Endogenous opioids may be involved in idazoxan-induced food intake. - PDF Download Free (2024)

Neuropharmacology Vol. 31, No. 8, pp. 771-776, 1992 Printed in Great Britain. All rights reserved

0028-3908/92 $5.00 + 0.00 Copyright 0 1992 Pergamon Press Ltd



and D. J. NUTT

Reckitt and Colman Psychopharmacology Unit, Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 ITD, U.K. (Accepted 6 April 1992)

Summery-In this study it has been shown that the unexpected increase in food consumption, produced by the a,-adrenoceptor antagonist idazoxan (10 mg/kg, i.p.) in rats, was significantly attenuated by small doses of the opioid antagonist ( - )-naloxone (0.1, 1 mg/kg, i.p.) and totally inhibited by a small dose of naltrexone (1 mg/kg, Lp.). On the other hand, idazoxan-induced feeding was not affected by ( + )-naloxone (0.1, 1 mg/kg, i.p.), which is inactive at opioid receptors. In addition, idazoxan-induced food consumption was not blocked by the b-opioid antagonist, naltrindole (0.1, 1mg/kg, i.p.) nor by the p/a-antagonist, RX8008M (16-methyl cyprenorphine; 0.1, 1 mg/kg, i.p.), which clearly discriminates between p/a- and K-opioid receptor function in oioo. These findings suggest that idazoxan may lead to the release of endogenous opioid peptides, which subsequently stimulate feeding by activation of K-, as opposed to por &opioid receptors. This response is unlikely to be due to a,-adrenoceptor blockade, since other highly selective a,-adrenoceptor antagonists do not increase food intake and, instead may reflect the high affinity of idazoxan for non-adrenoceptor idazoxan binding sites. Key words-idazoxan, receptor sub-types.


idazoxan binding sites, food intake, endogenous opioids, opioid

It was recently demonstrated that the q-adrenoceptor antagonist idazoxan increased food intake in freely-feeding rats (Jackson, Griffin and Nutt, 1991). This finding was paradoxical in the light of the wellknown stimulatory effects of qadrenoceptor agonists on food consumption @anger, 1983a; McCabe, De Bellis and Leibowitz, 1984; Goldman, Marino and Leibowitz, 1985). One possibility is that idazoxan-induced food intake may be attributed to its high affinity for non-adrenoceptor idazoxan binding sites (see review by Michel and Insel, 1989). In support of this observation, RX81 1059 (2-ethoxy idazoxan; Doxey, Lane, Roach, Smith and Walter, 1985) and RX821002 (2-methoxy idazoxan; Langin, Lafontan, Stillings and Paris, 1989), which act more selectively than idazoxan at a,-adrenoceptors, having only low affinity at non-adrenoceptor idazoxan binding sites (Langin, Paris and Lafontan, 1990; Mallard, Tyacke, Hudson and Nutt, 1991), do not increase food intake in freely-feeding rats (Jackson ef al., 1991). Moreover, non-adrenoceptor idazoxan binding sites are concentrated in areas of the brain, such as the hypothalamus and the area postrema (Hudson, Mallard and Nutt, 1991), which have been implicated in the control of food intake.

*To whom correspondence should be addressed at: Pharmaceutical Research Division, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 M&v, Denmark. tPresent address:‘Pfizer Central Research, Sandwich, Kent CT13 9NJ, U.K.

The exact mechanisms underlying idazoxaninduced food intake are unknown. Direct confirmation of the involvement of non-adrenoceptor idazoxan binding sites awaits the development of selective agonists and antagonists. However, the pharmacology underlying the feeding response to idazoxan (and perhaps non-adrenoceptor idazoxan binding sites) can be explored indirectly, using antagonists of those neurotransmitter systems which are thought to play a role in the regulation of appetite. One example of the above is the endogenous opioid system. Thus, administration of naturally-occurring opioid peptides or of synthetic opioid agonists increases food intake during the day (when control levels are low). On the other hand, opioid antagonists suppress the increase in feeding which occurs in rats at night and which coincides with elevated levels of endogenous opioids in the CNS (see Reid, 1985; Cooper, Jackson, Kirkham and Turkish, 1988, for reviews). In the current study, the possible involvement of opioid receptors in idazoxan-induced food intake has been investigated using the established opioid antagonists, naloxone and naltrexone (which cannot readily discriminate between the different types of opioid receptor in z&o). Moreover, since selective p(- (Jackson and Sewell, 1985; Gosnell, Levine and Morley, 1986), K- (Jackson and Sewell, 1984; Jackson and Cooper, 1985; Hewson, Hill, Hughes, Leighton and Turner, 1987) and 6 - (Gosnell et al., 1986) opioid agonists increase fobd intake in rats, the studies were





extended to include the selective 8-opioid antagonist, naltrindole (Portoghese, Sultana and Takemori, 1988, 1990; Rogers, Hayes, Birch, Traynor and Lawrence, 1990; Takemori, Sofuoglu, Sultana, Nagase and Portoghese, 1990; Crook, Kitchen and Hill, 1991) and also RX8008M (16-methyl cyprenorphine), which clearly distinguishes between p(- and K-receptor function in isolated tissues (Smith, 1987) and in whole animal work (Birch and Hayes, 1987; Hayes and Birch, 1988; Birch, Hayes, Sheehan and Tyers, 1988; Jackson and Kitchen, 1989a, b).



Animals and environment Male Wistar rats (25&350 g, Bantin & Kingman) were individually housed (in polypropylene cages with metal grid floors) at 23 &-2°C on a 14:lO hr lightaark cycle (lights on at 05:OO hr), with free access to a powdered standard rat diet (Biosure, Manea, Cambridgeshire) and tap water at all times. The powdered diet was contained in glass feeding jars (10 cm dia; 8 cm deep) with metal lids. Each lid had a hole (3 cm dia) cut in it to allow access to the food. The animals were accustomed to these conditions for at least 1 week before experimentation began.












Experimental procedures On the day of test, the animals were randomly allocated to treatment groups, each containing at least 6 animals. All procedures began at 09 : 00 hr so that measurements were carried out during the light period when the food intake of control animals was minimal. Feeding jars were weighed (to the nearest 0.1 g) at the time of administration of drug and after 1 hr. Variations in body weight were accounted for by expressing the results as g/kg rat weight (treatment group means f SEM). Drugs and injections The following drugs were used: idazoxan (2-[2-( 1,4benzodioxanyl)]-2-imidazoline), ( - )-naloxone, ( + )naloxone, naltrexone, RX8008M and naltrindole. Idazoxan, RX8008M and naltrindole were synthesized at Reckitt & Colman, Hull. Naltrexone and ( - )-naloxone were purchased from Research Biochemicals Incorporated. ( + )-Naloxone was a gift from Dr A. E. Jacobsen, National Institutes of Health, Bethesda, Maryland, U.S.A. Idazoxan, naltrexone and the enantiomers of naloxone were dissolved in 0.9% saline. The RX8008M and naltrindole were dissolved in saline at pH 3.0. Drugs were administered intraperitoneally in a volume of 1 ml/kg. Doses of drugs are expressed as the hydrochloride salt. A dose of 10 mg/kg of idazoxan was chosen since it produced a large increase in food intake, in the first hour after administration of the drug (Jackson et al., 1991). Doses of opioid antagonists were based on those shown to block opioid receptors in other behavioural studies in rats (e.g.

Fig. 1. Effect of (a) ( - )-naloxone and (b) ( + )-naloxone on the food intake induced by idazoxan (10 mg/kg). Groups of 6 rats were injected intraperitoneally with vehicle (0); idazoxan (m); idazoxan plus naloxone 0.1 mg/kg (m) or idazoxan plus naloxone 1 mg/kg (H). Values represent mean intakes k SEM. Significant differences from the vehicle-treated control group are indicated by *P < 0.05 and from the group given idazoxan alone by tP -C0.05.

Jackson and Sewell, 1984; Birch and Hayes, 1987; Jackson and Kitchen, 1989b; Jackson, Ripley and Nutt, 1989; Crook et al., 1991). Animals were given pretreatment with naltrindole for 30 min. All other antagonists were administered at the same time as idazoxan. Statistical analysis Statistical comparisons between mean group intakes were made using analysis of variance and Dunnett’s test (two-tailed). RESULTS

The large increase in food intake, induced by idazoxan (10 mg/kg, i.p.), was significantly and dosedependently attenuated by the opioid antagonist ( - )-naloxone (0.1, 1 mg/kg, i.p.), as shown in Fig. l(a). In contrast, the ( + )-enantiomer of naloxone (0.1, 1 mg/kg, i.p.) had no effect on this response (Fig. lb). Idazoxan-induced feeding was not totally abolished by ( - )-naloxone, since animals treated



Fig. 2. Effect of naltrexone on the food intake induced by idazoxan (10 mg/kg). Groups of 8 rats were injected intraperitoneally with vehicle (0); idazoxan (m) or idazoxan plus naltrexone 1 mg/kg (UU)). Values represent mean intakes f SEM. Significant differences from the vehicletreated control group are denoted by *P i 0.05 and from the group given idazoxan alone by tP < 0.05.

with the opioid antagonist and idazoxan still ate significantly more than the vehicle-treated group. However, complete blockade was achieved using the more potent opioid antagonist naltrexone (1 m&kg, i.p.; Fig. 2). Thus, animals treated with idazoxan and naltrexone ate similar amounts to controls and significantly less than the animals treated with idazoxan alone. On the other hand, idazoxan-induced food consumption was not significantly inhibited by either the selective 6 -opioid antagonist naltrindole (0.1, 1 mg/kg, i.p.; Fig. 3a) or by the p/6-opioid antagonist RX8008M (0.1, 1 mg/kg, i.p.; Fig. 3b). The doses of opioid antagonist, used in the current study, had no inherent effects on food intake during the light phase (Jackson and Sewell, 1984; unpublished observations).

food intake


intake and the food intake induced by pharmacological manipulation have been associated with increased endogenous opioid activity in the CNS (see Reid, 1985; Cooper et al., 1988). Thus, the increase in food intake, induced by idazoxan, could be mediated by the release of endogenous opioids that subsequently initiate feeding behaviour by activation of opioid receptors. It is unlikely that the blockade of idazoxan-induced feeding by naloxone and naltrexone involves a direct interaction, since idazoxan is not active at opioid receptors (Doxey, Roach and Smith, 1983). An important consideration is that naloxone and naltrexone may decrease idazoxan-induced food intake by non-specific mechanisms. However, this is unlikely since there is no evidence that opioid antagonists reduce feeding by interfering with motor function or by producing malaise (see Cooper et al., 1988). Moreover, some forms of feeding behaviour are not modified by opioid antagonists. Thus, they do not appear to suppress food intake during the day (as mentioned in the Results section; although it should be noted that this may be difficult to detect







2 -i


.P E



In this study it was demonstrated that small doses of the opioid antagonists, naloxone and naltrexone, inhibited idazoxan-induced food intake in rats. The stereoselective attenuation of idazoxan-induced feeding by ( - )-naloxone, but not by the (+ )enantiomer, which is over 1000 times less active at opioid receptors (Iijima, Minamikawa, Jacobson, Brossi and Rice, 1978), confirms the involvement of opioid receptors in this response. Furthermore, naltrexone more effectively antagonized idazoxaninduced feeding than did naloxone. This is consistent with the known potency of these compounds at opioid receptors (Verebey and Mule, 1975). As reported in the introduction, opioid antagonists reduce food intake in other conditions, for instance, the feeding that occurs in rats at night and the feeding induced by treatment with compounds such as the benzodiazepines and 2-deoxy-D-glucose (Reid, 1985; Cooper et al., 1988). However, both nocturnal food






Fig. 3. Effect of (a) naltrindole and (b) RX8008M on the food intake induced by idazoxan (lOmg/kg). Groups of 6 rats were injected intraperitoneally with vehicle (0); idazoxan 10 mg/kg (m); idazoxan plus antagonist 0.1 mg/kg (a) or idazoxan plus antagonist 1 mg/kg (H). Values represent mean intakes + SEM. Significant differences from the vehicle-treated control group are indicated by *P < 0.05.



due to the low levels of feeding of control animals) or in a variety of other paradigms (Goudie and Demellweek, 1980; Deakin and Longley, 1981; Ostrowski, Rowland, Foley, Nelson and Reid, 1981; Sanger, 1983b; Morley, Levine, Gosnell and Billington, 1984; Levine, Morley, Kneip, Grace and Brown, 1985). It is interesting to speculate which type of opioid receptor may be involved in the effects of idazoxan on food intake. Selective agonists at either p- (Jackson and Sewell, 1985; Gosnell et al., 1986) K- (Jackson and Sewell, 1984; Jackson and Cooper, 1985; Hewson et al., 1987) or 6- (Gosnell et al., 1986) opioid receptors all increase food intake in rats. These responses are blocked by naloxone and naltrexone (Jackson and Sewell, 1984,1985; Jackson and Cooper, 1985; unpublished observations) high-lighting the limitations of these opioid antagonists, which cannot discriminate between the different types of opioid receptor in tGco. However, more selective opioid antagonists have recently become available, including naltrindole and RX8008M. Naltrindole acts over 70 times more selectively at 6-receptors, in comparison with p(- and K-receptors, as shown in isolated tissue preparations by a number of workers (Portoghese et al., 1988, 1990; Rogers et al., 1990; Takemori et al., 1990; Colin Smith, personal communication). This selectivity profile (over a lOO-fold) has been confirmed in receptor binding studies (Rogers et al., 1990; Takemori et al., 1990). Given in vice, naltrindole blocks the antinociceptive effects of 6- but not p- and ~-agonists in mice (Portoghese et nl., 1988; Takemori et al., 1990; Gacel, Fellion, Baamonde, Dauge and Roques, 1990). Similar observations have been made, following its central administration to rats (Calcagnetti and Holtzman, 1991). Furthermore, the 1 mg/kg dose of naltrindole, used in the current study, has been shown to block d-mediated swim-stress-induced antinociception in this species (Jackson et al., 1989) and also inhibits the increase in tail immersion latencies, produced by highly selective 6 -agonists in rats (Crook et al., 1991), without effecting the antinociception produced by p-agonists (Crook et al., 1991; unpublished observations). Therefore, the lack of effect of naltrindole on idazoxan-induced feeding, in the current study, precludes a major role for 6-opioid receptors in this response. The above observation is supported by the finding that idazoxan-induced food intake is also resistant to RX8008M. This compound has been characterized in isolated tissue preparations as a p/6+elective antagonist. with low affinity at K-WeptOrS (e.g. it acts over 30-fold more selectively at p- and S-receptors than ~-receptors; Smith. 1987). It reduces the antinociceptive effects of both p- and S-agonists in rats after intracerebroventricular administration (Fanselow, Calcagnetti and Helmstetter, 1989) and, in small doses, blocks p- but not K-responses in rats, when given peripherally. Thus, a I mg/kg dose of RX8008M


(similar to that used in the current study) produces large (over 20-fold) shifts in the antinociceptive dose-response curves for the p-agonists morphine and

fentanyl in mice, without effecting the antinociception induced by ~-agonists even in doses 30 times greater (Birch et al., 1988; Hayes and Birch, 1988). Moreover, this dose of RX8008M completely blocks the increase in tail immersion latencies, induced by the p-agonist D-Ala2-MePhe4-Gly-ol’-enkephalin in neonatal rats

(Jackson and Kitchen, 1989b), whilst having no affect on K-mediated responses, at a dose of lOmg/kg (Jackson and Kitchen, 1989a). In addition, RX8008M (1 mg/kg) blocks the anti-diuretic effects of p -agonists in water-loaded rats but does not block the diuretic effects of K-agonists in doses up to 16 times greater (Birch and Hayes, 1987). From these results it could be speculated that the appetitive effects of idazoxan may be mediated by IC- as opposed to either p - and S -opioid receptors and it would be interesting to confirm this directly using the recently developed selective ~-antagonist norbinaltorphimine (Portoghese, Lipkowski and Takemori, 1987; Takemori, Ho, Naeseth and Portoghese, 1988). Unfortunately, this compound has poor systemic bioavailability and is very expensive, therefore it generally has to be given by the central route. The low affinity of RX8008M for rc-opioid receptors and its good bioavailability, after peripheral administration, makes it a useful alternative approach for studying the K-receptor component of endogenous opioid activity. The possibility that idazoxan may result in the release of endogenous opioid ligands for K-opioid receptors, e.g. the dynorphins (Chavkin, James and Goldstein, 1981; Huidobro-Toro, Yoshimura, Lee, Loh and Way, 1981), has not been examined directly as yet, however, it may be relevant that high levels of dynorphins (Goldstein and Ghazarossian, 1980) K-opioid receptors (Boyle, Meecham, Hunter and Hughes, 1990) and non-adrenoceptor idazoxan binding sites (Hudson et al., 1991) have been detected in the hypothalamus-an area particularly associated with the control of food intake. In conclusion, idazoxan produces a large increase in food intake which appears to be mediated through the release of an endogenous opioid and activation of opioid receptors. Preliminary experiments with selective opioid antagonists suggest that p- and 8-opioid receptors are not involved in this response, which may instead be mediated through k--opioid receptors. It is interesting to speculate that this effect of idazoxan may be linked to its high affinity at non-adrenoceptor idazoxan binding sites and thus may give some indication of the neurochemical and behavioural actions of these novel sites-the function of which is currently unknown. Acknowledgement-We would like to thank Dr A. E. Jacobson for his gift of ( + )-naloxone as mentioned in the Methods section.

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