Opioids, Reward and Addiction: An Encounter of Biology ...

[()-4-[(-R*)--((2S*,5R*)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide]
could induce conditioned place preference, which could
be prevented by pretreatment with naltrindole (Longoni
et al., 1998). In addition, morphine-induced place preference,
which could not be blocked with the antagonist
ICI 174,864 (Shippenberg et al., 1987) was shown to be
abolished by the nonspecific antagonist naltrindole as
well as by the receptor subtype antagonists BNTX ( 1)
and naltriben ( 2) (Suzuki et al., 1994b; Kamei et al.,
1997, but see Piepponen et al., 1997). In addition, the
capacity of morphine to elicit conditioned place preference
was found to be profoundly reduced in mice pretreated
i.c.v. with antisense oligodeoxynucleotide to
receptor mRNA (Suzuki et al., 1997a). Recently, it was
also shown that both 1 and 2 receptor subtypes are
involved in opioid place-conditioning, since both the 1
agonist DPDPE and the 2 agonist [D-Ala 2 ]-deltorphin II
induced place preference, both of which could be inhibited
by specific antagonists (BNTX and naltriben, respectively)
(Suzuki et al., 1996c, 1997c). Treatment with
the nonpeptide agonist TAN-67 did not induce place
preference but enhanced the ability of morphine to induce
conditioned place preference. This effect of TAN-67
could be antagonized with naltrindole, a nonselective
antagonist as well as BNTX and naltriben, implicating
both receptor subtypes ( 1 and 2) in this effect (Suzuki
et al., 1996b; Kamei et al., 1997). Similar to receptors,
uncoupling of receptors from G proteins with pertussis
toxin, administered i.c.v., inhibited the development of
DPDPE-induced place preference (Suzuki et al., 1991).
Stimulation of -opioid receptors induces place aversion.
Systemic and i.c.v. injections of the -opioid agonists
U50,488H, U69,593, and E-2078 and the opioid
agonist-antagonist bremazocine induced aversion
(Iwamoto, 1985; Mucha and Herz, 1985; Mucha et al.,
1985; Shippenberg and Herz, 1987, 1988, 1991; Bals-
Kubik et al., 1989; Funada et al., 1993; Shippenberg et
al., 1993). In addition, morphine-induced preference is
abolished by the agonists U50,488H and E-2078 (Funada
et al., 1993; Bolanos et al., 1996). Intracerebroventricular
dynorphin A(1–17) has been shown to induce
naloxone-antagonizable place preference (Iwamoto,
1988). This effect is, however, not necessarily mediated
through receptors, since dynorphin A(1–17) has affinity
for receptors as well. In addition, metabolization of
this peptide could yield a product with agonist activity at
receptors (Höllt, 1986).
There seems to be general agreement that stimulation
of -opioid receptors induces conditioned place preference,
whereas blockade of receptors induces place
aversion. Stimulation of receptors induces conditioned
place aversion, but blockade of receptors does not seem
to induce significant place-conditioning. With regard to
the involvement of receptors, stimulation of receptors
with specific ligands induces place preference, whereas
blockade of receptor has no major effects on place-
OPIOIDS, REWARD AND ADDICTION 367
conditioning. However, the role of receptors in the
place preference induced by morphine is not clear.
2. Sites of Action. Studies into possible sites of action
for opioids to induce place-conditioning have found two
main areas: the NAC and VTA. With respect to the
latter, injections of morphine, an enkephalin analog, and
DAMGO into the VTA have been shown to cause place
preference (Phillips and LePiane, 1980, 1982; Phillips et
al., 1983; Bozarth, 1987b; Bals-Kubik et al., 1993; Olmstead
and Franklin, 1997b). Injections of morphine in
sites adjacent to the VTA were without effect (Phillips
and LePiane, 1980; Bozarth, 1987b; Olmstead and
Franklin, 1997b). The place preferences induced by intra-VTA-administered
morphine or [D-Ala 2 ]-metenkephalin
could be abolished by systemic pretreatment
with naloxone (Phillips and LePiane, 1980, 1982) while
preference induced by systemic morphine could be
blocked by intra-VTA injections of naloxone methiodide
(Olmstead and Franklin, 1997b). Intra-VTA injections of
the -opioid antagonist CTOP or naloxone induced place
aversion, which were inhibited by 6-hydroxydopamine
(6-OHDA)-induced lesions of the NAC (Shippenberg and
Bals-Kubik, 1995). The main effect of receptor stimulation
in the VTA seems to be inhibition of -aminobutyric
acid release (Johnson and North, 1992; Klitenick et
al., 1992). In this respect, it is worth noting that the
place preference induced by peripheral administration
of morphine could be prevented with intra-VTA infusion
of the -aminobutyric acid type B agonist baclofen (Tsuji
et al., 1996). Infusion of agonists (U50,488H, E-2078)
into the VTA induced place aversion as well (Bals-Kubik
et al., 1993).
Morphine administered into the NAC was shown to
result in place preference (Van der Kooy et al., 1982), but
negative results with morphine or DAMGO administered
into the NAC have also been published (Bals-
Kubik et al., 1993; Olmstead and Franklin, 1997b; Schildein
et al., 1998). Electrolytic as well as extensive
NMDA- or kainic acid-induced lesions of the NAC have
been shown to inhibit the development of morphineinduced
place preference (Kelsey et al., 1989; Olmstead
and Franklin, 1996). Similar to the VTA, administration
of the antagonist CTOP or naloxone as well as the
agonists U50,488H and E-2078 into the NAC resulted in
place aversions (Bals-Kubik et al., 1993; Shippenberg
and Bals-Kubik, 1995). 6-OHDA-induced lesions of the
NAC abolished the place preference induced by peripheral
injections of morphine and the place aversions induced
by U69,593 (Shippenberg et al., 1993, but see
Olmstead and Franklin, 1997a) but not the aversions
induced by intra-NAC-injected CTOP or naloxone (Shippenberg
and Bals-Kubik, 1995).
There are a number of other sites that have been
proposed to mediate the place preference induced by
morphine or enkephalin and place aversion induced by
-opioid agonists, respectively, but the involvement of
these sites has not been thoroughly investigated. For