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Naltrexone, Naltrindole, and CTOP Block Cocaine-Induced Sensitization to Seizures and Death

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Naltrexone, Naltrindole, and CTOP Block Cocaine-Induced Sensitization to Seizures and Death Peptides, Vol. 18, No. 8, pp. 1189–1195, 1997 Copyright © 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0196-9781/97 $17.00 1 .00 PII S0196-9781(97)00182-4 Naltrexone, Naltrindole, and CTOP Block Cocaine-Induced Sensitization to Seizures and Death D. BRAIDA,1 E. PALADINI, E. GORI AND M. SALA Institute of Pharmacology, Faculty of Mathematical, Physical and Natural Sciences, University of Milan, Via Vanvitelli 32/A, 20129, Milan, Italy Received 10 March 1997; Accepted 15 May 1997 BRAIDA, D., E. PALADINI, E. GORI AND M. SALA. Naltrexone, naltrindole, and CTOP block cocaine-induced sensitization to seizures and death. PEPTIDES 18(8) 1189–1195, 1997.—ICV injection for 9 days of either naltexone (NTX) (5, 10, 20, 40 mg/rat) or a selective m peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 mg/rat) or d (naltrindole) (NLT) (5, 10, 20 mg/rat) subtype opioid receptor antagonist affected sensitization to cocaine (COC) (50 mg/kg, IP) administered 10 min after. NTX (5 and 40 mg/rat), NLT (10 and 20 mg/rat), and the peptide CTOP (0.25–0.5 mg/rat) attenuated seizure parameters (percent of animals showing seizures, mean score and latency) in a day-related manner. The DD50 (days to reach 50% of death) value for COC was 2.69, whereas it was 9.67 and 7.27 for NTX 5 and 40 mg/rat, 8.59 for NLT (10 mg/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 mg/rat respectively). These findings suggest a concurrent involvement of m- and d-opioid receptor subtype in COC-induced sensitization to toxic effects. © 1997 Elsevier Science Inc. m- and d-Opioid receptor Pharmacological kindling Lethality Central administration Rat THE exact mechanism by which cocaine (COC) produces its been studied on the development of COC-induced pharmacologi- toxicity is not well understood even though episodes of human cal kindling. The present study was designed to investigate a behavioral toxicity have been attributed to the development of highly m-selective opioid peptide, CTOP, and a d-selective one, sensitization (32). In COC addicts, sensitization may have impor- naltrindole (NLT), both administered centrally on COC-induced tant consequences such as drug-induced panic attacks, paranoia, seizures and death in the rat in comparison with NTX, a nonse- seizures, and lethality (29). lective opiate antagonist. There is a growing body of evidence to support an opioid CTOP has been proved the most potent and highly selective modulation of COC-induced sensitization to biochemical and be- conformationally restricted somatostatin octapeptide analogue for havioral effects. In fact, pretreatment either with naltrexone (NTX) m-opioid receptors. The peptide is able to inhibit [3H]naloxone (8,19,36,41) or with different opioid subtype receptor antagonists binding at m sites in rat brain membrane preparation with an IC50 (7,10,17,28,33) in combination with COC prevented the develop- of 2.80 nM (without NaCl) and possesses a Ki value of 0.18 nM ment of sensitization to locomotor activity and reward. Other (15). In addition, the peptide, when administered ICV at a dose of studies, even if contradictory, suggest that opiate receptors are 1 mg/rat, was able to antagonize morphine-induced analgesia in the important in modulating toxic effects of COC after both acute and cold water tail flick test (1). repeated administration. Pretreatment with naloxone failed to NLT is a nonpeptide ligand that potently antagonizes the d block acute COC lethality in rats, and the incidence of seizures and agonists (DADLE and DPDPE) on smooth muscle preparations of death was significantly potentiated by pretreatment with morphine mouse vas deferens with a Ke value in the range of 0.1–0.3 nM (9). On the other hand, the partial opioid agonist buprenorphine (31) and it is able to block intrathecally DPDPE-induced antino- protected against the lethal effect of COC in mice, whereas NTX ciception in the tail flick test in mice (25). had no such effect (47). In addition, daily pretreatment with In our study, the range of doses chosen for the two selective peripheral NTX completely antagonized COC-induced sensitiza- opiate antagonists were previously shown to selectively block m tion to seizures and death (35). and d agonist-induced antinociception without producing an anal- The influence of d- and m-opioid receptor subtypes has not gesic effect of their own (5,40,46). Requests for reprints should be addressed to D. Braida. 1189 1190 BRAIDA ET AL. METHOD post hoc comparisons (Tukey’s multiple comparison test) were subsequently made to ascertain pairwise differences between Animals means. Mean seizure scores were analyzed by nonparametric anal- Male Wistar albino rats (Charles River Italia, Calco, Como, ysis of variance (Kruskal–Wallis test) using a chi-square parameter Italy) weighing 200–220 g were used. Animals were housed in followed by post hoc comparisons, when appropriate. When com- individual cages in a climate-controlled colony room with a 12-h pared with COC data, incidence of seizures and death was ana- dark–light cycle (lights on at 0800 h) with food and water available lyzed by Fisher’s exact probability test. The same data were ad lib. All animals were handled daily throughout the first week trasformed into probit and linear regression of probit data on log of after their arrival, and experimental testing began 7 days after this the days was calculated. The days to attain 50% of death (DD50) habituation period. was calculated according to Lison (24). The DD50 obtained from different treatments were compared using Student’s t-test. Surgery For ICV administration, animals were anesthetized with 400 RESULTS mg/kg IP of chloral hydrate (Sigma Chemical Co., St. Louis, MO) Animals that had received one of the different doses of each and prepared according to Altaffer et al. (2) by implanting a antagonist 10 min before the IP injection of saline showed no stainless steel cannula (o.d. 0.50 mm, i.d. 0.22 mm) into the brain obvious behavioral changes except a slight arousal at the highest right ventricle according to the coordinates indicated by a stereo- dose of NLT (20 mg/rat) and CTOP (3 or 6 mg/rat) (data not taxic atlas (30). To ascertain the accuracy of ICV injections, at the shown). end of the experiment rats were injected with 3 ml of a saturated Daily administration of COC induced a progressive increase in solution of Evans blue (BDH) by the same route and immediately the percentage of rats that convulsed from the first (61%) to ninth killed. Macroscopic examination of the brain confirmed that only day (100%), indicating the development of behavioral sensitization the area around the lateral ventricle was stained. Only animals with (Fig. 1). This increase was linearly related to the log of the days. histologically correct placements were employed. Repeated injections of NTX (5 mg/rat) in combination with Animal care was in accordance with state regulations govern- COC produced a linearly related lower increase of seizures that did ing the care and treatment of laboratory animals. not significantly differ from COC alone. Higher doses (10 and 20 mg/rat) significantly reduced the incidence of seizures from the Procedure third day (p , 0.01, Fisher’s test). The highest dose (40 mg/rat) led Five days postoperatively rats were randomly assigned to dif- to a significant reversal from the first to the last day (p , 0.001, ferent groups of 10–15 each, and injected ICV, once a day, Fisher’s test) in a linear-related manner. between 0900 and 1100 h, with sterile water (3 ml/rat ICV) or one Daily administration of NLT (5 mg/rat) with COC significantly of the increasing doses of NTX (5, 10, 20, 40 mg/rat), NLT (5, 10, reduced seizures from day 6 (p , 0.01, Fisher’s test). NLT (10–20 20 mg/rat), or CTOP (0.125, 0.25, 0.5, 1, 3, 6 mg/rat) 10 min before mg/rat) significantly reversed COC-induced seizures starting from IP injection of COC (50 mg/kg) or saline (SAL) (5 ml/kg) for 9 the first day (p , 0.001, Fisher’s test) in a linear-related manner. days at most, with 2 drug-free days each week. Immediately after Administration of CTOP (0.125, 0.25, 0.5 mg/rat) in combina- IP treatment animals were observed for 30 min in the plastic cages tion with COC did not affect the seizure incidence on the first day. (42 3 26 3 15 cm) in which they were normally housed for However, repeated injections of 0.25 and 0.5 mg/rat reduced sei- behavioral signs of seizures and lethality. Each trained observer zure incidence from the third to the last day, and 0.125 mg/rat from was blind to the drug conditions of the animals and to the purposes the sixth day (p , 0.01, Fisher’s test). Because the results for of the experiment. seizures and death with CTOP 3 and 6 mg/rat did not significantly differ from COC they were not shown in the figures. Seizures As expected, daily administration with COC increased the mean seizure score and decreased the mean latency from the first Behavioral seizures were assessed by a six-point scoring scale to the last day in a linear-related manner (Fig. 2). Only the highest according to (26): (0) no signs of convulsion; (1) shaking the head dose of NTX significantly reduced the mean score and increased or twitching individual trunk muscles; (2) repeated clonic spasms the mean latency on the first day [p , 0.05, Kruskal–Wallis test for of the trunk; (3) clonic spasm of the forelimb; (4) clonic–tonic score and F(4, 70) 5 5.49, p , 0.005, ANOVA, for latency] but convulsions with the animal falling on its side, followed by pos- from the third day all doses had significant effects (p , 0.05; p , tictal depression; (5) repeated severe tonic–clonic or lethal con- 0.01 depending on the dose and the day of treatment, see the vulsions.
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