Jo~~rnal of Psychopharmacology 1 l(4) (1997) 361-365 81997 British Association for Psychopharmacology(ISSN 0269-881 1) SAGE Publications, London. Thousand Oaks. CA and New Delhi The use of the plasma concentration-effect relationship as a tool for the study of the mechanism of action of naloxone effects on mood and endocrine function Alfonso F. Martin del Campo1,Vinicio Granados-Soto2, Patricia Aguirre-Baiiuelos 2 , Mnrio CrirdcnnsS nncl Gil1)crto Castnficdn-I-IernGndez2 'Departamento de Psico-Neuroendocrinologia, Znstitulo Mexicano de Psiquiatria, Calz. Mixico-Xochimilco 101, Tlalpan, 14370 Mixko, D.R. 'Seccidn de l'intpiutica Experimental, Departamenlo de Farmacologia y Ilbxicologia, Centro de Znvestigacidn y de Estudios Avanzados del Znstitulo Politicnico Nacional, Mixico, D.R and 3Dcpartamento de Biologia de la Reproduccidn, Znstituto Nacional de la Nutricidn 'Salvador Zubircin', Mixico, D.E: The relationship between naloxone-plasma concentrations and their effects on mood and endocrine function was studied. Ten healthy volunteers received 1.0 mg/kg i.v. naloxone or placebo following a randomized double- blind design. Effects on mood, determined by a visual analogue scale and luteinizing hormone (LH) and naloxone-plasma concentrations were measured at selected times. Naloxone induced significant effects on confusion, bewilderment and indifference, and an increment in LH levels. The timecourse of the responses on confusion and bewilderment was similar to that of naloxone-plasma concentration, suggesting that these effects are directly related to the action of naloxone on its receptors. Responses for indifference and LH, however, exhibited a delayed onset. This delay could be due to an indirect action, i.e. to the participation of additional physiological mechanisms in a cascade-liko manner. The rosults show that analysis of tho concentration-effect relationship can be a useful tool for understanding naloxone effects on mood and cndocrinc function. Key words: concentration-effect relationship; endocrine function; endogenous opioid system; mood; naloxonc The discovcry of endogenous opioids has resultcd in a number of hypotheses concerning the possible rolcs of these substances in the regulation of mood, mental state and endocrine function in man (Hughes el al., 1975; Bloom el al., 1976; Belluzi and Stein, 1977). Naloxone, an opioid antagonist, has been used as a tool to test these ideas. There is evidence that naloxone produces changes in mood, as it has been reported that administration of this drug to healthy volunteers resulted in dysphoria (Cohen el al., 1983; Grevert el al., 1983; Martin del Canipo el al., 1994). Moreover, opioid blockade in man also results in endocrine effects, such as an increase in the circulating levels of luteinizing hormone (LH) and cortisol (Mcndclson el al., 1979; Grcvcrt el al., 1983; Grossman and Recs, 1983; Joycc and Donald, 1987; Martin dcl Cdmpo el al., 1994). These observations, however, have been made after the administration of relatively high doses (I .O mg/kg or higher). Notwithstanding this, at the peripheral levcl, naloxone produces a clear opioid blockadc at doses of 0.1 mg/kg or less. In fact, these doses arc used for the reversal of opioid intoxication. Nonetheless, studies in wHich naloxone was given at this dosc Icvcl, showcd littlc or no cffcct on the rno& of normal subjects (Grevert and Goldstein, 1977; Jones and I lcr~ii~ig, 1979; I:ilc eld Silvcrs(oric, 198 1; I locli~i-Sriric rind Masek, 1981; Martin del Campo et al., 1992). Naloxone is a dose-selective antagonist. At low doses, naloxone blocks p- opioid receptors. At higher doses, it blocks other opioid receptors. Furthermore, at even higher doses, naloxone interacts on other neurotransmitter systems, such as GABA (Dingledine el al., 1978). Since high naloxone doses are required to elicit affective responses, it is likely that these; effects involve not only opioid receptors, but also other neurotransmitter systems. It should be borne in mind that the study of the realation of mood in man is a complicated task. The effects produced by naloxone may not be solely due to direct 'action on its receptors, but may also involve the inhibition or activation of :itltlitionnl ~ic~~rolr~~~is~~iitlcr systclns tri~gcrcd by opioitl blockadc, in a cascadc-likc fashion, i.c. tlic actual nicasured response would bc indirectly related to the primary drug effect (Dayneka el al., 1993; Jusko and KO, 1994). If this is the case, it can be expected that the onset of the measured response will be delayed with respect to drug concentration (Jusko and KO, 1994). On thc othcr hand, if the mcasurcd response is directly linked to thc primary drug effect and the drug is rapidly distributed to its site of action, thcrc should bc a dircct rchtionship betwecn drug conccntrntion and the measurcd