Abstract
The role of central kappa opioid receptors in the regulation of feeding and reward was evaluated using electrical brain stimulation paradigms in combination with the selective kappa antagonist, norbinaltorphimine (nor-BNI). Lateral ventricular injection of 10.0 and 50.0 nmol doses of nor-BNI increased the lateral hypothalamic stimulation frequency threshold for eliciting feeding behavior but had no effect on threshold for self-stimulation in the absence of food. This result is identical to those previously reported for naloxone and antibodies to dynorphin A and suggests that opioid activity is associated with feeding behavior rather than the eliciting brain stimulation. A further similarity between naloxone, dynorphin antiserum, and nor-BNI is their preferential effect on feeding threshold values obtained later, rather than initially, in a post-injection test session. This pattern of threshold elevation is shown to differ from that of the appetite suppressants, amphetamine and phenylpropanolamine, which elevate threshold uniformly throughout a post-injection test. The signature pattern of threshold elevation produced by opioid antagonism is consistent with the hypothesis that opioid activity is involved in the maintenance rather than the initiation of feeding. Specifically, it is hypothesized that a dynorphin A/kappa receptor mechanism is triggered by food taste and sustains feeding behavior by facilitating incentive reward.
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References
Apfelbaum M, Mandenoff A (1981) Naltrexone suppresses hyperphagia induced in the rat by a highly palatable diet. Pharmacol Biochem Behav 15:89–91
Arjune D, Bodnar RJ (1990) Suppression of nocturnal, palatable and glucoprivic intake in rats by the κ opioid antagonist, norbinaltorphimine. Brain Res 534:313–316
Arjune D, Standifer KM, Pasternak GW, Bodnar RJ (1990) Reduction by central β-funaltrexamine of food intake in rats under freely-feeding, deprivation and glucoprivic conditions. Brain Res 535:101–109
Ball GG (1973) Vagotomy: effect on electrically elicited eating and self-stimulation in the lateral hypothalamus. Science 184:484–485
Beczkowska IW, Bodnar RJ (1991) Mediation of insulin hyperphagia by specific central opiate receptor antagonists. Brain Res 547:315–318
Brown DR, Holtzman SG (1979) Suppression of deprivation-induced food and water intake in rats and mice by naloxone. Pharmacol Biochem Behav 11:567–573
Burton MJ, Rolls ET, Mora F (1976) Effects of hunger on the responses of neurones in the hypothalamus to the sight and taste of food. Exp Neurol 53:508–519
Calcagnetti DJ, Calcagnetti RL, Fanselow MS (1990) Centrally administered opioid antagonists, nor-binaltorphimine, 16-methyl cyprenorphine and MR2266, suppress intake of a sweet solution. Pharmacol Biochem Behav 35:69–73
Carr KD (1990) Effects of antibodies to dynorphin A and β-endorphin on lateral hypothalamic self-stimulation in ad libitum fed and food-deprived rats. Brain Res 534:8–14
Carr KD, Aleman EO, Bak TH, Simon EJ (1990) Effects of parabrachial opioid antagonism on stimulation-induced feeding. Brain Res 545:283–286
Carr KD, Bak TH, Gioannini TL, Simon EJ (1987) Antibodies to dynorphin A (1–13) but not β-endorphin inhibit electrically elicited feeding in the rat. Brain Res 422:384–388
Carr KD, Bak TH, Simon EJ, Portoghese PS (1989) Effects of the selective kappa opioid antagonist, nor-binaltorphimine, on electrically-elicited feeding in the rat. Life Sci 45:1787–1792
Carr KD, Simon EJ (1983) Effects of naloxone and its quaternary analogue on stimulation-induced feeding. Neuropharmacology 22:127–130
Carr KD, Simon EJ (1984) Potentiation of reward by hunger is opioid mediated. Brain Res 297:369–373
Carr KD, Wolinsky TD (1993) Chronic food restriction and weight loss produce opioid facilitation of perifornical hypothalamic self-stimulation. Brain Res (in press)
Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the κ receptor. Science 215:413–415
Coons EE, Cruce JAF (1968) Lateral hypothalamus: food current intensity in maintaining self-stimulation of hunger. Science 159:1117–1119
Coons EE, White HA (1977) Tonic properties of orosensation and the modulation of intracranial self-stimulation: The CNS weighting of external and internal factors governing reward. Ann NY Acad Sci 290:158–179
Dum J, Gramsch C, Herz A (1983) Activation of hypothalamic β-endorphin pools by reward induced by highly palatable food. Pharmacol Biochem Behav 18:443–447
Fouriezos G, Hansson P, Wise RA (1978) Neuroleptic-induced attenuation of brain stimulation reward in rats. J Comp Physiol Psychol 92:661–671
Gosnell BA, Majchrzak MJ (1989) Centrally administered opioid peptides stimulate saccharin intake in nondeprived rats. Pharmacol Biochem Behav 33:805–810
Gratton A, Wise RA (1988a) Comparisons of refractory periods for medial forebrain bundle fibers subserving stimulation-induced feeding and brain stimulation reward: a psychophysical study. Brain Res 438:256–263
Gratton A, Wise RA (1988b) Comparisons of connectivity and conduction velocities for medial forebrain bundle fibers subserving stimulation-induced feeding and brain stimulation reward. Brain Res 438:264–270
Hernandez L, Hoebel BG (1989) Food intake and lateral hypothalamic self-stimulation covary after medial hypothalamic lesions or ventral midbrain 6-hydroxydopamine injections that cause obesity. Behav Neurosci 103:412–422
Hoebel BG (1968) Inhibition and disinhibition of self-stimulation and feeding: hypothalamic control and post-ingestional factors. J Comp Physiol Psychol 66:89–100
James IF, Goldstein A (1984) Site-directed alkylation of multiple opioid receptors. Mol Pharmacol 25:337–342
Jenck F, Gratton A, Wise RA (1987a) Opioid receptor subtypes associated with ventral tegmental facilitation of lateral hypothalamic brain stimulation reward. Brain Res 423:34–38
Jenck F, Quirion R, Wise RA (1987b) Opioid receptor subtypes associated with ventral tegmental facilitation and periaqueductal gray inhibition of feeding. Brain Res 423:39–44
Khachaturian H, Watson SJ, Lewis ME, Coy D, Goldstein A, Akil H (1982) Dynorphin immunocytochemistry in the rat central nervous system. Peptides 3:941–954
Kirkham TC, Blundell JE (1986) Effect of naloxone and naltrexone on the development of satiation measured in the runway: comparisons withd-amphetamine andd-fenfluramine. Pharmacol Biochem Behav 25:123–128
Kirkham TC, Cooper SJ (1988) Attenuation of sham feeding by naloxone is stereospecific: evidence for opioid mediation of orosensory reward. Physiol Behav 43:845–847
Le Magnen J (1983) Body energy balance and food intake: a neuroendocrine regulatory mechanism. Physiol Rev 63:314–386
Levine AS, Grace M, Billington CJ, Portoghese PS (1990) Norbinaltorphimine decreases deprivation and opioid-induced feeding. Brain Res 534:60–64
Levine AS, Grace M, Billington CJ (1991) β-Funaltrexamine (β-FNA) decreases deprivation and opioid-induced feeding. Brain Res 562:281–284
Lynch WC (1986) Opiate blockade inhibits saccharin intake and blocks normal preference acquisition. Pharmacol Biochem Behav 24:833–836
Lynch WC, Watt J, Krall S, Paden CM (1985) Autoradiographic localization of kappa opiate receptors in CNS taste and feeding areas. Pharmacol Biochem Behav 22:699–705
Magnan J, Paterson SJ, Tavani A, Kosterlitz HW (1982) The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn-Schmiedeberg's Arch Pharmacol 319:197–205
Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1987) Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 7:2445–2464
Margules DL, Moisset B, Lewis MJ, Shibuya H, Pert CB (1978) β-Endorphin is associated with overeating in genetically obese mice (ob/ob) and rats (fa/fa). Science 202:988–991
Morley JE, Levine AS (1980) Stress-induced eating is mediated through endogenous opiates. Science 209:1259–1261
Morley JE, Levine AS (1983) Involvement of dynorphin and the kappa opioid receptor in feeding. Peptides 4:797–800
Norgren R (1970) Gustatory responses in the hypothalamus. Brain Res 21:63–77
Norgren R (1976) Taste pathways to hypothalamus and amygdala. J Comp Neurol 166:17–30
Norgren R, Leonard CM (1973) Ascending central gustatory pathways. J Comp Neurol 150:217–238
Portoghese PS, Lipkowski AW, Takemori AE (1987) Binaltorphimine and nor-binaltorphimine, potent and selective κ-opioid receptor agonists. Life Sci 45:1287–1292
Rolls ET, Murzi E, Yaxley S, Thorpe SJ, Simpson SJ (1986) Sensory-specific satiety: food-specific reduction in responsiveness of ventral forebrain neurons after feeding in the monkey. Brain Res 368:79–86
Rowland N, Bartness TJ (1982) Naloxone suppresses insulin-induced food intake in novel and familiar environments but does not affect hypoglycemia. Pharmacol Biochem Behav 16:1001–1003
Schaefer GJ (1988) Opiate antagonists and rewarding brain stimulation. Neurosci Biobehav Rev 12:1–17
Sewell RDE, Jawaharlal K (1980) Antagonism of 2-deoxy-d-glucose-induced hyperphagia by naloxone: possible involvement of endorphins. J Pharm Pharmacol 32:148–149
Shippenberg TS, Bals-Kubik R (1991) Motivational effects of opioids: neurochemical and neuroanatomical substrates. In: Almeida OFX, Shippenberg TS (eds) Neurobiology of opioids. Springer, Berlin Heidelberg New York, pp 331–349
Siviy SM, Calcagnetti DJ, Reid LD (1982) A temporal analysis of naloxone's suppressant effect on drinking. Pharmacol Biochem Behav 16:173–175
Stapleton JM, Lind MD, Merriman VJ, Reid LD (1979) Naloxone inhibits diazepam-induced feeding in rats. Life Sci 24:2421–2426
Streather A, Bozarth MA (1987) Effect of dopamine-receptor blokkade on stimulation-induced feeding. Pharmacol Biochem Behav 27:521–524
Takemori AE, Ho BY, Naeseth JS, Portoghese PS (1988) Norbinaltorphimine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther 246:255–258
Ukai M, Holtzman SG (1988) Effects of β-funaltrexamine on ingestive behaviors in the rat. Eur J Pharmacol 153:161–165
Veening JG, Swanson LW, Cowan MW, Nieuwenhuys R, Geeraedts, LMG (1982) The medial forebrain bundle of the rat. II. An autoradiographic study of the topography of the major descending and ascending components. J Comp Neurol 206:82–108
West TEG, Wise RA (1988) Nucleus accumbens opioids facilitate brain stimulation reward. Soc Neurosci Abstr 14:1102
Wise RA (1989) Opiate reward: sites and substrates. Neurosci Biobehav Rev 13:129–133
Zamir N, Palkovits M, Brownstein MJ (1983) Distribution of immunoreactive dynorphin in the central nervous system of the rat. Brain Res 280:81–93
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Carr, K.D., Papadouka, V. & Wolinsky, T.D. Norbinaltorphimine blocks the feeding but not the reinforcing effect of lateral hypothalamic electrical stimulation. Psychopharmacology 111, 345–350 (1993). https://doi.org/10.1007/BF02244951
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DOI: https://doi.org/10.1007/BF02244951