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 ϩ .00 PII S0196-9781(97)00182-4 , , 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 ␮g/rat) or a selective ␮ peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 ␮g/rat) or ␦ (naltrindole) (NLT) (5, 10, 20 ␮g/rat) subtype affected sensitization to cocaine (COC) (50 mg/kg, IP) administered 10 min after. NTX (5 and 40 ␮g/rat), NLT (10 and 20 ␮g/rat), and the peptide CTOP (0.25–0.5 ␮g/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 ␮g/rat, 8.59 for NLT (10 ␮g/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 ␮g/rat respectively). These findings suggest a concurrent involvement of ␮- and ␦- subtype in COC-induced sensitization to toxic effects. © 1997 Elsevier Science Inc.

␮- and ␦-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 ␮-selective , CTOP, and a ␦-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 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) ␮-opioid receptors. The peptide is able to inhibit [3H]

(8,19,36,41) or with different opioid subtype receptor antagonists binding at ␮ 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 ␮g/rat, was able to antagonize -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 ␦ 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 (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 ␮ tion to seizures and death (35). and ␦ agonist-induced antinociception without producing an anal- The influence of ␦- and ␮-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 ␮g/rat) and CTOP (3 or 6 ␮g/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 ␮l 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 ␮g/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 ␮g/rat) significantly reduced the incidence of seizures from the Procedure third day (p Ͻ 0.01, Fisher’s test). The highest dose (40 ␮g/rat) led Five days postoperatively rats were randomly assigned to dif- to a significant reversal from the first to the last day (p Ͻ 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 ␮l/rat ICV) or one Daily administration of NLT (5 ␮g/rat) with COC significantly of the increasing doses of NTX (5, 10, 20, 40 ␮g/rat), NLT (5, 10, reduced seizures from day 6 (p Ͻ 0.01, Fisher’s test). NLT (10–20 20 ␮g/rat), or CTOP (0.125, 0.25, 0.5, 1, 3, 6 ␮g/rat) 10 min before ␮g/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 Ͻ 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 ␮g/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 ϫ 26 ϫ 15 cm) in which they were normally housed for However, repeated injections of 0.25 and 0.5 ␮g/rat reduced sei- behavioral signs of seizures and lethality. Each trained observer zure incidence from the third to the last day, and 0.125 ␮g/rat from was blind to the drug conditions of the animals and to the purposes the sixth day (p Ͻ 0.01, Fisher’s test). Because the results for of the experiment. seizures and death with CTOP 3 and 6 ␮g/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 Ͻ 0.05, Kruskal–Wallis test for of the trunk; (3) clonic spasm of the forelimb; (4) clonic–tonic score and F(4, 70) ϭ 5.49, p Ͻ 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 Ͻ 0.05; p Ͻ tictal depression; (5) repeated severe tonic–clonic or lethal con- 0.01 depending on the dose and the day of treatment, see the vulsions. The incidence of seizure and death (%) and the latency to legend to Fig. 2). For 5 and 40 ␮g/rat a linear regression to the log the first seizure (seconds) were recorded. of the days was obtained for both seizure parameters. Daily administration of NLT (5 ␮g/rat) with COC significantly Drugs reduced the mean seizure score from day 6 (p Ͻ 0.05, Kruskal– COC hydrochloride, dissolved in 0.9% NaCl and administered Wallis test). Starting from the first day of treatment 10 and 20 at a volume of 5 ml/kg, NTX hydrochloride, and NLT hydrochlo- ␮g/rat of NLT significantly reduced the score (p Ͻ 0.05, p Ͻ 0.01, ride dissolved in sterile water and administered at a volume of 3 Kruskal–Wallis test) in a linearly related manner. The ␦ antagonist also significantly increased the seizure latency [F(3, 28) ϭ 3.69, ␮l/rat were purchased from Sigma Chemical Co. CTOP (D-Pen- p Ͻ 0.02; F(3, 56) ϭ 15.6, p Ͻ 0.0002; F(3, 71) ϭ 7.51, p Ͻ Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) purchased from Peninsula (Merseyside, UK) was dissolved in sterile water and administered 0.002; F(3, 64) ϭ 5.25, p Ͻ 0.003, for days 1, 3, 6, and 9, at a volume of 3 ␮l/rat. respectively]. Post hoc comparisons showed that both the higher doses (10 and 20 ␮g/rat) protected against COC from the first to ninth day, whereas the lowest dose was active starting only from Data Analysis day 6. Mean Ϯ SEM of latencies was compared by one-way analysis Finally, administration of CTOP (0.125, 0.25, 0.5, 1 ␮g/rat) in of variance (ANOVA) for repeated measures. When appropriate, combination with COC did not affect the seizure score on the first OPIOID SYSTEM AFFECTS COC TOXICITY 1191

0.01 for the sixth day and F(6, 62) ϭ 5.88, p Ͻ 0.0001 for ninth day]. Tukey’s test showed that CTOP (0.25 and 0.5 ␮g/rat) was active starting from day 3, and the lowest dose 0.125 ␮g/rat on day 9. Only for CTOP 1 ␮g/rat a linear regression to the log of the days was obtained for both seizure parameters. Daily administration of COC progressively increased the inci- dence of death from the first to the last day in a linearly related

manner (Fig. 3) with a DD50 of 2.69 days (fiducial limits: 1.71 and 4.23 days). Increasing doses of NTX did not alter the lethal effect of COC on the first day, but significantly reduced it from the third day (p Ͻ 0.05, p Ͻ 0.01, Fisher’s test). For 5 and 40 ␮g/rat a linear

regression was obtained with a DD50 of 9.67 (fiducial limits: 6.67 and 13.80 days) and 7.27 (fiducial limits: 5.14 and 10.29 days),

respectively. These DD50 values were significantly different from COC alone (p Ͻ 0.02, Student’s t-test). Lethality was completely blocked in rats pretreated with NLT 5 ␮g/rat until the third day, and from the dose of 10 ␮g/rat the protection against COC-induced death was dose dependent until the last day (p Ͻ 0.05, p Ͻ 0.01, p Ͻ 0.001, Fisher’s test). Starting from the third day a linear regression curve was calculated for 5

and 10 ␮g/rat with a DD50 of 5.90 (fiducial limits: 2.57 and 13.51 days) and 8.59 (fiducial limits: 5.56 and 18.74 days), respectively.

Only the last DD50 was significantly different from COC alone (p Ͻ 0.05, Student’s t-test). Daily pretreatment with 0.25 ␮g/rat of CTOP protected against COC-induced lethality starting from the third day (p Ͻ 0.01, Fisher’s test). On the ninth day, 0.125 and 0.5 ␮g/rat were needed to significantly reduce the incidence of death (p Ͻ 0.05, Fisher’s test). All the tested doses produced a significant day–response

curve with a DD50 of 5.74 (fiducial limits: 3.80 and 8.66 days for 0.125); 6.11 (fiducial limits: 4.60 and 8.00 days for 0.25); 5.95 (fiducial limits: 4.29 and 8.24 days for 0.5); 4.30 (fiducial limits: 2.52 and 7.34 days for 1).

DISCUSSION This work shows that either a nonselective opiate antagonist, NTX, or the selective ␮ and ␦ receptor subtype antagonists, injected ICV, modulate COC-induced sensitization to seizures and death. We confirmed that NTX, even when administered centrally, attenuated all the seizure parameters considered in a dose-depen- dent manner (from 5 to 40 ␮g/rat), suggesting a central mechanism of the opiate system on COC-induced toxicity. This attenuation did not significantly change over 9 days. Our results with NTX do not clarify the specific opioid receptor subtype involved in COC- induced seizures, because the doses of NTX employed (5–40 ␮g/rat) presumably interact with both ␮ and ␦ types, as previously demonstrated for naloxone (44). The present study did determine the contribution of ␮ and ␦ receptor subtypes on COC-induced seizures. Unlike NTX, NLT is a stable nonpeptide antagonist that acts selectively at ␦ receptors in FIG. 1. Effect of daily increasing doses of different opiate antagonists vitro (31), whereas CTOP is a peptide that selectively antagonizes administered ICV on COC (50 mg/kg IP)-induced seizures. SW ϭ sterile ␮-mediated responses (16,40). Both these selective antagonists water. Linear regression lines of percent (probit) of rats with seizures were attenuated the incidence and the intensity of seizures and increased plotted against log of the days. *p Ͻ 0.05, **p Ͻ 0.01 vs. the correspond- the latency in a dose-dependent manner. However, whereas pre- ing cocaine treatment (Fisher’s exact probability test). treatment with NLT, from 10 ␮g/rat, completely blocked all the seizure parameters for the first 3 days, pretreatment with CTOP was active starting from the day 3 at the doses of 0.25 and 0.5 day. However, doses of 0.25 and 0.5 ␮g/rat reduced this parameter ␮g/rat, indicating a belated role of the ␮ receptor subtype in the from day 3 to the last, and 0.125 ␮g/rat from day 6 (p Ͻ 0.05, p Ͻ development of COC-induced sensitization and early involvement 0.01, Kruskal–Wallis test). of the ␦ receptor subtype. The decrease in efficacy of NLT during Regarding latency, CTOP pretreatment significantly increased the last sessions might be attributable to the fact that higher doses it from day 6 in comparison to COC alone [F(6, 104) ϭ 4.00, p Ͻ are required to ensure a complete block when sensitization to 1192 BRAIDA ET AL.

FIG. 2. Effect of daily increasing doses of different opiate antagonists administered ICV in combination with COC (50 mg/kg, IP) on the mean score and the mean latency to the first seizure. Linear regression lines of the score and the latency were plotted against log of the days. *p Ͻ 0.05, **p Ͻ 0.01 vs. the corresponding COC treatment; $p Ͻ 0.05, $$p Ͻ 0.01 vs. the corresponding NTX or NLT 5 ␮g/rat group (ANOVA followed by Tukey’s test). OPIOID SYSTEM AFFECTS COC TOXICITY 1193

response in a dose-related manner (0.3–10 mg/kg, IP) (23). In contrast, acute ICV injection of the ␮ antagonist beta-funaltrex- amine and the ␦ antagonist ICI174,864 had no effect on electrically induced seizures in rats (44,45). Therefore, the specific involvement of opioid receptor subtypes in COC-induced sensitization to seizures control has not yet been fully investigated. Several procedural differences between the present study and those cited (species, route of administration, range of doses, acute or chronic schedule, type of test) make it impossible at present to reconcile these different findings with COC. It is important to stress that acute (27) and chronic (42) COC is accompanied by increased plasma concentrations of ␤-endorphins and decreased concentrations in the anterior lobe of the pituitary, suggesting that COC affects the system in the brain. Forman and Estilow (12) reported that ␤-endorphin levels and release were consistently elevated in rats given repeated COC following a regimen similar to ours. An eptileptiform electrocortical pattern was described in rats after ICV injection of ␤-endorphin (14,18), and there is evidence that morphine can modify amygdaloid kindling whereas acutely administered naloxone and NTX (10 mg/kg IP) reduce both sei- zure stage severity and after discharge duration in rats (39). Pretreatment with NTX (5–40 ␮g/rat) resulted in significant protection against COC-induced death from day 3 of treatment. At the end of the experiment NTX achieved a near complete block, except at the last session (day 9) when the opiate antagonist was still different from COC but much less so. This suggests that much higher doses of NTX may be needed to achieve complete protec- tion. As for seizures, there was a different pattern for both the selective antagonists. NLT fully prevented COC-induced death from days 3 to 6. CTOP, however, partly attenuated the COC- induced response at doses from 0.125 to 0.5 ␮g/rat only on the last day, except for the dose of 0.25 ␮g/rat, which protected against death from the third day. Higher doses (1 ␮g/rat) and the highest (3–6 ␮g/rat, data not shown) were completely inactive. These findings suggest a concomitant role of opiate receptor subtypes in COC-induced sensitization. The lack of protection by high doses of CTOP is unclear. A possible explanation could relate to our behavioral observation that these doses, per se, induced a certain degree of arousal. This is not surprising because Badiani et al. (4) also reported a stimulatory effect of CTOP when administered into the VTA. As shown for naloxone (11), moderate to high doses of CTOP can produce epileptiform activity through a mechanism that involves an interaction with the GABA system, raising the possi- bility that modification of kindling seizures by opioid antagonists may involve both brain endorphins and GABA. Data regarding a protective effect of opiate antagonists on COC-induced lethality are limited to acute and peripheral admin- FIG. 3. Effect of daily increasing doses of different opiate antagonists istration of naloxone/NTX, which have shown no effect (9,38,48). administered ICV on COC (50 mg/kg, IP)-induced lethality. Linear regres- In our experiments, it was impossible to detect any effect of the sion lines of percent (probit) of death were plotted against log of the days. opiate antagonists because the dose of COC already had a weak *p Ͻ 0.05, **p Ͻ 0.01, ***p Ͻ 0.001 vs. the corrisponding COC treatment lethal effect on the first day. (Fisher’s exact probability test). The involvement of different opioid receptor subtypes is borne out by our findings regarding the number of days to reach 50% of death. Both NTX and NLT, but not CTOP, significantly prolonged seizures becomes maximal. In agreement with this finding, Negus survival, suggesting a predominant role of the ␦ receptor subtype et al. (28) reported that NLT appears to become less effective with in COC-induced toxicity. This is surprising because death due to repeated administration on antagonizing COC-induced self-admin- COC has been mainly linked to respiratory depression (48), which istration in monkeys. could be better antagonized by the ␮ subtype, which is known to No reports are available on the possible interference of ␮- mediate opiate-induced respiratory depression (33). However, a selective opioid antagonists on COC effects. A ␮-opioid antago- selective NLT antagonism on -induced respiratory im- nist, (30 mg/kg, IP), caused a significant rise in the pairment is reported (13), suggesting an involvement of ␦ receptor electroshock seizure threshold in mice, whereas NLT reduced the in the mediation of opioid-related respiratory impairment. 1194 BRAIDA ET AL.

It can be argued that the ␦ receptor subtype antagonizes other blocked the development of sensitization in the rat (17). On this causes of death induced by COC. Besides seizures, death from basis, an involvement of the ␬ subtype receptor in COC-induced COC also results from myocardial infarction, cerebrovascular sensitization to convulsions and death cannot be excluded a priori. events (6,22,43), and hyperthermia (6). However, relationships A further consideration is that chronic COC has been shown to between these events are difficult to disentangle. It seems unlike by enhance ␥-aminobutyric acid and glutamate release by altering that ␦ antagonists affect COC-induced hyperthermia. To date, presynaptic GABAB receptors within the rat dorso-lateral septal there is no evidence of any effect of ␦ activity on ␤-endorphin- nucleus (37), indicating an involvement of GABA trasmission in induced hyperthermia (20). However, an acute positive hemody- COC toxicity. namic effect was found using ICI-154,129, a ␦-selective opiate In conclusion, COC-induced sensitization to toxic effects may antagonist, but not , a selective ␮ antagonist, in a be blocked by ␦- and ␮-opioid subtype antagonists. These results model of right heart failure in dogs, where the ␦ antagonist reduced together with recent findings (3) showing a significant increase, at the vascular effects of ␤-endorphin (21), indicating that the ␦- least in the level of ␮ receptor mRNA in nucleus accumbens after opioid receptor subtype block may be beneficial against COC- 3 days of COC treatment, provide a further insight into the role of induced cardiovascular toxicity. ␮- and ␦-opioid receptors subtype in the development of sensiti- That seizures and lethality in response to acute COC may be zation to COC and suggest an useful approach for the treatment of mediated by distinct mechanisms and occur coincidentally as COC addicts. reported by Ritz and George (34) is consistent with our findings that the incidence of seizures on the first day (60%) was different from lethality (15%). However, the repeated COC-induced sei- ACKNOWLEDGEMENTS zures and death seem linked to a common opiate mechanism This research was supported by grant No. 95.02286.CT04 from the because the opiate antagonists, mainly ␦, showed a similar pattern Italian National Research Council (C.N.R.) to E.G., a grant (‘‘60%,’’ 1995) for both parameters. At present, the interference of ␬ subtype from the Italian Ministry for University and Scientific and Technological opiate receptors on COC-induced behavioral sensitization is lim- Research (M.U.R.S.T.) to M.S, and a grant from Centro di Farmacologia ited to locomotor activity. U-69598 in combination with COC Comportamentale.

REFERENCES 1. Adams, J. U.; Geller, E. B.; Adler, M. W. Receptor selectivity of icv and methionine-: comparison with morphine and reversibil- morphine in the rat cold water tail-flick test. Drug Alcohol Depend. ity with naloxone. Brain Res. 147:327–337; 1978. 35(3):197–202; 1994. 15. Gulya, K.; Pelton, J. T.; Hruby, V. J.; Yamamura, H. I. Cyclic 2. Altaffer, F. B.; De Balbian, V.; Halls, J.; Long, C. J.; D’Encarnacao, somatostatin octapeptide analogues with high affinity and selectivity P. A. A simple and inexpensive cannula technique for chemical stim- toward mu opioid receptors. Life Sci. 38:2221–2229; 1986. ulation of the brain. Physiol. Behav. 5:119–121; 1970. 16. Gulya, K.; Krivan, M.; Nyolczas, N.; Sarnyai, Z.; Kovacs, G. Central 3. Azaryan, A. V.; Coughlin, L. J.; Bu`za`s, B.; Clock, B. J.; Cox, B. M. effects of the potent and highly selective mu D-Phe- Effect of chronic cocaine treatment on ␮- and ␦-opioid receptor Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) in the mice. Brain Res. mRNA levels in dopaminergically innervated brain regions. J. Neuro- 150:355–360; 1988. chem. 66(2):443–448; 1966. 17. Heidbreder, C. A.; Babovic–Vuksanovic, D.; Shoaib, M.; Shippen- 4. Badiani, A.; Leone, P.; Stewart, J. Intra-VTA injections of the mu- berg, T. S. Development of behavioral sensitization to cocaine: Influ- opioid antagonist CTOP enhance locomotor activity. Brain Res. 690: ence of kappa opioid receptor agonists. J. Pharmacol. Exp. Ther. 112–116; 1995. 275:150–163; 1995. 5. Calcagnetti, D. J.; Holtzman, S. G. Delta opioid antagonist, naltrin- 18. Henriksen, S. J.; Bloom, F. E.; McCoy, F.; Ling, N.; Guillemin, R. dole, selectively blocks analgesia induced by DPDPE but not DAGO Beta-endorphin induces nonconvulsive limbic seizures. Proc. Natl. or morphine. Pharmacol. Biochem. Behav. 38(1):185–190; 1991. Acad. Sci. USA 75:5221–5225; 1978. 6. Catravas, J. D.; Waters, I. W. Acute cocaine intoxication in the 19. Houdi, A. A.; Bardo, M. T.; Van Loon, G. R. Opioid mediation of conscious dog: Studies on the mechanism of lethality. J. Pharmacol. cocaine-induced hyperactivity and reinforcement. Brain Res. 497:195– 198; 1989. Exp. Ther. 217:350–356; 1981. 20. Huidobro-Toro, J. P.; Way, E. L. Rapid development of tolerance to 7. Comer, S. D.; Lac, S. T.; Curtis, L. K.; Carroll, M. E. Effects of the hyperthermic effect of beta-endorphin and cross-tolerance between buprenorphine and NTX on reinstatement of cocaine-reinforced re- the and beta-endorphins. Eur. J. Pharmacol. 65:221–231; sponding in rats. J. Pharmacol. Exp. Ther. 267:1470–1476; 1993. 1980. 8. Corrigall, W. A.; Coen, K. M. Opiate antagonists reduce cocaine but 21. Imai, N.; Kashiki, M.; Woolf, P. D.; Liang, C. S. Comparison of not nicotine self-administration. Psychopharmacology (Berlin) 104: cardiovascular effects of mu- and delta-opioid receptor antagonists in 167–170; 1991. dogs with congestive heart failure. Am. J. Physiol. 267:H912–917; 9. Derlet, R. W.; Tseng, C.; Tharratt, S.; Albertson, T. E. The effect of 1994. morphine and naloxone on cocaine toxicity. Am. J. Med. Sci. 13:165– 22. Isner, J. M.; Chokshi, S. K. Cardiac complications of cocaine abuse. 169; 1992. Annu. Rev. Med. 42:133–138; 1991. 10. De Vries, T. J.; Babovic-Vuksanovic, D.; Elmer, G.; Shippenberg, 23. Jackson, H. C.; Nutt, D. J. Differential effects of selective mu-, kappa- T. S. Lack of involvement of ␦-opioid receptor in mediating the and delta-opioid antagonists on electroschock seizure threshold in rewarding effects of cocaine. Psychopharmacology (Berlin) 120:442– mice. Psychopharmacology (Berlin) 103:380–383; 1981. 448; 1995. 24. Lison, L. Statistica applicata alla Biologia sperimentale. Milan: Am- 11. Dingledine, R.; Iversen, L. L.; Breuker, E. Naloxone as a GABA brosiana; 1961. antagonist: Evidence from iontophoretic, receptor binding and convul- 25. Mizoguchi, H.; Narita, M.; Nagase, H.; Tseng, L. F. Antisense oli- sant studies. Eur. J. Pharmacol. 47:19–27; 1978. godeoxynucleotide to a delta-opioid receptor blocks the antinocicep- 12. Forman, L. J.; Estilow, S. Cocaine influence beta-endorphins levels tion induced by cold water swimming. Regul. Pept. 59(2):255–259; and release. Life Sci. 43:309–315; 1988. 1995. 13. Freye, E.; Latasch, L.; Portoghese, P. S. The delta receptor is involved 26. Moiseev, I. N.; Shandra, A. A.; Godlevskii, L. S. Cytophotometric in sufentanil-induced respiratory depression-opioid subreceptors me- study of change in glutamate dehydrogenase and GABA transaminase diate different effects. Eur. J. Anaesthesiol. 9(6):457–462; 1992. in the cerebral cortex during metrazol kindling. Bull. Exp. Biol. Med. 14. Frenk, H.; Urca, G.; Liebeskind, J. C. Epileptic properties of leucine- 97:422–424; 1984. OPIOID SYSTEM AFFECTS COC TOXICITY 1195

27. Moldow, R. L.; Fischman, A. J. Cocaine induced secretion of ACTH, 39. Stone, W. S.; Eggleton, C. E.; Berman, R. F. Opiate modification of beta-endorphin, and corticosterone. Peptides 8:819–822; 1987. amygdaloid-kindled seizures in rats. Pharmacol. Biochem. Behav. 28. Negus, S.; Mello, N. K.; Portoghese, P. S.; Lukas, S. E.; Mendelson, 16:751–756; 1981. J. H. Role of delta opioid receptors in the reinforcing and discrimina- 40. Suh, H. H.; Tseng, L. F. Different types of opioid receptors mediating tive stimulus effect of cocaine in rhesus monkeys. J. Pharmacol. Exp. analgesia induced by morphine, DAMGO, DPDPE, DADLE and beta- Ther. 273:1245–1256; 1995. endorphin in mice. Naunyn Schmiedebergs Arch. Pharmacol. 342:67– 29. O’Brien, P. Drug addiction and drug abuse. In: Goodman Gilman, A., 71; 1990. Ed. The pharmacological basis of therapeutics. New York: Pergamon 41. Suzuki, T.; Shiozaki, Y.; Msukawa, Y.; Misawa, M.; Nagase, H. The Press; 1996:557–577. role of mu- and kappa-opioid receptors in cocaine-induced conditioned 30. Paxinos, G.; Watson, C. The rat brain in stereotaxic coordinates. New place preference. Jpn. J. Pharmacol. 58:435–442; 1992. York: Academic Press; 1982. 42. Sweep, C. G. J.; Wiegant, V. M.; De Vry, J.; Van Ree, J. M. 31. Portoghese, P. S.; Sultana, M.; Takemori, A. E. Naltrindole, a highly Beta-endorphin in brain limbic structures as neurochemical selective and potent non-peptide delta opioid receptor antagonist. Eur. correlate of psychic dependence on drugs. Life Sci. 44:1133–1140; J. Pharmacol. 146:185–186; 1988. 1989. 32. Post, R. M.; Weiss, S. R. B. Sensitization, kindling, and anticonvulsant 43. Tella, S. R.; Karupolu, G. R.; Schindler, C. W.; Goldberg, S. R. in mania. J. Clin. Psychiatry 50:23–26; 1989. Pathophysiological and pharmacological mechanism of acute cocaine 33. Rang, H. P.; Dale, M. M.; Ritter, J. M. drugs. In: Rang, toxicity in conscious rats. J. Pharmacol. Exp. Ther. 262:936–946; H. P.; Dale, M. M.; Ritter, J. M., Eds. Pharmacology. London: 1992. Churchill Livingstone; 1995:609–631. 44. Tortella, F. C.; Robles, L.; Mosberg, H. I. Evidence for mu opioid 34. Ritz, M. C.; George, F. R. Cocaine induced seizures and lethality appear to be associated with distinct central nervous system binding receptor mediation of enkephalin-induced electroencephalographic size. J. Pharmacol. Exp. Ther. 264:1333–1343; 1993. seizure. J. Pharmacol. Exp. Ther. 240:571–577; 1987. 35. Sala, M.; Braida, D.; Colombo, M.; Terzi, F.; Leone, M. P.; Gori, E. 45. Tortella, F. C.; Echevarria, E.; Robles, L.; Mosberg, H. I.; Holaday, Influence of opioid system on behavioral sensitization induced by J. W. Anticonvulsant effect of mu (DAGO) and delta (DPDE) en- cocaine in the rat. Regul. Pept. 50:S199; 1994. kephalins in rats. Peptides 9:1177–1181; 1988. 36. Sala, M.; Braida, D.; Colombo, M.; Groppetti, M.; Sacco, S.; Gori, E.; 46. Tseng, L. F.; Henneberry, B.; Collins, K. A. The antinociception Parenti, M. Behavioral and biochemical evidence of opioidergic in- induced by ␤-endorphin administered intrathecally is mediated by the volvement in cocaine sensitization. J. Pharmacol. Exp. Ther. 274:450– activation of ␮- and ␬-opioid receptors in the rat. Naunyn Schmiede- 457; 1995. bergs Arch. Pharmacol. 351:464–468; 1995. 37. Shoji, S.; Simms, D.; McDaniel, W. C.; Gallagher, J. P. Chronic 47. Witkin, J. M.; Johnson, R. E.; Jaffe, J. H.; Goldberg, S. R.; Grayson, cocaine enhances gamma-aminobutyric acid and glutamate release by N. A.; Rice, K. C.; Katz, J. L. The partial opioid agonist, buprenor- altering presynaptic and not postsynaptic gamma-aminobutyric (B) phine, protects against lethal effects of cocaine. Drug Alcohol Depend. receptors within the rat dorsolateral septal nucleus. J. Pharmacol. Exp. 27:177–184; 1991. Ther. 280(1):129–137; 1997. 48. Witkin, J. M.; Newman, A. H.; Nowak, G.; Katz, J. L. Role of 38. Shukla, V. K.; Goldfrank, L. R.; Turndorf, H.; Basinath, M. Antago- dopamine D1 receptors in the lethal effects of cocaine and a nism of acute cocaine toxicity by buprenorphine. Life Sci. 49:1887– quaternary methiodide analog. J. Pharmacol. Exp. Ther. 267:266– 1893; 1991. 274; 1993.