Endogenous opiates and behavior: 2023.

This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Endogenous opiates and behavior: 2022.

This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Conditioned preference and avoidance induced in mice by the rare sugars isomaltulose and allulose.

Isomaltulose, a slowly digested isocaloric analog of sucrose, and allulose, a noncaloric fructose analog, are promoted as "healthful" sugar alternatives in human food products. Here we investigated the appetite and preference conditioning actions of these sugar analogs in inbred mouse strains. In brief-access lick tests (Experiment 1), C57BL/6 (B6) mice showed similar concentration dependent increases in licking for allulose and fructose, but less pronounced concentration-dependent increases in licking for isomaltulose than sucrose. In Experiment 2, B6 mice were given one-bottle training with a CS+ flavor (e.g., grape) mixed with 8% isomaltulose or allulose and a CS- flavor (e.g., cherry) mixed in water followed by two-bottle CS flavor tests. The isomaltulose mice showed only a weak CS+ flavor preference but a strong preference for the sugar over water. The allulose mice strongly preferred the CS- flavor and water over the sugar. The allulose avoidance may be due to gut discomfort as reported in humans consuming high amounts of the sugar. Experiment 3 found that the preference for 8% sucrose over 8% isomaltulose could be reversed or blocked by adding different concentrations of a noncaloric sweetener mixture (sucralose + saccharin, SS) to the isomaltulose. Experiment 4 revealed that the preference of B6 or FVB/N mice for isomaltulose+0.01%SS or sucrose over 0.1%SS increased after separate experience with the sugars and SS. This indicates that isomaltulose, like sucrose, has postoral appetition effects that enhances the appetite for the sugar. In Experiments 5 and 6, the appetition actions of the two sugars were directly compared by giving mice isomaltulose+0.05%SS vs. sucrose choice tests before and after separate experience with the two sugars. In general, the initial preference the mice displayed for isomaltulose+0.05%SS was reduced or reversed after separate experience with the two sugars although some strain and sex differences were obtained. This indicates that isomaltulose has weaker postoral appetition effects than sucrose.

Endogenous opiates and behavior: 2021.

This paper is the forty-fourth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2021 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonizts and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Differential patterns of opioid and dopamine D1 receptor antagonism on nutritive and non-nutritive sweetener intakes in C57BL/6:129 hybrid mice relative to inbred C57BL/6 and 129 mice.

Opioid and dopamine (DA) D1 receptor antagonists differentially reduce nutritive and non-nutritive sweetener intakes in inbred mouse strains. Sucrose intake was more effectively reduced by naltrexone in C57BL/6 (B6) mice relative to 129P3 (129) mice, but more effectively reduced by SCH23390 in 129 mice relative to B6 mice. Opioid and DA D1 antagonists differentially reduced saccharin intakes in B6 mice relative to other strains. Given these differential patterns in sweetener intake in B6 and 129 mice, the present study examined whether systemic naltrexone (0.01-5 mg/kg) and SCH23390 (50-1600 nmol/kg) reduced intakes of 10 % sucrose or 0.2 % saccharin solutions over a 120 min time course in first-generation hybrid mice (B6:129) of B6 and 129 parents and reduced low-nutritive sweetener intakes in 129 mice. Naltrexone (5 mg/kg) significantly reduced 10 % sucrose intake in B6:129 hybrid mice more like that of 129 than B6 mice. In contrast, SCH23390 (400-1600 nmol/kg) reduced 10 % sucrose intake in B6:129 hybrid mice more effectively than that observed in B6 or 129 parental strains. Because 129 mice consumed relatively low amounts of 0.2 % saccharin, they were tested with a more attractive low-nutritive solution containing 0.2 % saccharin and 2 % sucrose. Naltrexone failed to reduce saccharin intake in B6:129 hybrid mice but suppressed saccharin+sucrose intake in 129 mice more like that observed in B6 mice. SCH23390 similarly inhibited saccharin or saccharin+sucrose intakes in hybrid B6:129, 129, and B6 mice with B6 mice more resistant to the lowest SCH23390 dose. Thus, whereas sucrose intake in B6:129 hybrid mice exhibited similar sensitivity to opioid and to a lesser degree DA D1 antagonism to their 129, but not B6 parents, opioid and DA D1 mediation of low- and non-nutritive sweet intake produced unique profiles among B6:129 hybrid and B6 and 129 strains which does not support a simple heritability explanation.

Endogenous opiates and behavior: 2020.

This paper is the forty-third consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2020 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Acquisition and expression of fat conditioned flavor preferences following dopamine D1, opioid and NMDA receptor antagonism in C57BL/6 mice.

Objectives: Inbred mouse strains differ in the pharmacology mediating sugar and fat intake and conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice are differentially sensitive to dopamine (DA) D1, opioid and muscarinic receptor antagonism of sucrose, saccharin or fat intake, and to DA, opioid, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonism of acquisition of sucrose-CFP. DA D1, opioid and NMDA receptor antagonists differentially alter fat (Intralipid)-CFP in BALB/c and SWR mice. The present study examined whether naltrexone, SCH23390 or MK-801 altered acquisition and expression of Intralipid-CFP in C57BL/6 mice.Methods: In acquisition, groups of male food-restricted C57BL/6 mice received vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 µg/kg) before 10 training sessions in which mice alternately consumed two novel-flavored 5% (CS+) and 0.5% (CS-) Intralipid solutions. Six two-bottle CS choice tests followed with both flavors mixed in 0.5% Intralipid without injections. In expression, C57BL/6 mice underwent the 10 training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 µg/kg).Results: Fat-CFP acquisition in C57BL/6 mice was significantly though marginally reduced following naltrexone, SCH23390 and MK-801. Fat-CFP expression was similarly reduced by naltrexone, SCH23390 and MK-801 in C57BL/6 mice. Discussion: C57BL/6 mice were more sensitive to DA D1, opioid and NMDA antagonists in the expression of fat-CFP relative to sugar-CFP, but were less sensitive to DA D1 and NMDA antagonists in the acquisition of fat-CFP relative to sugar-CFP.

Differential fructose and glucose appetition in DBA/2, 129P3 and C57BL/6 × 129P3 hybrid mice revealed by sugar versus non-nutritive sweetener tests.

Inbred mouse strains differ in their postoral appetite stimulating response (appetition) to fructose as demonstrated in intragastric (IG) sugar conditioning and oral sugar vs. nonnutritive conditioning experiments. For example, FVB and SWR strains show experience-induced preferences for 8% fructose over a 0.1% sucralose + 0.1% saccharin (S + S) solution, whereas C57BL/6 (B6) and BALB/c strains do not. All strains, however, learn to prefer 8% glucose to S + S after experience, which is attributed to the potent appetition actions of this sugar. The present study extended this analysis to DBA/2 (DBA) and 129P3 (129) inbred mice. In Experiment 1A, ad libitum fed DBA and 129 mice preferred S + S to fructose before and after separate experience with the two sweeteners, indicating an indifference to the postoral nutrient effects of the sugar. When food restricted (Experiment 1B), 129 mice continued to prefer S + S to fructose while DBA mice showed equal preference for the sweeteners after experience, indicating some sensitivity to fructose appetition. In Experiment 1C, both strains acquired significant preferences for glucose over S + S after experience, confirming their sensitivity to postoral glucose appetition. Experiment 2 revealed that C57BL/6 × 129P3 (B6:129) hybrid mice responded like inbred B6 mice and 129 mice in acquiring a preference for glucose but not fructose over S + S. This is of interest because sweet "taste-blind" P2 × 2 / P2 × 3 double-knockout (DKO) mice on a B6:129 genetic background prefer fructose to water in 24 h tests, which is indicative of fructose appetition. Whether differences in the genetic makeup of DKO and B6:129 hybrid mice or other factors explain the fructose appetition of the DKO mice remains to be determined.

Endogenous opiates and behavior: 2019.

This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2019 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak.

Almost a half century of research has elaborated the discoveries of the central mechanisms governing the analgesic responses of opiates, including their receptors, endogenous peptides, genes and their putative spinal and supraspinal sites of action. One of the central tenets of "gate-control theories of pain" was the activation of descending supraspinal sites by opiate drugs and opioid peptides thereby controlling further noxious input. This review in the Special Issue dedicated to the research of Dr. Gavril Pasternak indicates his contributions to the understanding of supraspinal mediation of opioid analgesic action within the context of the large body of work over this period. This review will examine (a) the relevant supraspinal sites mediating opioid analgesia, (b) the opioid receptor subtypes and opioid peptides involved, (c) supraspinal site analgesic interactions and their underlying neurophysiology, (d) molecular (particularly AS) tools identifying opioid receptor actions, and (e) relevant physiological variables affecting site-specific opioid analgesia. This review will build on classic initial studies, specify the contributions that Gavril Pasternak and his colleagues did in this specific area, and follow through with studies up to the present.

Acute d-fenfluramine, but not fluoxetine decreases sweet intake in BALB/c, C57BL/6 and SWR inbred mouse strains.

Dopamine, opioid and muscarinic receptor antagonists differentially reduce sucrose and saccharin intakes across inbred mouse strains. Whereas these systems stimulate sweet intake, serotonin signaling inhibits food intake. The present study examined whether fluoxetine (0.1-10 mg/kg) or d-fenfluramine (0.1-6 mg/kg) differentially inhibited sucrose or saccharin intake in BALB/c, C57BL/6 and SWR mice. Fluoxetine marginally altered sucrose intake in all strains. d-fenfluramine significantly, but quite similarly reduced (ID40) sucrose and saccharin intake in BALB/c (5.7 vs. 5.8 mg/kg), C57BL/6 (4.4 vs. 4.3 mg/kg) and SWR (4.6 vs. 5.6 mg/kg) mice, suggesting serotonin-induced inhibition of orosensory mechanisms in all three inbred mouse strains.

Endogenous Opiates and Behavior: 2018.

This paper is the forty-first consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2018 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (2), the roles of these opioid peptides and receptors in pain and analgesia in animals (3) and humans (4), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (5), opioid peptide and receptor involvement in tolerance and dependence (6), stress and social status (7), learning and memory (8), eating and drinking (9), drug abuse and alcohol (10), sexual activity and hormones, pregnancy, development and endocrinology (11), mental illness and mood (12), seizures and neurologic disorders (13), electrical-related activity and neurophysiology (14), general activity and locomotion (15), gastrointestinal, renal and hepatic functions (16), cardiovascular responses (17), respiration and thermoregulation (18), and immunological responses (19).

Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation.

Fused in sarcoma (FUS) is a predominantly nuclear multifunctional RNA/DNA-binding protein that regulates multiple aspects of gene expression. FUS mutations are associated with familial amyotrophic lateral sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non-cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which Fus is selectively depleted in OL (FusOL cKO). The FusOL cKO mice show increased novelty-induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate-limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the FusOL cKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the FusOL cKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.

Characterization of Burn Eschar Pericytes.

Pericytes are cells that reside adjacent to microvasculature and regulate vascular function. Pericytes gained great interest in the field of wound healing and regenerative medicine due to their multipotential fate and ability to enhance angiogenesis. In burn wounds, scarring and scar contractures are the major pathologic feature and cause loss of mobility. The present study investigated the influence of burn wound environment on pericytes during wound healing. Pericytes isolated from normal skin and tangentially excised burn eschar tissues were analyzed for differences in gene and protein expression using RNA-seq., immunocytochemistry, and ELISA analyses. RNA-seq identified 443 differentially expressed genes between normal- and burn eschar-derived pericytes. Whereas, comparing normal skin pericytes to normal skin fibroblasts identified 1021 distinct genes and comparing burn eschar pericytes to normal skin fibroblasts identified 2449 differential genes. Altogether, forkhead box E1 (FOXE1), a transcription factor, was identified as a unique marker for skin pericytes. Interestingly, FOXE1 levels were significantly elevated in burn eschar pericytes compared to normal. Additionally, burn wound pericytes showed increased expression of profibrotic genes periostin, fibronectin, and endosialin and a gain in contractile function, suggesting a contribution to scarring and fibrosis. Our findings suggest that the burn wound environment promotes pericytes to differentiate into a myofibroblast-like phenotype promoting scar formation and fibrosis.

Acquisition and expression of sucrose conditioned flavor preferences following dopamine D1, opioid and NMDA receptor antagonism in C57BL/6 mice.

The study of inbred mouse strains is a useful animal model to assess differences in ingestive behavior responses, including conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice display differential sensitivity to dopamine (DA) D1, opioid and muscarinic cholinergic receptor antagonism of sucrose or saccharin intake as well as to muscarinic cholinergic antagonism of acquisition (learning) of sucrose-CFP. Given that DA D1, opioid and N-methyl-D-aspartate (NMDA) receptor antagonists differentially alter sucrose-CFP in BALB/c and SWR inbred mice, the present study examined whether systemic administration of naltrexone, SCH23390 or MK-801 altered acquisition and expression of sucrose-CFP in C57BL/6 mice. In acquisition experiments, male food-restricted C57BL/6 mice were treated with vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 µg/kg) 30 min prior to each of ten daily sessions in which they alternately consumed a flavored (CS+, e.g. cherry) 16% sucrose solution and a differently-flavored (CS-, e.g. grape) 0.05% saccharin solution followed by six two-bottle CS choice tests mixed in 0.2% saccharin without injections. SCH23390 and MK-801, but not naltrexone eliminated sucrose-CFP acquisition in food-restricted C57BL/6 mice. In expression experiments, food-restricted C57BL/6 mice underwent the ten training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 µg/kg). SCH23390 more effectively reduced the magnitude of sucrose-CFP expression than naltrexone or MK-801 in food-restricted C57BL/6 mice. Thus, dopamine D1 and NMDA receptor signaling is essential for learning of sucrose-CFP in C57BL/6 mice.

Endogenous opiates and behavior: 2017.

This paper is the fortieth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2017 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Strain differences in muscarinic cholinergic receptor antagonism of fat intake and acquisition and expression of fat-conditioned flavor preferences in male BALB/c, C57BL/6 and SWR mice.

Murine strain differences occur for both intakes of and preferences for sugars and fats. Previous studies demonstrated that the muscarinic cholinergic receptor antagonist, scopolamine (SCOP) more potently reduced sucrose and saccharin intakes in inbred C57BL/6 and BALB/c than SWR mice, sucrose-conditioned flavor preferences (CFP) expression in BALB/c, but not C57BL/6 or SWR mice, and sucrose-CFP acquisition in BALB/c relative to SWR and C57BL/6 mice. Although fat intake and fat-CFP are observed in all three strains, strain-specific effects were previously observed following dopamine D1, opiate and NMDA receptor antagonism of sweet and fat intake and CFP. The present study investigated whether muscarinic receptor antagonism differentially affected fat (Intralipid) intake and preferences in these strains by examining whether SCOP altered fat (Intralipid) intake and fat-CFP expression and acquisition in BALB/c, C57BL/6 and SWR mice. SCOP (0.1-10 mg/kg) significantly reduced Intralipid (5%) intake in all three strains across 2 h. In fat-CFP expression experiments, food-restricted mice consumed one flavored (conditioned stimulus (CS)+, 5 sessions) Intralipid (5%) solution and a differently-flavored (CS-, 5 sessions) Intralipid (0.5%) solution. Two-bottle CS choice tests with the two flavors mixed in 0.5% Intralipid occurred following vehicle and two SCOP doses (1, 5 mg/kg). SCOP elicited small, but significant reductions in fat-CFP expression in BALB/c and C57BL/6, but not SWR mice. In fat-CFP acquisition experiments, separate groups of BALB/c, C57BL/6 and SWR mice were treated prior to the ten acquisition training sessions with vehicle or two SCOP (2.5, 5 mg/kg) doses followed by six two-bottle choice tests without injections. SCOP eliminated fat-CFP acquisition in all three strains. Thus, muscarinic receptor signaling mediates learning, and to a lesser degree maintenance of fat-CFP while maximally inhibiting fat intake in the three strains.

Endogenous opioid modulation of food intake and body weight: Implications for opioid influences upon motivation and addiction.

This review is part of a special issue dedicated to Opioid addiction, and examines the influential role of opioid peptides, opioid receptors and opiate drugs in mediating food intake and body weight control in rodents. This review postulates that opioid mediation of food intake was an example of "positive addictive" properties that provide motivational drives to maintain opioid-seeking behavior and that are not subject to the "negative addictive" properties associated with tolerance, dependence and withdrawal. Data demonstrate that opiate and opioid peptide agonists stimulate food intake through homeostatic activation of sensory, metabolic and energy-related In contrast, general, and particularly mu-selective, opioid receptor antagonists typically block these homeostatically-driven ingestive behaviors. Intake of palatable and hedonic food stimuli is inhibited by general, and particularly mu-selective, opioid receptor antagonists. The selectivity of specific opioid agonists to elicit food intake was confirmed through the use of opioid receptor antagonists and molecular knockdown (antisense) techniques incapacitating specific exons of opioid receptor genes. Further extensive evidence demonstrated that homeostatic and hedonic ingestive situations correspondingly altered the levels and expression of opioid peptides and opioid receptors. Opioid mediation of food intake was controlled by a distributed brain network intimately related to both the appetitive-consummatory sites implicated in food intake as well as sites intimately involved in reward and reinforcement. This emergent system appears to sustain the "positive addictive" properties providing motivational drives to maintain opioid-seeking behavior.