Pharmacological prospects for α2-adrenoceptor antagonist therapy

TiPS -July

1992 [Vol. 131

277

Pharmacological prospects for a2-adrenoceptor antagonist therapy Michel Berlan, Jean-Louis Montastruc and Max Lafontan The discovery of various a*-adrenoceptor subtypes in numerous fissues and studies of az-adrenoceptor-mediated mechanisms has generated considerable interest in their physiological functions. It has also increased possibilities for the design of new pha~Rco~ogica1 tools and for the study of the pharmacologic&~impact of new drugs. ~~-Adre~ocepto~ ure locuted pre- and posts~aptically both in the central noradrenergic pathways and on the autonomic nerve endings. It is difficult to dissociate cw2-adrenoceptor-mediated autoregulation, involving presynaptic receptors, from actions dependent on post- and extrajunctional ar2-adrenoceptor activation. A lot of ar2-adrenoceptors are subject to pe~anent tonic acfivation by the sympathe~c ne~ous system. Max Lafontan and colleagues review the major a&ions of ff~-adr~oceptors and consider the sites of impact of cut-antagonists that could initiate further research for putative applications of these drugs. Many of the possible targets for &z-adrenoceptor antagonists have not yet been explored clinically.

The sympathetic nervous system exerts tonic control over a large number of tissues and organs. Its activity is regulated in the CNS by various physiological conditions (rest, physical activity, changes in ambient temperature, stress, emotions). Precise adaptation to all such conditions is achieved through the modulation of both noradrenaline release from nerve endings and adrenaline release from the adrenal medulla. Responses to these neurotransmitkrs are mediated via adrenoceptors located post- and extrajunctionally on the effecters or presynaptically on autonomic nerve endings. Adrenoceptors are a complex family of receptors that includes several subtypes within each or, ar2 and p class.

The localization of uz-adrenoceptors in the CNS and prejunctionally on autonomic nerve endings facilitates their role in the modulation of neurotransmitter release. The functional antagonism between the two components (sympathetic and parasympathetic) of the autonomic nervous system is strengthened by presynaptic control; thus the activated sympathetic nervous system inhibits the parasympathetic system by stimulating presynaptic ru,-adrenoceptors on choline+ pathways. olz-Adrenoceptors have also been identified on most organs controlled by the sympathetic nervous system. Those receptors located outside the synapses largely escape the direct influence of noradrenaline released within the synapse.

M. Bedan is Assaciafe Professor and 1-L. Mant~s~u~ is Professor at the ~eps~~ent of Medical and Clinicat PkQ?Y?MCOtOgy, Facutty of Medicine, 37 Alft!es Jules Guesde, 31073 Toulouse, France. M. Lafontan is Director of Research at fke Insfitut National de lQ Sanf6 et de la Reckercke Mtidicale (INSERM), hsfitut Louis Bugnard, ~Qculty of Med~~~e~Chili Rmgueil, 31054 Touiouse Cedex, France. All work in Unit 317 of INSERM.

Physiology of ~~~drenocep~rs Three separate genes encoding different ara-adrenoceptor subtypes have been identified in humansl. Their detailed pharmacoIogicaI properties, organ and tissue distribution have not yet been fully determined.

Binding and functional studies have shown that most organs with a metabolic function (fat tissue, enterocytes and liver) contain post- or extrasynaptic oa-adrenoceptors that control some tissue functions (e.g. glycogenolysis, lipolysis, absorption of water and ions by the enterocytes and renal tubules). A role for oa-adrenoceptors has also been described in endocrine and exocrine glands (pancreas, adrenal medulla and salivary glands). Certain functions of the hypophysis or neurohypophysis, such as growth hormone or arginine vasopressin secretion, are under aa-adrenoceptor controL Involvement of cw,adrenoceptors in the regulation of some CNS functions has also been suggested on the basis of physiological and behavioural studies2. For example, ff2-adrenoceptor stimulation reduces arterial blood pressure, cardiac activity and thermogenesis, and increases food intake. Table I lists physiological functions that are modulated by stimulation of oz-adrenoceptors as identified using adrenaline, synthetic partial agonists (clonidine or p-aminoclonidine) and the full agonist UK14304 (see also Refs 3, 4). The most commonly used antagonists are yohimbine, rauwolscine and idazoxan. It is often difficult to differentiate the direct effects of agonists on target cells in vim from those arising from a central action; 4x2-adrenoceptor ligands can indirectly modify the biological activity of the target by modifying the activity of autonomic centres. It is also difficult to dissociate cu2-adrenoceptor-mediated autoregulation, involving presynaptic receptors, from actions dependent on the post- and ex~ajunction~ 02-adrenoceptors. It is probable that their location (pre- or postsynaptic) both in the central noradrenergic pathways and on the autonomic nerve endings dictates that many cr*-adrenoceptors will be subject to tonic stimulation by the sympathetic nervous system. However, there are at least two examples where aa-adrenoceptors escape the influence Of SFpathetic nerve ending activity: in blood platelets3#4 and in non-innervated arterial smooth muscles5,6. For some other targets the possibility of tonic stimulation of ara-adrenoceptors is still under @ 1~2,Ekevier Science Publishers

Ltd (UK)

TiPS -July 1992 [Vol. 131

278 TABLEI.Effactonvariousbiologicalfunctionsof activating rut-adrenoceptors OrsanmmcHon Central and sympathetic nelvoussystems

f2tWdfOVaSCUlarSystwn

lntemalsecn?tions

Effect’

References

1

neuromediator release

Featherstone, J. A. eta/. (1967) J. Gerontd. 43,271-276 Milliday, R. eta/. (1969) Psychopharmaco/ogy99.563-566 Coldman. C. K. et al. (19651 Eur. J. Pharmacol. 115.11-19 Laverty, I% andlaylo;, K. I\il. (1969) Br. J. Pharma&. 35, 253-264 Langer, S. Z. et al. (1977) Nature 265,646-650

arterial mnus arterial pressure heart rate

Docherty, J. R. eta/. (1979) Br. J. Pharmacol. 67,421-422P Schmitt, H. efal. (1971) Eur. J. Pham?aco/.14,96-100 Boissier, J. Ft. eta/. (1966) Eur. J. Pharmacol. 2,333-339

Parameterstudied plasma adrenaline and noradrenaline vigilance food intake thermogenesis

i , sedation t

I

thyr;r;;Ulating

t

thyroxine

Krulich. L. et a/. (1962) Endocrino/cvv 110.796-605 Brown,.M. J. et& (1965) C/in. Sci. i%,13%139s Strandhoy, J. W. ef al. (1960) LifeSci. 27.2513-2516 Nakaki, f eta/. (1961)j. Ph&macol. Exp. Ther. 216, 607-616 Yamashuta, K. eta/. (1960) Life%. 27,1127-l 130

saliva Secretion gut water reabsorption gut movement

Green, G. J. eta/. (1979) Eur. J. Pharmacol. 56,331X336 Fogel, R. et al. (1990) Digest. Dis. Sci. 35,737-742 Scott, S. M. et a/.(1990) J. Gasfroinfest Moti/ity2,159A

growth hormone arginine vasopression insulin

glycogenofysis lipoiysis

I

:

Metz, S. A. et a/. (1976) Diabetes 27,554-562 Lafontan, M. and Berian, M. (1960) Eur. J. Pharmacol. 66, 67-93

platelet aggregation

t

Nahorski, S. R. eta/. (1965) C/in. Sci. 66,39-42s

‘The d&ction of the variationcan be the resultof a direct effect on the target cell bearing cu,-receptorsand also an indirect effect by modulating activiQ in higher centres. For example, the decrease in arterial blood pressure by central reduction of sympathetic tone overrides a direct increase of vascular tone promoted by cu,-receptoragonism.

debate. For example, in white fat cells, only 2-S% of the adipocytes receive direct sympathetic innervation; the activity of a very large proportion of the arz-adrenoceptars should therefore not be directly influenced by the sympathetic nervous system. In the many other targets of the sympathetic nervous system (enterocytes, pancreatic @cells, hepatocytes, myocytes of the urogenital system, intestine or vascular system), the pathways involved in arzadrenoceptor-mediated responses are not fully determined. Extrasynaptic arz-adrenoceptors are a target for circulating adrenaline (or specific pharmacological compounds) for which they have a higher affinity than noradrenaline7**. The physiological integration of these receptors in the overall budget of the organism is of interest since adrenaline, a hormonal amplifier of sympathetic activation, does not distinguish between azu2-adrenoceptorbearing targets. In some cases, ar2-adrenoceptor activation is very appropriate; the inhibition of insulin release by adrenaline during intense physical effort maintains the high levels of blood glucose required by the muscles

(could ar2-adrenoceptor-mediated inhibition of the exocrine salivary and pancreatic secretions and the stimulation of water reabsorption by the small intestine and colon help maintain osmolarity during effort?). However, in other cases activation of ofz-adrenoceptors appears to be inappropriate. For example, the physiological relevance of catecholamine-induced inhibition of lipolysis is not fully understood. +Adrenoceptor function and antagonists ar2-Adrenoceptor agonists such as clonidine, ar-methyldopa, guanabenz and rilmenidine are used clinically in the treatment of hypertension. By contrast, aZ-adrenoceptor antagonists are not considered to be therapeutically very useful. Only yohimbine (which also interacts with 5-HT and dopamine receptors4) is clinically available. It is used to treat impotence’, but its short half-life is limiting. arz-Adrenoceptor antagonists are a heterogeneous group of molecules chemically unrelated to catecholamines. Recently, many pharmaceutical companies have synthesized arz-adrenoceptor ant-

agonists with different chemical structures in attempts to improve selectivity relative to dopamine and 5-HT receptors and (YI- and P-adrenoceptors. Antagonists that are structurally related to yohimbinelO have similar affinities for a*-adrenoceptors, but their affinities for cul-adrenoceptors vary considerably. This is reflected in their relative selectivities: 10-15 for yohimbine, 100-250 for idazoxanl’, and up to 5000 for atipamezole12. The imidazoline moiety on the agonists clonidine and UK14304, and in a family of antagonists (idazoxan, atipamezole), confer upon them the ability to bind to the nonadrenoceptor sites called ‘imibinding dazoline-guanidinium sites’ whose functions have not been elucidated13. In this review, the major actions of ar2-adrenoceptors, and the main targets for ar2-antagonists, are considered in isolation to facilitate delineation of functions and potential therapeutic indications. However, it is difficult to separate accurately the roles of pre-, postand extrasynaptic receptors in .interpreting the overall pharmacodynamic effect of an a2-adrenoceptor antagonist, because of the

TiPS -1uly 1992 iVol.131 complex interdependence of the functions mediated by these receptors. In general, an in viva pharmacological response to an a2adrenoceptor antagonist is only observed if the receptor is subject to basal tonic stimulation; occupation of the site by the antagonist will then oppose the agonist stimulus. However, in the absence of tone, an indirect action may be observed resulting from activation of the para- and/or orthosympathetic autonomic nervous systems. An assessment of the tone of arz-adrenoceptors can only be undertaken in whole animals or on organs in situ where autonomic innervation is preserved.

Central effects The regional distribution of ar2adrenoceptors has been studied in rat braini*; less is known in humans. Nevertheless, orz-adrenoceptors are considered to play a major role in the integration of autonomic, viscerosensory and affective information. Blood pressure regulation is one CNScontrolled activity that is clearly modified by uz-adrenoceptor stimulation or blockade3”. The tonic activity of the or,adrenoceptors located on central noradrenergic pathways can be deduced from the increase in noradrenaline turnover and noradrenaline levels in the cerebrospinal fluid observed after yohimbine15,1”. Yohimbine stimulates wakefulness and vigilance, and increases nervous tension and attentiveness. According to the noradrenaline hypothesis of depression, there is a selective depletion of noradrenaline in the brain. Thus, oz-adrenoceptor antagonists were predicted to possess antidepressant properties since they stimulate presynaptic release of noradrenaline and may accelerate the onset of action of antidepressant drugs17Js. Production of catecholamine metabolites is decreased in the brain and noradrenergic transmission is attenuated in some forms of depression”. Moreover, it has been postulated that central l3-adrenoceptors are supersensitive in some forms of depressive illness and there is some evidence that central j3-adrenoceptors are downregulated more rapidly in the presence of cuz-adrenoceptor antagonists

279 in rat brain20. Thus, blockade of the auto-feedback by an ozadrenoceptor antagonist could be predicted to correct this dysfunction. Although combined therapy with a standard antidepressant and az-adrenoceptor antagonists failed to confirm this hypothesis in human$‘, yohimbine was found to improve the benefits of electroconvulsive treatment of depressive patients”. At present, the clinical benefits of selective arz-adrenoceptor antagonists in depression are not established. Clonidine and other centrallyacting c42-agonists are potent analgesic agents. They reduce anaesthetic requirements, possibly by inhibiting the central noradrenergic systems involved in modulation of sleep and cortical arousal, and stabilize haemodynamic effects during surgeryzs. arz-Adrenoceptor antagonists can quickly reverse the hypnoticanaesthetic properties of arzadrenoceptor agonists and could be useful in short surgical procedures”. Stimulation of arz-adrenoceptors by direct injection of noradrenaline or clonidine into the ventromedial hypothalamic centre (the satiety centre) causes a powerful orectic response in animals. Chronic administration of clonidine increases food intake and weight gain in the monkey and arz-adrenoceptor antagonists reduce food intake in the mouse, the monkeyz5 and the do<. These results support a tonic role of the arz-adrenoceptors located on noradrenergic pathways entering the ventromedial hypothalamus. Among other CNS-controlled functions, preliminary studies that irz-adrenoceptor suggest antagonists facilitate memory retrieval in the ratz7 and yohimbine decreases the reaction time to visual stimuli in humar#. Neurotransmltter release The prejunctionai arz-adrenoceptor is a vital element in a local feedback system that modulates neurotransmitter release. uzAdrenoceptor agonists attenuate sympathetic tone via a decrease of noradrenaline release from the sympathetic nerve endings29 and release from the adrenaline adrenal medulla30. Conversely, arsadrenoceptor antagonists increase

the release of noradrenaline (and, at high doses, the release of adrenaline), resulting in the blockade of the cuz-adrenoceptors located centrally and/or prejunctionally on the sympathetic nerve endings31. The released catecholarnines can also have the secondary action of stimulating autonomic nervous system-controlled functions through their effect on other &adrenoceptors and/or arladrenoceptors also present on some target organs. This is the case, for example, in the pancreatic islet g-cells, adipose tissue and kidney (Fig. 1).

Cardiovascularandmnal function!5 Like all the tissues innervated by the sympathetic nervous system, the heart has prejunctional arz-adrenoceptors that mediate noradrenaline release, but the existence of postjunctional ar2adrenoceptors is not established. tu2-Adrenoceptor antagonists cause tachycardia and increased blood pressure in animals. However, yohimbine causes only weak cardiovascular changes that are often absent in healthy subjects even though the concentration of plasma noradrenaline increases32. This is probably explained by the low 02/01-selectivity of yohimbine. orz-Adrenoceptors are largely distributed in vascular smooth muscles and it is now accepted that arterial vasoconstriction may be mediated by a mixed population of junctional oi- and extrajunctional ~2-adrenoceptors. However, the respective contribution of both kinds of ar-adrenoceptors is unknown. Postjunctional cr2adrenoceptors play an important role in the control of cutaneous blood flows3. They contribute to the control of the microcirculation in the skin and in skeletal muscle. Moreover, the sympathetic regulation of venous function and the control of total systemic venous capacitance also involves i: ikk adrenoceptor contribution. Stimulation of c+adrenoceptors in the kidney reduces the release of renin in viva in the rat?. Yohimbine increases renin release=, thus supporting a tonic inhibitory role for renal ar2-adrenoceptors in renin secretion. Here, the receptors are found mainly on the endings of the nerves afferent to the kidney. In fact, the increase in

TiPS - ]uly 1992 [Vol. 131

m.

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of the different types of noradrenetgic innervation. a: centralnoradrenergic system. The cy2-adrenoceptors (A) are located endings&ding of an antagonist increases the release of noradrenaline (NA) and increases the activity of the

eflierent nente stimulating other receptor @-adrenoceptors ( @8 ) or a,-adrenoceptors or others]. However, the activityof tie efferent nerve decreases ifit alsO bears a2-mcqMm Theactivity of the thatamic, hypothalamic, limbic and corti& central noradrenergic pa ths, as we/t as the b&ar vegetative centres, can therefore be modified by a2-antagonists. &I: peripheral noradrenergic system. b: effector m or@ noradrenetgic innervation. Binding of antagonist to the central a2adrenoceptors and to the nerve endings activatesthe lwyadrenergic system,therebyimiirectlysb*mulatii?g the effector by acting on other receptors (/3-, a,-adrenoceptors). Blockade of the m.a2-adremmq&rs of the effectoris without consequence.c: the effector re&ves both noradrenergicand cholinergic tkm. 8indii of antagonist to the centrat a,-adrenoceptors and the nerve endings activates the noradrenergic and -2z &vi&e&c sys&ns, the&y indirectly stimulating the effector by actions on other receptors [a,-, @- antior muscarinic acety/cho/ine (m ) receptor]. d: the effector receives both cholinergic and noradrenergic innervation. The noradrenegic innervation is essentially directed towards the cholinetgic endings since few adrenegic nerves make contact with the effector. Bindingof antagonist to the central a=-adrenoceptors and the nerve endings activates the cholinergic system, thereby indilectty stimulating the effect by activating the acetylcholine receptors &$) ow

b

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autonomic

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circulating plasma catecholamine concentrations appears to mediate yohimbine-induced renin release since the fi-adrenoceptor antagonist propranolol prevents the rise in plasma renin activity in renal deneivated anirnal~~. Fhdoaineandneuroendocrine fllllCtiOllS

Stimulation of ar2-adrenoceptors on pancreatic p-cells inhibits the secretion of insulhP. In humans and experimental animals, intravenous administration of ar2antagonists such as phentolamine or yohimbine increases basal insulin secretion and peak insulin release during glucose stimulation3738. This action is directly attributable to blockade of the ar2adrenoceptors on the pancreatic cell and also to activation of both the choline@ and noradrenergic systems, since the insulinsecreting action of yohimbine is reduced by vagotomy and abolished by l3-adrenoceptor antagonists”. Pancreatic or-adrenoceptors appear not to be subject to tonic adrenergic occupation. Although the mechanism of action

pancreaticfl-cell

salivarygland

of the ar2-adrenoceptor antagonists on insulin secretion is not established, their use to block the ar2adrenoceptors on the pancreatic islet may represent a strategy to enhance insulin secretion for the treatment of non-insuhn-dependent diabetes. Adrenaline secretion by the adrenal medulla is under cholinergic control. In vitro stimulation of ar2-adrenoceptors in adrenal medulla cells inhibits the secretion of adrenaline40. The inhibitory action on adrenaline secretion of ar2-adrenoceptor agonists administered in vivo is mainly of central origin: it results from a lowering of the activity of the adrenaline-secreting centres. Yohimbine did not modify the release of adrenaline after splanchnit nerve stimulation4*. Administration of yohimbine in conscious dogs, although promoting an activation of the sympathetic nervous system assessed by increment of plasma noradrenaline concentration, has no adrenalinesecreting effect at low doses (6 0.05 mg kg-l i.v.); however, higher doses (3 0.5 mg kg-l i.v.)

intestinalmyocytes

increase the blood concentration of adrenaline through central activation38. Thyroid stimulating hormone stimulates thyroxin secretion via a cAMPdependent step. In vitro, noradrenaline activates the ar2reversing this adrenoceptors effect. No data are available on whether thyroid cell receptors are subject to tonic stimulation. Clonidine increases release of growth hormone and decreases release of arginine vasopressin. az-Adrenoceptor antagonists have no effect on spontaneous secretion of growth hormone but totally suppress its release triggered by clonidine42. Liver and adipose tissue Hyperglycaemia, induced with clonidine or guanabenz, is resistant to j3-adrenoceptor antagonists but is reduced by a2-adrenoceptor antagonists41. It is caused primarily by release of growth hormone, which stimulates hepatocyte gluconeogenesis and attenuates peripheral glucose utilization43. cw2-Adrenoceptors are particularly abundant in human adipo-

TiPS -July

2992 [Vol. 131

cytes. Their stimulation inhibits lipolysi 5 in the subcutaneous abdominal and gluteal deposits, where they outnumber l3-adrenoceptorsU. Administration of Qadrenoceptor antagonists raises the plasma concentrations of nonesterified fatty acids, glycerol and noradrenaline. g-Adrenoceptor antagonists potently reduce lipomobilization. Thus the effect of a+-adrenoceptor antagonists is secondary to the activation of the P-adrenoceptor of adipose tissue by noradrenaline32*38. It is not known if the ar2-adrenoceptors of adipose tissue are under tonic control by the sympathetic nervous system. oz-Adrenoceptor antagonists indirectly increase lipomobilization by activating the sympathetic nervous system at doses that do not noticeably modify cardiovascular parameters3’. With low concentrations of plasma adrenaline and noradrenaline at rest, the arz-adrenoceptors could play an essential role in the control of basal levels of lipolysis. During sustained exercise it is theoretically possible that these receptors could afford protection against excessive lipolysis caused by a decrease in circulating insulin concentrations, or by activation of P-adrenoceptors in some fat deposits possessing a great density of crz-adrenoceptors. Salivary secretion and digestive tract Clonidine and other arz-adrenoceptor agonists cause dry mouth. Yohimbine increases salivary secretion by stimulating the chorda tympani through both a central effect and blockade of the ar2adrenoceptors located on the parasympathetic nerve endings45*46. Thus, the oz-adrenoceptors on the efferent cholinergic pathway appear to be subject to a tonic stimulation by the sympathetic nervous system. Acute admirdstration of yohimbine restores normal salivation in patients treated with tricyclic antidepressants4’. occur on ar2-Adrenoceptors epithelial cells of small intestine and colon villosities. Their stimulation increases the absorption of water and inhibits the secretion of electrolyteP. This effect on absorption, in association with inhibition of gut motility induced by ars-adrenoceptor agonists, ex-

281 plains the constipation that occurs as a side-effect of clonidine. The inhibition of motoricity can mainly be attributed to a decrease in activity of the parasympathetic system via stimulation of the presynaptic oz-adrenoceptors. Blocking these receptors accelerates intestinal transit in rat4g and should promote reduction of intestinal water absorption. The tonic status of these receptors in the intestinal tract suggests that cuz-adrenoceptor antagonists may be useful in the treatment of constipation. 0

cl

cl

The great number of binding studies carried out over the past decade, covering most tissues and organs, has determined the presence and/or the location of oz-adrenoceptors. Their physiological role has remained confused, however, in some organs. arz-Adrenoceptors have been identified in the CNS and most tissues and cells controlled by the sympathetic nervous system, where they mediate a large number of functions. However, the large variety of effects mediated by ar2adrenoceptors and the absence of appropriate targeting due, in part, to the lack of suitable tools for or2adrenoceptors, have hindered therapeutic research. Although ozantagonists are the only class of drugs to interact with adrenoceptors without a current therapeutic indication, their effects on pancreas, digestive tract and adipose tissue encourage such prospects. There is now pharmacological and genetic evidence that ar2adrenoceptors represent a heterogeneous population of receptors with at least three subtypes encoded by different genes in humans. Previously established structure-activity relationships for arz-adrenoceptor-interacting drugs need complete re-evaluation to determine the receptor subtype(s) involved in the control of functional effects. The future therapeutic use of arzadrenoceptor antagonists will also depend on their selectivity and on their ability to cross the bloodbrain barrier. The cwz-antagonist molecules that penetrate the CNS will bring about effects such as activation of the sympathetic nervous system, which could be a therapeutic endpoint of some

neurological and metabolic diseases. Further, cuz-adrenoceptor antagonist drugs discriminating post-junctional cu2-adrenoceptors will preferentially block lu2adrenoceptor-mediated sympathetic transmission and the actions of circulating catecholamines. Thus, improved therapies could result from the concepts of ar2adrenoceptor heterogeneity. 1 Kobilka, B. K. et al. (1987) Science 338, 650-656 2 Goldberg, M. R. and Robertson, D. (1983) Pharmacol. Reu. 35,14%178 3 McGmtb. J. C., Brown, C. M. and Wilson,V. G. (1989) Med. Res. Rrn. 9, w-533 4 Nichols, A. J- and Ruffolo, R. R. Jr (1991) in Adrenocepfars: MolecuInr Biology, Biochemistry and Phanaacology (Ruffolo, R. R. Jr, ed.), Prog. Basic Uin. Phannacol., Vol. 8, pp. 115-179, Karger 5 Ruffolo, R. R. Jr, Waddel, J. E. and Yaden, E. L. (1981) J. Phanxacol. Exp. Ther. 217,235-240 6 Bentley, G. A. and Widdop, R E. (1987) Brit. J. Pharmacol. 92, X21-128 7 Lafontan, M. end Be&n, M. (1982) Eur. 1. Phanxacol. 82,107-111 8 Ariens, E. 1. and Siionis. A. M. (1983) ’ Biachem. Pharmacal. 32,1539-1!345. 9 Susset, J. G. et al. (1989) .1. Ural. 143, 1360-1363 10 Pettibone, D. J. et al. (1987) NuuxynSchmied. Arch. Phurmucol. 336,16%175 11 Doxey, J. C., Lane, A. C., Roach, A. G. and Virdee, N. K. (1984) NaunynSchmied. Arch. Pharmacol. 325, l&l44 l2 Viisnen, R., Savola, J. M. and Saano, V. (1989) Arch. Int. Phanacodvn. Ther. 297, 190-204 13 Atlas, D. (1991) Biochem. Pharmucal. 41, 1541-1549 14 Unnerstal, J. R. and Kubar, M. J. (1988) in Epinephrine in Central Netwous System (Stolk, I. G., IJ’Pricbard, D. C. and Fuxe, K., eds), pp. 48-59, Oxford University Press 15 Brasbeny, C. Q. and Adams, R. N. (1986) Eur. J. Phnrmacal. l29,175-188 16 Peskind. E. R., Weitb, R. C., Dorsa, D. M., .Gumbrecht, G. and Raskind, M. A. (1989) Newoendocrinoi. 50, 286-291 17 Langer, S. Z. (1988) in Psychophannncolonv. The Third Generation of Pragress (Me&er, H. Y., ed.), pp. 151-157, R&en press 18 Osman, 0. T., Rudorfer, M. V. and Potter, W. Z. (1989) Arch. Gen. Psych. 46, 286-291 19 Mass, J. W. (1975) Arch. Gen. Psych. 32, 1357-1361 20 Crew. F. T., Paul, S. M. and Goodwin, F. K. (1981)~Nuture 298,787-789 21 Chamey, D. S., Pryce, L. M. and Heninger, G. R. (1986) Arch. Gen. Psych. 43,1155-1161 22 Sachs, G. S.. Pollack, M. M., Brotman, A. W:, Farhedi, A. M. and Gelenberg, A. J. (1986) J. Clin. Psychiatry 47,508-510 23 Ghignogne, M., Quintin, L., Duke, P. C., Kehler, C. H. and Calvillo, 0. (1986) Anesthesiology 64,36-42 24 Karuvaara, S., Kallio, A., Salonen, M., Tuominen, J. and Scheinin, M. (1991)

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. I 30 An&de, F. et al. (l!%n Br. I. Pkarmncol. 91,%1-&l . .

31 Gokibzrg, M. R., Xollistec A. S. and Robertson, D. (1983) H~e~e~ion 5, z2-7?8 32 Gal&&y, J. et ul. (1988) Eur. 1. Cliri. Invest. 18,.587-594 33 Wiette, R. N., Hieble, J. P. and Sauemelcb. C. F. (1991) J. Pkarmacol. Eq. Tker. 2% 599-6as 34 IWinger, W. A., Keaton, T. K,

35 36 37 38 39

40

41 42

Campbell, W. M. and Harper, D. C. (1976) Circ, Res. 38, 35-46 Pfister. S. L. and Keeton, T. K. (1988) Naunyn-Schmiedeberg’s Arch. Pharmacot. 337,35x6 Nakati, T., Nakadate, T., Ishii, K. and K&o, R. (1981) J. Phurmac& Exp. 7’her. 216.607-618 Ah&n, B., Lundquist, I. and J;irhult, J. (1984) Acta Endocrinol. 105,78-82 Tao&s. M.. Be&m. M., Montastruc. P. and L&m&n, M.-(1988) 1. Pharma~ol. Exp. Ther. 247,1172-X80 Ribes, G., Hilaires-Buys, D., Gross, R.. Blayac, J, P. and LoubatieresMariani, M. M. (1989) Eur. J. Pkarmacol. X2,207-214 Sakurai. S.. Waoa, A.. Izumi, F.. Kobaya&i, g. and Yang&a. N. (1983) Nnunyn-Schmiedeberg’s Arch. Pharmacol. 324.15-19 Sham& T. R., Wakade, T. D., Malbotra, P. K. and Wakade, A. R. (1986) Eur. 1. Pharmacol. 122,167-172 Gbigo, E. et at. (1990) N~~endoc~~-

Use af ir: tyIivoapparent pA2 analysis in assessment of opioid abuse liability J. H. Woods, G. ginger and C. I? Frmce Abuse liability testing ofopioid drugs wus originally motivated by attempts to separate the unulgesic effects of opioids from their 1ikeZihood for abuse. It has become spurt that the h~mun po~~l~t~o~group likely to abttse o~iojds has little overlap with the population group re@ring opioids to treat pain, theref&e there is no longer a need to separate these two properties of opioids. This is fortunate, since, as reviewed here by Jim Woods and colleagues, the results of the plethora of studies that have attempted to distinguish these two p~pe~‘~ in known opioi~ s~o~gly indicate that they are inseparub~. Evuluution of the abuse poten~ul of novel opioids remains, however, critically important in deciding on governmental restrictions on their accessibility. In addition, opioid abuse liability testing contributes enormously to our understanding of the behavioral mechanism of action of these drugs, and in surprising and help~l ways has increased our uppreciatio~ of the various test systems used to garner info~u~on about them. There are few substances in history that could have caused so much misery, and also given so much relief f!rom misery, as opioid drugs. The desire to separate two of the predominant attributes of opioids - their ability to promote drug-seeking behavior and drug taking, and their ability to relieve I. H. Woods is Professor ofPharmacology aud Psychology, and G. Winger is Associate Research Stied-f, Department of Pharmacology, University of Mickigun, Ann Arbor, MI 48109, and C. P. France is Assistuti Professor, Depaftmenf of Phurmacology and Experimental Therapeutics, Tke Louisiana State University Medical Center, New Orleans, LA 70119, USA.

pain - has been a driving force in much of the research on assessment of the abuse liability of this group of substances. Although it has recently been established that patients receiving or taking opioid drugs for relief of pain are at little risk of becoming opioid abusers’ even if they control directly the frequency and dose of intravenous delivery, the need to continue careful evaluation of the abuse liability of opioid drugs remains strong. Data obtained from such evaluations are critical for governmental decisions about regulation and control of new opioid drugs. Furthermore, abuse

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OfOQU 2.473-476 43 Di”*T&io, N. W., Cieslinski, L., Matthews, W. D. and Storer, B. (1984) . 1. Pkarmacol. Exp. The,: 228, i68-173 44 Mauri@e, P., &lit&y, J., Bedan, M. and Lafontan. M. 11987) Eur. 1. Clin. Invest. 17,156&5 . ’ ’ 45 Cbatelut, E., Rispail, Y., Rerlan, M. and Montastruc, J-L. (1989) Brif. 1. Clin. Pharmacol. 28.366-368 46 Montastruc, P., Be&n, M. and Montastruc, J-L. (1989) Brit. 1. Pkarmaco!. 98,101-104 47 Rispail, Y., Schmitt, L., Berlan, M., Montastruc, J-L. and Montrastruc, P. 11989) Eur. -1. Clin. Pharmacol. 39. 425-426 48 Gaginella, T. S. 11984) Trends P~~a~o~. Scir5,387-399 . r 49 Theodorou, V., Fioramonti, J. and Bueno, L. (1989) J. Gsstrointest. Mot. 1, 85-89 LJKl43a 5-bromo-6-(2-imidazoline-2-y]~~o)q~o~e

liability testing has provided a continuous source of indispensable isolation about opioid drugs. Data generated by a variety of techniques for identifying chemicals as opioid-like, and data resulting from the many procedures used to compare these opioids to pharmacological standards, form the basis of our current understanding of the multifaceted pharmacology, biochemistry and neurochemistry of opioid drugs. This article seeks to demonstrate how opioid abuse liability testing continues to expand our knowledge about these compounds. Abuse liability testing involves a number of procedures, each contributing complementary information about the likelihood that a given compound has a risk of being abused. The attributes, described by Stolerman {TiPS, May 1992, pp. 170-17~3, include measures of physiological dependence capacity, and measures of the reinforcing and discriminative stimulus effects of psychoactive drugs have been applied frequently in investigations of opioid drugs. Some information on evaluation of the analgesic effects of opioid drugs is also included in this article because it is related to the clinical use of opioid drugs, and because it has provided data complementary to measurements directly related to their abuse.

PhysioIogical dependence

Early opioid abuse liability testing was based on the hypothesis