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Blockade of O-Opioid Receptors Prevents Morphine-Induced Place Preference in Mice

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Blockade of O-Opioid Receptors Prevents Morphine-Induced Place Preference in Mice Blockade of o-Opioid Receptors Prevents Morphine-Induced Place Preference in Mice Tsutomu Suzuki', Michiharu Yoshiike', Hirokazu Mizoguchi', Junzo Kamei', Miwa Misawa' and Hiroshi Nagase2 'Department of Pharmacology , School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142, Japan 2Basic Research Laboratories , Toray Industries, Inc., 111 Tebiro, Kamakura 248, Japan Received May 12, 1994 Accepted June 18, 1994 ABSTRACT-Effects of highly selective 5-opioid receptor antagonists on the morphine-induced place preference in ddY and p,-opioid receptor deficient CXBK mice were investigated. Pretreatment with naltrin dole (NTI: a non-selective 5-opioid receptor antagonist), 7-benzylidenenaltrexone (BNTX: a selective 5, opioid receptor antagonist) or naltriben (NTB: a selective 52-opioid receptor antagonist) abolished the mor phine-induced place preference in ddY mice in a dose-dependent manner. These findings suggest that the morphine-induced place preference may be mediated by both d, and 52-opioid receptors. On the other hand, in p,-opioid receptor deficient CXBK mice, pretreatment with these selective 5-opioid receptor an tagonists did not affect the morphine-induced place preference, although pretreatment with ;3-funaltrex amine (13-FNA: a selective p-opioid receptor antagonist) significantly inhibited the morphine-induced place preference. [D-Pen 2,D-Pen5]enkephalin (DPDPE: a 0,-opioid receptor agonist) and [D-Ala2, Glu4]deltorphin (deltorphin II: a 52-opioid receptor agonist) induced a significant place preference in ddY mice, but not in CXBK mice. These results suggest that d, and 52-opioid receptors in the nucleus accumbens that are related to the DPDPE and deltorphin II-induced place preference may be dysfunctional and/or poor in CXBK mice. These findings also indicate that 5, and 52-opioid receptors may be involved in the modulation of the reinforcing effect of morphine. Keywords: Conditioned place preference, Morphine, 5-Opioid receptor agonist, 5-Opioid receptor antagonist, CXBK mouse Work over several years has suggested interactions be 5, and 52-receptors, has been reported (9-11). More tween p and 5-opioids. Recently, Porreca and colleagues recently, Miyamoto et al. (12, 13) have reported that 52 have confirmed that at sub-antinociceptive doses 5-opioid opioid receptors are involved in the development of acute receptor agonists modulate antinociceptive responses to and chronic dependence on morphine and that continu p-opioid receptor agonists (1). Thus administration ous blockade rather than intermittent blockade of 52 of the selective 5-agonist [D-Pen 2,D-Pen']enkephalin receptors is necessary to inhibit morphine dependence. (DPDPE) at a dose that by itself produces no anti The p and 5-agonists may have similar effects on the nociception potentiates the potency of i.c.v. morphine. mesolimbic dopaminergic (DAergic) system, which may Numerous attempts have been made to study the role account for their similar effects on motivation, motor be of various opioid-receptor types in the development of havior and biochemical analyses (14-16). Activation of morphine tolerance and physical dependence. , -Opioid the mesolimbic DAergic system by ,o-agonists and 5 receptors, especially, are known to play a major role in agonists can elicit a reinforcing effect in addition to the the development of morphine tolerance and dependence motor-activating effect (17, 18). Furthermore, Koob (19) (2-4). Morphine is a ,u-preferring agonist, but it also in proposed that the mesolimbic DAergic, projection is teracts with 5 and K-opioid receptors both in vitro and in a key component of the opioid reward mechanism. vivo (5). Recently, the involvement of 5 and K-opioid DPDPE acts as a S,-opioid receptor agonist (9), while [D receptors in the development of morphine tolerance and Ala2,Glu4]deltorphin (deltorphin II) acts as a 52-opioid dependence has been reported (6 8). More recently, evi receptor agonist (10). While DPDPE has been shown to dence for the presence of 5-opioid receptor subtypes, i.e., produce a significant place preference (14), the motiva tional effect of deltorphin II is not yet clear. It has been ing a 900-sec session was then measured automatically by shown that the morphine-induced place preference is not an infrared beam sensor (KN-80; Natsume Seisakusyo, antagonized by the peptide o-opioid receptor antagonist Tokyo) in a blinded fashion. The position of the mouse ICI 174,864 (3 tag, i.c.v.) (14). However, the effects of o1 was defined by the position of its forelimbs and head. All and o2-opioid receptor antagonists on the reinforcing sessions were conducted under conditions of dim illumina effect of morphine are not yet clear. tion (40 lux) and white masking noise. Mice exhibited no On the other hand, it is well known that the CXBK preference for either of the place states under these condi strain of mouse, which is derived from a cross between tions. the C57BL/6 and BALB/c strains, is deficient in central pl-opioid receptors (20). It is possible that the role of the Effects of NTI, BNTX and NTB on the morphine-in interaction between p and 5-opioid receptors in mor duced place preference phine-induced place preference can be clarified by using The control mice were injected s.c. with saline (10 p,-opioid receptor deficient CXBK mice. ml/kg) instead of drugs in each of the conditioning ses In the present study, the effects of the non-selective o sions. After their daily injection of saline, these mice were opioid receptor antagonist naltrindole (NTI), the selec confined to one compartment on one day and to the other tive o1-opioid receptor antagonist 7-benzylidenenal compartment on the next day. This process was repeated trexone (BNTX) and the selective d2-opioid receptor 3 times. Before the start of the experiments, either saline antagonist naltriben (NTB) on the morphine-induced control (black or white-floored compartment place) was place preference in ddY mice and i1-opioid receptor randomly chosen to be the substitute for the drug-associat deficient CXBK mice were investigated. Moreover, we ed place. also examined the motivational effects of o-opioid recep Morphine (1, 5 and 10 mg/kg) and saline were injected tor agonists in ddY and CXBK mice. s.c. into ddY mice on alternate days. The ddY mice were immediately confined to each compartment after the injec MATERIALS AND METHODS tion. NTI (0.5 and 1 mg/kg), BNTX (0.35 and 0.7 mg/kg) and NTB (0.1 and 0.5 mg/kg) were injected s.c. at 30, 20 Animals and 30 min before the conditioning or the morphine injec Male ddY mice (Tokyo Experiment Animal Co., Ltd., tion, respectively. Drugs and saline were injected on alter Tokyo) weighing 20 to 30 g were housed in groups of nate days. 10 15 in a temperature-controlled room at 22 ± 1 C with For CXBK mice, morphine (5 mg/kg) and saline were a 12 hr light-dark cycle (light on 8:00 a.m. to 8:00 p.m.). injected s.c. on alternate days. NTI (0.5 mg/kg), BNTX Male CXBK mice weighing 18 to 31 g at the beginning of (0.7 mg/kg) and NTB (0.5 mg/kg) were injected s.c. at the experiments were obtained from Jackson Labora 30, 20 and 30 min before the morphine injection, respec tories (Bar Harbor, ME, USA). Laboratory chow and tively. Furthermore, the selective p-opioid receptor an water were available ad libitum. tagonist l-funaltrexamine ((3-FNA; 10 mg/kg) was inject ed s.c. 24 hr before the morphine injection. Drugs and sa Place conditioning line were injected on alternate days. Conditioning was conducted by an unbiased procedure according to Suzuki et al. (21, 22). The apparatus used Place conditioning produced by DPDPE and deltorphin was a shuttle box (15 x 30 x 15 cm: w x 1x h) that was II divided into two compartments of equal size. One com DPDPE (15 nmol) or deltorphin II (4 nmol) and saline partment was white with a textured floor and the other were injected i.c.v. to ddY and CXBK mice on alternate was black with a smooth floor. days. Several opioids were given into the lateral cerebral For conditioning, mice were immediately confined to ventricle of mice (2.5 tal/mouse) according to the method one compartment after drug injections and to another of Haley and McCormick (23). The control mice were in compartment after saline injections. The pairings of injec jected i.c.v. with saline (2.5 tat/mouse) instead of drugs in tion (drug or saline) and compartment (white or black) each of the conditioning sessions. were counterbalanced across all of the subjects. Con ditioning sessions (3 for drug: 3 for saline) were conduct Drugs ed for a 60-min period once a day. On day 7, conditioning The drugs used in the present study were morphine was tested as follows: the partition separating the two hydrochloride (Sankyo Co., Tokyo), [D-Pen 2,D-Pen 5] compartments was raised 7 cm above the floor, and a neu enkephalin (DPDPE; Peninsula Laboratories, CA, tral platform was inserted along the seam separating the USA), [D-Ala2,Glu4]deltorphin (deltorphin II, Peninsula compartments. The time spent in each compartment dur Laboratories), naltrindole methanesulfonate hydrate (NTI), 7-benzylidenenaltrexone tartrate (BNTX), RESULTS naltriben methanesulfonate (NTB) and 13-funaltrexamine hydrochloride (j3-FNA). NTI, BNTX, NTB and (3-FNA Effect of NTI, BNTX and NTB on the morphine-induced were synthesized by us. All of the drugs were dissolved in place preference saline. As shown in Figs. 1 and 2, the s.c.-saline control mice exhibited no preference for either compartment. The Data analysis mean conditioning scores in MY and CXBK mice were Conditioning scores represent the time spent in the 20.5 ± 40.1 sec and 37.5 ± 45.5 sec, respectively.
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