be fulls sequenced, is mainly concentrated in the posterior lobe of the pituitary gland. Thus this peptide may be involved in responses to changes ir .rater and s~it balance, and possibly in processes associated ~xith birth and suckling.

The possible roles of enkcphalin-likc peptides in the adrenal medulla are intrigu- ing. In ,~rtain animals, such as the co*L there are extremely high levels of these peptides in the adrenal chromaffin cells where they are stored gi th the catecholamines. Recent studies bx tt-Y. [ . Yang and E. C:~sta TM and by O. I t . Vb, ero,, and colleagues tt indicate that there are opiate receptors in adrenal membrane,,. that the opioid pcptidcs ~rc rclca~:d in parallel mith the catecholamines bx such stimuli as stress, nicotine or ncrxc ,tmmla- tion and that the cnkephalin', can inhibit the release of catecholamines. S+ l /den- friend and his colleagues ha~e also sho~ n that the adrenal chromaffin granules contain putative enkephalin-like precursor proteins and a heterogeneous mixture of enkephalin re!ated peptide~ including met-enkephalin, leu-enkephalin and the heptapeptide tyr-gly-gly-phe-mct-arg- phe~=. It seems perfectly teasible t hat these

pepl=des may ha~c an intra-adrcnal aclion on both the cortex and medulla and an extra-adrenal hormonal action on other ~r i phc ra l tissues. The adrenal opiold t~.p- tidex+ .: h.',l~tcnsi~c and I1 i,, pt,~siblc that the} nia~ alm~ be inxokcd in Ix.rwhcral ~a~ldi lator mechantsm~.

Gastro-intestinal roles

I t is interesting to .,Fccculatc that one ,q the most ++idel} u,q:d action:, ot opiate,, I,, her the relict ot d.~entc~ and diarrhoea and )et ++e ;~re ',till far trom under',,~,mding tht2 mechanism of ;.lotion X~:c arc sim:larlx ignorant o f the ga~tro-inlc,,tinal tunction~ of the endogenous opioid l~:ptlden. It i~ quite lr~,,sible that pitai lar 3 and/or adrenal circulating opioid peptldes ma~ act ,m the gut and it,, :],,,,ociated qructurcs, ho~c~cr the ea~,trointeqinal tr,=ct l,, lt,,cl! richl} cndo~ cd +~ i lh stor:.'s ot the opioid [v,:ptldc- There is in fact a greater total of cnkuph,t- lins in the gut than m the brain t,n ;in organ basis. .Mcthiontne-cnkephalin and leucine-cnkephalin arc the prcdommant opioid peptidc,, to bc found in the gut and ;.Ire mainlx concentrated in nervous ,.trtl~- turcstL although thcx are al,~+ pre,,cnt m

[.~lll t I\ t ~ptold l~l.'p|id,k', v~ tit: T's+,~blc ~',tl phi ta[ ,t¢1 Is a t¢~

(;-~. ,-t M Moth,onto.

'~ G t ! I lcucmc u'llk~ [+h.Lilrl

~1-(~ t i } -%| R f ~drvt l , l [ I'<T,t~d~.

~1 -tb(,-|--I 14, Rd-P, I'-K-K £,-0 ' I)~norPhm

-r-L,I-K N-X-HK-K-(,-Q ~ t ndoUq:m

t'odc [ ~ phcn~k, kmmc

L~ :" glutammc R - arginm¢ '~ : t~,~r,.V.,lll¢

All other t¢ller~ rt..lc[ t,~ hlq Idt.:~ t,~ .nmno acM c G gbcme

24 TIPS-January 1981

secretory cells of the stomach, jejunum and pancreas, l'here are very nmeh smaller amounts of/3-endorphin-like peptides (less than I% of eakephalin content) which appear to be localized in secretory cells.

The actions t;l opioids on the gut seem to be directed towards an inhibition of neuronal activity, inhibition of hormone release (including somatostatin and secre- tin) and inhibition of exocrine pancreatic ~eretion anti of water transfer into the intestinal lumen, There is no evidence for a direct action on intestinal smooth mu~le. The effects of opioid pcptidcs on gastric secretion arc controversial; morphine is known to augment oxyntic cell secretion but this is probably related to histamine release by the alkaloid since the enkcpha- lins are apparently without effect t't.

The eom.tipating effect of the opioids classically invol~es a decrease in gastric contractile activity and delayed emptying and inhibition of intestinal propulsive activity and of sc,;retions. The overall effect is increased intestinal tone. a lengthened transit time and increased fluid readsorp- tion. These effects may involve the inhibition of acetylcholine release and that of the non-cholinergic, non-adrenergic, intrinsic inhibitory transmitter. Inhibition of fluid transti:r is probably associated with opiate receptor mediated inhibition of prosta- glandin stimulated adenyl cyclase activity.

The role of endogeno~ s opioids in peristalsis has recetved particular attention. Narcotic antagonist treatment of the iso- lated guinea-pig, rabbit, rat and eat ileum Trcndelenburg preparation slereospecific increase in

ever many of these issues should be resol- ved il resem~ch continues at !ts present pace in thi,~ field. It is likely that the endogenous opioM pcptides are quite ancient in phylogcnetic terms, exter, ding !n distribution down ~o coelenterate ~ Their overall role has probably changed with evolution and it is my view that the!' at:l as mod- ulators rather than as priqle movers in physiok~gical proces~s. It' ~emains to be seen whether ne~ therapeutic principles or applicz~tion,~ arise from otfioid peptide research but the presen¢ outlook is e ncoura~ing.

Reading list 1 I iugbe% 3. Kosterlitz. |1. W. and Smith, T. ( 1 q?7)

Br, 1. I'harvuwoL 61.63q--647 2 ~'hldzbcq:. M., Lundberg, J. M., lt6kfi: lt, T,.

Tcrcnius, I.,, Brandt, J.. Eldc. R. P. and Gold- slein, M. (1117~) Nel, ro.wience 3. I 169-1186

3 S,.huhzberg, M., H6kfelt. T.. Tcrcniu.~, 1_, EIf~in, I, -G.. Lundberg, J. M.. Brandt. J., Eldc, R. P. and Golds(eta, M, I. 19701Neur~:xci~'nc'e 4, 249-270

4 Rot,son, L, E. and Kosterlitz, tl. W. (1979) Pro¢. R. Soc. Load. (B) 205,425~-132

5 Wittier. M., Schulz, R, and Hertz. A. (19811) Li]e SoL 14, 163-1711

6 Hiller. J. M. and Simon, E. 2. (19701 Eur. J. PharmacoL 60, 389-390

7 Jcan-Baplistc. E. and Rizack, L|. A. (10~01 Ltfi" ,t;c~. 27. 135-142

8 Arrigo-Rcma. R. mid Ferri, S. (19801 ~*,|#r, J. Pharmm, L 64. ~5-8~

9 Goldstein. A.. Tachihana, S., Lowney. I,, I., Hun- kapiller, M . . n d H ~ d . I.. (19791 Pro('. Naa. A~-ad. SO. U.S.A. 76, 6666-66711

I(1 Kumakur. i .K. . Gtddoni, A,, Yang, H-Y, T., Saiani, L, ;rod (.'t,sta, E. I I Ogll'l in Neural I'elm&,s and Nemomd ('otNnll~,flk'olion (('OMLi, t'., and Trabucch~, M,. ¢dsL Raven Pros,,

I I Vix.eros. I). H.. [)iliberto. E..I., ;ia,'um, [-. ;rod ('h;mg, K.-J. 11979) MoL Pharmacol. 16, 1101-111)8

12 ~;tern. A. S.. I.e,'is. R. V.. K|ntura. S.. Rossier. J. and Udcvt~'k, nd. S. (1')79)Proe. Nat/. Acad. Set. U.,'~.A, 76, 6680--66~3

13 Schtdtzbcrg, M., H6klelt. T.. Nilsson, (i., Tercnius, L.. Rehfield. J. F., Bnw, n, M., Elde, R. P., (ioldstetn, M. and Stud, S. (191~0) Neuros(i- em e 5.6~'.~744

14 Ga,,c(,gne. A. D., tlir, t, B. It.. Recd, J. D. and Shay,. B. (198(I) Br. J. PharmaeoL 69, 527-534

15 Kromer. W., Prct,,lafi, W. and Wc.inoff. R. (10,~0) Li]e Sci. 26, 1857-1F.65

John Itughes was horn m London where he obtained his firs~ degree at ('I elsea College and Ph.D. with Dr John Van(, at the hlstaute o f Basic Medical Science,~. After two year~ in tlJe Dept. Pharmacology, Yale Uni- versity he ioined the Universi o" of Aberdeen where, first in the Department ¢.f P/mnnacology and then m the Unit for Reaearrh tm Addicmr Dungs, hL~ inten, sts changed from eawcholamines uJ opiates and opknd pep(ides, tie is now Pro~.t~or o f Phar, naeological Bfiwhrmi.~try in tire DeparOnent o f BmehemLwry, hnpe,ial Colh,ge, London.

Ad renal i ne-med iated

precise location and function of these /-¢-adrenoceptors has not been established. The following discussion relates to a hypothesis on a possible peripheral mode of action of/3-adrenoceptor blocking drugs involving prejunctional B-adrenoceptors.

Prejunctional/3-adrenoceptors

Although the amount of transmitter noradrenaline released by sympathetic nerves is ultimately under the control of the central ner,'ous system, which controls the

Concluding remarks

Research into the physiological roles of the opioid peptidcs has been fitcilitated by the availability of relatively specific antagonists. Yet it is apparent that still more specific antagonists are required. At the present time there is suggestive but not compelling evidence for both humoral and neurohumoral roles for the endogenous opioid peptides. Their wide distribution and overlapping actions and receptor specificities confu~ any interpretatkm of the roles of the individual peptides. How-

activity", The o~erall effect of naloxone is to decrease the inten:al between peristaltic ~ ayes and to prolong the bursts of peristaltic activity. These effects are accompanied by a slight increase in smooth muscle tone. Opioids and opioid pep(ides have opposite effects. These results are consistent with a neuronal role fl)r the cnkephalins, in mod- ulating the intrinsic reflex arc that controls peristalsis.

Drng,~ which block /]-adrcnoceptors are effective in the treatment of essential hyper;-:nsion. As a group,/3-adrenoceptor block.ng drugs all produce antihyperten- sivc effects despite considerable differences in their other pharmacological prop- erties such as intrinsic sympathomimetic activity, membrane stabilizing activity and penetration into the central nervous system. ~.Thus it has been suggested that their antihypertensive activity is due to ,8-adrenoceptor blockade, although the

effect of /3-adrenoceptor blocking drugs? H. Majewski and M. J. Rand Department o/Pharmacology. Univer.wt~" o f Melbourne. Vieloria, 3052, A ustralm.

hypertension: a clue to the antihypertensive

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Peripheral opiate receptor mechanisms