A bi-directional mu-opioid-opioid connection between the nucleus of the accumbens shell and the central nucleus of the amygdala in the rat

The central nucleus of the amygdala (CeA) and the nucleus of the accumbens shell (NAc) have been shown to be involved in opioid-mediated feeding behavior. The present study examined whether mu-opioid signalling between the CeA and NAc affected feeding. Male Sprague-Dawley rats were fitted with one cannula placed in the CeA and two cannulae placed in the NAc, which allowed for coadministration of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in one site and the opioid antagonist naltrexone (NTX) in the other site. Single injection of DAMGO (2.4 nmol) into the CeA and bilateral injections of DAMGO (2.4 nmol) into the NAc stimulated feeding (P<0.05). The DAMGO-induced increase of food intake following injection into the CeA was decreased by bilateral injection of NTX (13.2 and 26.5 nmol) into the NAc at 2- and 4-h postinjections (P<0.05). In the reverse situation, the DAMGO-induced increase of food intake following injection into the NAc was decreased by injection of NTX (13.2 and 26.5 nmol) into the CeA at 1-, 2-, and 4-h postinjections (P<0.05). These results suggest that a bi-directional mu-opioid-opioid signalling pathway exists between the CeA and the NAc, which influences feeding.     

Alterations in food intake by opioid and dopamine signaling pathways between the ventral tegmental area and the shell of the nucleus accumbens

Reward is an important factor motivating food intake in satiated animals. Two sites involved in the reward response are the ventral tegmental area (VTA) and the nucleus accumbens shell region (sNAcc), between which communication is partially regulated by opioids and dopamine (DA). Previous studies have shown that the mu-opioid agonist Tyr-D-Ala-Gly-MePhe-Gly(ol)-enkephalin (DAMGO) dose-dependently enhances food intake in satiated animals when injected into either the VTA or the sNAcc. The enhanced intake elicited by DAMGO injected into the sNAcc was dose-dependently blocked by injection of naltrexone (NTX) bilaterally into the VTA, indicating an opioid-dependent signaling pathway from the sNAcc to the VTA in mediation of food intake. In the present study, we cannulated animals bilaterally in both the VTA and the sNAcc to further study the nature of opioid- and DA-dependent communication between the sites. Food intake elicited by DAMGO (2 or 5 nmol) injected unilaterally into the VTA was dose-dependently diminished by bilateral injection of NTX (2.5, 5, and 25 g/side) or the D1 antagonist SCH 23390 (3, 1, 0.3, 0.15, 0.05, and 0.015 nmol/side) into the sNAcc. When DAMGO (5 nmol) was injected into the sNAcc, the resulting food intake was decreased by doses of SCH 23390 ranging from 0.05 to 100 nmol/side injected bilaterally into the VTA, but not by equimolar doses of Raclopride, a D2 antagonist. These results, combined with previous findings, suggest a signaling pathway between the VTA and the sNAcc in which opioids and DA facilitate feeding in an interdependent manner.     

Intra-amygdalar injection of DAMGO: effects on c-Fos levels in brain sites associated with feeding behavior

It is well known that the mu opioid agonist, Tyr-D-Ala-Gly-(me) Phe-Gly-ol (DAMGO), increases food intake in rats when injected into a variety of brain sites including the central nucleus of the amygdala (CeA). Immunohistochemical studies measuring c-Fos immunoreactivity (IR) suggest that the CeA contributes to opioid-related feeding. In the current study, we injected 2 nmol of DAMGO and measured food intake, c-Fos IR levels in various brain sites involved in feeding behavior, and mu opioid receptor internalization. We also studied the effect of CeA-injected DAMGO on LiCl-induced increases in c-Fos IR in the amygdala. As was expected, intra-CeA injection of DAMGO increased food intake of rats over a 4-h period. DAMGO injection into the CeA also resulted in mu opioid receptor internalization in the CeA, indicating activation of mu opioid receptor expressing neurons in this site. Administration of DAMGO into the CeA increased c-Fos IR levels in the shell of the nucleus accumbens (NAcc), but not in 17 other brain sites that were studied. We also found that intra-CeA injection of DAMGO, prior to LiCl injection, decreased c-Fos IR levels in the CeA compared to vehicle-injected rats. Thus, intra-CeA administration of DAMGO may increase feeding, in part, by activating neurons in the shell of the nucleus accumbens and by inhibiting activity of selected neurons in the CeA.     

Differential effects of neuropeptide Y and the mu-agonist DAMGO on 'palatability' vs. 'energy'.

Differential effects of neuropeptide Y (NPY) and mu-opioid DAMGO on 'palatability' vs. 'energy'. A variety of studies suggest that NPY is an important manager of energy metabolism. In contrast, the opioid peptides appear to influence the 'rewarding' aspects of feeding. In the current study, we stimulated feeding by injecting NPY (110 pmol) or the mu-opioid agonist DAMGO (2 nmol) into the paraventricular nucleus of rats. Following injection, rats were given free access to laboratory chow and a 10% sucrose solution. Animals injected with saline derived 10% of their kilocalories from the chow and 90% from the sucrose solution (total kcal/4 h=12.2+/-1. 0). Those rats injected with NPY derived 48% of their energy from chow and 52% from the sucrose solution (total kcal/4 h=24.8+/-1.7). The DAMGO-injected rats derived only 15% of their kilocalories from chow and the remainder from the sucrose solution (total kcal/4 h=23. 0+/-2.3). Thus, while NPY and DAMGO both stimulated energy intake compared to saline controls (P<0.0001), the effect on intake of a palatable dilute energy solution (0.4 kcal/g) vs. a 'bland' laboratory chow (3.95 kcal/g) was different. The results of this study reinforce the notion that NPY has a major effect on energy needs, whereas opioids influence the 'rewarding' characteristics of foods.     

Central effect of mu-opioid agonists on antral motility in conscious rats

Centrally applied opioids delay gastric emptying and inhibit intestinal transit. However, the mechanism of inhibitory effects of central opioids on gastric motility still remains unclear. It also remains unclear which opioid receptor (mu, delta, and kappa) stimulation affects gastric motility. We studied the central effect of opioids on antral motility in conscious rats. A strain gauge transducer was implanted on the gastric antrum to record the circular muscle contractions. The area under the curve of the antral motility, calculated as a motility index, was evaluated before and after the intracerebroventricular (icv) injection of various opioid agonists in each rat. [D-Ala2, N-Me-Phe4, Gly5-ol] enkephalin (DAMGO, 0.1-10 nmol), a mu-opioid selective agonist, significantly inhibited antral motility in a dose-dependent manner (n=4). The motility index was significantly decreased to 47.3+/-10.8% (n=4) of controls at 20 min after icv injection of DAMGO (1.0 nmol). In contrast, [D-pen2, L-Pen5] enkephalin (DADLE, 1.0 nmol), a delta-opioid selective agonist, and U50,488 (1.0 nmol), a kappa-opioid selective agonist, had no significant effects on antral motility. Pretreatment with subcutaneous guanethidine (5 mg/kg) and propranolol (1 mg/kg), but not phentolamine (1 mg/kg), significantly antagonized the inhibitory effect of DAMGO (1.0 nmol). Reduced motility index induced by DAMGO (1.0 nmol) was restored from 48.7+/-3.5% to 88.6+/-10.9% (n=5) and 80.4+/-2.2% (n=5) by guanethidine and propranolol, respectively. Our findings suggest that central mu-opioid receptor has major inhibitory effects on antral motility in conscious rats. The inhibitory effects of mu-opioid receptors are mediated via sympathetic pathways and beta-adrenoceptors.     

5-HT1B receptors modulate the feeding inhibitory effects of enterostatin

Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has been shown to alter 5-HT release in the brain, and non-specific 5-HT antagonists blocked the anorectic response to icv enterostatin. The aim of this study was to further identify which 5-HT receptor subtype mediates the enterostatin feeding behavior and whether this effect occurs due to action in the PVN. Wild-type and 5-HT2C receptor-/- (KO) mice and normal Sprague-Dawley rats were used in these experiments. All animals were fed a high fat diet. Enterostatin (120 nmol, i.p.) reduced the intake of high fat diet in 5-HT2C receptor mutant mice (saline 4.54 +/- 0.47 kcal vs. Ent 2.53 +/- 0.76 kcal) 1 h after injection. A selective 5-HT1B antagonist (GR55526, 40 mg/kg body weight, i.p.) blocked the enterostatin hypophagic effects in these KO mice. Rats were implanted with cannulas into the amygdala and the ipsilateral PVN. The 5-HT receptor antagonists metergoline (non-specific receptor subtypes 1 and 2), or ritanserin (selective 2C), or GR55562 (selective l B) was injected into the PVN prior to enterostatin (0.01 nmol) injection into the amygdala. Enterostatin reduced food intake (saline: 5.80 +/- 0.59 g vs. enterostatin 3.47 +/- 0.56 g, P < 0.05 at l h). Pretreatment with either metergoline (10 nmol) or GR55526 (10 nmol) but not ritanserin (10 nmol) into the PVN attenuated the anorectic response to amygdala enterostatin. The data imply that the enterostatin anorectic response may be modulated by 5-HT1B receptors and that a neuronal pathway from the amygdala to the PVN regulates the enterostatin response through activation of 5-HTlB receptors in PVN.     

Opioid-induced feeding: Localization of sensitive brain sites

These experiments were designed to identify brain sites at which opioids might act to influence ingestive behavior and to determine which opioid receptor types are involved. After food deprivation, rats were given microinjections of naloxone into several brain regions and food intake was measured. Injections into or near the paraventricular (PVN) or ventromedial (VMH) hypothalamic nuclei or the globus pallidus (GP) reduced food intake; injections into the striatum or lateral hypothalamus (LH) were ineffective. A second study examined the ingestive effects of roughly equimolar doses (1.43-1.75 nmol) of dynorphin A (DYN), beta-endorphin (beta-END), and D-Ala2,D-Leu5-enkephalin (DADLE) when injected into 4 different brain regions. Only DYN significantly increased food intake, and this effect was seen only with injections into the PVN and VMH. Beta-END stimulated water intake when injected into the PVN, VMH and GP but not the LH. Further studies indicated that with PVN injections, DYN was effective at a dose as low as 0.47 nmol, and that a higher dose of DADLE (4.39 nmol) did stimulate food intake. These studies support an important role for dynorphin and the kappa opioid receptor in the regulation of feeding and suggest that the opioid regulation of food and water intake can be differentiated both by sites of action and by effective agonists.     

Microinjection of galanin-like peptide into the medial preoptic area stimulates food intake in adult male rats

Galanin-like peptide (GALP) is a neuropeptide implicated in the regulation of feeding behaviour, metabolism and reproduction. GALP is an endogenous ligand of the galanin receptors, which are widely expressed in the hypothalamus. GALP is predominantly expressed in arcuate nucleus (ARC) neurones, which project to the paraventricular nucleus (PVN) and medial preoptic area (mPOA). Intracerebroventricular or intraparaventricular (iPVN) injection of GALP acutely increases food intake in rats. The effect of GALP injection into the mPOA on feeding behaviour has not previously been studied. In the present study, intra-mPOA (imPOA) injection of GALP potently increased 0-1-h food intake in rats. The dose-response effect of imPOA GALP administration on food intake was similar to that previously observed following iPVN administration. The effects of GALP (1 nmol) or galanin (1 nmol) on food intake were then compared following injection into the PVN, mPOA, ARC, dorsal medial nucleus (DMN), lateral hypothalamus and rostral preoptic area (rPOA). GALP (1 nmol) increased food intake to a similar degree when injected into the imPOA or iPVN, but produced no significant effect when injected into the ARC, DMN, lateral hypothalamus or rPOA. Similarly, galanin (1 nmol) significantly increased food intake following injection imPOA and iPVN. However, the effect was significantly smaller than that following administration of GALP (1 nmol). Galanin also had no significant effect on food intake when administered into the ARC, DMN, lateral hypothalamus and rPOA. These data suggest that the mPOA and the PVN may have specific roles in mediating the orexigenic effect of GALP and galanin.     

Muscarinic receptor antagonism causes a functional alteration in nucleus accumbens mu-opiate-mediated feeding behavior

Intra-nucleus accumbens (Acb) infusion of cholinergic muscarinic antagonist, scopolamine (10 microg/0.5 microl), markedly reduced fat intake elicited by intra-Acb treatment of the mu-opioid receptor agonist, DAMGO, with 30 min and 4h pretreatment intervals. Intra-Acb scopolamine infusions also reduced food intake in food-deprived rats, but not water intake in water-deprived rats. Hence, Acb muscarinic manipulations exhibit some specificity for feeding, perhaps via interactions with the striatal opioid system.     

Feeding response to central orexins

Orexin A and orexin B were microinjected into the perifornical hypothalamus (PFH), lateral hypothalamus (LH), hypothalamic paraventricular nucleus (PVN), and ventral tegmental area (VTA) of male Sprague-Dawley rats. Orexin B (15 nmol) was also injected into the lateral cerebral ventricle (i.c.v.). Orexin A (>/=500 pmol) stimulated feeding in the PFH and LH, but not in the VTA or PVN. Orexin B stimulated feeding only when injected i.c.v.     

Opioid receptor subtype antagonists differentially alter GABA agonist-induced feeding elicited from either the nucleus accumbens shell or ventral tegmental area regions in rats

Food intake is significantly increased by administration of either GABAA (e.g., muscimol) or GABAB (e.g., baclofen) agonists into either the shell region of the nucleus accumbens (NAC) or the ventral tegmental area (VTA); these responses are selectively blocked by pretreatment with corresponding GABAA and GABAB antagonists. Previous studies found that a single dose (5 microg) of the general opioid antagonist, naltrexone reduced feeding elicited by muscimol, but not baclofen in the NAC shell, and reduced feeding elicited by baclofen, but not muscimol in the VTA. The present study compared feeding responses elicited by either muscimol or baclofen in either the VTA and NAC shell following pretreatment with equimolar doses of selective mu (0.4, 4 microg), delta (0.4, 4 microg), or kappa (0.6, 6 microg) opioid receptor subtype antagonists. Muscimol (25 ng) and baclofen (200 microg) each significantly and equi-effectively increased food intake over 4 h following VTA or NAC shell microinjections. Muscimol-induced feeding elicited from the VTA was significantly enhanced by mu or delta antagonists, and was significantly reduced by kappa antagonists. Baclofen-induced feeding elicited from the VTA was significantly reduced by mu or kappa, but not delta antagonists. Muscimol-induced feeding elicited from the NAC was significantly reduced by either mu, kappa or delta antagonists. Baclofen-induced feeding elicited from the NAC was significantly reduced by kappa or delta, but not mu antagonists. These data indicate differential opioid receptor subtype antagonist-induced mediation of GABA receptor subtype agonist-induced feeding elicited from the VTA and NAC shell. This is consistent with previously demonstrated differential GABA receptor subtype antagonist-induced mediation of opioid-induced feeding elicited from these same sites. Thus, functional relationships exist for the elaborate anatomical and physiological interactions between these two neurochemical systems in the VTA and NAC shell.     

Excitatory amino acid receptor subtype agonists induce feeding in the nucleus accumbens shell in rats: opioid antagonist actions and interactions with mu-opioid agonists.

Administration of mu-opioid receptor subtype agonists into the nucleus accumbens shell elicits feeding which is dependent upon the normal function of mu-, delta- and kappa-opioid receptors, D(1) dopamine receptors and GABA(B) receptors in the nucleus accumbens shell for its full expression. Whereas the AMPA antagonist, DNQX administered into the nucleus accumbens shell elicits a transient, though intense feeding response, feeding is elicited by excitatory amino acid agonists administered into the lateral hypothalamus. The present study examined whether excitatory amino acid agonists elicited feeding following administration into the nucleus accumbens shell of rats, whether such feeding responses were altered by opioid antagonist pretreatment, and whether such feeding responses interacted with feeding elicited by mu-opioid agonists. Both AMPA (0.25-0.5 microg) and NMDA (1 microg) in the nucleus accumbens shell significantly and dose-dependently increased food intake over 4 h. Both feeding responses were blocked by naltrexone pretreatment in the nucleus accumbens shell. The mu-opioid agonist, [D-Ala(2),NMe-Phe(4),Gly-ol(5)]-enkephalin in the nucleus accumbens shell significantly increased food intake which was significantly enhanced by AMPA cotreatment. This enhanced feeding response was in turn blocked by pretreatment with either general or mu-selective opioid antagonists. In contrast, cotreatment of NMDA and the mu-opioid agonist in the nucleus accumbens shell elicited feeding which was significantly less than that elicited by either treatment alone. These data indicate the presence of important interactions between excitatory amino acid receptors and mu-opioid receptors in the nucleus accumbens shell in mediating feeding responses in nondeprived, ad libitum-fed rats.     

Identification of central sites involved in butorphanol-induced feeding in rats

Butorphanol (BT), a mixed kappa- and mu-opioid receptor agonist, induces vigorous food intake in rats. Peripheral injection of BT seems to increase food intake more effectively than intracerebroventricular administration. To further elucidate the nature of BT's influence on consummatory behavior, we examined which feeding-related brain areas exhibit increased c-Fos immunoreactivity (IR) following subcutaneous injection of 4 mg/kg body weight BT, a dose known to induce a maximal orexigenic response. We also evaluated whether direct administration of BT into the forebrain regions activated by peripheral BT injection affects food intake. Peripheral BT administration induced c-Fos-IR in the hypothalamic paraventricular nucleus (PVN), central nucleus of the amygdala (CeA), and nucleus of the solitary tract (NTS). However, 0.1-30 microg BT infused into the CeA, failed to increase food intake 1, 2, and 4 h after injection. Only the highest dose of BT (30 microg) injected into the PVN increased feeding. These results suggest that the PVN, CeA, and NTS mediate the effects of peripherally-injected BT. The PVN or CeA are probably not the main target sites of immediate BT action.     

The pharmaco-ontogeny of the paraventricular alpha 2-noradrenergic receptor system mediating norepinephrine-induced feeding in the rat.

The present study was undertaken to assess the functional ontogeny of alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN) that mediate noradrenergic stimulation of feeding in the rat. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PVN or third ventricle. On the following day, each pup was implanted with an intra-oral cannula for oral infusion of milk or water that could be swallowed or rejected. Following a 1-h period of satiation, each pup received an intracerebral injection of saline, or a single dose of norepinephrine (NE, 0.01-100.0 nmol) or the alpha 2-noradrenergic receptor agonist clonidine (0.01-1.0 nmol). Milk or water intake was then assessed following a 1-h period of infusion. Injection of NE into the PVN and third ventricle significantly enhanced milk intake at 2 days of age. NE was 10-fold more potent in the PVN than in the ventricle. While paraventricular injections of NE stimulated milk and water intake equally at 2 days of age, NE produced a greater stimulation of milk than water intake at 15 days of age. Like NE, clonidine significantly enhanced milk intake at 2 days of age following injection into the PVN. Collectively, these findings suggest that alpha 2-noradrenergic receptors, mediating noradrenergic stimulation of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in the adult rat, these findings indicate that alpha 2-noradrenergic receptors relevant to feeding are located in the vicinity of the PVN.     

Effect of opioid receptor ligands injected into the rostral lateral hypothalamus on c-fos and feeding behavior

The lateral hypothalamic area (LHa) is an important brain site for the regulation of food intake. Central injection of opioids increases food intake, and the LHa contains mu and kappa opioid receptors, both of which are involved in feeding behavior. It is unclear whether opioids impact feeding when injected directly into the rostral portion of the LHa (rLHa) in rats. We performed a series of studies in which free-feeding rLHa-cannulated rats were injected with opioid agonists (DAMGO, morphine, dynorphin, U-50488H) followed by the measurement of food intake at 1, 2, and 4 h postinjection. To determine whether opioid receptor ligands administered into the rLHa affect neuronal activation in this brain site, we studied cFos immunoreactivity (cFos IR) in response to rLHa stimulation with naltrexone. We found that the only compound that stimulated feeding behavior was morphine. The other agonists had no effect on food consumption. Naltrexone injection into the rLHa increased neural activation in the LHa, indicating the presence of functional opioid receptors in this region. These data suggest that although neuronal activity is affected by opioid agents acting in the rLHa, administration of selective mu and kappa opioid ligands in this subdivision of the LHa does not have a reliable effect on feeding behavior.     

The amygdala is critical for opioid-mediated binge eating of fat

Endogenous opioid peptides within the nucleus accumbens are thought to mediate the hedonic aspects of food intake, particularly foods such as fat and sugar. In view of evidence that the amygdala also regulates positive affect, we hypothesized this brain region participates in the control of opioid-mediated food intake. The robust increase in the intake of fat following intra-accumbens administration of the mu-opioid agonist D-Ala2,Nme-Phe4,Glyol5-enkephalin (DAMGO) was completely blocked by concurrent temporary inactivation (muscimol, GABA(A) agonist) of either the basolateral or central nucleus of the amygdala. In summary, we demonstrate that amygdala inactivation prevents the intra-accumbens opioid induced "binge" eating of fat, possibly through reducing the hedonic properties of high-fat palatable food.     

Potentiation of the excitatory action of NMDA in ventrolateral periaqueductal gray by the mu-opioid receptor agonist,DAMGO

Several lines of evidence have suggested that mu-opioids, generally regarded as inhibitory, also have effects that stimulate neural activity. To look for possible excitatory opioid action in the rat periaqueductal gray (PAG), we first re-examined data from a previous study and found that met-enkephalin could evoke a delayed, sluggish excitation, suggestive of modulation by the opioid on the action of certain excitants. This observation, coupled with other studies that show mu-opioids can modulate NMDA receptor activation, prompted us to perform extracellular recording of the responses of single ventrolateral PAG (vlPAG) neurons in brain slices to DAMGO, a mu-opioid, and to NMDA. When applied alone, DAMGO at nM concentrations, like met-enkephalin, often evoked the delayed excitation and occasionally an inhibition. When applied after a brief exposure to NMDA, DAMGO at doses as low as 0.1 nM potentiated the excitation produced by a subsequent pulse of NMDA. This occurred, depending on cell type, in 23-100% of vlPAG neurons. The potentiating action of DAMGO was blocked by naloxone, suggesting it was mediated by mu-opioid receptors. Characterization of these mu-opioid actions revealed that the potentiation and the delayed excitation, unlike the inhibition, was not blocked by another opioid antagonist, nalmefene, nor by an inhibitor of the G protein of the G(i) class, N-ethylmaleimide. Moreover, the potentiating action was distinct from the inhibition in that it was: (a) enhanced by repeated opioid applications, (b) exhibited low effective doses, (c) had a long time course (minutes to develop and last tens of minutes) and (d) was present in distinct though overlapping cell populations. These data reveal an unconventional action of opioids in PAG neurons, that is, a potentiation of excitation produced by NMDA. This effect appeared mechanistically distinct from opioid inhibition or disinhibition and may be related to established examples of direct opioid excitation. These observations may help understanding behaviorally important mechanisms linked to acute and chronic opioid functions in the vlPAG.     

Differential effects of neuropeptide Y and the μ-agonist DAMGO on ‘palatability' vs. ‘energy'

Differential effects of neuropeptide Y (NPY) and μ-opioid DAMGO on ‘palatability' vs. ‘energy'. A variety of studies suggest that NPY is an important manager of energy metabolism. In contrast, the opioid peptides appear to influence the ‘rewarding' aspects of feeding. In the current study, we stimulated feeding by injecting NPY (110 pmol) or the μ-opioid agonist DAMGO (2 nmol) into the paraventricular nucleus of rats. Following injection, rats were given free access to laboratory chow and a 10% sucrose solution. Animals injected with saline derived 10% of their kilocalories from the chow and 90% from the sucrose solution (total kcal/4 h=12.2±1.0). Those rats injected with NPY derived 48% of their energy from chow and 52% from the sucrose solution (total kcal/4 h=24.8±1.7). The DAMGO-injected rats derived only 15% of their kilocalories from chow and the remainder from the sucrose solution (total kcal/4 h=23.0±2.3). Thus, while NPY and DAMGO both stimulated energy intake compared to saline controls (P<0.0001), the effect on intake of a palatable dilute energy solution (0.4 kcal/g) vs. a ‘bland' laboratory chow (3.95 kcal/g) was different. The results of this study reinforce the notion that NPY has a major effect on energy needs, whereas opioids influence the ‘rewarding' characteristics of foods.     

The kappa-opioid antagonist GNTI reduces U50,488-, DAMGO-, and deprivation-induced feeding, but not butorphanol- and neuropeptide Y-induced feeding in rats

Antagonists selective for either kappa- [e.g. nor-binaltorphimine (nor-BNI)] and mu- (e.g. beta-funaltrexamine) opioid receptors have previously been shown to reduce both kappa- and mu-opioid-induced feeding. In the present studies, the anorectic effects of GNTI, a newly synthesized antagonist selective for kappa-opioid receptors, were studied in rats. GNTI (0.032-0.32 nmol; i.c.v.), administered 15 min prior to food access, reduced feeding induced by the kappa-opioid agonist U50,488 (producing a 70% maximal decrease), the mu-opioid agonist DAMGO (90% maximal decrease), and 24 h acute food deprivation (60% maximal decrease). GNTI did not reduce the orexigenic effects of butorphanol, an agonist that binds to both kappa- and mu-opioid receptors, and neuropeptide Y (NPY). Taken together, these results suggest that GNTI is a potent anorectic agent and opioid antagonist in rats. Like nor-BNI, GNTI reduced feeding induced by both kappa- and mu-opioid agonists. However, unlike nor-BNI, GNTI did not alter the orexigenic effects of butorphanol or NPY. Given the selectivity of GNTI and its effectiveness in several of the present experiments, its potency, and its short duration of action compared to nor-BNI, GNTI may serve to be a useful tool to study behavioral effects mediated by kappa-opioid receptors.     

Beta-funaltrexamine (beta-FNA) decreases deprivation and opioid-induced feeding.

We studied the effect of the mu antagonist, beta-funaltrexamine (beta-FNA) on deprivation and opioid-induced feeding. Intracerebroventricular pre-treatment of 20 h deprived rats with 0.1, 1, 10 and 20 nmol of beta-FNA decreased feeding by 24%, 50%, 50% and 38% during the first hour. Central administration of beta-FNA (0.1, 1 and 10 nmol) also decreased feeding induced by the mu opioid agonist, DAMGO by 57%, 60% and 71%. Feeding induced by the delta agonist, DSLET, was decreased by pre-treatment with beta-FNA; but only during the 1-2 h time points, a time when relatively little food was ingested. Intraventricular injection of beta-FNA failed to alter feeding stimulated by the kappa opioid agonist, U-50,488H. These data further substantiate a role for the opioid receptor in deprivation and opioid-induced feeding.