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89:1379-1412, 2009. doi:10.1152/physrev.00005.2009
Physiol Rev
Julie Le Merrer, Jérôme A. J. Becker, Katia Befort and Brigitte L. Kieffer
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Reward Processing by the Opioid System in the Brain
Institut de Ge ´ne ´tique et de Biologie Mole ´culaire et Cellulaire, De ´partement Neurobiologie et Ge ´ne ´tique; Institut
National de la Sante ´ et de la Recherche Me ´dicale U964; and Centre National de la Recherche Scientifique
UMR7104, Illkirch; and Universite ´ de Strasbourg, Strasbourg, France
I. Introduction
II. Anatomy of the Brain Opioid System
III. Local Pharmacological Manipulation of the Opioid System
A. The endogenous opioid system and natural reinforcement
B. The endogenous opioid system and drugs of abuse
C. Perspectives: extending studies to animal models of drug addiction
IV. Genetic Manipulation of the Opioid System, Reinforcement, and Drug Dependence
A. Opioid receptor knockout mice
B. Opioid peptide knockout mice
C. Conclusion
D. Perspectives: towards genetic manipulation of the opioid system in targeted neuronal
V. Modifications of Opioid System Gene Expression Under Chronic Drug Exposure
A. Opioid receptor mRNA levels
B. Opioid peptide mRNA levels
C. Conclusion
D. Perspectives: adaptations of opioidergic systems, significance, and implications
VI. General Conclusion
Le Merrer J, Becker JAJ, Befort K, Kieffer BL. Reward Processing by the Opioid System in the Brain. Physiol
Rev 89: 1379–1412, 2009; doi:10.1152/physrev.00005.2009.—The opioid system consists of three receptors, mu, delta,
and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopio-
melanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding
stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops.
Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and
relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous
opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We
review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral
pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout
on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on
expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural
sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from
human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for
our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.
The discovery of the opioid system stems from the
use of opium in ancient history. Opium, extracted from
poppy seeds (Papaver somniferum), has powerful pain-
relieving properties and produces euphoria. Morphine,
named after the god Morpheus, is the most active ingre-
dient of opium. Today morphine remains the most widely
used pain killer in contemporary medicine, despite an
array of adverse side effects (respiratory depression, con-
stipation, drowsiness, tolerance, and dependence). Her-
oin was synthesized chemically by morphine diacetyla-
tion in the late 1800s and was commercialized as the first
nonaddictive opiate to treat cough and asthma. The
strong addictive properties of heroin were soon acknowl-
edged, and both heroin and opium were prohibited in
Physiol Rev 89: 1379–1412, 2009;
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1910. Today heroin is a main illicit drug of abuse, and
opiate addiction represents a major public health issue
(for review, see Ref. 394).
The existence of opioid binding sites in the brain was
established in 1973, and these were later referred as to
mu, delta, and kappa opioid receptors. In 1975, two pen-
tapeptides, Met- and Leu-enkephalin, were characterized
as the first endogenous ligands for these receptors. Many
peptides followed, forming the opioid peptide family (5).
Enkephalins, dynorphins, and ?-endorphin are produced
by proteolytic cleavage of large protein precursors known
as preproenkephalin (Penk), preprodynorphin (Pdyn),
and proopiomelanocortin (POMC), respectively. All opi-
oid peptides share a common NH2-terminal Tyr-Gly-Gly-
Phe signature sequence, which interacts with opioid re-
ceptors. Genes encoding opioid peptide precursors were
isolated in the late 70s-early 80s, and receptor cloning was
achieved later. The first opioid receptor gene was isolated
by expression cloning in 1992 and soon followed by the
identification of several homologous genes (reviewed in
Ref. 190). The opioid receptor gene family includes four
members encoding mu (Oprm1), delta (Oprd1), kappa
(Oprk1), and the nonopioid orphaninFQ/nociceptin (Oprl1)
receptors. Opioid receptors are membrane receptors with
a seven-transmembrane topology. These receptors belong
to the large G protein-coupled receptor superfamily,
which comprises several hundred members within the
mammalian genome.
Opioid peptides and receptors are broadly expressed
throughout peripheral and central nervous systems and
have been the subject of intense investigations for several
decades. The opioid system plays a central role in noci-
ception and analgesia, and the main aspects of opioid-
regulated pain mechanisms have been reviewed recently
(102, 430). The opioid system also regulates numerous
physiological functions, including responses to stress,
respiration, gastrointestinal transit, as well as endocrine
and immune functions. Most aspects of endogenous opi-
oid activity are reviewed comprehensively each year (for
example, see Ref. 41).
Importantly, this system also plays a key role in
modulating mood and well-being, as well as addictive
behaviors. How does this neuromodulatory system medi-
ate or regulate the rewarding properties of drugs of abuse
and contribute to the development of addiction? These
questions are being investigated actively; relevant data
were reviewed and discussed several years ago (131, 362,
389, 409). Here we review current knowledge of the role
of the opioid system in hedonic control and of genetic
regulations of the system following drug exposure, with a
specific emphasis on recent data from rodent models and
a focus on the neurocircuitry and behavioral aspects of
opioid function.
Opioid receptors and peptides are both broadly ex-
pressed throughout the brain. Figure 1 presents an up-
dated overview of the anatomy of the opioid system in the
rodent brain (rat and mouse). Figure 1A summarizes the
distribution pattern of mu, delta, and kappa opioid bind-
ing sites (receptor protein), as determined by ligand au-
toradiography (144, 176, 193, 212, 226, 229, 230, 298, 343,
346) and the distribution of cell bodies expressing opioid
receptors, based on the detection of mRNAs by in situ
hybridization (ISH) (99, 129, 154, 227, 398). Figure 1B
illustrates the distribution of opioid peptide containing
FIG. 1. Anatomical distribution of opioid receptors (A) and peptides (B) in the rodent brain (rat and mouse). Only brain regions for which data
are available in the literature are represented. Colors correspond to each of the three opioid receptor or peptide precursor. Densities are represented
by symbols of different sizes, from low to high. A: receptors. Top panel represents the distribution of opioid receptor proteins as determined by
ligand autoradiography. Maximal Bmax(receptor densities, radiolabeled ligands) values reported in the literature for mu and delta receptors were
?170–200 fmol/mg tissue equivalent (IP and olfactory bulbs, respectively). Maximal Bmaxvalues recorded for kappa receptors were 80–100 fmol/mg
(Cl; Refs. 144, 193, 346). Bottom panel summarizes the localization of cell bodies expressing opioid receptors based on the detection of mRNAs by
in situ hybridization. B: peptides. Top panel depicts the pattern of distribution of opioid peptides by immunohistochemistry. Bottom panel maps cell
bodies expressing opioid peptides, as evaluated both by immunohistochemical and in situ hybridization studies. Note: for immunohistochemical
mapping, data based on antibodies for peptide precursors were used in priority. When not available, data based on antibodies for final peptides were
used, with priority given to peptides issued from a single precursor (?-endorphin and dynorphin). Refer to text for further comments. Amb, nucleus
ambiguus; AD, anterodorsal thalamus; AL, anterior lobe, pituitary; AON, anterior olfactory nucleus; Arc, arcuate nucleus, hypothalamus; BLA,
basolateral nucleus, amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus, amygdala; Cl, claustrum; CL, centrolateral thalamus;
CM, centromedial thalamus; CoA, cortical nucleus, amygdala; CPu, caudate putamen; CrbN, cerebellar nuclei; DMH, dorsomedial hypothalamus;
DMR, dorsal and medial raphe ´; DTN, dorsal tegmental nucleus; En, endopiriform cortex; Ent, entorhinal cortex; FrCx, frontal cortex; G, nucleus
gelatinosus, thalamus; G/VP, globus pallidus/ventral pallidum; HbL, lateral habenula; HbM, medial habenula; HPC, hippocampus; IL, intermediate
lobe, pituitary; IP, interpeduncular nucleus; LC, locus coeruleus; LD, laterodorsal thalamus; LG, lateral geniculate, thalamus; LH, lateral hypothal-
amus; LRN, lateral reticular nucleus; MD, mediodorsal thalamus; Me, median eminence; MEA, median nucleus, amygdala; MG, medial geniculate;
MM, medial mammillary nucleus; MV, medial vestibular nucleus; NAc, nucleus accumbens; NL, neuronal lobe, pituitary; NRGC, nucleus reticularis
gigantocellularis; NTS, nucleus tractus solitarius; OCx, occipital cortex; PAG, periaqueductal gray; PCx, parietal cortex; Pir, piriform cortex; PN,
pontine nucleus; PnR, pontine reticular; PO, posterior thalamus; POA, preoptic area; PPTg, pedunculopontine nucleus; PrS, presubiculum; PV,
paraventricular thalamus; PVN, paraventricular hypothalamus; RE, reuniens thalamus; RN, red nucleus; RM, raphe ´ magnus; SON, supraoptic
nucleus; SN, substancia nigra; SNT, sensory trigeminal nucleus; STN, spinal trigeminal nucleus; TCx, temporal cortex; Th, thalamus; Tu, olfactory
tubercle; Tz, trapezoid nucleus; VL, ventrolateral thalamus; VM, ventromedial thalamus; VMH, ventromedial hypothalamus; VPL, ventroposterolat-
eral thalamus; VTA, ventral tegmental area; ZI, zona incerta.
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neuronal fibers and cell bodies as assessed by immuno-
histochemistry (28, 107, 114, 187–189, 208, 226, 230), with
ISH studies completing the mapping of opioid cell bodies
(150, 251, 258, 296, 297).
Opioid receptors are expressed primarily in the cor-
tex, limbic system, and brain stem. Binding sites for the
three opioid receptors overlap in most structures, but
some structures exhibit higher expression of one receptor
over the others. Mu is the most expressed opioid receptor
in the amygdala [but not the central nucleus, amygdala
(CeA)], thalamus (TH), mesencephalon, and some brain
stem nuclei. Kappa is the most represented receptor in
the basal anterior forebrain, including the claustrum (Cl)
and endopiriform cortex (En), olfactory tubercle (Tu),
striatum (caudate putamen and nucleus accumbens), pre-
optic area (POA), hypothalamus, and pituitary. The delta
receptor is the most abundant receptor in the olfactory
tract (olfactory bulbs, anterior olfactory nucleus, Tu, me-
dial amygdala) and in the cortices, including whole neo-
cortex and regions of the amygdala (AMG) that derive
ontogenically from the cortex (basolateral, cortical, and
median nuclei of the AMG; Ref. 364), and is also highly
expressed in the striatum. Mu and kappa coexist in most
structures, whereas the distribution of delta is more re-
stricted (low expression in the hypothalamus, thalamus,
mesencephalon, and brain stem). In a few structures, only
one receptor type is detected: mu binding sites only are
detected in four thalamic nuclei (lateral geniculate thala-
mus, ventrolateral thalamus, ventromedial thalamus, and
posterior thalamus), the sensory trigeminal nucleus
(SNT) and nucleus ambiguus (Amb), and delta binding
sites are singly represented in the pontine nucleus (PN).
Kappa binding sites only are found in seven brain regions
that are part of the stress axis (Cl, paraventricular hypo-
thalamus, arcuate nucleus, supraoptic nucleus, Me, CeA,
and pituitary). Notably, ligand autoradiography studies
(144, 193, 226, 227, 229, 230, 343, 346) failed to detect
significant kappa binding in the hippocampus, although
consistent pharmacological and electrophysiological data
indicate the presence of kappa receptors in this region
(for example, Refs. 89, 106, 207, 340, 416).
The sites of opioid receptor expression (mRNA) gen-
erally match the distribution of binding sites (protein),
suggesting that many neurons synthesizing opioid recep-
tors are local neurons. Some structures show both mRNA
and binding sites for only one receptor type: delta in the
PN, mu in the Amb and some thalamic nuclei (ventrolat-
eral, ventromedial, and posterior), and kappa in the Me.
Noticeable exceptions exist to the general concomitant
presence of mRNA and binding sites, with most frequent
cases being detectable transcripts in the absence of bind-
ing sites (obvious for delta receptor). Such mismatches
could reveal that receptors synthesized in some brain
regions (mRNA only) are mostly transported to projection
areas where they are localized presynaptically (binding
sites only). Alternatively, these mismatches may reflect a
lower sensitivity of ligand autoradiography in detecting
binding sites compared with high detection efficiency in
ISH studies.
Opioid peptide immunoreactivity (IR) in projection
fibers overlaps largely with the localization of opioid re-
ceptors. Penk is the most abundant and widely distributed
opioid precursor and is best detected in the thalamus,
where it overlaps with mu receptors. Pdyn is present in
most brain structures, with the highest concentration in
the nucleus accumbens (NAc) and near absence in the
thalamus. POMC shows a more restricted distribution and
is absent from cortical structures except for the AMG.
Penk-expressing cell bodies (mRNA and immunore-
activity) are the most abundant in the brain. Pdyn cell
bodies are also widespread, with a hot spot in the hypo-
thalamus matching high kappa receptor density. In con-
trast, POMC cell bodies are highly restricted and only
detected in three regions of the brain: the arcuate nucleus
of the hypothalamus (Arc), nucleus tractus solitarius
(NTS, brain stem), and pituitary [anterior lobe (AL) and
intermediate lobe (IL)]. However, some mRNA can be
detected in other regions by PCR (211). Neurons from the
Arc and NTS project mostly to limbic, mesencephalic, and
brain stem subcortical regions, where high POMC IR is
detected. Mismatches exist between the distribution of
opioid peptide IR and the localization of cell bodies, with
the most frequent cases being IR detected in fibers with
no visible cell bodies (obvious for POMC). These discrep-
ancies between peptide and cell body maps, assessed by
the same IR technique, suggest that an important propor-
tion of opioid peptides is released by projecting neurons.
Altogether, the anatomical studies show widespread
expression of most components of the opioid system.
Pharmacological studies have shown best affinities of
?-endorphin and enkephalin for mu and delta receptors,
and preferred binding of dynorphins at the kappa recep-
tors, although selectivity factors do not exceed one-order
of magnitude (228). The overall anatomical distribution of
peptides and receptors is consistent with the notion of
distinct Penk-POMC/mu-delta and Pdyn/kappa systems at
some brains sites.
In the wild, animals spend most of their time engaged
in behaviors necessary for their survival and that of their
genes, such as foraging for food and water, avoiding
predators, looking for sexual partners, or caring for pups.
These goal-directed behaviors must be flexible and plastic
so that animals can constantly adapt to their environment
(185). In this context, emotions have evolved that encour-
age animals to engage in behaviors with a beneficial out-
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come and avoid behaviors that could reduce their chance
of survival (58). Positive emotions, such as pleasure, he-
donism, or reward, when associated with the ability to
learn from experience, can act to increase the probability
of the occurrence of a particular behavior, a phenomenon
called positive reinforcement (see Refs. 112, 326).
The view that distributed interconnected neural sys-
tems could support positive reinforcement developed
from the discovery of specific brain sites supporting self-
stimulation (271) and the concurrent identification of as-
cending monoamine pathways (87). The mesolimbic do-
paminergic projections, that originate from the ventral
tegmental area (VTA) and project to various regions of the
forebrain with a major input to the NAc, occupy a central
position within the reinforcement circuit (20, 58, 112, 168,
183, 185, 270). Nonetheless, accumulating experimental
evidence argues against dopamine (DA) mediation of re-
ward processes per se (37, 58, 112, 326, 333, 412). As a
result of this debate, the concept of the reinforcement
circuit has expanded beyond the VTA-NAc to include
other structures (202, 265; see Fig. 2).
Opioid peptides and receptors are expressed through-
out the reinforcement network, placing the opioid system
in a key position to modulate this circuit. Experimental
data have accumulated over nearly 50 years showing that
the opioid system is involved with reinforcement pro-
cesses. Globally, systemic mu and, to a lesser extent, delta
agonists produce positive reinforcement, whereas kappa
agonists induce aversion, hallucinations, and malaise.
Conversely, mu and delta antagonists suppress the posi-
tive reinforcing properties of natural rewards and opiate
or nonopioid drugs, whereas kappa antagonists facilitate
these effects (reviewed in Refs. 339, 389, 390). Systemic
drug effects, however, reflect multiple actions of opioid
compounds at several brain sites, not all of which are
involved in reinforcement. In this section, we focus on
studies using intracranial injection techniques that allow
a precise localization of brain sites where opioids modu-
late reinforcement. Methodological issues related to phar-
macological, anatomical, and behavioral specificities fol-
lowing intracranial infusions have been reviewed previ-
ously (44, 136, 171).
A. The Endogenous Opioid System and
Natural Reinforcement
Among numerous natural appetitive stimuli, food,
drinks, and potential mates are the most potent to trigger
positive reinforcement in animals and, as such, are widely
FIG. 2. Schematic representation of the brain reinforcement circuit. Brain sites of reinforcement are integrated in a circuit based on their
connectivity and putative functional roles. BNST, bed nucleus of the stria terminalis; CPu, caudate putamen; LH, lateral hypothalamus; mPFC, medial
prefrontal cortex; NAc, nucleus accumbens; PAG, periaqueductal gray; POA, preoptic area; VP, ventral pallidum; VTA, ventral tegmental area.
[Adapted from Kelley (183) and Koob and Le Moal (202).]
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used in animal studies. Studies using food reinforcement
have raised considerable interest in neuroscience and
produced extensive experimental evidence that the opi-
oid system plays a role in the reinforcing properties of
diets (solid or liquid). Less is known about the neurobio-
logical processes supporting sexual reinforcement, al-
though some studies indicate that here also the opioid
system is recruited.
1. Food reinforcement
A complex, widespread neuronal circuitry mediates
sensory, metabolic, and integrative processes controlling
food intake (39) and opioid peptides and receptors are
present in most regions of this network (38, 138, 185).
Feeding can be qualified as either homeostatic (providing
the necessary intake of calories to sustain life) or nonho-
meostatic (driven by other processes, such as reward/
hedonics, and often resulting in a higher intake than
needed). Opioids are involved in both types of food in-
take, depending on the brain region, suggesting that this
system plays a role in energy-driven feeding as well as
food hedonics. Glass et al. (138) and later Bodnar (42)
reviewed the vast amount of work produced over the last
three decades on the pharmacology of feeding behavior.
These authors dedicated specific sections to studies using
intracerebral microinjection techniques, which we update
here with a particular focus on food reinforcement. Brain
sites where agonists and antagonists modulate feeding
behavior are summarized in Figure 3 (data from literature
reviewed below, see also Refs. 175, 383).
A) NAC AND VTA. In accordance with the view of a
reinforcement circuit centered on dopaminergic struc-
tures and their anatomical targets, research on the food
reinforcement has focused on the NAc and VTA. These
two structures play a pivotal role in the control of food
intake (19, 185). Injections of mu or delta but not kappa
receptor agonists into the NAc or VTA stimulate feeding
(reviewed in Refs. 19, 42). The hyperphagia induced by
intra-NAc infusion of mu receptor agonists depends on
macronutrient content and the taste of the food. Kelley
and collaborators (19, 184) proposed that activating the
ventral striatal opioid system encodes the positive affect
induced by tasty and/or high-energy foods and triggers
behavioral responses associated with food-seeking. Con-
sistent with this idea, Pecina and Berridge (287, 288)
demonstrated that the shell of the NAc contains a hedonic
hotspot in which the stimulation of mu receptors in-
creases the "liking" for food reward, as measured by the
amplification of positive affective orofacial reactions to
sucrose in rats, and the "wanting" for food as reflected by
increased eating behavior. Opioid stimulation in a larger
region surrounding this hotspot also triggers food intake
but has no effect on "liking" reactions to taste (287, 288).
The inactivation of mu receptors in the shell of the NAc by
infusion of the irreversible mu receptor antagonist ?-fun-
altrexamine (?-FNA) induced a persistent decrease in the
consumption of a palatable glucose solution, with no
effect on the intake of standard chow. In comparison, the
peptidic mu receptor antagonist CTAP produced only a
transient decrease in glucose consumption. These results
provide further evidence that the NAc supports respond-
ing for orosensory reward (400). Consistent with this
view, Woolley et al. (413) explored the role of accumbal
opioid receptors in flavor preference. In a first study, the
authors investigated the role of mu opioid receptors in the
NAc in a flavor choice paradigm where two nutritionally
identical, but differentially flavored, palatable food pellets
were available. Intra-NAc DAMGO selectively increased,
whereas naltrexone decreased, consumption of the pre-
ferred food (413). Using a sensory specific satiety para-
digm, these authors demonstrated that the mu receptor
FIG. 3. Brain sites where opioid agonists or antagonists modulate
food intake. A: brain sites where opioid receptor agonists injected
locally either increase or decrease food intake. B: brain sites where
microinjections of opioid receptor antagonists decrease feeding behav-
ior. Food was either standard chow or palatable (energy-dense) diet.
Food intake was either basal or induced by food deprivation, intracere-
bral electrical stimulation, or local pharmacological injection. Opioid
agonists and antagonists modulate food intake mainly through regula-
tion of hedonic evaluation, but also contribute to these behaviors by
modulating integration of sensory processes or the regulation of energy
needs. AMG, amygdala; Arc, arcuate nucleus, hypothalamus; CPu, cau-
date putamen; DMH, dorsomedial hypothalamus; LH, lateral hypothala-
mus; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; PAG,
periaqueductal gray; PBN, parabrachial nucleus; PVN, paraventricular
hypothalamus; VP, ventral pallidum; VTA, ventral tegmental area.
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agonist DAMGO injected into the NAc selectively in-
creases consumption of a prefed flavor, reversing the
sensory specific satiety effect, while the antagonist nal-
trexone potentiated this effect. Conversely, injecting the
kappa receptor agonist U-50,488H into the NAc of rats
decreased the consumption of the prefed flavor, but in-
creased the intake of the non-prefed flavor. Together,
these data suggest that opioid peptides released in the
NAc during consumption of palatable foods can produce
opposite effects on flavor preference depending on the
opioid receptors they activate (414, 415).
The mechanism by which the striatal opioid system
interacts locally with other neurotransmitters to regulate
feeding behavior remains to be clarified. High-fat feeding
induced by intra-NAc DAMGO was unaffected by prior
infusion of D1 and D2, AMPA, or nicotinic receptor an-
tagonists into this structure. In contrast, the opioid recep-
tor antagonist naltrexone blocked DAMGO-induced feed-
ing, and the muscarinic receptor antagonist scopolamine
injected into the NAc reduced feeding in both DAMGO-
treated and control rats. These data suggest that the
effects of ventral striatal opioid receptor stimulation on
palatable food intake are independent of the activation of
DA and glutamate receptors but may recruit cholinergic
signaling (408).
Opioid regulation of food consumption in the NAc
depends not only on local mechanisms, but also on con-
nections with distant brain sites (185); in that respect, the
cross-talk between the NAc and VTA has been particularly
well studied. Food intake elicited by infusion of the mu
receptor agonist DAMGO into the VTA was dose-depen-
dently decreased by injections of the opioid receptor
antagonist naltrexone or the D1 DA receptor antagonist
SCH-233390 into the NAc (220). Together with previous
data from the same group (221), these results suggest that
opioid peptides and DA interact within the VTA-NAc path-
way (and reciprocal) to regulate feeding. Moreover, the
general opioid receptor antagonist naltrexone, and mu
(?-FNA) or delta (naltrindole), but not kappa (nor-binal-
torphimine) receptor antagonists preinfused into the VTA
dose-dependently reduced DAMGO-induced feeding elic-
ited from the NAc. Reciprocally, nonselective antagonists
infused into the NAc decreased mu-induced feeding trig-
gered from the VTA. Thus the bidirectional opioid-opioid
feeding interaction between the VTA and NAc involves all
opioid receptor subtypes (43). The accumbal opioid sys-
tem has been shown to interact with orexinergic signaling
to modulate food intake. The opioid receptor antagonist
naltrexone injected into the NAc shell suppressed the
increase in food-intake produced by an infusion of
orexin-A into the lateral hypothalamus (LH, 365). More-
over, infusing the orexin-1 receptor antagonist SB-334867
into the VTA blocked the increase in high-fat appetite
induced by DAMGO injected into the NAc. This result
suggests that activation of accumbal mu receptors re-
cruits orexin neurons in the perifornical region. In turn,
orexin released from perifornical neurons would stimu-
late orexin-1 receptors in the VTA to facilitate the intake
of palatable food (425).
Together with previous results published in the field
(reviewed in Refs. 42, 138, 185), the above experimental
data clearly indicate that mu opioid receptors potently
induce feeding behavior from the NAc or VTA, an effect
exerted through regulation of the affective response to
food, i.e., palatability.
B) VENTRAL PALLIDUM. As a major output structure of the
NAc (421), the ventral pallidum (VP) plays a role in food
reinforcement (39). Interestingly, the VP contains a simi-
lar hedonic hotspot as the NAc in its posterior section
(287, 347, 371), where stimulation of mu opioid receptors
generates an increase in both "liking" and "wanting" for
food reward. The mu receptor agonist DAMGO, when
injected into the posterior VP, increased hedonic "liking"
reactions to oral sucrose but conversely suppressed these
reactions when infused into the anterior and central VP.
Concerning the "wanting" aspect, DAMGO stimulated
food intake when injected into the posterior and central
VP and suppressed eating when delivered into the ante-
rior VP. These results show that opioid-mediated in-
creases in food reward and eating behavior in the VP are
related but dissociable (347). Injecting the mu receptor
agonist DAMGO into the VP produced a biphasic effect on
saccharin intake and further demonstrated the modula-
tory role of VP mu receptors on the consumption of
palatable food (338).
Smith and Berridge (347) looked for neurobiological
and functional interactions between the two opioid hedo-
nic hotspots of the NAc and VP. Naloxone injected into
the NAc blocked the increase in hedonic "liking" reac-
tions triggered by intra-VP injection of DAMGO, and re-
ciprocally blocked "liking" reactions triggered by intra-
NAc injection of DAMGO when injected into the VP.
When injected into the NAc, naloxone attenuated the
stimulation of food intake ("wanting") produced by in-
tra-VP DAMGO. In contrast, when injected into the VP,
naloxone failed to affect the increased food consumption
induced by intra-NAc DAMGO. Thus the NAc opioid hot-
spot is sufficient to stimulate eating behavior and is inde-
pendent of VP opioid activation (347). In conclusion, com-
pared with NAc and VTA receptors, pallidal mu opioid
receptors are the most efficient in modulating food intake.
C) HYPOTHALAMUS. The hypothalamus plays a central
role in the control of food intake and the regulation of
energy balance, through its multiple connections with
brain stem, limbic, and cortical structures (39, 185, 259).
Among the numerous hypothalamic nuclei, the paraven-
tricular hypothalamus (PVN), lateral hypothalamus (LH),
Arc, and dorsomedial hypothalamus (DMH) have been
identified as sites where opioid peptides modulate eating
(42, 185, 355). Activating mu receptors in the PVN by local
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agonist injection produces an increase in food intake.
Conversely, blocking mu or kappa receptors, but not delta
receptors, reduces deprivation-induced feeding (reviewed
in Ref. 42). Naleid and collaborators tested the hypothe-
sis, based on their previous results (137), that opioids in
the PVN would modulate food intake based on energy
needs more than palatability. Intra-PVN DAMGO stimu-
lated sucrose and fat feeding in rats that preferred fat
diets, but had no effect on either diet intake in sucrose-
preferring animals. Naltrexone decreased fat intake in
both groups but had no effect on sucrose intake. Thus
activation of opioid receptors in the PVN modulates feed-
ing depending on diet preference and nutrient type, as
well as on energy needs (263). Finally, morphine injected
into the LH stimulated feeding behavior (215). Whether
this effect involves a role of LH opioids on the hedonic
aspect of food, however, remains to be examined.
D) AMYGDALA. AMG lesions implicate the AMG in food
intake (39, 159). Within the AMG, the CeA is traditionally
considered as part of the taste pathway (269) and has
been proposed to regulate the emotional aspects of food
intake (138). The mu receptor agonist DAMGO injected
into the CeA increased food intake (134, 213). Conversely,
infusion of the opioid receptor antagonist naltrexone de-
creased food intake, but only for preferred diets, suggest-
ing that endogenous opioids in this structure are involved
in modulating food reward rather than energy needs
(137). Intra-NAc DAMGO-induced feeding depends on the
integrity of AMG function, as it was completely sup-
pressed by pharmacological inactivation of either the ba-
solateral or central nuclei of the AMG (BLA and CeA; Ref.
407). Furthermore, Kim et al. (192) presented evidence for
the existence of a bidirectional opioid connection be-
tween the shell of the NAc and the CeA. Indeed, naltrex-
one injected into the CeA reduces food intake triggered by
DAMGO infused into the NAc, and vice versa (192). Thus
the AMG, and more specifically the CeA, are part of an
opioid limbic network modulating food reinforcement.
E) PARABRACHIAL NUCLEUS. The parabrachial nucleus
(PBN) is part of the taste pathway and is involved in
sensory mechanisms modulating food intake (39, 269).
Mu receptor activation in this region triggers food intake,
whereas kappa receptor stimulation or mu receptor
blockade decreases feeding behavior (60, 260, 261, 267,
410). A long-lasting decrease in the consumption of stan-
dard, but not palatable, chow was observed after an infu-
sion of the irreversible mu receptor antagonist ?-FNA into
the PBN, as well as a blockade of the increase in palatable
food intake induced by intra-PBN DAMGO (401). These
results suggest that opioids in the PBN, unlike the struc-
tures reviewed above, play a role in the control of homeo-
static rather than reward-driven feeding.
F) NTS. The NTS contains the first central synapse of
the gustatory system (374) and as such is an essential link
in the chain of food reward. Activation of mu receptors in
the NTS increased feeding, an effect suppressed by mu
receptor blockade in the CeA (139). Moreover, opioid
receptor antagonists injected into the NTS reduced feed-
ing responses elicited by intra-PVN injections of neu-
ropeptide Y (NPY; reviewed in Ref. 42). Further study will
be needed to determine whether opioids in the NTS mod-
ulate homeostatic or reward-driven feeding.
2. Sexual reinforcement
As with food intake, the control of the multiple as-
pects of sexual behavior relies on a complex neurocir-
cuitry, where the components of the opioid system are
well represented (73, 135, 166, 248, 295, 387). Opioids are
commonly described as exerting an inhibitory influence
on male and female sexual activity. Indeed, systemic opi-
oid receptor agonists impair, and antagonists facilitate,
sexual behavior (9). Local injections of opioid receptor
agonists and antagonists have provided a partial mapping
of the brain sites where endogenous opioids influence
sexual behavior.
A) NAC AND VTA. Local injections of opioid receptor
antagonists into the mesoaccumbens DA pathway have
failed to reveal a major contribution of accumbal opioid
system to sexual behavior. The kappa receptor antagonist
nor-BNI injected into the NAc increased female directed
behavior in male rats (214). However, when using a con-
ditioned place preference (CPP) protocol to specifically
assess sexual reinforcement (see Refs. 286, 294), Agmo
and Gomez (2) could not detect an effect of intra-NAc
injections of the opioid receptor antagonist methylnal-
oxonium on an ejaculation-induced CPP. Similarly, the
opioid receptor antagonist naloxone infused into the NAc
did not affect paced mating-induced CPP in female rats
(126). In contrast, opioid agonists, when injected at low
doses into the VTA, facilitated sexual behavior in male
rats, whereas naloxone decreased the percentage of sex-
ually active rats (reviewed in Ref. 385) and prevented the
anticipatory behavioral activation prior to the introduc-
tion of a female rat (386). Injections of the kappa receptor
agonist nor-BNI into the VTA increased female directed
behavior (214). It is not clear, however, whether intra-
VTA opioid effects on sexual behavior are mediated
through reinforcement mechanisms or an effect on so-
matomotor control of sexual performance. Taken to-
gether, experimental data indicate that the opioid system
in the VTA, and to a lesser extent in the NAc, modulates
sexual behavior.
B) HYPOTHALAMUS. The hypothalamus is critically in-
volved in coordinating the behavioral sequences as well
as autonomic and endocrine responses associated with
reproductive behavior (248, 314, 342). In the anterior
region of the hypothalamus, the sexual dimorphic medial
preoptic area (MPOA) has received much attention as a
critical brain substrate for the control of sexual behavior
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(23, 104, 166, 295, 387), where opioids can exert their
modulatory effects (9, 166, 387). Briefly, opioid receptor
agonists injected directly into the MPOA inhibited or de-
layed masculine copulatory activity in rats, except for low
doses of morphine or dynorphin-A-(1O13) (reviewed in
Ref. 387; see also Refs. 241, 385) and inhibited female
sexual behavior under certain conditions (reviewed in
Refs. 292, 293). Conversely, opioid receptor blockade in
the MPOA can facilitate male sexual behavior depending
on the experimental conditions (387). These data indicate
that opioid receptors in the MPOA participate to the
control of sexual behavior. Interestingly, some authors
have used CPP to measure sexual reinforcement and its
modulation by opioidergic manipulations in the MPOA.
The opioid receptor antagonist methylnaloxonium in-
fused into the MPOA blocked a CPP produced by ejacu-
lation (2). Consistent with this, naloxone microinjected
into the MPOA, before each conditioning session, sup-
pressed paced mating-induced CPP in female rats (126).
These latter data suggest that opioids in the MPOA are
involved, more specifically, with sexual reinforcement.
At the interface between the central and peripheral
autonomic nervous systems, the PVN plays an important
role in the control of genital responses (248). In males, the
PVN participates in the control of penile erection (10)
under the inhibitory influence of endogenous opioids.
Indeed, when injected into this structure, opioid agonists
markedly impaired penile erection (reviewed in Refs. 9
and 10).
The ventromedial nucleus of the hypothalamus
(VMH) is involved in female sexual behavior, under the
critical influence of estrogens (57, 117). Opioid peptides
and opiates injected into the VMH can inhibit female
sexual behavior (reviewed in Ref. 292). Such inhibition
could reflect an influence of opioids in the VMH on sexual
reinforcement, as suggested by the suppression of paced
mating-induced CPP observed following intra-VMH nalox-
one infusion in female rats (126).
C) AMYGDALA. The cortical and medial divisions of the
AMG, which send a major projection to the MPOA, have
been implicated in the neural control of sexual perfor-
mance, more specifically in the processing of sex-related
olfactory information (387). The activation of opioid re-
ceptors in the corticomedial AMG may exert an inhibitory
influence on this processing (246, 247). However, a role
for this region in sexual reinforcement cannot be ex-
cluded, as naloxone infused into the medial nucleus of the
AMG (MeA) suppressed paced mating-induced CPP in
female rats (126). The basolateral division of the AMG
(BLA) plays a role in conditional aspects of sexual behav-
ior (315) and expresses high densities of opioid receptors.
Unfortunately, the role of these receptors in sexual rein-
forcement has not yet been studied.
3. Conclusion
The data reviewed above clearly demonstrate that
brain opioids play a critical role in modulating food and
sexual reinforcement.
With regard to food, intracerebral pharmacological
studies, in accordance with systemic data, support the
now widely accepted view that the central opioid system
mediates the hedonic evaluation (palatability) of energy-
dense foods (19, 24, 42, 282, 289). Thus opioids in reward
sites (VTA, NAc, VP, AMG) participate preferentially in
the modulation of nonhomeostatic feeding. New animal
models of food reinforcement have been developed that
tease out rewarding from motivational/learning aspects of
reinforcement and show how opioids in these regions are
mainly involved in the former and DA in the latter (19, 24,
289). Opioids in the brain stem (NTS, PBN) also partici-
pate in the integration of sensory and metabolic aspects
of food intake. In addition, opioids in the hypothalamus
(PVN, Arc) are involved in the regulation of energy needs,
in tight connect with reward structures where they also
control the emotional processing of food intake (138).
The role of opioid peptides and receptors in other brain
structures involved in the control of feeding behavior,
especially limbic structures such as the hippocampus,
septum, or bed nucleus of the stria terminalis (BNST), has
not been examined.
Studies in the field of sexual reinforcement clearly
implicate central opioids, especially in the MPOA. Other
naturally reinforced behaviors, most notably social behav-
iors such as pair bonding, mother-infant attachment, and
social play, also recruit the brain opioid system (reviewed
in Ref. 390; see also Refs. 252, 256, 264, 284, 418). To date,
however, data from intracerebral pharmacological studies
are too scarce to draw a clear picture of the relevant
neuronal network.
B. The Endogenous Opioid System and Drugs
of Abuse
Drug addiction is a chronic disorder that builds up
from initial recreational drug use and progresses towards
compulsive drug seeking and intake. The reinforcing
properties of abused drugs are thought to be responsible,
in interaction with various environmental factors, for the
initiation of drug taking. Once repeated drug use is estab-
lished, complex neuroadaptative mechanisms develop
that lead to dependence, craving, and relapse and contrib-
ute to the maintenance of repeated drug intoxication
(201). A current hypothesis in the field of drug addiction
is that drugs of abuse abnormally recruit neuronal path-
ways and transmitter systems responding to natural rein-
forcement and progressively alter their function (112, 168,
186, 266, 356). The mesolimbic DA system has received
most attention in this regard. The opioid system, which
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mediates hedonic evaluation of natural rewards, repre-
sents another key substrate for the deleterious effects of
drugs of abuse. Indeed, the reinforcing properties of many
abused drugs depend on the activation of mu opioid re-
ceptors (for review, see Refs. 72, 191), which thus may be
a potential molecular gateway to drug addiction (72).
Research with animal models has led to significant
progress in understanding the neurobiological basis of
drug reinforcement and addiction. Most of these models
assess the direct and acute reinforcing properties (posi-
tive or negative) of drugs. As such, these models explore
the initial stage of drug addiction, characterized by re-
peated intoxication in nondependent individuals (201).
Two models are most widely used: CPP and operant
self-administration (see Refs. 244, 329, 378 for methodol-
ogy). In these two models, drugs can be administered
intracerebrally, either to map brain sites of reinforcement
or to study how activation in these sites interferes with
reinforcement induced by systemic drug administration.
Figure 4 illustrates the location of brain sites where
opioid receptors contribute to drug reinforcement, both
opiate and nonopiate. In this section we update reviews
presented a decade ago by Shippenberg and Elmer (339),
McBride et al. (244), and Van Ree et al. (389).
1. Drug reinforcement
A) VTA AND NAC. The mesolimbic dopaminergic sys-
tem has long been considered the major neurobiologi-
cal substrate mediating opiate reinforcement (25, 101,
197, 339, 389). Consequently, the characterization of
opioid-sensitive brain sites has focused mainly on the
VTA and NAc.
Van Ree and de Wied (388) were the first to demon-
strate that rats readily self-administer an opioid receptor
agonist into the VTA; a follow-up study confirmed this
finding (47). Since then, an overwhelming number of stud-
ies using either intracerebral self-administration or CPP
in rats and mice have confirmed the involvement of the
VTA in opiate reinforcement (reviewed in Refs. 244, 339,
389). Further work has attempted to identify, more pre-
cisely, the opioid receptors and neurotransmitter systems
recruited by intra-VTA opiate reinforcement. Intra-VTA
infusions of a subthreshold dose of heroin, combined with
a nonrewarding systemic dose of the benzodiazepine al-
prazolam (which facilitates GABA transmission), pro-
duced a significant CPP (395). This finding indicates that
systemic facilitation of GABA tone potentiates the rein-
forcing properties of centrally applied opiate drugs. The
mu receptor agonist endomorphin induced a CPP when
FIG. 4. Brain sites where opioid agonists or antagonists modulate
drug reinforcement. A: brain regions where injections of opioid agonists
have direct positive or negative reinforcing properties. B: brain sites
where microinjections of opioid antagonists inhibit the reinforcing ef-
fects of opioid drugs given systematically. C: brain areas where local
injections of opioid antagonists decrease reinforcing properties of sys-
temic nonopioid drugs (ethanol, cocaine, or nicotine). Reinforcement
was assessed using animal models of drug-induced conditioned place
preference or self-administration. Brain regions represented on this
figure were reported to be sensitive to local opioid injections at least
once in the literature. Conflicting results might have been reported in
other studies, most often using a different animal model. Noteworthy,
most brain areas where opioid manipulations impact on drug reinforce-
ment express all three types of opioid receptors. Amb, nucleus am-
biguus; AMG, amygdala; BNST, bed nucleus of the stria terminalis; CPu,
caudate putamen; dRF, dorsal reticular formation; HPC, hippocampus;
LH, lateral hypothalamus; lTh, lateral thalamus; mPFC, medial prefron-
tal cortex; mTh, medial thalamus; NAc, nucleus accumbens; PBN, para-
brachial nucleus; PAG, periaqueductal gray; POA, preoptic area; PPTg,
pedunculopontine nucleus; R, red nucleus; SN, substancia nigra; VP,
ventral pallidum; vRF, ventral reticular formation; VTA, ventral tegmen-
tal area; vTh, ventral thalamus.
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injected into the VTA or NAc, an effect suppressed by a
prior infusion of the mu receptor antagonist CTOP and
the opioid receptor antagonist 3-methoxynaltrexone in
the VTA or NAc, respectively (369). In another study, the
mu receptor agonist endomorphin induced a CPP when
infused into the posterior VTA, but not the anterior VTA
or the NAc. Moreover, rats self-administered endomor-
phin into the VTA. These results indicate that mu recep-
tors in the VTA are critically involved in reinforcement
and that the VTA is not functionally homogeneous (422).
Wild-type and delta opioid receptor knockout mice, but
not mu receptor knockout mice, self-administered mor-
phine into the VTA, and systemic naloxone suppressed
self-administration. Mu, but not delta, receptors in the
VTA thus appear to be critical for the rewarding proper-
ties of intra-VTA morphine infusions (96).
The mechanism by which accumbal opioid receptors
contribute to opiate reinforcement remains debatable.
Early evidence indicated that rats self-administer opioid
receptor agonists into the NAc (140, 272), but intra-NAc
infusions of mu or delta receptor agonists do not support
a CPP (reviewed in Ref. 244). In contrast, intra-NAc mi-
croinjections of the kappa receptor agonist U-50,488H
produce a conditioned place aversion (CPA; Ref. 22).
Preinfusing (?)-morphine (inactive isomer) into the pos-
terior shell of the NAc attenuated a CPP induced by
(?)-morphine (active isomer) injected into this structure
(370). A CPP to systemic morphine in rats was suppressed
by pretest intra-NAc injection of the mu receptor agonist
DAMGO, the delta receptor agonist DPDPE, or the kappa
receptor agonist U-50,488H. The authors proposed that
stimulation of mu and delta opioid receptors in the NAc
compete with systemic opiate seeking by producing di-
rect reinforcing effects, while stimulation of kappa recep-
tors produces aversive effects (217). Mice self-administer
morphine into the NAc, but not into the caudate putamen
(CPu), an effect that is reduced by systemic naloxone.
These results suggest that the NAc, but not the CPu, is
involved in the reinforcing properties of opiates (93). In a
subsequent study, the authors observed that the D2/D3DA
receptor antagonist sulpiride administered before testing
reduced (although transiently) intra-VTA but not intra-
NAc, morphine self-administration. This work shows that
maintenance of intra-VTA, but not intra-NAc, self-admin-
istration involves activation of D2/D3 DA receptors (95).
Intra-accumbal injections of opioid receptor antago-
nists suppress systemic opiate reinforcement (reviewed
in Refs. 244, 339, 389). Recent studies have further char-
acterized this phenomenon. The irreversible mu receptor
antagonist ?-FNA injected into the caudal, but not the
rostral part, of the NAc decreased the reinforcing proper-
ties of intravenous heroin. Thus the caudal portion of the
nucleus accumbens might be more critically involved in
mediating the reinforcing properties of opiates (236). The
opioid receptor antagonist methylnaloxonium reduced
heroin self-administration when injected into the shell of
the NAc of morphine-dependent rats, whereas it had no
effect in nondependent rats (but see Ref. 382). The au-
thors propose that opioid receptors in the NAc contribute
to opioid reinforcement only in dependent animals (396).
When injected into the NAc, the mu receptor antagonist
CTOP, the D1 DA receptor antagonist SCH23390, the D2
DA receptor antagonist raclopride or the combination of
SCH23390 and CTOP, but not of the delta receptor antag-
onist naltrindole, dose-dependently decreased break-
points to self-administer intravenous speedball (combina-
tion of cocaine and heroin). Therefore, the activation of
DA and mu receptors, but not delta receptors, in the NAc
is critical for the reinforcing effects of speedball (79).
Opioid receptors in the VTA and NAc not only con-
tribute to opiate reinforcement, but also contribute to the
reinforcing effects of nonopioid, systemic drug injections.
A number of studies have explored this phenomenon over
the last decade, using local injections of opioid receptor
agonists or antagonists and a variety of drugs including
cocaine, speedball, nicotine, and alcohol.
The participation of opioid receptors in the VTA
and/or the NAc in ethanol reinforcement has generated
considerable interest over the last decade, with consistent
data from operant models of ethanol oral self-administra-
tion. Intra-VTA microinjection of the opioid receptor an-
tagonist methylnaloxonium immediately before a test ses-
sion decreased an ethanol-induced CPP in mice, whereas
intra-NAc methylnaloxonium had no effect. This study
suggests that a CPP to ethanol depends primarily on the
activation of opioid receptors in the VTA (29). Infusion of
the opioid receptor antagonist methylnaloxonium into the
AMG or the NAc decreased operant responding for etha-
nol solution in rats, at lower doses in the AMG than in the
NAc, indicating that opioid receptors in the AMG and NAc
may be involved in the regulation of ethanol self-admin-
istration (155). Microinjecting the delta receptor antago-
nist naltrindole into the NAc or BLA reduced operant
responding for ethanol solution in rats, whereas the mu
antagonist CTOP was effective only in the AMG. Thus mu
and delta opioid receptors in the NAc and BLA are in-
volved in the regulation of ethanol self-administration
(169). A selective decrease in operant behavior for etha-
nol, but not saccharin, solution was observed in alcohol-
preferring rats after an injection of the mu receptor an-
tagonist nalmefene into the VTA or NAc. When injected
into the hippocampus, nalmefene reduced both ethanol
and saccharin consumption. This work provides evidence
that nalmefene suppresses ethanol-motivated behavior
through the blockade of opioid receptors in the NAc or
VTA (178). In a two bottle choice paradigm, the delta
receptor agonist DPDPE injected into the VTA decreased,
while the delta receptor antagonist TIPP-? increased,
ethanol intake in rats. These findings suggest that activa-
tion of delta receptors in the VTA acts to inhibit ethanol
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consumption (232). Altogether, these results demonstrate
that operant responding for ethanol solution depends on
the activation of mu and delta opioid receptors in the NAc
and AMG, and to a lesser extent on the recruitment of
VTA opioid receptors.
Opioid receptors in the VTA and NAc contribute to
cocaine reinforcement. The mu receptor antagonist CTAP
injected into the core of the NAc or rostral VTA, but not
the caudal VTA, CPu or medial shell of the NAc attenu-
ated the development of a cocaine CPP. In contrast, CTAP
infused into the medial shell, but not the core, of the NAc
blocked the expression of a cocaine-induced CPP (349).
In rats trained to self-administer intravenous cocaine,
infusing the mu receptor agonist DAMGO into the VTA
decreased operant behavior. In contrast, the mu receptor
antagonist CTOP reduced self-administration only slightly, and
the kappa receptor agonist U-50,488H and antagonist nor-
binaltorphimine (norBNI) had no consistent effect. These
data show that the activation of ventral tegmental mu, but
not kappa, receptors interfere with cocaine reinforcement
(81). Similarly, infusing the irreversible mu receptor an-
tagonist ?-FNA into either the NAc or the VTA attenuated
systemic cocaine self-administration under a progressive
ratio schedule (402). In a subsequent study by the same
group, the delta receptor antagonist naltrindole 5?-
isothiocyanate (5?-NTII) decreased systemic cocaine self-
administration when microinjected into the NAc, but in-
creased operant responding for the drug when injected
into the VTA, and had no effect when injected into the
AMG, indicating that delta receptors can modulate co-
caine reinforcement in a different direction depending on
the brain site (403). Finally, infusing the irreversible mu
receptor antagonist ?-FNA into the VTA (or the VP, see
below), but not into the NAc, of trained rats, reduced
rates of responding for a speedball to levels of responding
for cocaine infusions, suggesting that heroin facilitates
cocaine self-administration by attenuating feedback inhi-
bition from the NAc to the VTA (235).
As for cocaine, pharmacological manipulation of opi-
oid receptors in the VTA or NAc alters intravenous nico-
tine self-administration. In rats trained to self-administer
nicotine, a high dose of the mu receptor agonist DAMGO
into the VTA reduced operant responding for nicotine,
with no effect on cocaine self-administration. The authors
concluded that nicotine exerts its reinforcing properties
by recruiting mu receptors in the VTA (82).
In conclusion, the data reviewed above demonstrate
the contribution of mu and possibly delta receptors in the
VTA and NAc to mediate the positive reinforcing proper-
ties of opiates. Moreover, receptor blockade in these two
regions decreases conditioned responses for nonopioid
drugs given peripherally, strongly suggesting that the re-
inforcing effects of such drugs involve local release of
endogenous opioids.
B) VENTRAL PALLIDUM. In addition to its participation in
food reinforcement, the VP contributes to drug reinforce-
ment (88, 143, 157, 165). However, only a few studies have
assessed the contribution of VP opioids to drug intake
over the past decade. In one example, morphine injec-
tions into this region produced a CPP (278). Interestingly,
naloxone injected into the VP produced CPA, an effect
that was reproduced using the mu antagonist CTOP.
These results suggest that mu receptors in the VP, acti-
vated by endogenous opioid peptides, modulate basal
affective states (345).
Experimental evidence suggests that activation of
opioid receptors in the VP contributes to systemic opiate
reinforcement. Repeated intrapallidal morphine injec-
tions facilitated a CPP induced by a low dose of systemic
morphine. Peripheral pretreatment with the opioid recep-
tor antagonist naloxone or dopaminergic antagonists sup-
pressed the CPP, indicating that the facilitatory effects of
intra-VP morphine involve activation of mu and dopami-
nergic receptors (424).
Few studies have addressed a possible contribution
of the pallidal opioid system to cocaine reinforcement. A
CPP to cocaine was attenuated when intrapallidal nalox-
one was administered before the test session, at a dose
that had no aversive properties, indicating that mu recep-
tors in the VP are involved in mediating cocaine reinforce-
ment (345). The mu receptor antagonist CTAP injected
into the VP reduced reinstatement of drug seeking in-
duced by a cocaine-priming injection (367). Conversely,
intra-VP morphine reinstated operant behavior, an effect
blocked by coinjection of CTAP, and facilitated by sys-
temic cocaine administration. The authors conclude that
cocaine seeking is modulated, in part, through corelease
of enkephalins and GABA from NAc projections to the VP
(367). Finally, ?-FNA into the VP shifted the dose-re-
sponse curve for a cocaine/heroin combination towards
that maintained by cocaine alone. Thus pallidal mu-opioid
receptors contribute to the facilitating effect of heroin on
cocaine reinforcement (235). Taken together, these data
provide strong evidence that the activation of mu recep-
tors in the VP participates in mediating cocaine reinforce-
ment. The possibility that the region also participates in
the reinforcing properties of other drugs of abuse remains
C) AMG AND EXTENDED AMG. Beyond a critical involve-
ment in emotional learning, the AMG plays a key role in
reward evaluation and appetitive conditioning (21, 158,
262, 327). Moreover, the CeA shares with the shell of the
NAc and the BNST similar morphology, immunoreactiv-
ity, and connectivity. Together, these structures form the
extended amygdala (6, 61, 97), which plays a key role in
reinforcement (196, 198, 201, 334, 399).
The experimental evidence that the AMG is involved
in opiate reinforcement is inconsistent (122, 312, 423).
Mice self-administered morphine into the AMG (94). How-
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ever, intra-amygdala (lateral nucleus) injections of mor-
phine failed to produce CPP in rats (278). The direct
rewarding or aversive effects of opioid receptor agonists
and antagonists injected into the AMG have not been
studied further; thus the role of the dense amygdalar
opioid system in opiate reinforcement remains to be clar-
ified. One study addressed the role of opioid receptors in
the two other major components of the extended AMG,
the shell of the NAc and BNST. The opioid receptor
antagonist methylnaloxonium dose-dependently suppres-
sed heroin self-administration when injected into the
BNST, whereas it had no effect in nondependent rats. The
authors suggest that opioid receptors in the BNST partic-
ipate to the reinforcing effects of opiates in dependent
animals (396).
With regard to nonopioid reinforcement, some stud-
ies have explored the contribution of opioid peptide re-
lease in the AMG to the reinforcing properties of ethanol.
Infusion of the opioid receptor antagonist methylnaloxo-
nium into the AMG decreased operant responding for
ethanol solution in rats, at lower doses than did injections
into the NAc (155). Moreover, microinjecting the delta
receptor antagonist naltrindole into the NAc or the BLA
reduced operant responding for an ethanol solution,
whereas the mu receptor antagonist CTOP was effective
only in the AMG (169). In line with these results, the
opioid receptor antagonist naltrexone infused into the
CeA, but not more dorsally into the CPu, reduced operant
responding for ethanol in alcohol-preferring rats. Naltrex-
one also reduced sucrose-maintained responding when
sucrose was presented alone, but not when sucrose was
concurrently given with ethanol. These data indicate that
opioid receptors within the CeA selectively modulate eth-
anol-maintained responding (118). Altogether, these stud-
ies suggest that mu and delta receptors in the AMG, and
more precisely in the BLA and CeA, play an important role
in modulating ethanol reinforcement.
D) OTHER, LESS STUDIED, STRUCTURES. The septum was the
first brain region to be identified as a brain stimulation
site in rats (271). However, the role of its two main
divisions, the lateral septum (LS) and medial septum
(MS), in reinforcement has not been much explored fur-
ther (336). Rats self-administer morphine (357) and Met-
enkephalin (358) into the septum. More recently, mice
were reported to self-administer morphine into the LS and
the MS, suggesting that both main septal divisions are
involved in morphine reinforcement (66). Systemic pre-
treatment with the opioid receptor antagonist naloxone,
the D1 DA receptor antagonist SCH-23390 or the D2 an-
tagonist sulpiride prevented intra-LS morphine self-ad-
ministration. This work indicates that intra-LS morphine
self-administration depends on opioid and dopaminergic
mechanisms (209). We are not aware of studies using
local injections of opioid antagonists to evaluate the role
of septal opioid receptors and peptides in mediating sys-
temic opiate or nonopioid drug reinforcement.
The hippocampus has a critical role in learning and
memory processes but is also implicated in motivation
and drug reinforcement, through a direct interaction with
the NAc (105, 154, 174, 335, 373). A few studies have
addressed the role of the dorsal hippocampus in opiate
reinforcement using local injections of morphine (re-
viewed in Refs. 244, 339). Altogether the data suggest that
morphine injected into the CA3 and CA4/dentate gyrus,
but not the CA1, of the dorsal hippocampus, produces
direct reinforcing effects. Such effects were not further
characterized during the last decade. Moreover, to our
knowledge, the role of hippocampal opioid peptide re-
lease in systemic opiate or nonopioid drug reinforcement
has not been investigated.
In addition to an essential involvement in food rein-
forcement, the hypothalamus has been proposed to mod-
ulate drug intake (103, 151, 281, 325). Rats self-administer
morphine into the LH (273), which is a major brain site for
electrical self-stimulation. Intra-LH morphine supports
self-administration in mice (64, 65, 93). However, results
from CPP studies are less consistent (reviewed in Ref.
244). Injection of the opioid receptor antagonist naltrex-
one into the LH interfered with intravenous heroin self-
administration in rats, suggesting that opioid receptors in
this structure contribute to opiate reinforcement (80).
Unfortunately, no pharmacological manipulations of the
LH opioid system have been performed since 1997, either
to investigate the direct reinforcing effects of opioid re-
ceptor agonists or antagonists or to identify a role for LH
opioid system in mediating nonopioid drug reinforce-
ment. Opioids in the MPOA are of interest for their con-
tribution to sexual reinforcement (see sect. IIIA2). The
peptide agonist D-Ala2-Met5-enkephalinamide (DALA) mi-
croinjected into the MPOA produced CPP in rats, suggest-
ing that the release of opioid peptides in this region could
represent one of the anatomical substrates for sexual
reinforcement (1).
Electrophysiological, neuroimaging, and lesion stud-
ies have suggested that the medial region of the thalamus
contributes to reinforcement (18, 124, 182, 243, 405).
However, very little is known about the involvement of
the abundant thalamic population of mu-opioid receptors
in mediating drug reinforcement. Microinjections of the
irreversible mu receptor antagonist ?-FNA into the medial
thalamus, prior to each conditioning session, blocked the
acquisition of a CPP for morphine. In contrast, ?-FNA
infused after the last morphine conditioning session, and
23 h before the test, had no effect on a CPP. Thus mu-
opioid receptors in the medial thalamus may play a role in
the acquisition, but not the expression, of a morphine CPP
In addition to well-characterized roles in defensive
behavior and pain control, the periaqueductal gray (PAG)
Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
on October 1, 2009
Downloaded from
Page 15
participates in drug reinforcement (48). Opiates injected
into the PAG exert direct rewarding effects, inducing
self-administration as well as a CPP (reviewed in Refs. 64,
244). Moreover, the nonselective opioid receptor antago-
nist naloxone injected into the PAG can suppress CPP to
systemic morphine, indicating that opioid peptide release
in this region is necessary for the expression of a mor-
phine CPP (278). In contrast, high doses of morphine
injected directly into the dorsal part of the PAG produced
a CPA, an effect that was not blocked by previous micro-
injection of the mu receptor antagonist CTOP, but was
significantly reduced by prior systemic treatment with the
kappa receptor antagonist nor-BNI. Microinjecting CTOP
alone, or the kappa receptor agonist U,50488H, produced
an aversion, whereas injections of Nor-BNI did not. These
results suggest that blocking mu or activating kappa re-
ceptors in the PAG both produce a CPA (330).
Some experimental evidence suggests that the pe-
dunculopontine tegmental nucleus (PPTg) is involved in
drug reinforcement (277) and more particularly in sys-
temic opiate reinforcement (279), although local injection
of morphine failed to produce a CPP in rats (278). Over
the last decade, two studies have implicated the PPTg
opioid system in cocaine and nicotine reinforcement. In
trained rats, microinjection of the mu receptor agonist
DAMGO reduced intravenous cocaine or nicotine self-
administration under a fixed ratio schedule of reinforce-
ment. The mu receptor antagonist CTOP did not affect
self-administration, but reversed the effects of DAMGO
when coadministered with it. These data demonstrate
that mu receptors in the PPTg influence cocaine and
nicotine reinforcement (81, 83).
2. Dependence
Dependence reflects the development of complex
neuronal adaptations in response to repeated and/or pro-
longed drug administration. Dependence is revealed,
when drug use ceases, by a complex withdrawal syn-
drome associating physical (or somatic) signs with an
intensely aversive emotional state also called motiva-
tional withdrawal (199). In animal models of physical
dependence, the experimenter scores various somatic
signs after spontaneous (discontinuation of treatment) or
precipitated (injection of a pharmacological antagonist)
withdrawal of the drug (see, for example, Refs. 51, 225).
Animal models of motivational withdrawal include with-
drawal-induced disruption of a previously acquired oper-
ant task for food or a CPA after pairing of an environment
with precipitated withdrawal (15, 361). Very few studies
have combined these withdrawal models with an intrace-
rebral pharmacological approach to explore the role of
opioids in dependence, and they all dealt with opiate
A) VTA AND NAC. Only weak somatic signs were scored
after injecting opioid receptor antagonists into the VTA or
NAc of morphine-dependent rats (69, 177), indicating that
these regions play only a minor role in physical depen-
dence to opiates. In contrast, intra-NAc and, to a lesser
extent, intra-VTA injections of the opioid receptor antag-
onist methynaloxonium disrupted operant responding for
food and induced a CPA in morphine-dependent rats (203,
361). These results indicate that opioid receptor inactiva-
tion in the NAc can reproduce the aversive stimulus ef-
fects of opiate withdrawal and designate opioids in the
NAc as an important brain substrate for motivational
aspects of dependence and aversive states (see also Refs.
59, 199).
B) EXTENDED AMG. The AMG is not a critical brain
substrate for physical opiate dependence. Indeed, inject-
ing opioid receptor antagonists into this structure pro-
duced only weak somatic signs of withdrawal in mor-
phine-dependent rats (69, 177). Injections of methynal-
oxonium into the amygdaloid complex produced a CPA in
morphine-dependent rats at moderate doses, suggesting
that opioids in this region can modulate motivational
aspects of dependence to opiates (361). Despite a recent
evidence for a role of the BNST in opiate dependence (14,
348), the contribution of local opioids in this structure to
this phenomenon remains unexplored.
C) PAG. The PAG contributes to physical drug depen-
dence (48, 54, 69). Bozarth and Wise (46) showed that
repeated morphine injections into this structure produce
somatic signs of withdrawal after challenge with a sys-
temic opiate antagonist. This result was replicated in
further studies using morphine (45) or the enkephalin
analog [D-Ala2,Met5]-enkephalinamide (120). Moreover,
opioid receptor antagonists trigger a severe physical with-
drawal syndrome when injected into the PAG of adult or
infant rats made dependent on morphine (reviewed in
Ref. 69; see also Ref. 177). Altogether, these results indi-
cate that opioids in the PAG participate in physical opiate
dependence. In contrast, blocking opioid receptors in this
structure by injecting locally methynaloxonium had no
effect on a previously acquired operant responding for
food (203) or only produced a mild CPA (361) in mor-
phine-dependent rats, suggesting that periaqueductal opi-
oids play a limited role in the motivational effects of
opiate withdrawal.
D) LOCUS COERULEUS. The role of the locus coeruleus
(LC) in physical opiate dependence is now questioned
(55, 69, 98, 197, 224, 309). Some experimental evidence
supports the idea that opioids in this region are recruited
during physical withdrawal. Indeed, intra-LC injections of
opioid receptor antagonists in rats made dependent on
systemic morphine produced severe somatic signs of
withdrawal, whereas chronic infusion of morphine into
the LC induced physical dependence in rats (reviewed in
Ref. 69).
Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
on October 1, 2009
Downloaded from


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Under Republican leadership, a Senate committee on high-skill guest worker visas focuses on outsourcing and job losses, not the need for more high-skill workers.
Ken O'Neill, who is deaf, offers advice on how to present a disability when applying for a job.
Research shows that many members of groups underrepresented in academic science seek careers that express values beyond pure research.
A new report finds that female scientists face a combination of racial and gender biases.
In The Brilliant Club, Amina Yonis found an opportunity to help level the playing field for students from disadvantaged backgrounds.
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In an era when scientists are increasingly exposed, they need to be careful to distinguish between scientific criticism and personal attacks.
Erich Jarvis's upbringing during the civil rights movement helped provide the tools for success as he pursued studies of human languages and songbirds.
By staying balanced, focused, and organized, Lesley Yellowlees has risen through the ranks while maintaining a vibrant family life.
The agency continues working to equalize treatment for same-sex and opposite-sex spouses.
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Do researchers looking for jobs in industry need to be good at socializing as well as science? An article in C&E News explores industrial hiring trends suggesting that the answer is "yes."
During her long career, physicist Mildred Dresselhaus has won many awards, including the National Medal of Science. We sat down with her for a chat.
A controversial study argues that women who pursue math-intensive academic careers are just as likely to succeed as men.
Prepared by graduate students, a report details the difficult conditions adjuncts face at one public university.
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Baby you're a butterfly! Katy Perry spreads her wings in a symbolic rehearsal for Canada's Much Music awards
Her estranged husband Russell Brand has been explicitly opening up about the end of his marriage as he does the promotion for new film Rock of Ages.
But Katy Perry has more subtle ways of sending messages to her fans about her life separated from the comedian.
In a symbolic show during the Much Music Video Awards rehearsal in Toronto, Canada today, she showed that she had begun a freeing new life with the help of her set design.
Colourful set: Today Katy was pictured rehearsing with a giant set of butterfly wings
In a colourful display, the singer could be seen practicing her vocals on a huge platform.
Before long a giant gathering of material opened up to form a butterfly with herself stood in the middle.
While it is not known what her get-up will be for the real thing tomorrow night, she wore a revealing black lace shirt which showed off her bra with light leggings for the run-through.
Cocoon: Katy prepared to make her metamorphosis during the rehearsal for the Much Music Video Awards
Flying free: Katy's set design could symbolise the start of her new life without Russell Brand
Energetic: Perry hopped down form the high platform where she will be seen on TV tomorrow night
Meanwhile dancers climbed in the trees around her as a camera crew maneuvered their way around the star.
She tweeted: 'Tomorrow's MMVA performance is inspired by Crazy Town's "Butterfly" & the 80's film "Cocoon" #metamorphosis'
Yesterday the butterfly detail could also be seen on her demure frock.
Perry chose to keep her curves under wraps as she greeted fans in the country.
The American singer, who is up for Favourite International Artist at the Canadian event, was pictured arriving for a sound check in an outfit which belied her customary bubblegum pop style.
Doing the promotional rounds: Katy Perry prepared for an appearance the Much Music Video Awards in Canada by greeting her fans
Considering she has flashed her bottom in a minidress in London recently, her decision to remain modest about her curves was surprising.
The 27-year-old wore a high neck floral frock which fell below the knee as she graced the stage for a run through of her appearance in Toronto.
Katy wore flat black pumps to match her flattering black leather waist sash as she was shown around the platform she will be performing and presenting on Sunday evening.
The purple-haired beauty didn't sing or dance at the 9pm practise, which was watched by an audience, instead she used the time to familiarise herself with what she had to work with.
Keeping more to the imagination: Katy showed up for her sound check at 9pm but she didn't sing or dance in her demure floral frock
Famous frame: The purple-haired star wore a black leather waist belt to clinch in her curves
Perry made sure to give her admirers a wave and a smile as she worked on one of the penultimate evenings for placing votes towards the prestigious annual set of gongs.
She has been working hard on the promotional circuit since landing in the country.
Earlier in the day she greeted fans at the screening of her documentary Part of Me which was held at the Scotiabank Theatre.
Earlier she was at the screening of her documentary, Katy Perry: Part of Me held at the Scotiabank Theatre in Toronto
Vote for me! She snapped pictures with young fans
Last attempt: She asked fans to vote for her via her Twitter page yesterday
She willingly whipped off her sunglasses to pose for pictures with fans and even took charge of the shutter button herself at one point.
The down-to-earth lady reminded the public of her desire to walk away with a trophy on Twitter.
She wrote: 'HAPPY to b back in Toronto & to be nominated for UR Fave Int'l Artist! U can still vote if u like, wink wink! http://mmva.muchmusic.com/vote'
Flashing the flesh: Perry recently whipped up a storm in London as she wore her usually skimpy gear of a minidress and fishnet tights
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Dana Berliner (May 31, 196? – ) was born in southern California, where her father, Michael Berliner, was the first executive director of the Ayn Rand Institute and a professor of education at California State University and her mother, Dr. 1,140 more words
Tags » Ayn Rand Institute
Global warming and environmentalism by the numbers
During 2009, The Heartland Institute held its Second International Conference on Climate Change (ICCC-2). In this talk, Ayn Rand Institute Executive Director Dr. Yaron Brook, who has a Phd in finance, looks at the global warming issue and the environmentalist movement from an investor and environmentalist point of view and why people still support them.
Climate change reconsidered: A Heartland Institute briefing panel at the Ayn Rand Institute
During 2013 The Ayn Rand Institute hosted a panel discussion on the topic of climate change at its headquarters in Irvine, California. The event was moderated by Keith Lockitch and panelists were Joe Bast President and CEO of the Heartland Institute, Dr. 15 more words
Yaron Brook chews out a communist at a lecture in Poland
Ayn Rand Institute Executive Director Yaron Brook tells a communist how life really is under capitalism during a Q & A period after delivering a lecture at a university in Poland*. 46 more words
Free Speech and the Danish Cartoons: A Panel Discussion
The aftermath of the Charlie Hebdo shooting has been mixed. Fortunately, the government of France has decided it will tackle Islamic totalitarianism and European countries like Germany have… 70 more words
The Value of Ayn Rand in an Introductory Philosophy Course
The discipline of philosophy is something to be held inviolate; the classroom likewise. One might be inclined to ask, what is the function of teaching provocative material to an introductory level philosophy class? 2,485 more words


text:
Life Time Fitness Acquires 232,000-SF Building in Harrison
NEW YORK CITY-Life Time Fitness has acquired an office/distribution facility in Harrison, New York. The health club bought the 232,000-square-foot building at One Gannett Drive. The building formerly housed a Gannett printing press operation.
Life Time Fitness has plans to make a state-of-the-art fitness center at the 24-acre site. NAI James E. Hanson and NAI Friedland represented LTF Real Estate Company, which is trading as Life Time Fitness, in the deal. A CBRE team represented Gannett Satellite Information Network, Inc., the seller. For the full story, go to Commercial Property Executive .
GlobeSt.com News Hub is your link to relevant real estate and business stories from other local, regional and national publications.
Do business in the Southeast? Stay ahead of CRE trends and meet the dealmakers at RealShare Atlanta on April 30. Stay tuned for GlobeSt.com's new dedicated Atlanta page launching April 1 and sign up for Atlanta's weekly email digest coming April 4.
You can now be notified via email if this story is updated by clicking on the "Follow this Story" link. You must be a registered member to take advantage of this "members only" benefit.


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Learn the fundamentals of basketball with the one and only Matt Bonner!
Feb 2, 2011, 5:33 PM EDT
The NBA features many great teachers of the game. One could fill a book with notes of Kobe Bryant's footwork, or lessons of Luis Scola's infinite moves and counters in the post. Yet if asked to name the wisest of all the league's fine instructors, the entire basketball world would cry out Matt Bonner's name in unison.
Well, hypothetically ask, and thou shalt receive: Spurs.com has begun a recurring feature in which Bonner teaches us all about the finer points of the game. They only have his introduction to the series thus far, but sharpen your pencils — Coach B's about to drop some knowledge.
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Clermont County kicks off summer with Leave Your Kid in a Hot Car Outside of Wal-Mart Fest
BATAVIA, OH - The arrival of summer is never far away when Clermont County announces its annual "Leave Your Kid in a Hot Car Outside of Wal-Mart Fest." The annual celebration is a summer staple in Clermont County, and residents are already anticipating this year's festivities.
"This is one of those events that make Clermont County so special," said Chamber of Commerce President Archie Meecham. "Hundreds of folks from all around the county will gather in a parking lot celebrating our special knack for child rearing. We are happy to report that this event gets bigger every year, which is odd because you'd think it would thin out the population."
The festival will feature crafts, food, and rides for any children who eventually make their way out of the hot cars. There will also be a WalMart fashion show for moms, demonstrations on how to efficiently beat your children in a crowded shopping aisle, and a performance by the nationally renowned Kids on Leashes Drill team.
"I wait all winter for this festival," said Clermont resident Barbara Stone. "With all the horrible stuff in the world nowadays, it's good to have a nice old fashioned event like this. I love it because I can bring the whole family. Then, I can leave them in a hot car while I go enjoy myself."
41 year-old Batavia Resident Kenny Fulsom will receive an award at this year's festival for managing to survive in a hot car for over 36 years. Fulsom was left in the car behind a barn by his mother in 1976. He wasn't discovered until this year when Wal-Mart executives toured the plot of land for consideration as an expansion site.
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Home > England > Premier League > Norwich City > Squad > Profile: Kyle Lafferty
Kyle Lafferty Norwich City
Profile of the Northern Irish footballer Kyle Lafferty, who currently plays as a forward at Norwich City. The 27-year old player Lafferty joined Norwich from Palermo and wears the number 9 shirt.
Kyle Lafferty Career
Kyle Lafferty Videos
Your Comments on Kyle Lafferty
Kyle Lafferty Photos
Beta! Some pictures may be inaccurate...
Kyle Lafferty : Norwich City News
"Kyle Lafferty has revealed he would ìjump at the chanceî to rejoin Rangers."
2 days ago
"Kyle Lafferty has in qualifying so far Is Lafferty a new David Healy, shrugging off mediocre club figures to be prolific for Northern Ireland in European Championship qualifying? He has netted one league goal each for Norwich and Rizespor this term"
"Norwich City striker, Kyle Lafferty has been speaking ahead of Northern Ireland's friendly match with Scotland and has spoken about his love of Rangers and how he feels he has unfinished business at Ibrox."
3 days ago
"Lafferty, now on loan at Rizespor in Turkey from Norwich City, regrets he will be remembered by many people for those "daft things". And he admits he would relish the chance to come back to Glasgow and put things right."
2 days ago
"Kyle Lafferty, in fairness he wasn't alone The life long Rangers fan, who is currently on loan in Turkey with Rizespor from Norwich, is keen to 'change people's perceptions' of him having been involved in a string of on and off the field issues"
3 days ago
"Former Rangers striker Kyle Lafferty wants a return to Ibrox to change the fans' perception of him, according to his latest comments to the Daily Record."
3 days ago
"KYLE LAFFERTY has revealed he would relish the chance to return for the 38 goals he scored during four years in Scotland."
3 days ago
"Former Rangers bad boy Kyle Lafferty has admitted he wants a second me if Iíd go back there - and Iíd jump at the chance,í admitted Lafferty, who is under contract at Norwich until the summer of 2017 but currently on loan at Turkish side Rizespor."
3 days ago
Kyle Lafferty Career Honours
Source: wikipedia.org
Kyle Lafferty Wiki, Stats & Links
Kyle Lafferty - Wikipedia
Kyle Lafferty Stats @ Soccerbase.com
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An excellent Airbnb experience. Mikhail was very welcoming--he had a stocked kitchen waiting for me and great recommendations for the area. The bedroom is cozy and has great views looking out to the Rijksmuseum. Highly recommended.
Mike was very kind and helpful, he described all places to visit in his district and gave some recommendations. He is also a perfect host preparing some welcoming drinks and cookies, the flat is very nice and spacious.
Mikhail has one of the best loft ever, clean and completely furnished. He was really kind and bought for us an hair dryer. He received us with a bottle of wine and gave us all the info about the city. We will surely come back!
Absolutely raccomended!
We loved our stay at Mikhail's. The apartment is in a great location, at the centre of a very trendy area with lots of restaurants close by. It was easy to walk to most museums as well.
The apartment was tidy and welcoming with everything we needed and although we did not get to meet Mikhail on this occasion, we were left in the accommodating hands of his neighbour.
I would highly recommend Mikhail's apartment for a great stay in Amsterdam.
Nice stay. We enjoy our new year in Amsterdam
Good guest
Mikhail was a fantastic guest. He took great care of the apartment and left it in impeccable condition. I would absolutely recommend him as a guest.
I'm excited to have them as my guests!They were friendly and were easy to communicate. They left our place very very neat and tidy and were easy guests to have in the house! It was a pleasure to host them and recommend them without a second thought.
We are very pleased to have guests like Mikhail in our apartments. He was the first one in our Montevideo Apartment and we hope to have many more friendly and neat like him! Wish you all the best!
We were honoured naturally, to have " the Airbnb boss" in our windmill!
A wonderful evening on the countryside is what they wanted, and it is what they got. We were even invited for the evening ourselves!
Great people, love to have them back in the mill!
Thanks for coming Mikhail& friends !
Everything was good. Apartment left in great condition. And great communication
Mikhail is a really nice guy, but that was a big disappointment for me to see how irresponsible can be airbnb worker. Leaving the apartment opened with its key inside - that's shocking. He couldn't wait 2 more minutes till my housekeeper will come and take the keys. I'm really sorry to write this, situations can be different and I of course can understand a lot, but fact is the fact..
Спасибо, за то, что выбрали наши апартаменты. Всего Вам найлучшего. Будем рады видеть в Москве)
You can trust the former reviews! Mikhail is a very recommandable guest, with no "high cleaningness standard", in my opinion.
The short talk we had at his arrival gave me a great impression and I really would like to know him better. I enjoyed hosting him and his niece.
Very welcome back to my apartment!
Mikhail is a very nice guest, but warning: he has very high cleanliness standards! There was dust behind the microwave which he complained about, and though the house had been cleaned by the housekeeper, he felt as if the house had never been cleaned! When cleaned by the same housekeeper, other guests did not have this problem.
Other than this he was very understanding and mature.
Mikhail is a former housemate and current good friend, with whom i often share cooking contests and creative ideas, whether that's in english, dutch, or french!
He always has energy and is busy building businesses and communities. He knows all the russian expats of Amsterdam, and probably a good chunk of all the other nationalities, and is great at connecting us all together. He knows amsterdam like his pocket and is the man to turn to for advice and reviews on places to go out, to shop, and the latest music scene action.
He has very charming old europe manners and is an extremely courteous guest. He will make sure you have everything you need and is very respectful of your privacy.
In short, Mikhail is a fun, cultivated young entrepreneur, and a great host! I'd recommend anyone to stay with him, including my parents coming for a visit next week!


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Harley Davidson Boots
Need great biker gear to go with your awesome bike? Need protective gear to go with your dangerous job? What about footgear that expresses your personality? What you really need are Harley Davidson Boots - the gear you need on your feet. Harley Davidson knows that your style is a reflection of your personality. Whether you want hot Black Leather Harley Davidson Motorcycle Boots, steel toe safety to help you get through the workday, or fashionable Harley Davidson Women's Boot Styles, trust a company that's famous for making tools for the road - even when you are walkin' on it.
24 Item(s)
Harley Davidson Shoes: Men's Crossroads 94050 II Motorcycle Shoes
$114.00 Free Shipping 8 Reviews 399
Harley Davidson Shoes: Men's Black 94049 Steel Toe Hiking Shoes
$120.00 Free Shipping 5 Reviews 420
Harley Davidson Boots: Women's Leather Sadie Biker Boots 84068
$130.00 Free Shipping 5 Reviews 455
Harley Davidson Shoes: Men's Static 93027 Black Steel Toe Suede Shoes
$104.00 Free Shipping 1 Review 364
Harley Davidson Boots: Women's Serita Motorcycle Boots 85041
$137.00 Free Shipping 3 Reviews 480
Harley Davidson Shoes: Men's Leather/Nylon Chase Athletic Shoes 93009
$85.00 Free Shipping 4 Reviews 298
Harley Davidson Boots: Men's Steel Toe Motorcycle Boots 91144
$102.00 Free Shipping 3 Reviews 357
Harley Davidson Boots: Women's 6-Inch Khari Motorcycle Boots 84180
$97.00 Free Shipping 3 Reviews 340
Harley Davidson Boots: Men's Black Steel Toe Welted Pull-On Motorcycle Boots 95328
$139.00 Free Shipping No Reviews
Harley Davidson Shoes: Men's Black Athletic Hiking Shoes 94350
$98.00 Free Shipping 4 Reviews 343
Harley Davidson Boots: 95262 Men's Black Scout 7-Inch Harness Motorcycle Boots
$128.00 Free Shipping 1 Review 448
Harley Davidson Boots: Women's 10-Inch Christa Harness Motorcycle Boots 85298
$112.00 Free Shipping 1 Review 392
Harley Davidson Boots: Men's 10-Inch Leather Constrictor Motorcycle Boots 95276
$138.00 Free Shipping 3 Reviews 483
Harley Davidson Boots: Men's Brown 95263 Harness Motorcycle Boots 95263
$128.00 Free Shipping 1 Review 448
Harley Davidson Boots: Women's Black Leather Scrunchie Welted Motorcycle Boots 85416
$138.00 Free Shipping No Reviews
Harley Davidson Boots: Men's Steel Toe 6 Inch Cushioned Work Boots 95326
$129.00 Free Shipping No Reviews
Harley Davidson Boots: Men's Steel Toe 93120 Jason St EH Motorcycle Boots
$142.00 Free Shipping 1 Review 497
Harley Davidson Boots: 95264 Men's Black Side Zip Motorcycle Boots
$142.00 Free Shipping No Reviews
Harley Davidson Boots: Men's Black 93114 Josh Leather Motorcycle Boots
$152.00 Free Shipping No Reviews
Harley Davidson Boots: Men's 95055 Black Steel Toe EH Met Guard Work Boots
$150.00 Free Shipping No Reviews
Harley Davidson Shoes: Men's 93124 Hans St Steel Toe EH Work Shoes
$108.00 Free Shipping 1 Review 378
Harley Davidson Boots: Men's 93111 Millan Steel Toe EH Leather Boots
$118.00 Free Shipping 4 Reviews 413
Harley Davidson Boots: Women's Black 85259 Leather Jammie Motorcycle Boots
$112.00 Free Shipping No Reviews
Harley Davidson Boots: Women's 83668 Steel Toe Gabby Motorcycle Boots
$150.00 Free Shipping No Reviews
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24 Item(s)
I am writing to let you know just how pleased I was with your handling of my recent return/exchange experience. I returned a pair of boots for a factory flaw and your customer service representative Brandon made the entire process easy and most satisfactory. I appreciated the fact that there were no costs involved in returning my purchase to you and the fact that I received my replacement boots in a very short time without further effort from me. I am extremely pleased with the way that my return was handled and just wanted to thank the Working Person's Store for providing such excellent, prompt and most courteous customer service. I will be recommending your company highly to others and just wanted to say thank you again for such a satisfactory and hassle-free customer service experience!"
Larry G. from Red Bluff, CA