Context-Specific Morphine Withdrawal in Rats - APA PsycNET

Copyright 1990 by the American Psychological Association, Inc. 0735-7044/90/$00.75

Behavioral Neuroscience 1990, Vol. 104, No. 5, 704-710

Context-Specific Morphine Withdrawal in Rats: Duration and Effects of Clonidine John E. Kelsey, Jonathan S. Aranow, and Russell T. Matthews

This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Bates College Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence.

presence of opiates (see O'Brien, Ehrman, & Ternes, 1986, for a review), the few experimental reports of this phenomenon in animals (Hinson & Siegel, 1983; Mucha, Volkovskis, & Kalant, 1981; Raffa & Porreca, 1986; Siegel, 1978) are subject to alternative interpretations (Baker & Tiffany, 1985; Falls & Kelsey, 1989). Recently, however, Falls and Kelsey reported that a procedure sufficient to produce context-specific tolerance to the analgesic effects of morphine also produced a variety of context-specific morphine withdrawal symptoms. Specifically, rats that had previously received morphine paired with a particular environment were more likely to exhibit wet-dog shakes, lick their genitals, circle, rear, and excrete feces in that environment during salineand naltrexone-precipitated withdrawal than were rats that had previously received the same injections of morphine in another environment. Although it is thus possible to produce context-specific opiate withdrawal in an environment previously associated with opiates, the duration of this phenomenon is presently unknown. If Siegel is correct in assuming that these contextspecific withdrawal responses represent classically conditioned responses, then it should be possible to elicit contextspecific withdrawal responses several days or weeks after the last injection of morphine simply by reexposing the rats to the conditioning environment. Falls and Kelsey (1989) tested their rats for withdrawal only 24 hr after the last injection of morphine. Because withdrawal symptoms are often more severe in the presence of residual morphine (e.g., Jacquet, 1978; Stevens & Klemm, 1979), it is possible that their demonstration of context-specific withdrawal symptoms depended on the presence of residual amounts of morphine and that very little context-specific withdrawal would be observed in truly abstinent rats. Because of the theoretical and clinical relevance of Siegel's predictions, we examined in this study the magnitude of context-specific withdrawal 5 days after cessation of a regimen of morphine administration that Falls and Kelsey demonstrated was sufficient to produce contextspecific withdrawal 1 day after the last morphine injection. In addition, we examined the effects of the noradrenergic «2-receptor agonist clonidine on context-specific morphine withdrawal. Clonidine reduces many symptoms of acute opi-

Tolerance to opiates is context specific. For example, rats previously injected with morphine in one context or environment are more tolerant to the analgesic effects of morphine in that environment than are rats previously injected with the same amount of morphine in a different environment (e.g., Siegel, 1978; Siegel, Hinson, & Krank, 1978). Although the mechanisms underlying this context dependency are in dispute (e.g., Baker & Tiffany, 1985; Paletta & Wagner, 1986), Siegel and his coworkers have suggested that context-specific tolerance is caused by the development of classically conditioned responses that oppose, and are compensatory for, the direct effects of morphine (Hinson & Siegel, 1982; Siegel, 1979, 1983, 1989). In the previous example, a classically conditioned response of increased pain reactivity or hyperalgesia was assumed to develop to oppose the analgesic effects of morphine, thereby producing context-specific tolerance (Krank, Hinson, & Siegel, 1981). Extending this hypothesis, Siegel and his coworkers also argued that opiate withdrawal symptoms frequently reflect classically conditioned compensatory responses occurring in an environment previously associated with opiates (Hinson & Siegel, 1982; Siegel, 1979,1983). They further suggest that the occurrence of these aversive context-specific withdrawal symptoms in abstinent ex-addicts may precipitate relapse. There is evidence for context-specific withdrawal in both humans and animals in an environment associated with the absence of opiates, that is, with withdrawal (e.g., O'Brien, O'Brien, Mintz, & Brady, 1975; Wilder & Pescor, 1967). Although there are clinical reports of context-specific withdrawal in an environment previously associated with the This study was based on research submitted to Bates College by Jonathan S. Aranow as partial fulfillment of the requirements for a Bachelor of Science degree in biopsychology. The naltrexone hydrochloride was graciously donated by Endo Laboratories, Garden City, New York. Jonathan S. Aranow is now at the George Washington University Medical School, Washington, DC. Correspondence concerning this article should be addressed to John E. Kelsey, Department of Psychology, Bates College, Lewiston, Maine 04240. 704


CONTEXT-SPECIFIC MORPHINE WITHDRAWAL AND CLONIDINE

ate withdrawal in both humans and animals (e.g., Gold, Redmond, & Kleber, 1978; Sparber & Meyer, 1978; Tseng, Loh, & Wei, 1975) and is used clinically to treat acute opiate withdrawal (see Gossop, 1988, for a review). If the neural mechanisms underlying context-specific opiate withdrawal are identical to those underlying acute context-independent or nonassociative withdrawal, then clonidine should reduce both forms of withdrawal. On the other hand, if contextspecific withdrawal, by virtue of its dependence on associative processes, depends on different brain structures, then clonidine may not as effectively block its occurrence. These possibilities were examined by giving approximately half of the rats clonidine before testing for withdrawal. The general design for establishing context specificity was to place the rats into one of two groups: rats that received morphine paired with the testing environment (referred to as paired rats) and rats that received the same injections of morphine in another environment (referred to as unpaired rats). To the extent that withdrawal is context-specific, paired rats should subsequently emit more withdrawal symptoms in the testing environment than should unpaired rats. To examine the duration of the effect, we initially tested the rats for context-specific withdrawal in the testing environment 5 days after morphine abstinence. We then readdicted the rats to morphine and retested them for withdrawal in the testing environment 1 day after the last injection of morphine to examine context-specific acute withdrawal as in the study by Falls and Kelsey (1989). To examine the effects of clonidine, we injected approximately half of the rats in the paired and unpaired groups with clonidine before both postabstinence and acute withdrawal.

Method Subjects The subjects were 31 naive male Sprague-Dawley rats that weighed 260-388 g at the start of the experiment. They were housed individually in clear plastic cages with wood shavings as bedding in a colony that was lighted from 7:00 a.m. to 7:00 p.m. Food and water were available ad lib, except during testing.

Apparatus Three galvanized steel observation boxes (22 x 26 x 36 cm) with clear plastic fronts and removable screen-mesh floors were used for conditioning and the assessment of withdrawal. These boxes were kept in a distinct testing room that was illuminated by a 15-W red light. A paper towel saturated with orange-scented perfume (Oil Sweet Orange Valencia, Centflor Inc., NY) provided the testing room with a distinct odor. Extraneous noises were masked by a ventilation fan and white noise (70 ± 2 dB).

Procedure The 31 rats were randomly assigned to one of four groups of a 2 x 2 factorial design. Approximately half of the rats were designated as paired rats because they received morphine paired with the testing environment, and the remaining half were designated as unpaired rats because they received morphine in a separate environment, unpaired with the testing environment. Before testing for withdrawal,

705

approximately half the rats of the paired and unpaired groups received saline, whereas the other half received clonidine. Nine rats were in the paired-saline group, 7 were in the unpaired-saline group, 7 were in the paired-clonidine group, and 8 were in the unpairedclonidine group. Development of dependence. To establish context specificity and equate exposure to the two different environments, we used the following procedure. The paired rats were injected with saline in the morning in a room that was illuminated with white light and had no special odor or white noise. These rats were then injected with morphine in the distinct testing room in the afternoon. Conversely, the unpaired rats were injected with saline in the testing room in the morning and with morphine in the separate room in the afternoon. At approximately the same time each day, 1-3 paired rats were transported to the separate room in covered, white plastic cages, and 1-3 unpaired rats were transported to the testing room in their home cages. After 5 min, each rat was injected subcutaneously with isotonic saline. The paired rats were then returned to their white cages, and the unpaired rats were placed into the observation boxes. After 1 hr, all rats were returned to their home cages in the colony. Three hours later, the paired rats were taken to the testing room in their home cages, and the unpaired rats were taken to the other room in covered, white plastic cages. After 5 min, each rat was injected subcutaneously with morphine and placed in the observation box (paired rats) or returned to the white cage (unpaired rats). After 1 hr, all rats were returned to the colony. This procedure was repeated daily for 6 consecutive days during which the morphine doses were increased according to the following schedule: Day 1, 10 mg/kg; Day 2, 15 mg/kg; Days 3 and 4, 20 mg/ kg; Day 5, 30 mg/kg; and Day 6, 40 mg/kg. Morphine was taken from a stock bottle of 15 mg/cc (Lilly). Saline injections were given in a volume equivalent to that day's morphine injection. Postabstinence withdrawal. For 4 days after the last morphine injection, all rats received no further injections but were weighed at the usual times. On the 5th day of abstinence, all rats were assessed for withdrawal in the testing room in the afternoon at a time when they had previously received morphine. One hour before testing, each rat was injected subcutaneously with isotonic saline or 0.06 mg/kg clonidine hydrochloride in water at a volume of 1 cc/kg according to group assignment. After 55 min, each rat was brought to the testing room in its home cage. After 5 min, each rat was injected subcutaneously with 1 cc/kg isotonic saline and placed into the observation box in which it had been conditioned. During the course of three consecutive 5-min periods, the frequency of the five following withdrawal symptoms was recorded: wet-dog shakes (a sudden, violent shake of the head, shoulders, and body), genital licks (presumably reflecting ejaculation), circles (complete continuous circles), rears (balancing on hind paws), and jumps (all four paws off the ground). These symptoms were selected because all have been shown to be reliable indicators of opiate withdrawal (Blasig, Herz, Reinhold, & Zieglgansberger, 1973; Linseman, 1977; Wei, Loh, & Way, 1973) and can be unambiguously counted. After this 15-min observation period, each rat was removed from its box and injected subcutaneously with 6 mg/kg naltrexone hydrochloride (1 cc/kg) to enhance withdrawal. The rat was then immediately placed back into the observation box and withdrawal symptoms were observed as before during three consecutive 5-min periods. At the end of the 30-min observation period, the weight of feces excreted and the loss of body weight were recorded. Readdiction. Beginning on the next day, the rats were reconditioned and readdicted during 3 consecutive days using the method just described. Dosages of morphine were as follows: Day 1,15 mg/ kg; Day 2, 20 mg/kg; and Day 3, 30 mg/kg. One paired-saline rat and 1 unpaired-clonidine rat died during the readdiction process. Acute withdrawal. One day after their last morphine injection,

706

J. KELSEY, J. ARANOW, AND R. MATTHEWS SALINE

Table 1 Mean Amount (±SE) of Feces Excreted and Loss in Body Weight (in Grams) During the 30-Min Postabstinence Withdrawal Period for Paired and Unpaired Groups Injected With Saline or Clonidine

NALTREXONE

to 2.0 o 1.5 1.0

Feces excreted LJ O 0.0

Group A -- -

Paired Saline Clonidine Unpaired Saline Clonidine

3


(/I LJ

Weight loss

M

SE

M

SE

9 7

0.33 0.00

1.00 0.00

2.56 2.14

1.01 0.90

7 8

0.14 0.25

0.38 0.71

2.00 2.37

1.00 1.19

O

o

15 13 QL
8.00, ps < .01 (see Figure 1). Pairing x Precipitation interactions and subsequent simple effects tests indicated that because of the small number of symptoms occurring during naltrexone-precipitated withdrawal, the paired rats licked their genitals and reared more than did the unpaired rats only during the 15 min of salineprecipitated withdrawal. There were no significant effects of pairing or precipitation on wet-dog shakes or jumps because these responses seldom occurred. Similarly, there were no effects of pairing on feces excreted or weight loss (see Table 1). Effects of clonidine. Main effects of drug indicated that 0.06 mg/kg clonidine decreased genital licks, F(l, 27) = 32.77, p < .001, circles, F(l, 27) = 4.35, p < .05, and rears, F(l, 27) = 9.02, p < .01 (see Figure 1). Pairing x Drug interactions indicated that clonidine decreased genital licks, F ( l , 27) = 4.92, p < .05, and rears, F(l, 27) = 10.58, p < .01, and tended to decrease circles, F(l, 27) = 3.18, p < .09, in the paired rats more than it did in the unpaired rats (see Figure 1). Because of the small number of symptoms elicited during naltrexone-precipitated withdrawal, Drug x Precipitation interactions and subsequent simple effects tests indicated that clonidine decreased genital licks and rears only during salineprecipitated withdrawal. Clonidine did not significantly alter wet-dog shakes, jumps, feces excreted, or weight loss (see Table 1).

Acute Withdrawal As expected, somewhat more withdrawal symptoms, especially feces excreted and weight loss, were noted during acute withdrawal 1 day after the 3 additional days of morphine injections than were noted during postabstinence withdrawal (cf. Figures 2 and 3 with Figure 1 and Table 2 with Table 1). Moreover, in contrast to postabstinence withdrawal, the largest number of symptoms were generally observed during naltrexone-precipitated withdrawal, presumably indicating that more morphine remained in the rats' systems for naltrexone to block after 1 day of morphine abstinence than after 5 days of abstinence. Effects of pairing. Main effects of pairing indicated that the paired animals circled, F ( l , 25) = 4.77, p < .05, reared,

707

CONTEXT-SPECIFIC MORPHINE WITHDRAWAL AND CLONIDINE NALTREXONE

SAUNE

NALTREXONE

SAUNE

ex

°-8 0.6 0.4 0.2 LU O.O

— KO

CIRCLES

1.2 O 1.0

17

0.7


14

0.5

§0.3< Q

tL 0.1 5 ''

Q_ 21.0 ^0.5

10

15

20

25

TIME SINCE INITIAL INJECTION

1 ..

\

V

•Xx

,0

^^N^Z^-ELlA

0.0

5

10

15

30

(min)

\

i 6.30, ps < .05. Pairing x Precipitation interactions and subsequent simple effects tests indicated that the paired rats circled and reared more only during saline-precipitated withdrawal (see Figures 2 and 3). Although the paired rats tended to excrete more feces and lose more weight than the unpaired rats, no significant effects of pairing were observed on genital licks, wet-dog shakes, feces excreted, or weight loss (see Figure 3 and Table 2). Effects ofdonidine. Main effects of drug indicated that clonidine decreased genital licks, F(\, 25) = 15.09, p < .001 (see Figure 3), feces excreted, F(l, 25) = 33.84, p < .001, and weight loss, F(l, 25) = 9.87, p < .01 (see Table 2), and tended to decrease wet-dog shakes, F(l, 25) = 2.86, p < .10 (see Figure 3). Drug x Precipitation interactions and subsequent simple effects tests indicated that clonidine also decreased rearing during saline-precipitated withdrawal, F ( l , 46) = 11.57, p < .01 (see Figure 2). In contrast, these same interactions and simple effects tests indicated that during naltrexone-precipitated withdrawal

Figure 3. Mean number of genital licks and wet-dog shakes during saline- and naltrexone-precipitated withdrawal 1 day after the last injection of morphine. (Groups: Filled circles = paired-saline; open circles = paired-clonidine; filled triangles = unpaired-saline; open triangles = unpaired-clonidine.)

clonidine increased circles, F(l, 46) = 32.79, p < .001, rears, F(l,46) = 7.53,p< .0 1, and jumps, F( 1,46)= 13.76, p< .00 1 (see Figure 2). The absence of significant Pairing x Drug interactions indicated that these clonidine effects were roughly equivalent for both the paired and unpaired rats.

Discussion During acute withdrawal 1 day after the last injection of morphine, rats previously injected with morphine in a particular environment (paired rats) emitted more saline- and naltrexone-precipitated withdrawal symptoms (circles, rears, and jumps) in that environment than did rats previously injected with morphine in another environment (unpaired rats). With small exceptions likely to be due to differences in procedure, these results are similar to those of Falls and Kelsey (1 989), who had provided the clearest demonstration Table 2 Mean Amount (±SE) of Feces Excreted and Loss in Body Weight (in Grams) During the 30-Min Acute Withdrawal Period for Paired and Unpaired Groups Injected With Saline or Clonidine Feces excreted Group Paired Saline Clonidine Unpaired Saline Clonidine

Weight loss

M

SE

M

SE

8 7

8.13 1.14

3.80 1.57

10.25 6.86

3.77 3.93

7 7

6.43 0.86

3.87 0.90

9.43 4.29

4.69 1.25


708

J. KELSEY, J. ARANOW, AND R. MATTHEWS

of context-specific opiate withdrawal. Thus, the present results provide further evidence that opiate withdrawal symptoms as well as opiate tolerance can be context specific and are therefore likely to be the result of associative processes. Moreover, as predicted by Siegel (1979, 1983) these contextspecific withdrawal symptoms were greater in an environment previously associated with the presence of opiates (paired rats) than in an environment associated with its absence (unpaired rats). Further indicating that this context specificity reflected associative processes was the novel finding that reexposure to the pairing environment was sufficient to elicit context-specific withdrawal symptoms (genital licks, circles, and rears) even after 5 days of morphine abstinence. The finding that naltrexone failed to induce additional symptoms during postabstinence withdrawal suggests that most traces of morphine had cleared the rats' systems during the 5 days of abstinence. These findings imply that context-specific withdrawal reflects a relatively long-lasting learned response and that its expression does not depend on the presence of morphine. Thus, these results support the hypothesis that reintroduction of an abstinent ex-addict to an environment previously associated with opiates may be sufficient to induce withdrawal symptoms and perhaps relapse (O'Brien et al., 1986; Hinson & Siegel, 1982; Siegel, 1979, 1983). Insofar as these context-specific withdrawal symptoms reflect responses that are compensatory for the direct effects of morphine, for example, impotence and sedation (Jaffe, 1985), these data are consistent with the hypothesis that withdrawal symptoms frequently reflect classically conditioned compensatory responses that occur in the absence of morphine (Hinson & Siegel, 1982; Siegel, 1979, 1983). Whatever the appropriate explanation, it appears that habituation, a major competing hypothesis offered to account for the reduction of effects during development of context-specific opiate tolerance (Baker & Tiffany, 1985), cannot as easily account for the expression of novel symptoms during context-specific withdrawal (see Falls & Kelsey, 1989). In evaluating the conclusion that we have demonstrated long-lasting, clinically relevant, context-specific opiate withdrawal, two cautions must be noted. First, some of the symptoms, primarily feces excreted and weight loss, observed after 5 days of abstinence were less intense than those observed during acute withdrawal. Thus, context-specific withdrawal symptoms that occur after several days of abstinence may not be sufficiently intense or aversive to induce relapse. Second, two of the context-specific symptoms observed during postabstinence withdrawal (i.e., circling and rearing) may be instances of conditioned activity (Mucha et al., 1981) rather than reflections of conditioned withdrawal. However, the context-specific increase in genital licks, a behavior that in our experience occurs rarely in nonwithdrawing rats even when they are circling and rearing (see Falls & Kelsey, 1989), cannot be as easily dismissed and is likely to reflect withdrawal. To further assess these cautions, it will be instructive to determine whether more pairings with higher doses, a procedure designed to produce greater conditioning and more intense acute withdrawal, will produce more intense postabstinence context-specific withdrawal.

The finding that 0.06 mg/kg clonidine reduced most of the withdrawal symptoms, including genital licks, circles, rears, feces excreted, and weight loss, is consistent with the results of others (e.g., Britton, Svensson, Schwartz, Bloom, & Koob, 1984; Sparber & Meyer, 1978; Tseng et al., 1975). What is novel are two additional findings. First, clonidine was at least as, and often more, effective in reducing these symptoms in paired rats as in unpaired rats during both postabstinence and saline-induced acute withdrawal. This implies that associative or context-specific withdrawal relies on at least some of the same physiology used in nonassociative or contextindependent withdrawal. Of more clinical relevance, this result implies that clonidine may be useful not only in reducing symptoms during acute withdrawal but also in reducing context-specific withdrawal symptoms and possibly subsequent relapse in abstinent ex-addicts produced by returning to an environment previously associated with morphine. Second, this study indicates that although clonidine generally reduces postabstinence and saline-induced acute withdrawal symptoms, it enhances several of the symptoms precipitated by naltrexone during acute withdrawal. The capacity of clonidine to enhance the jumping elicited by opiate receptor blockers during acute withdrawal in rats has been observed by several investigators (Buccafusco, Marshall, & Turner, 1984; Tierney, Nadaud, Koenig-Berard, & Stinus, 1988; Tseng et al., 1975; van derLaan, 1985). However, the observation that clonidine can also enhance naltrexone-precipitated circling and rearing is apparently novel, although Tseng et al. noted that clonidine also increased "excitement" and locomotor activity during naloxone-precipitated acute withdrawal. Britton et al. (1984) and Tierney et al. (1988) have also noted that clonidine can increase teeth chattering during naloxone-precipitated acute withdrawal. The important question of whether these enhanced symptoms reflect enhanced, rather than reduced, withdrawal has not been addressed. Until it has, these observations suggest caution in the practice of combining both clonidine and opiate receptor blockers such as naltrexone to speed the process of acute opiate withdrawal in humans (e.g., Charney, Heninger, & Kleber, 1986; Kleber, Topazian, Gaspari, Riordan, & Kosten, 1987). In interpreting these effects of clonidine on naltrexoneprecipitated acute withdrawal in the present study, it should be noted that this was the second time these rats had experienced withdrawal, naltrexone, and clonidine within a short period of time. How this prior experience may have influenced the results is not known. However, the finding that the effects of pairing, naltrexone, and clonidine during acute withdrawal in this study are so similar to the effects reported in studies in which there was no prior experience (see previous paragraphs) suggests that our results did not depend on this prior experience. It has been suggested that clonidine reduces many of the symptoms of acute opiate withdrawal by acting as an a2receptor agonist to decrease the firing of critical norepinephrine neurons, perhaps in the locus coeruleus (Aghajanian, 1978; Gold, Byck, Sweeney, & Kleber, 1979), amygdala (Freedman & Aghajanian, 1985), or spinal cord (Franz, Hare, & McCloskey, 1982). However, the mechanisms by which


CONTEXT-SPECIFIC MORPHINE WITHDRAWAL AND CLONIDINE

clonidine enhances several of the same symptoms during naloxone- or naltrexone-precipitated acute withdrawal that it decreases during postabstinence and saline-precipitated acute withdrawal are not yet understood. Based on findings that serotonergic agonists inhibit the ability of clonidine to enhance naloxone-induced jumping during acute morphine withdrawal, van der Laan and Hillen (1986) argued that clonidine enhances naloxone-precipitated jumping by inhibiting serotonergic neurons. Whether this hypothesis also accounts for the enhanced circling and rearing that we observed remains to be determined. Given that the amygdala has been implicated in mediating jumping during opiate withdrawal (Calvino, Lagowska, & Ben-Ari, 1979; Lagowska, Calvino, & Ben-Ari, 1978), it may be informative to examine its role in these effects. References Aghajanian, G. K. (1978). Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature, 276, 186-188. Baker, T. B., & Tiffany, S. T. (1985). Morphine tolerance as habituation. Psychological Review, 92, 78-108. Blasig, J., Herz, A., Reinhold, K., & Zieglgansberger, S. (1973). Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia, 33, 19-38. Britton, K. T., Svensson, T., Schwartz, J., Bloom, F. E., & Koob, G. F. (1984). Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine. Life Sciences, 34, 133-139. Buccafusco, J. J., Marshall, D. C., & Turner, R. M. (1984). A comparison of the inhibitory effects of clonidine and guanfacine on the behavioral and autonomic components of morphine withdrawal in rats. Life Sciences, 35, 1401-1408. Calvino, B., Lagowska, J., & Ben-Ari, Y. (1979). Morphine withdrawal syndrome: Differential participation of structures located within the amygdaloid complex and striatum of the rat. Brain Research, 177, 19-34. Charney, D. S., Heninger, G. R., & Kleber, H. D. (1986). The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone. American Journal of Psychiatry, 143, 831-837. Falls, W. A., & Kelsey, J. E. (1989). Procedures that produce contextspecific tolerance to morphine in rats also produce context-specific withdrawal. Behavioral Neuroscience, 103, 842-849. Franz, D. N., Hare, B. D., & McCloskey, K. L. (1982). Spinal sympathetic neurons: Possible sites of opiate-withdrawal suppression by clonidine. Science, 215, 1643-1645. Freedman, J. E., & Aghajanian, G. K. (1985). Opiate and «2-adrenoceptor responses of rat amygdaloid neurons: Co-localization and interactions during withdrawal. Journal of Neuroscience, 5, 30163024. Gold, M. S., Byck, R., Sweeney, D. R., & Kleber, H. D. (1979). Endorphin-locus coeruleus connection mediates opiate action and withdrawal. Biomedicine, 30, 1-4. Gold, M. S., Redmond, D. E., & Kleber, H. D. (1978). Clonidine blocks acute opiate-withdrawal symptoms. Lancet, 2, 599-602. Gossop, M. (1988). Clonidine and the treatment of the opiate withdrawal syndrome. Drug and Alcohol Dependence, 21, 253-259. Hinson, R. E., & Siegel, S. (1982). Nonpharmacological bases of drug tolerance and dependence. Journal of Psychosomatic Research, 26, 495-503.

709

Hinson, R. E., & Siegel, S. (1983). Anticipatory hyperexcitability and tolerance to the narcotizing effect of morphine in the rat. Behavioral Neuroscience, 97, 759-767. Jacquet, Y. F. (1978). Opiate effects after adrenocorticotropin or /3-endorphin injection in the periaqueductal gray matter of rats. Science, 201, 1032-1034. Jaffe, J. H. (1985). Drug addition and drug abuse. In A. G. Oilman, L. S. Goodman, T. W. Rail, & R. Murad (Eds.), Goodman and Oilman's the pharmacological basis of therapeutics (7th ed., pp. 532-581). New York: Macmillan. Kleber, H. D., Topazian, M., Gaspari, J., Riordan, C. E., & Kosten, T. (1987). Clonidine and naltrexone in the outpatient treatment of heroin withdrawal. American Journal of Drug and Alcohol Abuse, 13, 1-17. Krank, M. D., Hinson, R. E., & Siegel, S. (1981). Conditioned hyperalgesia is elicited by environmental signals of morphine. Behavioral and Neural Biology, 32, 148-157. Lagowska, J., Calvino, B., & Ben-Ari, Y. (1978). Intra-amygdaloid applications of naloxone elicits severe withdrawal signs in morphine dependent rats. Neuroscience Letters, 8, 241-245. Linseman, M. A. (1977). Naloxone-precipitated withdrawal as a function of the morphine-naloxone interval. Psychopharmacology, 54, 159-164. Mucha, R. F., Volkovskis, C., & Kalant, H. (1981). Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance. Journal of Comparative and Physiological Psychology, 95, 351-362. O'Brien, C. P., Ehrman, R. N., & Ternes, J. W. (1986). Classical conditioning in human opioid dependence. In S. R. Goldberg & I. P. Stolerman (Eds.), Behavioral analysis of drug dependence (pp. 329-356). Orlando, FL: Academic Press. O'Brien, C. P., O'Brien, T. J., Mintz, J., & Brady, J. P. (1975). Conditioning of narcotic abstinence symptoms in human subjects. Drug and Alcohol Dependence, 1, 115-123. Paletta, M. S., & Wagner, A. R. (1986). Development of contextspecific tolerance to morphine: Support for a dual-process interpretation. Behavioral Neuroscience, 100, 611-623. Raffa, R. B., & Porreca, F. (1986). Evidence for a role of conditioning in the development of tolerance to morphine-induced inhibition of gastrointestinal transit in rats. Neuroscience Letters, 67, 229232. Siegel, S. (1978). Tolerance to the hyperthermic effect of morphine in the rat is a learned response. Journal of Comparative and Physiological Psychology, 92, 1137-1149. Siegel, S. (1979). The role of conditioning in drug tolerance and addiction. In J. D. Keehn (Ed.), Psychopathology in animals: Research and clinical implications (pp. 143-168). New York: Academic Press. Siegel, S. (1983). Classical conditioning, drug tolerance, and drug dependence. In R. G. Smart, F. B. Glaser, Y. Israel, H. Kalant, R. E. Popham, & W. Schmidt (Eds.), Research advances in alcohol and drug problems (pp. 207-246). New York: Plenum Press. Siegel, S. (1989). Pharmacological conditioning and drug effects. In A. J. Goudie & M. W. Emmett-Oglesby (Eds.), Psychoactive drugs: Tolerance and sensitization (pp. 115-180). Clifton, NJ: Humana Press. Siegel, S., Hinson, R. E., & Krank, M. D. (1978). The role of predrug signals in morphine analgesic tolerance: Support for a Pavlovian conditioning model of tolerance. Journal of Experimental Psychology: Animal Behavior Processes, 4, 188-196. Sparber, S. B., & Meyer, D. R. (1978). Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats. Pharmacology, Biochemistry and Behavior, 9, 319-325.


710

J. KELSEY, J. ARANOW, AND R. MATTHEWS

Stevens, D. R., & Klemm, W. R. (1979). Morphine-naloxone interactions: A role for nonspecific morphine excitatory effects in withdrawal. Science, 205, 1379-1380. Tierney, C, Nadaud, D., Koenig-Berard, E., & Stinus, L. (1988). Effects of two alpha2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats. American Journal of Cardiology, 61, 35D-38D. Tseng, L., Loh, H. H., & Wei, E. T. (1975). Effects of clonidine on morphine withdrawal signs in the rat. European Journal of Pharmacology, 30, 93-99. van der Laan, J. W. (1985). Effects of a,-agonists on morphine withdrawal behaviour: Potentiation of jumping mediated by