Central mechanisms of clonidine

tic antagonist, binds IO o,-receptors in the brain:. It appears therefore that the major step forward in the recent biochemical study of u-adrenoceptors is the demonstration of two a-adrenergic binding sites possessing the characteristics of pre- and postsynaptic receptors. Accordingly, a separate quantification of each variety of receptors must be achieved under the various conditions where a receptor change is suspected. Reading list I. Guirhency. and

P., Garay.

Meyer.

li.S.4.

P

H.

Proc.

P. and Bremncr.

Pharmocol. W.

R. P.. I.ery-Slarihal.

c

.%7r. .Alui

s<.r.

75.62R-62RY.

2. Greengrasr.

3. Kunos.

(1978)

K. (1979)

EW

J

55. 323-326.

ti..

Hoffman,

and hlucc~.

B..

E;wA.

1.. (IYW)

k.

.?~fure

h..

tian,

I/_MI&MI~

?7R, 254-255. 4.

Langer.

5.

2

(1977)

Br

.I.

Phormoiol.

60.

4u1497. 5.

I etbn~rz.R.

6.

Mach.

P.

J..

(1978) Sarure

J. ,19X7) Dauw, (London)

Fed. Proc J.

P.

and

37. I??-129. Ms~er.

P.

2:4,492-W.

What is clonidine toda)? Alany results from in Y;W crudiej performed with slomdine are xxsr3tent \vit!l a mechanrsm invobmg an agonist actron at central a-adremxeptors an-i this seem\ to be the most widclv held vie\r. Ho\re\er. there are many r:culrs nhizh arc not uholly compatible aith \u
Many publications are devoted today to clonidine and related compounds. The emergence of this drug during the last 15 years is due to the suggestions that (8 the drug lowers blood pressure by an action on the central nervous system, (ii) its central actions, as well as its peripheral .effects are due to activation of related receptors, a-adrenoceptors. namely C’lonidine is, therefore, a tool of inestimalble value for investigating the functions of central noradrenergic mechanisms. But the high scientific status of the drug emerged only progressively. The early days As for many other advances in pharmacological sciences, the discovery of clonidine was due to chance. However, it was also necessary that an intelligent and tenacious man (Wolf on this occasion. according to W. Kobinger) and a pharmaceutical company, C. H. Boehringer

Ingelheim. took advantak of the chance. The latter provided funds for the study of the drug not only by its own researchers. but also by academic scientists when the academic authorities considered the status of the drug top IOU or the nev concepts proposed by the project too hereticai to give financial support for a ‘rink venture’. Clonidine was synthesized in I961 b) Stable. in the modest hope that the drug uould be-as other imidazoline deritatiers are-a nasal decongestant or an adjuvant for shaving-soap formulatians. provoking pilorrection by its a-synpdkhomimetic properties. In the first clinical trrals, the drug U,I\ shown to produce marked side-efiects: sedation, hypotsnsion. bradycardia. The drug was. therefore, developed as an anrihypertexive agent. In 1966, Hoefke and Kobingcr’ published the first extensive pharmacological study. and ia\ ourable clinical reports appeared mcana hilr.

Does clonidine reduce blood pressure tonI:) by central effects?’ ” .‘ ’ E\periments ruggestmg an actron ot slomdine on central cardiova54ar regulation are numerous. In fact, when admini?;tered ir small doses mto the xrehral cavitrcs or into the vertebral artery. the drug cxr~e:, .I redu~rion in hlnod pressure. heart rate and >!mpatheti< drschargc. .Ilso b! the intr~\enous route. Jonidine reduces prrganplianx svmpatheti< drscharges. even m &hutfered animals. the&ore ruling gut an! retlexlv mediated eifecr The drug. injected unto the trunk ot J reirpienr dos. decreases the perfusion prstsure m the sutoperfuqed hind limb ~onne,I“\rlr., H.,:ip_I RW>l
72

TIPS - Novertther 1979

accordin,g -.o recent results. clonidine induces a hy,perpolarization of the gangliotiic cells of rats impairing transmission through the ganglia’. These effects may he contrrbutory factors for the c,ardiova:.;ular zffects of the drug, but their fmpcrnance is as. et undetermined.

found to antagonize strongly the effects of microiontophoretic applications of purine nucteotides on these neuroncs”. The meaning of these results is not wholly evaluated and their importance regarding the whole effects of the drug remains to bc defined.

IS dunidia? (only) an antibypertensive drutg?”

Are the sen?ral effects of clonidine due IO an aclioa on pre- or postsynaptic u-ndrenoceptors in the brain?s~7.U*14

Clonidine is usually referred to in Undoubtedly, some actions of cloniclinical studies as a ‘centrally acting antidine in the brain are due to an action on hypertensi :e agent”, and other central i.e. reducproperties of the drug are mentioned as presynaptic u-adrenoceptors, ‘sidef bradycardia, the appearance of high slow CAMP in guinea-pig cerebral cortical waves or the mydriasis which was shown slices). The histamine Hz receptor blockto be due to a reduction in parasympaing agent metiamide, injected intrathetic tw@. Therefore, in spite of the cerebroventricu!:rrly. has been found to action of both potent :-tagonistic reduce in rats, anaesthetized with yohimbine and piperoxan on these urethane, tbc hypotensioti induced by systems, they appear to be mediated postclonidine administered either by intrasynaptically. Thus, the pharmacological venous or by intracerebroventricular features of an a-adrettoceptor do not route. Recently, microiontophoretic indicate necessarily its pre- or postapplications of clonidine to neurones of synaptic location. In peripheral sites there the cerebral cortex of rats have been are also postsynaptic receptors easily

antagonized

by piperoxan and yohimbine.

Site(s) of Le centrally mediated cardiovasalar effecto of clonidine Medullary structures are considered the most sensitive sites for the sympathoinhibitory effects of clonidinep~‘“. Spinal preganglionic sympathetic neurones have also been found to be inhibited by clonidine’r. but appear to be less sensitive, and this finding fits in well with the view that bulbo-spinal noradrenergic pathways exert an inhibitory effect on the spinal sympathetic neurones. The hypothalamus may also be a site of action. Nevertheless, in spite of many ittvestigations. the medullary structures responsible for the action of clonidine have not been clearly determined. The nucleus tractus solitarii has been proposed as a site of action, because noradrenaline-containing neurones have been detected there, and the attractive hypothesis of a noradrenergic link in the baroreceptor pathway has been suggested. The S zone of the ventral face of the medulla obiongata is very sensitive to topical application of clonidine and may be a site of rts action. But bilateral destruction of these s.tructures did not impair to a great extent the sympathoinhibitory and hypotensive effects of clonidine9. In contrast, the central bradycardia caused by clonidine appears, in dogs and in cats, to be due to sensitization of baroreceptor impulses at the level of the nucleus tractus solitariir3. However, in contrast to the findings obtained in acute experiments, other sites of action, possibly at the level of the nucleus ambiguus, are involved in chronically NTS-lesioned dogs. Do donidiae and murphiae-like drugs act by a commonsfinal pathway? Clonidine and morphine-like agents possess several common properties: analgesia, sedation, centrally mediated hypotension, bradycardia and hypothermia. Furthermore, hotb groups of drugs reduce noradrenaline and acetylcholine release by a presynaptic stimulus. Noradrenergic mechanisms have been implicated in the effects of morphine-like agents and some o-adrenoceptor blocking agents have been shown to antagonize the antinociceptive effect of morphine-like agents. In addition, clonidiie has been shown to inreract with morphine withdrawal syndrome in animals” and to abolish most of its signs in humans3,1i. Therefore, interactions between morphine and clonidine appear to exist. It has been

TIPS - Novertnher 1979

‘3

suggested that clonidine and morphinclike drugs reduce noradrenaline release. leading to an increase in the number of the postsynaptic cl-adrenoceptors. After cessation of the treatment, due to this phenomenon, noradrenergic mechanisms are hyperactive and this may be the cause of morphine withdrawal syndrome as well as clonidine induced rebound. Although there may be similarities between clonidine and morphine-like agents, it is probably not justified IO assume that the mechanisms of action of both groups of drugs are the same. In fact, as regards the central cardiovascular effects of these drugs, there are differences in the site(s) of action. Clonidine has been shown to act at both medullary and spinal sites, but the morphine-like agent fentanyl was found to act only on medullary sites. In some dogs, clonidine, even in high doses, induced only a modest reduction in splanchnic discharges, but in these animals subsequent administration of fentanyl, even in small doses, caused a marked reduction of the discharges. This was best shown in dogs with lesions performed ventrally on the medulla. oblongata between the olivary complex and the lateral_ reticular nucleus. The vagally mediated bradycardia was shown to be due, for clonidine, to a sensitization of the transmission of baroreceptor impulses at the level of nucleus tractus solitarii. This effect could operate as well for morphine-like drugs, but additional sites of action appear to be involved, because bilateral lesions performed in the nucleus tractus solitarii failed to abolish bradycardia induced by fentanyl”. The nucleus ambiguus could be the main site for the vagally mediated bradycardia induced by fentanyl. In fact, lesions performed bilaterally in the nucleus ambiguus abolished fentanyl-induced bradycardia. In addition, injection of small doses of

Henri

Schmiu

University Head Far&y Mark

of

rook flrsi

of Paris.

rhe Departmenr oJ hieduine

Curie.

and higher

He is currendy

degrees al rhe Professor

of Pharmucolagy

of ihe Unrversrty

and in the

OJ Pwrre

cmd

fentanyl or of rhc morphinomimetic clonidinc adventure \rill aprcc \\i~il 111~ peptide D-ala:-enkcphalinamidc. into 111~ port : Ill~kus ambiguus. caused a marked and “Ou pench& d I’avan~ de\ hlallitlc\ dose-related bradycardia. withour changcara\elle5 ing sympathetic nerce activity (1 pubic, Its regardaient montcr cn un CICI ~pn~re unpublished results). Du fond de I’Ocean de\ c;~o~lr nouvelles” Jose Maria de Heredia (Lrs Conqiiistador~l

Other physiological and pharmacological implica(ions The reappraisal of the mechanism of the antihypertencive action of o-methylDOPA was also due to rhe result\ obtained wit2 clonidine. For the theory of the false neurotransmiller was substituted the concept that the met:hanism of action of o-methyl-DOPA is due to an inhibition of sympath&c tone r.xerted at cemral sites by its metabolire o .melhyl-noradrenaline. In fact, intracerebrobentricular administration of the o-adrcnoceptor blocking agent phentolamine abslished the hypntensive effect of a-methl;lDOPA. injected intravenously. In addition, a-methyladministration of noradrenaline into the cerebral cavities induced hypotension. JJrprisingly. the side-effecrs of a-methyl-DOPA Icere rediscovered and found fo resemble those of clonidine: sedation and dryness of the mouth, probably because the therapeutic doses of the drug have been increased. The pharmacological work performed on clonidine for the last 15 years appears to have been fruitful. Results obtained with clonidine have playe’d a key*role in supporting the sugges:ion that noradrenergic mechanisms control cardiovascular function in the brain by decreasing sympathetic tone and increasing vagal activity. The physiological importance of this proposal is srill the subjecr of investigation. Clonidine has ‘opened new and exciting fields of research in pharmacological

sciences. And those engaged early in the

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