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Psychopharmacology (1982) 77:322-326 Psychopharmacology Springer-Verlag 1982 Behavioral Effects of Morphine and Naloxone Following Chronic Morphine Administration Steven I. Dworkin* and Marc N. Branch University of Florida, Gainesville, Florida, USA Abstract. The effects of morphine, naloxone, and com- binations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s, and each response postponed shock for 20s. Acutely, morphine (0.10-3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10- 30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine re- sulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in com- bination with the daily morphine dose or substituted for the daily administration of morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioral effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24 h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended. Key words: Morphine - Naloxone - Avoidance - Shock- postponement schedules - Tolerance The effects of morphine, a narcotic analgesic agent, its antagonist naloxone, and combinations of these drugs on schedule-controlled behavior have been extensively studied (for a review see McMillan and Leander 1976). The effects of these drugs have been examined with a variety of procedures under which responding prevents, postpones, or terminates electric shock. Morphine generally decreases rates of re- sponding, whereas naloxone is usually without effect until very high doses are used. Doses of naloxone that do not alter responding when studied alone antagonize the effects of morphine when the drugs are administered in combination (Holtzman 1974, 1976). Repeated daily administration of morphine to either rats (Brady and Holtzman 1980; Gellert and Holtzman 1978; Leander et al. 1975) or pigeons (Young and Thompson 1978), * Present address andaddressfor offprint requests: Psychiatry Research Unit, Department of Psychiatry, Louisiana State University Medical Center, P.O. Box 33932, Shreveport, LA 71130, USA decreases sensitivity to the effect of morphine. In these studies with chronic morphine treatment, the effects of naloxone were also changed. Doses of naloxone that had little or no effect in morphine-free animals severely suppressed re- sponding during chronic morphine administration. This change in the effects of naloxone has been suggested to occur after physical dependence to morphine has developed (Brady and Holtzman 1980; Gellert and Sparber 1977; Gellert and Holtzman 1978). Since it is possible for tolerance to occur in the absence of physical dependence (Jaffe 1980), it is of interest to determine if the effects of naloxone would be altered after tolerance but not physical dependence had been acquired. Another aim of the present study was to evaluate the role of "reinforcement density" or "cost" in the development of tolerance to morphine under shock-postponement pro- cedures. Schuster et al. (1966) suggested that behavioral tolerance will develop when the initial effect of the drug results in a decreased frequency of reinforcement (for a review, see Corfield-Sumner and Stolerman 1978). In order to investigate this suggestion, comparable rates and patterns of responding in the presence of disparate contingencies must be engendered. The procedure used in the present study was devised so that different numbers of shocks would be delivered in three separate components of a multiple schedule when morphine was administered, thus resulting in different amounts of "cost" in the three components. Materials and Methods Two males squirrel monkeys (Saimiri sciureus) were main- tained at 95 % of their unresticted feeding weights (960 g for monkey 517 and 920g for monkey 520) by post-session supplemental feeding of Purina Monkey Chow. Between experimental sessions, the monkeys were housed in individual cages with unlimited access to vitamin-enriched water. One monkey (517) had been exposed previously to a multiple variable-ratio, variable-interval schedule of food presen- tation, as well as to several injections of 1.0 mg/kg delta-9- tetrahydrocannabinol (Branch 1976); the other (520) was experimentally naive. Experimental sessions were conducted in a Plexiglas restraining chair (cf. Hake and Azrin 1963). Three pairs of colored 2W lights and a response lever were mounted on the front wall of the chair. A downward force on the lever exceeding 20 g (0.196 N) produced a 40-ms click of a feedback relay mounted behind the front panel and was recorded as a response. A small Plexiglas stock located at the bottom of the chair held the tail so that electric current could be passed 0033-3158/82/0077/0322/$01.00

Behavioral effects of morphine and naloxone following chronic morphine administration

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Page 1: Behavioral effects of morphine and naloxone following chronic morphine administration

Psychopharmacology (1982) 77:322-326 Psychopharmacology �9 Springer-Verlag 1982

Behavioral Effects of Morphine and Naloxone Following Chronic Morphine Administration

Steven I. Dworkin* and Marc N. Branch

University of Florida, Gainesville, Florida, USA

A b s t r a c t . The effects of morphine, naloxone, and com- binations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s, and each response postponed shock for 20s. Acutely, morphine (0.10-3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10- 30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine re- sulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in com- bination with the daily morphine dose or substituted for the daily administration of morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioral effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24 h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.

K e y w o r d s : M o r p h i n e - N a l o x o n e - A v o i d a n c e - Shock- postponement schedules - Tolerance

The effects of morphine, a narcotic analgesic agent, its antagonist naloxone, and combinations of these drugs on schedule-controlled behavior have been extensively studied (for a review see McMillan and Leander 1976). The effects of these drugs have been examined with a variety of procedures under which responding prevents, postpones, or terminates electric shock. Morphine generally decreases rates of re- sponding, whereas naloxone is usually without effect until very high doses are used. Doses of naloxone that do not alter responding when studied alone antagonize the effects of morphine when the drugs are administered in combination (Holtzman 1974, 1976).

Repeated daily administration of morphine to either rats (Brady and Holtzman 1980; Gellert and Holtzman 1978; Leander et al. 1975) or pigeons (Young and Thompson 1978),

* Present address andaddressfor offprint requests: Psychiatry Research Unit, Department of Psychiatry, Louisiana State University Medical Center, P.O. Box 33932, Shreveport, LA 71130, USA

decreases sensitivity to the effect of morphine. In these studies with chronic morphine treatment, the effects of naloxone were also changed. Doses of naloxone that had little or no effect in morphine-free animals severely suppressed re- sponding during chronic morphine administration. This change in the effects of naloxone has been suggested to occur after physical dependence to morphine has developed (Brady and Holtzman 1980; Gellert and Sparber 1977; Gellert and Holtzman 1978). Since it is possible for tolerance to occur in the absence of physical dependence (Jaffe 1980), it is of interest to determine if the effects of naloxone would be altered after tolerance but not physical dependence had been acquired.

Another aim of the present study was to evaluate the role of "reinforcement density" or "cost" in the development of tolerance to morphine under shock-postponement pro- cedures. Schuster et al. (1966) suggested that behavioral tolerance will develop when the initial effect of the drug results in a decreased frequency of reinforcement (for a review, see Corfield-Sumner and Stolerman 1978). In order to investigate this suggestion, comparable rates and patterns of responding in the presence of disparate contingencies must be engendered. The procedure used in the present study was devised so that different numbers of shocks would be delivered in three separate components of a multiple schedule when morphine was administered, thus resulting in different amounts of "cost" in the three components.

M a t e r i a l s and M e t h o d s

Two males squirrel monkeys (Saimiri sciureus) were main- tained at 95 % of their unresticted feeding weights (960 g for monkey 517 and 920g for monkey 520) by post-session supplemental feeding of Purina Monkey Chow. Between experimental sessions, the monkeys were housed in individual cages with unlimited access to vitamin-enriched water. One monkey (517) had been exposed previously to a multiple variable-ratio, variable-interval schedule of food presen- tation, as well as to several injections of 1.0 mg/kg delta-9- tetrahydrocannabinol (Branch 1976); the other (520) was experimentally naive.

Experimental sessions were conducted in a Plexiglas restraining chair (cf. Hake and Azrin 1963). Three pairs of colored 2W lights and a response lever were mounted on the front wall of the chair. A downward force on the lever exceeding 20 g (0.196 N) produced a 40-ms click of a feedback relay mounted behind the front panel and was recorded as a response. A small Plexiglas stock located at the bottom of the chair held the tail so that electric current could be passed

0033-3158/82/0077/0322/$01.00

Page 2: Behavioral effects of morphine and naloxone following chronic morphine administration

through two brass plates resting on a shaved area of the tail. Electrode paste (EKG SOL) was applied to the shaved area to minimize changes in resistance. Shocks were 100 ms duration, 6mA in intensity and were delivered from a 650V (ac), 60 Hz source. The restraint chair was enclosed in a sound- attenuating chamber equipped with an exhaust fan. Sessions were monitored and controlled by a PDP8/f computer operating originally under SKED (Snapper et al. 1974, 1976) and later the SUPER SKED (Snapper and Inglis 1978) software systems. Data were recorded by the computer and a cumulative response recorder located in an adjacent room. White masking noise was continuously present in the ex- perimental room.

Procedure. The subjects were trained under shock-post- ponement schedules (Sidman 1953) with an intermittent shock contingency (Boren and Sidman 1957). In the post- ponement procedures, shocks were scheduled to occur at 4-s intervals (Shock-Shock, or S-S, interval) in the absence of responding, while each response postponed the occurrence of shock for 20s (Response-Shock, or R-S, interval). The avoidance schedules were presented in the context of a three- component multiple schedule. In the presence of white light, 100% of both the R-S and S-S shocks scheduled to be delivered to the monkey were actually presented. In the second component green light illuminated the chamber and a random 67 % of the scheduled shocks were presented. In the presence of a red light, a random 33 % of the scheduled shocks were presented. Components were 10 min in duration and occurred in a repeating sequence starting with the 100% schedule and ending with the 33 ~ schedule. Sessions were run 7 days a week and were terminated after three presentations of each component (90 min).

Drug Procedures. Drugs were first administered after 48 sessions under the multiple schedule. The inital data were used to determine the pretreatment time. The drug data reported here, therefore, were collected after both monkeys had been exposed to the avoidance schedule for over 200 sessions.

Morphine sulfate or naloxone hydrochloride (courtesy of Endo Laboratories, Inc., Garden City, New York) was dissolved in 0.9 ~ sodium chloride solution for injections. Control injections were made using 0.9 ~ sodium chloride solution. Drug injections were in a volume of 0.47 ml for 517 and 0.46 ml for 520. Injections during the acute series were made in the calf muscle. When morphine and naloxone were studied in combination, morphine was injected in the left calf muscle and naloxone was injected in the right calf muscle. Morphine injections were separated by at least 7 days and at least 3 control days separated naloxone injections.

During daily injections of morphine (3.0 mg/kg for mon- key 517 and 1.7 mg/kg for monkey 520), the injection site rotated among calf and thigh muscles. When naloxone was substituted for or given in combination with the daily dose of morphine, such substitutions or combinations were spaced at least 7days apart. Morphine injections were always given 30 rain prior to the start of the session and naloxone was administered immediately before the session. Drug doses were determined in terms of the salts, and each dose or combination was administered at least twice.

Analysis of Results. Since there were no systematic differences in drug effects for the three components of the multiple

323

schedule, these data were combined. Drug effects were expressed as changes in both the absolute rate of responding (in responses/min) and a number of shocks delivered. During the acute series, control values were calculated by averaging data from the days that preceded a drug injection. Effects of the administration of the saline vehicle and the administration of both morphine (30 rain before) and saline (immediately before the sessions) were also determined during both the acute and chronic series of morphine administration.

Results

Acquisition and Control Performance. Comparable control rates and patterns of responding occurred under the three components of the multiple schedule for both subjects. Initially, monkey 517 showed a much higher rate of respond- ing in the 100% component than in the other two com- ponents. This difference in response rates, however, disap- peared by session 27. Response rates in the three components were similar for monkey 520 from the beginning of training. Moderate, constant rates of responding that were similar from component to component were engendered with both subjects, with very few shocks delivered in any component.

Effects of Acute Administration of Morphine. The effects of a range of doses of morphine on response rates (responses/ min) under the avoidance schedule are shown in Fig. l (filled symbols). Morphine resulted in dose-related decreases in response rates for both subjects. Subject 520 was somewhat more sensitive to the rate decreasing effects of morphine than was monkey 517. For example, the largest dose administered to monkey 520, 1.7 mg/kg had behavioral effects similar to those produced by a dose of 3.0 mg/kg given to monkey 517.

Figure 2 (filled symbols) shows the acute effects of mor- phine on the mean number of shocks delivered during the session. Increasing doses of morphine resulted in a large increase in the number of shocks delivered. Monkey 520 also showed greater sensitivity to the effects of morphine on the number of shocks delivered than did monkey 517.

Effects of Acute Administration of Naloxone. The effects of a large range of doses of naloxone (0.1-30.0 mg/kg) were studied. Naloxone did not appreciably alter the rate of responding in any component of the multiple schedule. However, the temporal distribution of responding was altered by the largest dose. The change in temporal patterns resulted in an increase in the number of shocks delivered after 30.0 mg/kg naloxone. This dose had a somewhat greater effect on responding in monkey 520 than in monkey 517.

Effects of Combined Morphine-Naloxone Injections. Three doses of naloxone were studied in combination with the largest dose of morphine to determine whether the shock- increasing and rate-decreasing effects of acute morphine on the shock-postponement schedule could be antagonized by naloxone. The two larger doses of naloxone (1.0 mg/kg and 10.0 mg/kg restored patterns of responding, response rates and shock rates to those observed under control conditions. The lowest dose of naloxone (0.1 mg/kg) did not completely antagonize the behavioral effects of morphine with subject 520.

Effects of Chronic Morphine Administration. The initial effects of the administration of daily doses of morphine during the

Page 3: Behavioral effects of morphine and naloxone following chronic morphine administration

324

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Fig. 1. Effects of morphine on mean response rates during acute drug administration (filled symbols) or during daily administration of mor- phine (open symbols). During daily drugging dose effects were deter- mined by substituting other doses for the usual amount. Ranges are indicated by the vertical lines. Points above "S" show the effects of injecting the drug vehicle (isotonic saline). The points above "C" are means from the control sessions that preceded morphine or saline administration during the acute series.

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Fig. 2. Effects of morphine on the mean number of shocks delivered during acute drug administration (filled symbols) or during daily morphine administration (open symbols). Details are the same as for Fig. 1.

chronic series were very similar to its acute effects. Continued daily administration, however, of a fixed dose of morphine resulted in a reduction in rate-decreasing effects and a large decrease in the number of shocks received in both subjects (see Fig. 2, open circles). By session 30, response rates and shock delivery stabilized to a level seen during the rest of the chronic series.

Once a steady state of responding had developed under daily administrat ion of morphine, other doses of morphine, doses of naloxone (alone or in combinat ion with morphine), or saline occasionally were substituted for the normal daily injection at 7-day minimum intervals. The effects of the saline vehicle and several doses of morphine substituted for the chronic dose are shown in Figs. 1 and 2. Means and ranges of response rates or shocks delivered are shown. Injection of saline instead of the chronic dose of morphine resulted in either no difference or a slight increase in response rates compared to control days under the acute series for both

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Fig. 3. Antagonistic effects on rates of responding of a range of doses of naloxone given in combination with a fixed, rate-decreasing dose of morphine (filled circles). Filled points above "S" show the effects of injecting morphine and saline before the session. Open symbols show the effects of a fixed dose of morphine (3.0 mg/kg for 517, left and 1.7 mg/kg for 520, right) the day after naloxone was administered in combination with morphine during daily morphine administration. Open points above "S" show the effects the day after saline and morphine were administered during the chronic series. Ranges are indicated by the vertical lines

subjects. Chronic administrat ion of morphine resulted in small decreases in sensitivity of response rate to morphine. The shifts in the functions for number of shocks delivered, however, were considerably more pronounced. Few shocks were delivered at any dose (compare open and filled circles). The temporal pat tern and rate of responding following saline administrat ion during this phase were similar to those observed before the daily administrat ion of a fixed dose of morphine.

Effects of Naloxone During the Daily Administration of Morphine. The effects of several doses of naloxone given in combinat ion with a fixed dose of morphine during the chronic regimen are presented in Fig. 3 (filled circles). Every dose of naloxone studied antagonized the decrease in response rates produced by morphine for both subjects. In fact, rates of responding after naloxone injections during the chronic series were increased above those observed when naloxone and morphine combinations were studied under acute conditions. The lowest dose of naloxone studied in combinat ion with morphine was more effective in antagonizing the rate- decreasing effects of morphine during the chronic than during the acute series for monkey 520.

The effects of substituting several doses of naloxone for a fixed daily dose of morphine for both subjects were also studied. That is, a dose of naloxone was given instead of the daily morphine injection. The effects ofna loxone given alone were similar to the effects of naloxone given in combinat ion with the chronic doses of morphine, except that naloxone during the chronic series resulted iri slightly lower rates of responding when it was substituted for morphine.

Somewhat surprisingly, naloxone continued to antagon- ize the effects of morphine 24 h after administration. Figure 3 (open circles) shows that response rates after morphine injections continued to be elevated 24h after naloxone and the daily dose of morphine were given together. The number

Page 4: Behavioral effects of morphine and naloxone following chronic morphine administration

325

of shocks delivered was also decreased. This "day-after" effect was dose-related, with larger doses of naloxone result- ing in larger increases in response rate and decreases in shock frequency. The administration of naloxone alone (i.e., sub- stituted for the daily morphine dose) during the chronic regimen also resulted in a behavioral effect that lasted at least 24 h. These day-after effects were comparable to those observed after administration of naloxone and morphine.

Discussion

The daily administration of morphine did not alter the ability of naloxone to antagonize the rate-decreasing effects of morphine. It has been reported with both pigeons (Young and Thompson 1978) and rats (Brady and Holtzman 1980; Gellert and Holtzman 1978) that multiple daily exposure to mor- phine can change the behavioral effects of naloxone. Thus, doses of naloxone which have little effect on behavior before the chronic administration of morphine severely disrupt behavior in morphine-maintained subjects. It seems possible that the change in the effectss of naloxone observed in these studies was due to the precipitation by naloxone of an abstinence syndrome.

Even though substantial tolerance developed in the pre- sent study, most evidence suggests that the subjects did not develop physical dependence on morphine. When naloxone was either combined with or substituted for the daily dose of morphine, and when the daily dose of morphine was omitted (i.e., when only saline was administered), the most usual restult was performance that closely resembled baseline performance under non-drug conditions. Additionally, no overt signs of abstinence were observed throughout the study. These data, then serve to reinforce the view that tolerance to the effects of morphine can develop in the absence of physical dependence.

The effects of naloxone in the present study lasted much longer than previously reported in pigeons (Dykstra et al. 1974), squirrel monkeys (Holtzman 1976; Teal and Holtzman 1980), and humans (Blumberg and Dayton 1973). Young and Thompson (1978) reported that the rate and temporal patterning of key pecking by morphine-tolerant pigeons were not disrupted the day after naloxone was administered. Dykstra et al. (1974) examined the duration of action of several narcotic antagonists in pigeons under a multiple fixed- interval, fixed-ratio schedule of food presentation. They found that the ability of naloxone to antagonize the rate- decreasing effect of 10 and 30 mg/kg of morphine dissipated in less than 6 h. It is possible that the chronic administration of morphine resulted in some type of physiological per- turbation that altered the metabolism ofnaloxone. However, preliminary data from this laboratory indicate the duration of action of large doses of naloxone exceeds 24 h, when given to squirrel monkeys not on chronic morphine administration. Holtzman's (1976) data are similar to these in that the duration of the effects of naloxone was dose-related. In his study, however, naloxone (1.0-10.0 mg/kg) continued to antagonize the rate-decreasing effects of morphine on squirrel monkeys responding under a shock-postponement schedule for up to 4 h after administration.

Recently, Teal and Holtzman (1980) studied the antag- onism of the discriminative-stimulus effects of morphine by naloxone in squirrel monkeys. They reported that a large dose of naloxone (10.0 mg/kg) partially antagonized the effects of 3.0 mg/kg morphine for as long as 12 h. In the present study,

relatively larger doses of naloxone (17 and 30 mg/kg) antag- onized the effects of morphine for as long as 24h. It is possible, then, that the previous failure to report long-lasting effects of naloxone in squirrel monkeys may have been the result of using doses that are effectively smaller than those used in some parts of the present study.

It was somewhat surprising that response rates did not recover completely to baseline levels during the daily adminis- tration of morphine. The development of tolerance to the effects of morphine has been shown to be facilitated by continuous administration of the drug (McMillan 1973; Woods and Carney 1978 ; Young and Thompson 1978), and it has been suggested that continuous neuronal exposure may be necessary (Seevers and Deneau 1963). It is possible that the failure of complete tolerance to develop to the rate-decreasing effects in the present study may have been due partly to a failure to maintain consistently elevated blood levels. If it is assumed that the frequency of administration of morphine was insufficient to result in continuous "neuronal exposure" to the drug, then other mechanisms of tolerance development should be considered. One likely candidate is that the tolerance was "behavioral", i.e., that it represented the result of some sort of "adjustment" to the effects of the drug. Supporting this hypothesis is the fact that altough complete tolerance to the rate-decreasing effects of morphine did not occur, very nearly complete tolerance developed to the increase in shocks delivered under acute administration. That is, rate of responding recovered to a level that greatly reduced shock frequency, but once such a level was achieved, further increase in rate did not occur. In fact, it is possible to describe behavior under daily administration of morphine as more "efficient" than that observed under non-drug conditions because under control condition rates considerably in excess of the minimum needed to avoid all shocks were maintained; whereas under chronic morphine lower rates resulted in fairly efficient avoidance. Thus, this analysis provides support for the "response cost" hypothesis proposed by Schuster et al. (1966). Acknowledgements. This research was supported by Grant DA-01417 from the National Institute on Drug Abuse. Some of the data reported here were presented at the fifth annual convention of the Association for Behavior Analysis, Dearborn, MI, June 1979.

We thank R. Bellamy, M. Dearing, G. Galbicka, D. Lee, M. Pelick, and R. Scruggs for technical assistance, J. E. Smith and J. D. Lane (Shreveport, LA) for ciritical comments, and S. Hickox and S. Mirkis for help in the preparation of the manuscript. The naloxone was generously supplied by Endo Laboratories, Inc., Garden, City, NY.

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Received September 19, 1980; Final version March 8, 1982