0022-3565/98/2842-0633$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
JPET 284:633–636, 1998
Vol. 284, No. 2
Printed in U.S.A.
Neuropeptide Y Attenuates Naloxone-Precipitated Morphine
Withdrawal via Y5-like Receptors1
DAVID P. D. WOLDBYE, KRISTIAN KLEMP and TORSTEN M. MADSEN
Laboratory of Neuropharmacology, Department of Pharmacology, University of Copenhagen, (D.P.D.W., K.K.); Laboratory for Experimental
Neuropsychiatry, Department of Psychiatry, University Hospital, Rigshospitalet, Copenhagen (T. M. M.), Denmark.
Accepted for publication October 27, 1997
This paper is available online at http://www.jpet.org
The study of opioid dependence holds the promise of leading to pharmacological treatments for addiction as well as
gaining important knowledge of neural mechanisms of motivated behaviors. In experimental animals previously treated
with opioids, the precipitation of a range of withdrawal signs
by acute injection of opioid antagonists is considered a model
for studying opioid dependence (Bläsig et al., 1973, Koob et
al., 1992; Martin et al., 1963). NPY is a 36 amino acid
polypeptide that is widely and abundantly distributed in the
central nervous system (Tatemoto et al., 1982). Several characteristics of NPY are suggestive of a potential role in treatment or in basic mechanisms of opioid dependence. For instance, NPY neurons and/or binding sites are located in brain
regions (Chronwall et al., 1985; de Quidt and Emson, 1986;
Dumont et al., 1992) implicated in expression of opioid withdrawal, e.g., periaqueductal gray, hypothalamus and locus
coeruleus (Koob et al., 1992; Maldonado et al., 1992). Central
administration of NPY and NPY-related peptides causes analgesia (Broqua et al., 1996; Hua et al., 1991; Pich et al., 1990)
and anxiolysis (Wahlestedt and Reis, 1993), effects compatible with an inhibitory effect on opioid withdrawal. Reduced
levels of NPY in cerebral cortex and nucleus accumbens
resulting from repeated cocaine injections have been suggested to be causally involved in expression of cocaine withReceived for publication June 10, 1997.
1
This work was supported by the Danish Medical Research Council (121343), Ivan Nielsens Foundation, Eli and Egon Larsens Foundation, the Research Grant of Einar Geert-Jørgensen and his wife Ellen Geert-Jørgensen,
the Danish Psychiatric Research Foundation and the Gangsted Foundation.
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 17, 2017
ABSTRACT
The effects of intracerebroventricular injection of neuropeptide
Y (NPY) and various NPY-related peptides were studied on
naloxone-precipitated withdrawal from morphine in rats. The
withdrawal reaction was assessed using an overall motor
score, including jumping, wet dog shakes and other motorrelated signs as well as a nonmotor score. At doses of 3, 6 or
12 nmol, NPY strongly and dose-dependently reduced the
motor score. A less prominent inhibitory effect was revealed on
the nonmotor score. At 6 nmol, [Leu31,Pro34]-NPY, NPY 3-36,
peptide YY and human pancreatic polypeptide all significantly
attenuated the motor score, whereas NPY 13-36 was without
effect. This pharmacological profile suggests that the antiwithdrawal effect of NPY is mediated via the recently cloned Y5
receptor. Our data are consistent with a potential role for NPY
and Y5-like receptors in basic mechanisms and as a therapeutic target in opioid dependence and withdrawal.
drawal (Wahlestedt et al., 1991). By analogy, reduced levels
of NPY in hypothalamus and striatum after chronic morphine or codeine treatment (Pages et al., 1991, 1992) might
also be involved in opioid withdrawal. In feeding, which in its
basic pattern bears resemblance to that of opioid addiction,
there is evidence for a central interaction between NPY and
opioids. Thus central administration of NPY or opioids increases feeding, and naloxone decreases NPY-induced feeding (Levine and Morley, 1984; Levine et al., 1985; Stanley
and Leibowitz, 1985). Mildly pinching the tail of rats induces
eating, a phenomenon known as stress-induced eating (Morley and Levine, 1980). Rats subjected to repeated episodes of
stress-induced eating develop an addictive-like state as demonstrated by the display of withdrawal behavior when challenged with naloxone (Morley and Levine, 1980).
NPY receptors are G protein-coupled receptors associated
with inhibition of adenylate cyclase (Wahlestedt and Reis,
1993). At least six NPY receptor subtypes have been characterized on the basis of different pharmacological profiles
and/or genetic cloning of receptor proteins. The rank order of
potency of different NPYergic agonists is as follows
(Blomqvist and Herzog, 1997; Gerald et al., 1996; Wahlestedt
and Reis, 1993; Weinberg et al., 1996): The Y1 receptor binds
NPY, PYY $ [Leu31,Pro34]-NPY .. NPY 3-36, NPY13-36,
hPP; Y2 binds NPY, PYY $ NPY 13-36 .. [Leu31,Pro34]NPY, hPP; Y3 binds NPY .. PYY; Y4 (the PP1 receptor)
binds hPP .. NPY; Y5 (Gerald et al., 1996) binds NPY,
PYY $ NPY 3-36, [Leu31,Pro34]-NPY, hPP . NPY 13-36; Y6
ABBREVIATIONS: NPY, neuropeptide Y; hPP, human pancreatic polypeptide; PYY, peptide YY; WDS, wet dog shakes; i.c.v., intracerebroventricular.
633
634
Woldbye et al.
Vol. 284
(originally also termed Y5; Weinberg et al., 1996) binds NPY,
PYY $ [Leu31,Pro34]-NPY . NPY 13-36 . hPP.
Here, for the first time, it was examined whether i.c.v.
administration of NPY and various NPY-related peptides
could be used to inhibit naloxone-precipitated morphine
withdrawal.
Materials and Methods
Results
Effect on withdrawal scores. NPY caused a powerful
and significant attenuation of the morphine withdrawal mo-
Discussion
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 17, 2017
Male Wistar rats (Møllegården, DK; 280-320 g) kept under standard laboratory conditions were used in this study. Under equithesin
(SAD, Denmark; 3.3 ml/kg) anesthesia, a cannula for i.c.v. injection
was positioned into the right lateral ventricle (coordinates: 2.0 mm
from bregma on the coronal suture of the skull, 4.5 mm below the
surface of the skull) and were secured to the skull with jeweler’s
screws and a covering of dental cement (Woldbye et al., 1997). After
a postoperative recovery period of 3 to 4 days, morphine withdrawal
was induced according to a previous protocol (Lee et al., 1993). All
rats were given s.c. injections of morphine hydrocloride (Nycomed
DAK, Denmark) twice daily (9 a.m. and 9 p.m.) for 3 days with
increasing doses on each day (10, 20, 30 mg/kg). On the fourth day,
all animals received one single injection of morphine (30 mg/kg, s.c.)
at 9 a.m. Then, at 11.30 a.m., the rats received one single i.c.v.
injection (10 ml) containing 3, 6 or 12 nmol NPY (human synthetic,
#N-5017, Sigma, St. Louis, MO; n 5 5 in each group), 6 nmol NPY
3-36 (human synthetic, #H-3326, Bachem, Bubendorf, Switzerland;
n 5 5), 6 nmol NPY 13-36 (porcine synthetic, #N-6521, Sigma; n 5 5),
6 nmol [Leu31,Pro34]-NPY (human synthetic, #N-6146, Sigma; n 5
5), 6 nmol PYY (porcine synthetic, #P5801, Sigma; n 5 5), 6 nmol
hPP (#P-9903, Sigma; n 5 5), or vehicle (0.9% saline and 1% bovine
serum albumin; n 5 17) administered over a period of 1 min. At
12 a.m., all rats received an i.p. injection of naloxone hydrocloride
(Sigma, 10 mg/kg) dissolved in 0.9% saline to precipitate morphine
withdrawal.
During the next 2 hr, the rats were observed for signs of withdrawal and subsequently killed. The intensity of the withdrawal
reaction was assessed by a point scoring technique based on weighting the signs (Lee et al., 1993) with minor modifications. Two types
of withdrawal scores were used: a motor score based on motorrelated signs (i.e., jumping, WDS, head shakes, writhing, forelimb
tremor, digging, genital licking and mastication) and a nonmotor
score based on signs not directly involving motor activity (i.e., irritability, diarrhea and weight loss). Jumping was assigned a score of
2 for 1 to 2 times, 4 for 3 to 4 times, 6 for 5 to 6 times, 8 for 7 to 8
times, 12 for 9 to 12 times, 18 for 13 to 16 times, 24 for 17 to 20 times
and 36 for more than 20 times. WDS and head shakes scored 1 for 1
to 2 times, 2 for 3 to 4 times, 4 for 5 to 6 times, 6 for 7 to 8 times, 8
for 9 to 10 times, 12 for more than 10 times. Writhing was assigned
a score of 2 for 1 to 5 times and 4 for more than 5 times. Forelimb
tremor, digging, genital licking and mastication scored 2 for 1 to 5
times, 4 for 6 to 10 times and 6 for more than 10 times. Irritability
and diarrhea were given a score of 4 if present and 0 if absent.
Weight loss during the 2-hr observation period was scored 4 for a loss
of 6 to 10 g, 8 for a loss of 11 to 15 g, 12 for a loss of 16 to 20 g. The
sessions were videotaped to aid in the rating of the withdrawal
reaction. Rating was done by an observer ignorant as to whether
vehicle or an NPYergic agonist had been injected i.c.v. The withdrawal scores and single signs were analyzed using Kruskal-Wallis
one-way analysis of variance by ranks followed by Bonferroni-adjusted Mann-Whitney U tests (each experimental group vs. vehicle)
or Bonferroni-adjusted Fisher exact tests. A Bonferroni-adjusted P
value of less than 5% was considered significant.
tor score at all tested doses (fig. 1). Subsequent analysis of
the three doses (not including vehicle values) with Spearman’s rank order correlation coefficient showed this effect to
be dose-related (P , .05; Spearman’s r 5 – 0.57) with increasing effect at increasing doses. Significant reductions in the
motor score were also seen with 6 nmol PYY, NPY 3-36,
[Leu31,Pro34]-NPY and hPP. In contrast, the effect of NPY
13-36 was far from significant (P , .48, nonadjusted value),
consistent with mediation via Y5-like receptors.
In addition, there was a tendency for all tested doses of
NPY to decrease the nonmotor score. However, only pooling
of the three NPY dose groups revealed an overall significant
reduction by NPY (P , .01 vs. vehicle; Bonferroni-adjusted
with a factor 9). PYY significantly reduced the nonmotor
score while there was no clear effect with other NPYergic
agonists.
Effect on single withdrawal signs. The reduction in
motor and non-motor scores caused by NPY appeared to be
matched by reductions in all rated signs except weight loss
(table 1). Similarly, significant reductions or tendencies toward reduction in WDS, headshakes, forelimb tremor, digging, genital licking and writhing, were seen with PYY,
[Leu31,Pro34]-NPY, NPY 3-36 and hPP, whereas NPY 13-36
appeared either less potent or without effect. In contrast,
jumping, irritability and diarrhea, appeared reduced by NPY
13-36 and other NPY-related peptides but not by hPP.
Our study shows that i.c.v. administration of NPY causes a
powerful and dose-dependent attenuation of morphine withdrawal in rats. This effect was most pronounced on the withdrawal motor score. At 6 nmol, NPY 3-36, [Leu31,Pro34]NPY, hPP, and PYY all significantly reduced the motor score,
whereas NPY 13-36 was ineffective, suggesting that the overall antiwithdrawal effect is mediated via Y5 receptors. Consistent with this conclusion, several brain regions containing
Y5 receptor mRNA (Gerald et al., 1996; Gustafson et al.,
1996) have been implicated in morphine withdrawal either
because physical withdrawal can be precipitated by focal
Fig. 1. Effects of an i.c.v. injection of 3, 6, or 12 nmol NPY (n 5 5 per
group), vehicle (n 5 17) or various NPY-related peptides in a dose of 6
nmol (n 5 5 per group) on motor and nonmotor withdrawal scores for 2 hr
after i.p. injection of naloxone in rats previously treated with morphine.
Values are medians with 25 and 75% percentiles as error bars. *P , .05,
**P , .01 vs. vehicle; Bonferroni-adjusted Mann-Whitney U test after
significant Kruskal-Wallis. †P , .01 pooled NPY groups vs. vehicle;
Bonferroni-adjusted Mann-Whitney U test.
1998
635
NPY Attenuates Morphine Withdrawal
TABLE 1
Effects of NPY and NPY-related peptides on signs of morphine withdrawal [values represent means (S.E.M.)]
[Leu31,Pro34]
NPY 6 nmol
Motor signs
Jumping
WDS
Head shakes
Forelimb tremor
Digging
Genital licking
Writhing
Mastication
Nonmotor signs
Weight loss [g]
Irritability
Diarrhea
1 (0)
1 (1)
18 (8)
3 (2)
0.2 (0.2)
1 (4)
31 (13)
47 (11)
9
(2)
0%a
40%
hPP
6 nmol
PYY
6 nmol
NPY 3–36
6 nmol
NPY 13–36
6 nmol
Vehicle
5 (1)
0 (0)a
8 (2)
3 (2)
1.0 (1.0)
5 (1)
20 (12)
45 (12)
0 (0)a
0 (0)
1 (0)a
0 (0)a
0.0 (0.0)
0 (0)a
1 (1)
6 (3)a
1 (1)
0 (0)a
8 (3)
0 (0)a
0.2 (0.2)
3 (1)
2 (1)
38 (9)
2 (1)
10 (3)
28 (12)
8 (3)
1.2 (1.0)
8 (3)
97 (57)
103 (31)
8 (2)
10 (3)
26 (6)
17 (5)
2.1 (0.5)
9 (2)
54 (13)
47 (9)
9 (1)
40%
40%
7 (2)
40%
20%
9 (1)
80%
60%
7 (2)
80%
60%
4
(1)
0%a
0%
NPY
3 nmol
0 (0)a
0 (0)
10 (4)
2 (2)
0.4 (0.4)b
4 (3)
25 (13)
36 (6)
7 (1)
20%
20%b
NPY
6 nmol
0 (0)a
1 (1)
3 (1)
1 (1)
0.6 (0.6)b
1 (0)
4 (2)
14 (4)
8
(2)
0%a
0%b
NPY
12 nmol
0 (0)a
0 (0)a
1 (1)a
0 (0)a
0.0 (0.0)b
0 (0)a
6 (3)
37 (8)
7
(2)
0%a
0%b
a
P , .05 vs. vehicle (irritability and diarrhea, Bonferroni-adjusted Fisher exact test; other signs, Bonferroni-adjusted Mann-Whitney U test after significant KruskalWallis).
b
P , .05 pooled NPY groups vs. vehicle (Bonferroni-adjusted Fisher exact test or Mann-Whitney U test).
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 17, 2017
application of opioid antagonists or because lesioning attenuates withdrawal. Examples of this include anterior and
ventromedial hypothalamus (Kerr and Pozuelo, 1971; Maldonado et al., 1992), central amygdala (Calvino et al., 1979;
Maldonado et al., 1992; Tremblay and Charton, 1981), midline thalamic nuclei (Maldonado et al., 1992; Tremblay and
Charton, 1981; Wei et al., 1972), periaqueductal gray (Maldonado et al., 1992) and dorsal raphe nucleus (Bläsig et al.,
1976). All these regions are located fairly close to the ventricular system (Paxinos and Watson, 1986) with potentially
easy access for i.c.v. injected NPYergic agents.
Locus coeruleus, believed to be a key structure in expression of opioid withdrawal (Koob et al., 1992; Maldonado et al.,
1992), has not been mentioned as a Y5 mRNA expressing
region (Gerald et al., 1996; Gustafson et al., 1996). Consequently, Y5 receptor levels are probably so low in this region
that locus coeruleus is not likely to be important for antiwithdrawal effects of NPY.
We recently reported that Y5 receptors also appear to
mediate inhibitory effects on seizures as induced by kainic
acid (Woldbye et al., 1997). The exact location of these “antiseizure receptors” remains to be determined, but the hippocampus is one likely possibility, because this region contains a high concentration of Y5 mRNA (Gerald et al., 1996)
and is considered a primary focus of kainic acid seizures
(Sperk, 1994). WDS were first described in rats during morphine withdrawal (Martin et al., 1963) but also occur in
relation to seizures involving the hippocampus (MacLean,
1957). We previously showed that i.c.v. administration of
NPY suppresses WDS accompanying hippocampal seizures
(Woldbye et al., 1996). In fact, this observation prompted us
to examine the effects of NPY on morphine withdrawal in the
first place. However, the hippocampus appears not to be
involved in mediating withdrawal-related WDS or other
signs of opioid withdrawal attenuated by NPY in our study
(Mitchell et al., 1990; Tremblay and Charton, 1981). Consequently, hippocampal NPY receptors are not likely to be
targets for antiwithdrawal actions of NPYergic agents.
Consistent with an overall antiwithdrawal Y5-like receptor
mechanism, most individual withdrawal signs, including
WDS, appeared reduced via Y5-like receptors. Interestingly,
as for jumping, irritability, and diarrhea, the “antiwithdrawal pharmacological profile” seemed similar to that of Y6
receptors cloned in mice (Weinberg et al., 1996), NPY 13-36
appearing more potent than hPP. However, the Y6 receptor
gene is absent from the rat genome (Blomqvist and Herzog,
1997). One explanation for this discrepancy might be that
antiwithdrawal effects of NPY on jumping, irritability and
diarrhea are mediated by receptors not yet cloned in rats.
Alternatively, Y5 receptors mediate inhibitory effects on all
withdrawal symptoms, but hPP might for unknown reasons
be distributed more slowly and/or metabolized faster in brain
regions mediating jumping, irritability and diarrhea than in
regions mediating other withdrawal signs. Further clarification of this matter awaits the development of specific Y5
antagonists.
NPY administered i.c.v. exerts antinociceptive effects in
the hot plate paradigm in rats (Pich et al., 1990) and in the
writhing test in mice (Broqua et al., 1996). Several Y5 mRNA
expressing regions (Gerald et al., 1996; Gustafson et al.,
1996) in close proximity to the ventricular system have been
implicated in antinociception, including the periaqueductal
gray (Yaksh, 1979), nucleus raphe dorsalis (Klatt et al.,
1988), anterior hypothalamus (Takeshige et al., 1993) and
midline thalamic nuclei (Gescuk et al., 1994). Consequently,
antinociceptive actions at these sites might contribute to the
antiwithdrawal actions of NPYergic agents. In addition,
NPYergic antagonism of morphine withdrawal might also at
least in part be related to NPY-induced anxiolysis (Wahlestedt and Reis, 1993). Although previous studies have ascribed this anxiolytic effect of NPY to Y1 receptors (Heilig et
al., 1993; Wahlestedt et al., 1993), these studies do not rule
out involvement of Y5 receptors.
Our study suggests that Y5-like receptors might form a
potentially novel therapeutic target in opioid withdrawal and
dependence. Because Y5 receptors are mainly located in the
central nervous system (Gerald et al., 1996), Y5 agonists may
turn out to have only few peripheral side effects. As a potential central side effect, Y5 agonists might cause weight gain.
Thus the powerful feeding stimulatory effect of NPY (Levine
and Morley, 1984; Stanley and Leibowitz, 1985) appears to be
mediated via hypothalamic Y5 receptors (Gerald et al., 1996).
In addition, because NPY administered into the nucleus accumbens causes place preference (Josselyn and Beninger,
1993), NPYergic agonists could themselves be subject to
abuse. However, nucleus accumbens does not appear to con-
636
Woldbye et al.
tain Y5 receptors (Gerald et al., 1996; Gustafson et al., 1996),
and, consequently, this might not necessarily be a problem.
Chronic morphine treatment is associated with decreased
levels of NPY in hypothalamus (Pages et al., 1991). Decreased brain levels of NPY have been implicated in basic
mechanisms of cocaine withdrawal (Wahlestedt et al., 1991).
The present data suggest that decreased NPYergic neurotransmission might also be involved in basic mechanisms of
opioid dependence. In other words, exogenous application of
NPYergic agents might be antagonizing withdrawal by correcting a deficit in NPY in hypothalamus and possibly other
areas.
In conclusion, our study demonstrates that NPY causes a
powerful attenuation of morphine withdrawal via Y5-like
receptors, suggesting that NPY and Y5-like receptors deserve
attention with regard to basic mechanisms and possible therapeutic potential in opioid dependence and withdrawal.
The authors gratefully acknowledge the technical assistance of
Birgit H. Hansen and Merete Nielsen, and we thank Philip Just
Larsen for helpful comments and suggestions.
References
Bläsig J, Herz A, Reinhold K and Zieglgänsberger S (1973) Development of physical
dependence on morphine in respect to time and dosage and quantification of the
precipitated withdrawal syndrome in rats. Psychopharmacologia 33:19-38.
Bläsig J, Papeschi R, Gramsch C and Herz A (1976) Central serotonergic mechanisms and development of morphine dependence. Drug Alcohol Depend 1:221-229.
Blomqvist AG and Herzog H (1997) Y-receptor subtypes— how many more? TINS
20:294-298.
Broqua P, Wettstein JG, Rocher MN, Gauthier-Martin B, Riviere PJ, Junien JL and
Dahl SG (1996) Antinociceptive effects of neuropeptide Y and related peptides in
mice. Brain Res 724:25-32.
Calvino B, Lagowska J and Ben-Ari Y (1979) Morphine withdrawal syndrome:
Differential participation of structures located within the amygdaloid complex and
striatum of the rat. Brain Res 177:19-34.
Chronwall BM, DiMaggio DA, Massari VJ, Pickel VM, Ruggiero DA and O’Donohue
TL (1985) The anatomy of neuropeptide Y-containing neurons in the rat brain.
Neuroscience 15:1159-1181.
De Quidt ME and Emson PC (1986) Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system. II. Immunohistochemical analysis.
Neuroscience 18:545-618.
Dumont Y, Martel JC, Fournier A, St-Pierre S and Quirion R (1992) Neuropeptide Y
and neuropeptide Y receptor subtypes in brain and peripheral tissues. Prog Neurobiol 38: 125-167.
Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE,
Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S,
Hofbauer KG, Taber RI, Branchek TA and Weinshank RL (1996) A receptor
subtype involved in neuropeptide-Y-induced food intake. Nature 382:168-171.
Gescuk B, Lang S, Porrino LJ and Kornetsky C (1994) The cerebral metabolic effects
of morphine in rats exposed to escapable footshock. Brain Res 663:303-311.
Gustafson EL, Gerald C, Durkin MM, Smith KE, Walker MW, Moralishvilli A,
Vaysse PJ-J, Weinshank RW and Branchek TA (1996) Localization of the mRNA
encoding a novel NPY receptor subtype in rat brain. Soc Neurosci Abstr 22:1682.
Heilig M, McLeod S, Brot M, Heinrichs SC, Menzaghi F, Koob GF and Britton KT
(1993) Anxiolytic-like action of neuropeptide Y: Mediation by Y1 receptors in
amygdala, and dissociation from food intake effects. Neuropsychopharmacology
8:357-363.
Hua G-Y, Boublik JH, Spicer MA, Rivier JE, Brown MR and Yaksh TL (1991) The
antinociceptive effects of spinally administered neuropeptide Y in the rat: systematic studies on structure-activity relationship. J Pharmacol Exp Ther 258:243-248.
Josselyn SA and Beninger RJ (1993) Neuropeptide Y: Intraaccumbens injections
produce a place preference that is blocked by cis-flupenthixol. Pharmacol Biochem
Behav 46:543-552.
Kerr FWL and Pozuelo J (1971) Suppression of physical dependence and induction of
hypersensitivity to morphine by stereotaxic hypothalamic lesions in addicted rats.
Mayo Clin Proc 46:653-665.
Klatt DS, Guinan MJ, Culhane ES, Carstens E and Watkins LR (1988) The dorsal
raphe nucleus: a re-evaluation of its proposed role in opiate analgesia systems.
Brain Res 447:246-252.
Koob GF, Maldonado R and Stinus L (1992) Neural substrates of opiate withdrawal.
TINS 15:186-191.
Lee PHK., McNutt RW and Chang K-J (1993) A nonpeptidic delta opioid receptor
agonist, BW373U86, attenuates the development and expression of morphine
abstinence precipitated by naloxone in rat. J Pharmacol Exp Ther 267:883-887.
Levine AS and Morley JE (1984) Neuropeptide Y: A potent inducer of consummatory
behavior in rats. Peptides 5:1025-1029.
Levine AS, Morley JE, Gosnell BA, Billington CJ and Bartness TJ (1985) Opioids and
consummatory behavior. Brain Res Bull 14:663-672.
MacLean PD (1957) Chemical and electrical stimulation of hippocampus in unrestrained animals. AMA Arch Neurol Psychiat 78:128-142.
Maldonado R, Stinus L, Gold LH and Koob GF (1992) Role of different brains
structures in the expression of the physical morphine withdrawal syndrome.
J Pharmacol Exp Ther 261:669-677.
Martin WR, Wikler A, Eades CG and Pescor FT (1963) Tolerance to and physical
dependence on morphine in rats. Psychopharmacologia 4:247-260.
Mitchell CL, Grimes LM and Hong JS (1990) Granule cells in the ventral dentate
gyrus are essential for kainic acid-induced wet dog shakes but not those induced by
precipitated abstinence in morphine-dependent rats. Brain Res 511:338-340.
Morley JE and Levine AS (1980) Stress-induced eating is mediated through endogenous opiates. Science 209:1259-1261.
Pages N, Orosco M, Fournier G, Rouch C, Hafi A, Gourch A, Comoy E and Bohuon
C (1991) The effects of chronic administration of morphine on the levels of brain
and adrenal catecholamines and neuropeptide Y in rats. Gen Pharmacol 22:943947.
Pages N, Orosco M, Rouch C, Fournier G, Comoy E and Bohuon C (1992) Brain and
adrenal monoamines and neuropeptide Y in codeine tolerant rats. Gen Pharmacol
23:59-163.
Paxinos G and Watson C (1986) The Rat Brain in Stereotaxic Coordinates. Academic
Press, New York.
Pich ME, Zoli M, Zini I, Ferraguti F, Solfrini V, Tiengo M, Fuxe K and Agnati LF
(1990) Effects of central administration of neuropeptide Y on vigilance and pain
threshold in spontaneously hypertensive rats. Adv Pain Res Ther 13:55-63.
Sperk G (1994) Kainic acid seizures in the rat. Prog Neurobiol 42:1-32.
Stanley BG and Leibowitz SF (1985) Neuropeptide Y injected in the paraventricular
hypothalamus: A powerful stimulant of feeding behaviour. Proc Natl Acad Sci
USA 82:3940-3943.
Takeshige C, Oka K, Mizuno T, Hisamitsu T, Luo C-P, Kobori M, Mera H and Fang
T-Q (1993) The acupuncture point and its connecting central pathway for producing acupuncture analgesia. Brain Res Bull 30:53-67.
Tatemoto K, Carlquist M and Mutt V (1982) Neuropeptide Y –a novel brain peptide
with structural similarities to peptide YY and pancreatic polypeptide. Nature
296:659-660.
Tremblay EC and Charton G (1981) Anatomical correlates of morphine-withdrawal
syndrome: differential participation of structures located within the limbic system
and striatum. Neurosci Lett 23:137-142.
Wahlestedt C, Karoum F, Jaskino G, Wyatt RJ, Larhammer D, Ekman R and Reis
DJ (1991) Cocaine-induced reduction of brain neuropeptide Y synthesis dependent
on medial prefrontal cortex. Proc Natl Acad Sci USA 88:2078-2082.
Wahlestedt C and Reis DJ (1993) Neuropeptide Y-related peptides and their receptors —are the receptors potential therapeutic drug targets? Annu Rev Pharmacol
Toxicol 32:309-352.
Wahlestedt C, Pich EM, Koob GF, Yee F and Heilig M (1993) Modulation of anxiety
and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 259:
528-531.
Wei E, Loh HH and Way EL (1972) Neuroanatomical correlates of morphine dependence. Science 177:616-617.
Weinberg DH, Sirinathsinghji DJP, Tan CP, Shiao L-L, Morin N, Rigby MR, Heavens RH, Rapoport DR, Bayne ML, Cascieri MA, Strader CD, Linemeyer DL and
MacNeil DJ (1996) Cloning and expression of a novel neuropeptide Y receptor.
J Biol Chem 271:16435-16438.
Woldbye DPD, Madsen TM, Larsen PJ, Mikkelsen JD and Bolwig TG (1996) Neuropeptide Y inhibits hippocampal seizures and wet dog shakes. Brain Res 737:162168.
Woldbye DPD, Larsen PJ, Mikkelsen JD, Klemp K, Madsen TM and Bolwig TG
(1997) Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like
receptors. Nature Med 3:761-764.
Yaksh TL (1979) Direct evidence that spinal serotonin and noradrenaline terminals
mediate the spinal antinociceptive effects of morphine in the periaqueductal gray.
Brain Res 160:180-185.
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 17, 2017
Acknowledgments
Vol. 284
Send reprint requests to: Dr. David P.D. Woldbye, Laboratory of Neuropharmacology, Department of Pharmacology, University of Copenhagen, 3
Blegdamsvej, DK-2200, Copenhagen N, Denmark