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Associative and non-associative tolerance to morphine: Support for a dual-process habituation model
Life Sciences, vol. 42, pp. 1897-1906 Printed in the U.S.A.
Pergamon Press
ASSOCIATIVEAND NON-ASSOCIATIVETOLERANCE TO MCRPEKNE: SWF'ORT FOR A DUAL-FROCESSRARITUATIONMODEL Richard I. Dafters, Josephine Odber, and John Miller psychologyDepartment, Adam SmithBuilding, Glasgow University, Glasgow, Scotland, G12 8RT. (Received in final form March 11, 1988)
Some unique predictions of a dual-processhabituationmodel of morphine analgesic tolerance were examined concerning the interactions of drug-signalconditions and dose/frequencyparsmeters. The model assumes that tolerance is the result of a combinationof associative and non-associativehabituationmechanismswhich are differentially affected by dose and drug-signalconditions. In accordancewith predictions of the model, low doses and long interdrug intervals (IDI's) resulted in faster tolerance acquisition,greater tolerance retention, and higher levels of associativetolerence, than high doses and short IDI's. Alternative accounts of tolerance based on Pavlovian conditioningmechanisms omtexplain this pattern of results. The question of generality of these findings to other drugs and other response measures is discussed. A major developmentin the theoreticalanalysis of drug tolerancehas been the shift from explanationsbased entirely upon physiologicalmechanisms to those emphasizingenvironmentaland learning factors. The main impetus for shift of emphasis was an initial series of experimentson rats b Mitchell and his colleagues (1,2), and subsequentelaborationsby Siegel (3,45 , showing that tolersnoe to the analgesic effects of morphine is context-specific;that is, tolerance is msximal when tolerance induction and tolerance testing sre conducted in the same environment. This reseerch prompted Siegel's (1975) proposal that morphine tolerance be conceptualisedby a Pavlovian conditioningmodel (3). According to this model, environmentalcues reliably paired with morphine stimuli (CS's) which elicit a compensatory administrationserve as c&k%ned conditionedresponse (CCR). The form of this response is hypothesizedto be opposite in direction, or antagonistic,to the direct effect of the drug (RR). The acquisitionof this response with repeated drug-stimuluspairings produces the net reduction in observed drug effects characteristicof tolerance. Although the Pavlovian model has received considerableempirical support in the literature,including demonstrationsof such traditionalconditioning phenomena as extinction,latent inhibition,sensory pre-conditioning,and blocking (4,5), a major difficulty for the model has been the failure of numerous attempts to obtain direct evidence of compensatoryCRes when tolerant animals are presented with drug-paired stimuli in the non-drugged state (6-S). Also, evidence exists that associativemechanisms cannot account for all instances of morphine tolerance. For example, tolerance can develop, albeit at a reduced rate, when no reliable drug signsls are available (9,lO). 0024-3025188$3.00 + .OO Copyright (c) 1988 Pergamon Press plc
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Recently, a novel analysis of morphine tolerancehas been proposed which osn accommodateboth associativeand non-associativetolerance effects but which does not rely upon conditioningprocesses or on the existence of CCR's (11). This analysis is based on WagnerPs influentalpriming model of habitm tion (12). According to this model, the magnitude of unconditionedresponding to a presented stimulus (or drug) depends upon how "surprising"it is. A stimulus is more or less surprisingto the extent that it is already represented or "primed" in short-termmemory (STM). An expected event (i.e. one already primed in STM) elicits less stimulus processing and consequentlyevokes a diminishedresponse (conditioneddiminutionof the UR). This decreased responding constituteshabituation,or in the case of a drug, tolerance. An important feature of this model is that a stimulus (drug) may be primed in STM either non-associatively,by a prior recent presentationof that stimulus (self-generatedpriming) or associatively,by presentationof stimuli (such as a distinctivecontextI previously paired with the stimulus (associative priming). Thus, demonstrationsof context-specifictolerance axe to be seen as manifestationsof associativepriming; tolerancewhich develops in the absence of reliable contextualcues represents self-generatedpriming. This importantnew approach to morphine toleranceremains to be properly evaluated and the main aim of the present experimentis to test some unique predictionsof the model concerning the interactionsof drug dose/frequency parameterswith drug signal conditions. First, the model predicts that the proportion of tolerance that is context-specific(i.e. associativelyprimed) will vary inverselywith dxug dose and as a positive function of inter-dose interval (IDI). This is because low doses and long IDI's are less likely than high doses and short IDIts to produce prolonged maintenanceof a drug's properties in STM through self-generatedpriming. Thus, drug doses will be more "surprising"and thereforemore likely to be associatedwith the concurrent environmentalstimuli responsiblefor associativetolerance.Second, associative priming will result in greater retention of tolerance than self-generated tolerance. Tbis prediction follows from the fact that in self-generated priming a representationof the drug will not be present in STM at the time of the retention-testdose unless a previous drug administrationhas occurred recently; where tolerance is acquired through associativepriming, on the other hand, it is only necessary that the contextualcues (CS's) be present whenever the test dose is administeredfor tolerance to be manifest. Finally, the model suggests that the rate of tolerance developmentwill vary with dose/ frequency parameters and drug signal conditionsbut in sn interactivemanner which is difficult to predict. Certainly,in the absence of reliable drug signals tolerance developmentwill vary as a positive function of drug dose and a negative function of mI. This follows directly from the model since, on any given drug administration,the likelihoodof a representationof the drug already being primed in memory from a previous drug administration(selfgenerated),and hence producing tolerance,increaseswith dose and decreases with IDI. This predictionhas been confirmed in a recent study in which drugpaired cues were minimized by deliveringmorphine through chronic indwelling catheters (10). However, where reliable drug signals are present, it might be expected that the rate of tolerance developmentwill depend upon the relative strengths of associativeand non-associativecomponents. Since, as we have argued, associativepriming will be greater with low doses and long IDI's whereas non-associativepriming will be greater with high doses and short IDI's, changes in dose and ID1 parameterswill have opposite effects on associativeand non-associativetolerance.Thus, the model appears to predict that the presence of drug signals will weaken the positive dose-tolerancerelationshipsnd the negative IDI-tolerancerelationshipobserved by Seaman in a non-associativeparadigm@~It is even possible, with sufficientlysalient cues that associativemechanismsmay dominate the tolerance acquisitionprocess and produce faster toleranceacquisitionwith lower doses and longer IDI's.
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The present study sought to test these predictionsby comparing groups of rats acquiring tolerance under different dose and ID1 regimens which were designed to favour either associativeor non-associativemechanisms. For each group, morphine and placebo administrationswere paired with different distinctive environments,and tolerance to morphine analgesiawas assessed by sdministering a hot-plate nocioeption test after each drug injection. Following tolerance acquisitionthe proportion of associativetolerance in the different groups was assessed by administeringa test dose of morphine in the placebo environment (context-specificity test); the degree of attenuationof tolerance on this test reflects the degree to which tolerance is dependent upon drugpaired contextual stimuli. Finally, a further test dose of morphine (tolerance retention test) was administeredin the usual drug environmentafter a 28-day period in which the subjects had been left undisturbedin their homecages. Those rats which showed the greatest level of associativetolerance on the context-specificitytest were expected to show the highest level of tolerance retention. Materials and Methods The subjects were 48 male Wistar rats (Bsntin and Kingnan Limited, Hull, England) weighing 200-250g at the start of the experiment. They were individually caged and given free access to food and water throughout the experiment. The experimentwas carried out in two small adjacent testing rooms. One of these, the homecsge environment (HC), was illuminatedcontinuouslyby a standard 150-W 240-V strip light. The other room, the distinctiveenvironment (DE), was illuminatedby flashing light from a Griffon xenon stroboscope (2 flashes/set),oaourizea with an air-freshenerspray (Haze), and backgrouna white noise at 70 dB was continuous. In addition, a 15-W 240-v red lamp provided sufficientlight to enable analgesia assessmentsto be made and recorded. Responsivity to nociceptive stimulationwas determinedwith a conventional hot-plate apparatus (SocrelModel DSj7, Harvard Apparatus Ltd., Edenbridge, Kent) in which sensitivityto pain is assessed by observing the rats latency to lick a paw when placed on a metal plate heated to 54.2-10.2deg C. When a rat was tested, it was removed from its cage and placed on the hot-plate for 50 sec. The electronic timer was started by a foot switch as the rat was lowered onto the plate and stopped by the same means when the rat licked a paw or after 50 set if no response was made. All injectionswere subcutaneousin the dorsal surface of the neck, and rats received 5, 10, or 20 mg/kg of morphine sulphate in 10 mg/ml solution of O.* physiologicalsaline. The volume of physiological saline (placebo)injection was 1 ml/kg. All rats were thoroughlyfamiliarizedwith handling, weighing, and injection rituals prior to drug treatment. On each of 5 days of familiarization they were removed from their homecages, weighed, and injected with saline. Dmnediatelyfollowing each injection they were placed on the unheated plate of the analgesiometerand allowed to explore for 60 sec. Previous work in this laboratoryhas shown that in the absence of such familiarizationsessions, injection ritual/handlingcues may overshadowdrug-pairedenvironmentalstimuli and prevent the developmentof context-specifictolerance (15). Immediatelyfollowing the familiarizationperiod, the rats were assigned to one of three aose/lDI groups which, according to the habituationmodel, were expected to develop associativetolerance to differing degrees. Thus, rats in group MS5 (5 mg/kg of morphine once every 5 clays)should develop more associative tolerance than group MS20 (20 mg/kg of morphine once each aay), with group MS10 (10 mg/kg morphine on alternate days) falling somewherebetween. Saline injectionswere alternatedwith morphine injectionsand were given at the midpoint of the IDI. Thus, for example, if group MS10 received morphine at 10 a.m
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on Monday, Wednesday and Friday, saline would be injected at 10 a.m. onTuesday,
Thursday and Saturday. Half of the subjects in each dose/ID1 condition received morphine injectionsin room DE and saline in room HC; for the other half the drug-contextpairings were reversed. On drug treatment sessjom the rats were weighed and injected with the appropriatedose of morphine in the homecage room (HC), and then half of them (DRUGDE groups) were immediatelytransported in a mobile cage rack into room DE; the other half (DRUGHC groups) remained in room HC. 30 minutes after the injection each rat was tested on the hot-plate in its respectiveenvironment. DRUGDE rats remained in room DE for a further 90 minutes after testing before being returned to the homecage room. Cn saline treatment sessions, the procedure was identical except that all subjects were injected with saline, DRUGDE rats reme,inedin room HC while DRUGHC rats were transportedto room DE, and nociceptivetesting was not performed. The context-specificit test was administeredafter 16 injections (8 drug and 8 saline administrations 5 in groups MS5 and MSIO, and after 22 injections (11 drug end 11 saline administrations)in group MS20. The additional treatments were necessary in group MS20 because this group developed tolerancemore slowly than the other groups end required 3 additional treatmentsto achieve a comparablelevel of tolerance prior to the context-specificitytest. Cn the test all rats received their normal dose of morphine in room DE. This meant that for half of each dose/ID1 group (DRUGHC) morphine was experiencedin the absence of the usual environmentalcues. Hot-plate testing followed 30 minutes later as usual. Associative tolersnoe is indicatedby a loss of tolerance (increase in pawliok latency) in those subjects receiving en environment-change compared to those receiving drug in the usual drug environment. Following the test, the rats received 6 additionalinjections (3 drug and 3 saline) under identical conditions to those experiencedin the tolerance acquisition phase. This was intended to counteractany possible disruptive effects of the context-specificitytest on establisheddrug-contextassociations. Finally, rats in groups MS5 and MS20 remained treatment-freein a standard colony room of the adjacent animal house for 28 days prior to administration of the toleranceretention test (group MS10 subjects were omitted from this stage because of space limitationsin the holding rooms and because they aid not differ from MS5 subjects on the context-specificitytest). On the retention test all rats were injected with their appropriatedose of morphine, and tested on the hot-plate in their usual drug environment30 minutes later. Results Acquisitionof tolerance Two subjects from each of conditionsDRUGDE and DRUGHC in the MS10 group, and one subject from each condition in the MS20 group died early in training and N's for these groups were thereforereduced appropriately.Figure 1 shows tolerance acquisitionover the course of 8 drug treatmentsin groups MS5 and MSIO, and the 11 treatmentsin group MS20.
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r
FIG. 1 Group meen pawlick latencies e-reseed as a percentage of the initial latency during the acquisitionphase Data from DRUG-DE and DRDC-RC conditionshave been combined sinca an Anova, with Dose/ID1 group, Drug-environment,end Sessions 1 to 8) as factors, revealed no significanteffect of Drug-environment@ t1,36)=C.4g0 The differences in tolerance effects of Dose/lDI p<.OOl , and significantinteractionof these two factors p<.OOl . No other interactionsapproached significanoe. As a measure of rate of tolerauce acquisitionin the 3 Dose/ID1 groups, it was found that groups MS5, MSIO, and MS20 required means of 3.12, 6.5, end 7.78 drug treatments respectivelyto reach a criterion of 7596of initial An Anova revealed these group differences to be significant p<.OOfl while neither the Drug-environmentmain effect not the interactionof Post hoc factors were significantp(1,36)=1.10 and F(2,36)=.9 respectiveld. tests on the trials-to-criterionscores using the Scheff/emethod found significant differencesbetween groups MS5 end MS10 b<.Ofl end between groups MS5 and MS20 fi<.Ofl, but the differencebetween groups MS10 end MS20 just failed to reach significanoeat the .05 level.
3
Context-speoificity. Table 1 shows the group meau latencies (expressedas a percentage of initial latency) on the context-specificitytest (Test) end on the last session of acquisition (Baseline).
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TABLE
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I
Effect of Change of Drug-AdministrationEnvironment
MS10
(DGEC)
(DSDE)
(DzEC)
MS10
(7)
MS20 (DzEC)
MS20 (DZDE)
= Baseline
59.01+7.8
Test
$4.01+22.3 55.1624.7
58.99+5.4
64.70-+13.147.582.6
65.31-+11.0 52.67-+10.0
&.95-+11.4
69.9 212.2 47.132 8.8
46.4027.6
Data are presented as mean 2lS.D. An + indicates test values that sre significantlydifferent from the baseline measure, P < .05. Significsntattenuationof tolerance on the test day occurred only in groups MS~(DRUGHC) and mio(mu~~c) fi(7 = 2.06, p< .05, one-tailedand T(5)= 5.42, p<.OO5, one tailed respective1 s . In other words, an attenuationof tolerance occurred only in the two lowest dose/longestID1 groups and only in those subjects experiencinga change in drug context. The two groups did not differ in the degree of attenuationfi(12)= .lOfl. Two proceduralpoints are raised by our findings of a differencein associative tolerancebetween relativelyhigh dose/short ID1 snd low dose/long ID1 groups. One issue concerns our strategy of testing each group with their respective treatment dose. Although this method is not unique (14), it is perhaps more usual to administera standard test dose to all groups on the context-specificity test. Both strategieshave certain inherent difficulties(11). The former renders between-groupcomparisonsdifficult; the latter means that some groups experiencea dose change from tolerance acquisitionto the test trial which adds a confoundingfactor to the environment-change manipulation.In the present study, it was aecided to adopt the former strategy. The second question concerns the fact that in order to achieve a significantlevel of tolerance,subjects in group MS20 were given 3 more acquisitiontreatments than subjects in groups MS5 and MS10 prior to the test. While acknowledging this confoundingfactor, we believe that it is still reasonable to interpret the data as supportingthe predictionsof the dual-processmodel. After all, the data shows that group MS20 had acquired less associativetolerance than the other groups despite having greater opportunity (more drug treatments)to do so. Tolerance retention. Figure 2 shows the extent of toleranceretention following a 28 day drug-free period in a neutral environment (colony room) for groups MS5 and MS20. The columns representmean hotplate latencies on the last of the 3 morphine sessionswhich followed the context-specificitytest (baseline),snd on the retention test (test) for groups MS5 and MS20, expressed as a percentage of the initial latency. Again, scores from both drug-environmentconditionshave been combined since this factor was found not to be significant,@(1,26)=4.g by Anova. The figure suggests that a loss of tolerance (increasein latency) occurred over the 28-day m-free period in both groups and, more importantly, that the loss was greater in the high dose/short ID1 subjects (group MS20) than This was confirmed statistiin the low dose/long ID1 subjects (group MS5 cally by a significantmain effect of Dose . nificsnt interactionof Dose and Baseline vs Test factors
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c
100 110
i
90
J!j
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+
80 10 60 50 40
1255
PIG. 2 Pre- and Post-retentionlatencies (+ 1 SEM) The main effect of Baseline VE Test was also significant B (1,26)=17.86, Subsequent tests for simple main effect showed that the increase in latencies between the baseline and test sessions just reached significance <.Q$J and was highly significantfor group for Group MS5 ,$(1,14)=4.79, MS20 ~(1,12)=11.89, p <.OO5f . pc.oog.
Discussion In general the results provide support for the dual-processhabituationmodel. As predicted, the degree of associative tolerance, indexed by susceptibility to a context-specificitytest, was greater in subjects receiving low doses end long IDI's during tolerance developmentthan in subjects receiving high doses and short IDI's. This was expected since, according to the model, low doses administeredinfrequentlyare less likely to result in maintained activation of drug representationsthrow self-generatedpriming, drug presentationswill therefore be surprising and more likely to be associatedwith concurrent contextual stimuli. The fact that no differencewas found between groups MS5 and MS10 may simply reflect the fact that the dose and ID1 parameters experienced by these groups were not sufficientlydifferent from each other to generate different asymptotic levels of associative tolerance.Siegel!3Pavlovian model of tolerance does not address non-associativetolerance at all and therefore has little to say regarding the kind of interactionbetween dos&I peremeters end drug signals found here. In addition, a straightforwardconditioning approach requires that the magnitude of CR's and the UCS (drug dose) be positively related. The present results stsnd in direct contrast to this prediction. second prediction of the habituationmodel which was examined in the experiment concerned the retention of tolerance over a drug-free period. It was argued earlier that if tolerance is acquired non-associativelyit will only be manifest on a retention test if a representationof the drug has been primed in memory by a recent prior dose (self-generatedpriming). If tolerance is The
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acquired associatively,it is only necessery that the retention test be administered in the same drug-pairedcontext in which tolerancewas acquired, since the drug representationwill be primed by the contextualcues (associativelygenerated priming). As it is unlikely that significantself-generatedpriming could survive the 28-dey drug-free period used in the present experiment,it follows that the level of tolerence seen on the retention test will be proportional to the degree that it was associatively-acquired.This wes confirmed by the data. Tolerance retention was greater in subjects who had shown a hi level of associativetolerance on the context-specificitytest (group MS5$” than in subjectswho had shown a non-significantlevel (group MS2O). This finding confirms previous reports of the importanceof signalledas opposed to unsignallea drug presentationin producing long-term retention of tolerance (15,16), but in addition suggests that the mere presence of distinctivecontextualcues is not sufficient. It is also necessary that the drug dose and frequency peremetersused in acquisitionare such as to favour associativeas opposed to non-associativemeohanisms. The findings concerning the acquisitionof tolerance in the present study are certainly in accord with the habituationmodel, although in this case it is difficult to generate clear predictions. As argued previously,frequent high doses of drug favour non-associativetolerancemechanisms; infrequentlow doses favour associativemeohanisms. Thus, manipulationsof dose end frequency parameters will have opposite effects on associativeana non-associativetolerance. It is probable then, that the presence of distinctivecontextualcues paired with drug in the present experiment,by allowing associativemechanisms to operate, will weaken the predicted positive correlationbetween tolerance and dose/frequencyfound in unsignelleaprocedures (10,17). In fact our results suggest that associativemechanisms dominated the tolerance acquisitionprocess since tolerancewas acquired more rapidly in low dose/long ID1 subjects than in high dose/short ID1 subjects. This result is in accord with other published data showing that drug signaJ.sexert greater effects on tolerance at low rather then high doses (17,18),and at long rather than short lDI@s (ly), although only the latter study examined the rate of tolerance development. In the other papers, tolerance tests were conducted only after tolersncelevels were asymptotic. Again these results are difficult to reconcile with a Pavlovian analysis of tolerance since associativestrength normally increaseswith increases in magnitude of the UCS (i.e. increases in dose). It may be felt that the absence of augmented acquisitionin DRUG-DE groups relative to DRUGHC groups is problematicfor the dual-processhabituation model. We do not share this view since it implies that only DE is capable of forming an associationwith the drug state, whilst HC is associativelyneutral. This is not the case. It is not the absolute salience of discriminative stimuli that determines their associativepower but their discriminabilityfrom each other. The HC cues sre able to sot as potent discriminativestimuli precisely because they are contrastedwith another set of very different cues (arisingfrom DE), and from which they differ in terms of their relationshipto the drugged state. Indeed, where fully balanced designs have been used, with DRUGHC and DRUGDE grcups receiving tests in either the drug or no-drug environment, context-specificeffects occur irrespectiveof the acquisitionenvironment (22). One issue raised by our results requires further discussion. It may be argued that the apparent absence of associativetolerance in the high dose/short ID1 &roup (m20), as indicatedby the absence of a response to the context-speoifioity test, was due to over-shadowingof the contextualstimuli by interoceptive drug cues, which would be expected to feature more prominantlyunder high dose conditions. While there is evidence that interoceptivedrug cues may pley a role in associativetolerance (20) and that over-shadowingcan be a factor in trenssituationaltolerance (IT), we do not believe that this played a major role in the present experimentfor two reasons. First, if associative
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tolerance development to interoceptivecues in group MS20 was significantly strong to overshadow contextual cues on the context-specificitytest, it is hard to understand why it did not produce faster tolerance developmentin the tolerance acquisitionphase. It will be remembered that group MS20 required additional drug treatments to achieve a significantlevel of tolerence at all. Second, associativetolerance to interoceptivecues in group MS20 cannot explain the pattern of results observed on the retention test. Group MS20 showed less tolerance retention than group MS5 despite experiencinginteroceptive drug cues on that test that they had experiencedduring acquisition.Clearly, further work is required to elucidate the relative contributionsof exteroceptive end interoceptivecueing, end to determine the relative importanceof dose and IDI factors to associativeand non-associativetolerance. Finally, although the present results favour an habituationenalysis in preference to a Pavlwisn analysis of morphine analgesic tolerance, it is possible that with other response systems and other drugs, both analyses may be appropriate. A recent study suggests that classically-conditioned compensatory responses (CCR's)may contribute to associativetolerance in situationswhere the -elicited UR also exhibits a "oompensatoryl@ second phase (21). In this study, two responses to morphine were studied which showed different patterns of URss: tail-flick analgesia,which was found to consist only of a monophasic hypoalgesia,and aotivity, which was found to consist of a biphasti OR, with an initial hypoactivitybeing followed by a secondaryhyperactivity phase. In support of the dual-processmodel suggested, tolerance occurred in both measures but evidence of a CCR was found only in the activity measure. Acknowledgement This research was supported by a grant from the Scottish Home and Health Depsrtment, Grant No. K/MRS/SO/C826. References 1.
2. :: 5. ;: 8. 9. 10.
11. 12. 13. 14. 15. 16. 17.
W.H. ADAMS, S.Y. YE& L.A. WOODS end C.L. MITCHELL, J. P~Eu% Eb% The%, 168, 251-257 (1969). s. KAYAN, L.A. WOODS, end C.L. FHTCBELL, Eur. J. phiurn.&, 333-339 (19691 S. SIEGEL, J. Comp. Fhysiol. Psychol. 2, 498-506 (1975). S. SIEGEL, J. Ezp. Psych: Ani.Behav. Proc. 2, 1-13 (1977). R.I. DAFTER& M. HETHERINGTONend H. MoCARTNEY, Qu.J. Exp.Psch. 35, l-11 (1983). M.T. BARD0 and R,A. RTJGBES,Ph#xn.Bioohem.Behav. l0, 481-485 (1979). G.J. LaHOSTE, R.D. OLSON G.A. OLSON and A,J, KASTIN, Pharm.Biochem.and Behav. 3, 799-SO4 (1980). JOE. SHERMAN, Learning and Motivation,l0, 383-418 (1979). S.T. TIFFANY snd T.B. BAKER, J. Camp. Physiol. Psych. 2, 747-762 (1981). S,F. SEAMAN, in F.R. Brush and J.B. 0vermier (eds.),Affeot, conditioning and cognition: essays on the determinantsof behavior, 249-262 Hillsdale NJ: Erlbaum (1985). T.B. BBgER end S.T. TIFFANY, Psych. Rev. j2, 78-108 (1985). A.R. WAGNER. In: A. Dickinson and B.A. Boakes (Eds.) Mechanisms of learning and motivation,Hillsdale NJ: Erlbaum, 53-82 (1979). R.I. DAFl!ERSand L. BACH, Psychopharmacology, g, 101-106 (1985). S. KAYAN, R.K. FERGUSON and C.L. MITCHELL, J.Phsrm.Exp.Ther.185, 300-306 (1973). S. KAYAN and C.L. MITCRELL, Arch.Internat.Pharmacodynemie, s, 407-414 (1972). R.P. KESNER end T,B. BAKER. In: J.L. Martinez, R.A. Jensen, R.B. Messing, H. Rigter and J.L. McGaugh (Eds.). Eudogenouspeptides and learning and memory processes, New York: Academic Press, 479-518 (1981). T.B. BAKER end S.T. TlFFANY. cited in: T.B. Baker and S.T. Tiffany, Psych. Rev. 92, 78-10s (1985).
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R,E, HINSON and S, SIEGEL, Behav. Neurosci,2, 759-767 (1983). R.P, KESNER and D.G. COOK. Behax. Neurosci,41, 4-12 (1983). J. GREZLEFf,I,'&A.D. C.X. POULOS and R. CAPPFZL. Psychophamn,5, 159-162 (1984). M,S. PALETTA and A.R. WAGNER. Behav. Neurosci,100, 611-623 (1986). C.R. CROWELL, R.E. HINSON and S. SIM;EL. Psyohopharm.,11, 51-4 (1981).
Pergamon Press
ASSOCIATIVEAND NON-ASSOCIATIVETOLERANCE TO MCRPEKNE: SWF'ORT FOR A DUAL-FROCESSRARITUATIONMODEL Richard I. Dafters, Josephine Odber, and John Miller psychologyDepartment, Adam SmithBuilding, Glasgow University, Glasgow, Scotland, G12 8RT. (Received in final form March 11, 1988)
Some unique predictions of a dual-processhabituationmodel of morphine analgesic tolerance were examined concerning the interactions of drug-signalconditions and dose/frequencyparsmeters. The model assumes that tolerance is the result of a combinationof associative and non-associativehabituationmechanismswhich are differentially affected by dose and drug-signalconditions. In accordancewith predictions of the model, low doses and long interdrug intervals (IDI's) resulted in faster tolerance acquisition,greater tolerance retention, and higher levels of associativetolerence, than high doses and short IDI's. Alternative accounts of tolerance based on Pavlovian conditioningmechanisms omtexplain this pattern of results. The question of generality of these findings to other drugs and other response measures is discussed. A major developmentin the theoreticalanalysis of drug tolerancehas been the shift from explanationsbased entirely upon physiologicalmechanisms to those emphasizingenvironmentaland learning factors. The main impetus for shift of emphasis was an initial series of experimentson rats b Mitchell and his colleagues (1,2), and subsequentelaborationsby Siegel (3,45 , showing that tolersnoe to the analgesic effects of morphine is context-specific;that is, tolerance is msximal when tolerance induction and tolerance testing sre conducted in the same environment. This reseerch prompted Siegel's (1975) proposal that morphine tolerance be conceptualisedby a Pavlovian conditioningmodel (3). According to this model, environmentalcues reliably paired with morphine stimuli (CS's) which elicit a compensatory administrationserve as c&k%ned conditionedresponse (CCR). The form of this response is hypothesizedto be opposite in direction, or antagonistic,to the direct effect of the drug (RR). The acquisitionof this response with repeated drug-stimuluspairings produces the net reduction in observed drug effects characteristicof tolerance. Although the Pavlovian model has received considerableempirical support in the literature,including demonstrationsof such traditionalconditioning phenomena as extinction,latent inhibition,sensory pre-conditioning,and blocking (4,5), a major difficulty for the model has been the failure of numerous attempts to obtain direct evidence of compensatoryCRes when tolerant animals are presented with drug-paired stimuli in the non-drugged state (6-S). Also, evidence exists that associativemechanisms cannot account for all instances of morphine tolerance. For example, tolerance can develop, albeit at a reduced rate, when no reliable drug signsls are available (9,lO). 0024-3025188$3.00 + .OO Copyright (c) 1988 Pergamon Press plc
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Recently, a novel analysis of morphine tolerancehas been proposed which osn accommodateboth associativeand non-associativetolerance effects but which does not rely upon conditioningprocesses or on the existence of CCR's (11). This analysis is based on WagnerPs influentalpriming model of habitm tion (12). According to this model, the magnitude of unconditionedresponding to a presented stimulus (or drug) depends upon how "surprising"it is. A stimulus is more or less surprisingto the extent that it is already represented or "primed" in short-termmemory (STM). An expected event (i.e. one already primed in STM) elicits less stimulus processing and consequentlyevokes a diminishedresponse (conditioneddiminutionof the UR). This decreased responding constituteshabituation,or in the case of a drug, tolerance. An important feature of this model is that a stimulus (drug) may be primed in STM either non-associatively,by a prior recent presentationof that stimulus (self-generatedpriming) or associatively,by presentationof stimuli (such as a distinctivecontextI previously paired with the stimulus (associative priming). Thus, demonstrationsof context-specifictolerance axe to be seen as manifestationsof associativepriming; tolerancewhich develops in the absence of reliable contextualcues represents self-generatedpriming. This importantnew approach to morphine toleranceremains to be properly evaluated and the main aim of the present experimentis to test some unique predictionsof the model concerning the interactionsof drug dose/frequency parameterswith drug signal conditions. First, the model predicts that the proportion of tolerance that is context-specific(i.e. associativelyprimed) will vary inverselywith dxug dose and as a positive function of inter-dose interval (IDI). This is because low doses and long IDI's are less likely than high doses and short IDIts to produce prolonged maintenanceof a drug's properties in STM through self-generatedpriming. Thus, drug doses will be more "surprising"and thereforemore likely to be associatedwith the concurrent environmentalstimuli responsiblefor associativetolerance.Second, associative priming will result in greater retention of tolerance than self-generated tolerance. Tbis prediction follows from the fact that in self-generated priming a representationof the drug will not be present in STM at the time of the retention-testdose unless a previous drug administrationhas occurred recently; where tolerance is acquired through associativepriming, on the other hand, it is only necessary that the contextualcues (CS's) be present whenever the test dose is administeredfor tolerance to be manifest. Finally, the model suggests that the rate of tolerance developmentwill vary with dose/ frequency parameters and drug signal conditionsbut in sn interactivemanner which is difficult to predict. Certainly,in the absence of reliable drug signals tolerance developmentwill vary as a positive function of drug dose and a negative function of mI. This follows directly from the model since, on any given drug administration,the likelihoodof a representationof the drug already being primed in memory from a previous drug administration(selfgenerated),and hence producing tolerance,increaseswith dose and decreases with IDI. This predictionhas been confirmed in a recent study in which drugpaired cues were minimized by deliveringmorphine through chronic indwelling catheters (10). However, where reliable drug signals are present, it might be expected that the rate of tolerance developmentwill depend upon the relative strengths of associativeand non-associativecomponents. Since, as we have argued, associativepriming will be greater with low doses and long IDI's whereas non-associativepriming will be greater with high doses and short IDI's, changes in dose and ID1 parameterswill have opposite effects on associativeand non-associativetolerance.Thus, the model appears to predict that the presence of drug signals will weaken the positive dose-tolerancerelationshipsnd the negative IDI-tolerancerelationshipobserved by Seaman in a non-associativeparadigm@~It is even possible, with sufficientlysalient cues that associativemechanismsmay dominate the tolerance acquisitionprocess and produce faster toleranceacquisitionwith lower doses and longer IDI's.
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The present study sought to test these predictionsby comparing groups of rats acquiring tolerance under different dose and ID1 regimens which were designed to favour either associativeor non-associativemechanisms. For each group, morphine and placebo administrationswere paired with different distinctive environments,and tolerance to morphine analgesiawas assessed by sdministering a hot-plate nocioeption test after each drug injection. Following tolerance acquisitionthe proportion of associativetolerance in the different groups was assessed by administeringa test dose of morphine in the placebo environment (context-specificity test); the degree of attenuationof tolerance on this test reflects the degree to which tolerance is dependent upon drugpaired contextual stimuli. Finally, a further test dose of morphine (tolerance retention test) was administeredin the usual drug environmentafter a 28-day period in which the subjects had been left undisturbedin their homecages. Those rats which showed the greatest level of associativetolerance on the context-specificitytest were expected to show the highest level of tolerance retention. Materials and Methods The subjects were 48 male Wistar rats (Bsntin and Kingnan Limited, Hull, England) weighing 200-250g at the start of the experiment. They were individually caged and given free access to food and water throughout the experiment. The experimentwas carried out in two small adjacent testing rooms. One of these, the homecsge environment (HC), was illuminatedcontinuouslyby a standard 150-W 240-V strip light. The other room, the distinctiveenvironment (DE), was illuminatedby flashing light from a Griffon xenon stroboscope (2 flashes/set),oaourizea with an air-freshenerspray (Haze), and backgrouna white noise at 70 dB was continuous. In addition, a 15-W 240-v red lamp provided sufficientlight to enable analgesia assessmentsto be made and recorded. Responsivity to nociceptive stimulationwas determinedwith a conventional hot-plate apparatus (SocrelModel DSj7, Harvard Apparatus Ltd., Edenbridge, Kent) in which sensitivityto pain is assessed by observing the rats latency to lick a paw when placed on a metal plate heated to 54.2-10.2deg C. When a rat was tested, it was removed from its cage and placed on the hot-plate for 50 sec. The electronic timer was started by a foot switch as the rat was lowered onto the plate and stopped by the same means when the rat licked a paw or after 50 set if no response was made. All injectionswere subcutaneousin the dorsal surface of the neck, and rats received 5, 10, or 20 mg/kg of morphine sulphate in 10 mg/ml solution of O.* physiologicalsaline. The volume of physiological saline (placebo)injection was 1 ml/kg. All rats were thoroughlyfamiliarizedwith handling, weighing, and injection rituals prior to drug treatment. On each of 5 days of familiarization they were removed from their homecages, weighed, and injected with saline. Dmnediatelyfollowing each injection they were placed on the unheated plate of the analgesiometerand allowed to explore for 60 sec. Previous work in this laboratoryhas shown that in the absence of such familiarizationsessions, injection ritual/handlingcues may overshadowdrug-pairedenvironmentalstimuli and prevent the developmentof context-specifictolerance (15). Immediatelyfollowing the familiarizationperiod, the rats were assigned to one of three aose/lDI groups which, according to the habituationmodel, were expected to develop associativetolerance to differing degrees. Thus, rats in group MS5 (5 mg/kg of morphine once every 5 clays)should develop more associative tolerance than group MS20 (20 mg/kg of morphine once each aay), with group MS10 (10 mg/kg morphine on alternate days) falling somewherebetween. Saline injectionswere alternatedwith morphine injectionsand were given at the midpoint of the IDI. Thus, for example, if group MS10 received morphine at 10 a.m
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HabituationModel of Morphine Tolerance
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on Monday, Wednesday and Friday, saline would be injected at 10 a.m. onTuesday,
Thursday and Saturday. Half of the subjects in each dose/ID1 condition received morphine injectionsin room DE and saline in room HC; for the other half the drug-contextpairings were reversed. On drug treatment sessjom the rats were weighed and injected with the appropriatedose of morphine in the homecage room (HC), and then half of them (DRUGDE groups) were immediatelytransported in a mobile cage rack into room DE; the other half (DRUGHC groups) remained in room HC. 30 minutes after the injection each rat was tested on the hot-plate in its respectiveenvironment. DRUGDE rats remained in room DE for a further 90 minutes after testing before being returned to the homecage room. Cn saline treatment sessions, the procedure was identical except that all subjects were injected with saline, DRUGDE rats reme,inedin room HC while DRUGHC rats were transportedto room DE, and nociceptivetesting was not performed. The context-specificit test was administeredafter 16 injections (8 drug and 8 saline administrations 5 in groups MS5 and MSIO, and after 22 injections (11 drug end 11 saline administrations)in group MS20. The additional treatments were necessary in group MS20 because this group developed tolerancemore slowly than the other groups end required 3 additional treatmentsto achieve a comparablelevel of tolerance prior to the context-specificitytest. Cn the test all rats received their normal dose of morphine in room DE. This meant that for half of each dose/ID1 group (DRUGHC) morphine was experiencedin the absence of the usual environmentalcues. Hot-plate testing followed 30 minutes later as usual. Associative tolersnoe is indicatedby a loss of tolerance (increase in pawliok latency) in those subjects receiving en environment-change compared to those receiving drug in the usual drug environment. Following the test, the rats received 6 additionalinjections (3 drug and 3 saline) under identical conditions to those experiencedin the tolerance acquisition phase. This was intended to counteractany possible disruptive effects of the context-specificitytest on establisheddrug-contextassociations. Finally, rats in groups MS5 and MS20 remained treatment-freein a standard colony room of the adjacent animal house for 28 days prior to administration of the toleranceretention test (group MS10 subjects were omitted from this stage because of space limitationsin the holding rooms and because they aid not differ from MS5 subjects on the context-specificitytest). On the retention test all rats were injected with their appropriatedose of morphine, and tested on the hot-plate in their usual drug environment30 minutes later. Results Acquisitionof tolerance Two subjects from each of conditionsDRUGDE and DRUGHC in the MS10 group, and one subject from each condition in the MS20 group died early in training and N's for these groups were thereforereduced appropriately.Figure 1 shows tolerance acquisitionover the course of 8 drug treatmentsin groups MS5 and MSIO, and the 11 treatmentsin group MS20.
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r
FIG. 1 Group meen pawlick latencies e-reseed as a percentage of the initial latency during the acquisitionphase Data from DRUG-DE and DRDC-RC conditionshave been combined sinca an Anova, with Dose/ID1 group, Drug-environment,end Sessions 1 to 8) as factors, revealed no significanteffect of Drug-environment@ t1,36)=C.4g0 The differences in tolerance effects of Dose/lDI p<.OOl , and significantinteractionof these two factors p<.OOl . No other interactionsapproached significanoe. As a measure of rate of tolerauce acquisitionin the 3 Dose/ID1 groups, it was found that groups MS5, MSIO, and MS20 required means of 3.12, 6.5, end 7.78 drug treatments respectivelyto reach a criterion of 7596of initial An Anova revealed these group differences to be significant p<.OOfl while neither the Drug-environmentmain effect not the interactionof Post hoc factors were significantp(1,36)=1.10 and F(2,36)=.9 respectiveld. tests on the trials-to-criterionscores using the Scheff/emethod found significant differencesbetween groups MS5 end MS10 b<.Ofl end between groups MS5 and MS20 fi<.Ofl, but the differencebetween groups MS10 end MS20 just failed to reach significanoeat the .05 level.
3
Context-speoificity. Table 1 shows the group meau latencies (expressedas a percentage of initial latency) on the context-specificitytest (Test) end on the last session of acquisition (Baseline).
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HabituationModel of Morphine Tolerance
TABLE
Vol. 42, No. 19, 1988
I
Effect of Change of Drug-AdministrationEnvironment
MS10
(DGEC)
(DSDE)
(DzEC)
MS10
(7)
MS20 (DzEC)
MS20 (DZDE)
= Baseline
59.01+7.8
Test
$4.01+22.3 55.1624.7
58.99+5.4
64.70-+13.147.582.6
65.31-+11.0 52.67-+10.0
&.95-+11.4
69.9 212.2 47.132 8.8
46.4027.6
Data are presented as mean 2lS.D. An + indicates test values that sre significantlydifferent from the baseline measure, P < .05. Significsntattenuationof tolerance on the test day occurred only in groups MS~(DRUGHC) and mio(mu~~c) fi(7 = 2.06, p< .05, one-tailedand T(5)= 5.42, p<.OO5, one tailed respective1 s . In other words, an attenuationof tolerance occurred only in the two lowest dose/longestID1 groups and only in those subjects experiencinga change in drug context. The two groups did not differ in the degree of attenuationfi(12)= .lOfl. Two proceduralpoints are raised by our findings of a differencein associative tolerancebetween relativelyhigh dose/short ID1 snd low dose/long ID1 groups. One issue concerns our strategy of testing each group with their respective treatment dose. Although this method is not unique (14), it is perhaps more usual to administera standard test dose to all groups on the context-specificity test. Both strategieshave certain inherent difficulties(11). The former renders between-groupcomparisonsdifficult; the latter means that some groups experiencea dose change from tolerance acquisitionto the test trial which adds a confoundingfactor to the environment-change manipulation.In the present study, it was aecided to adopt the former strategy. The second question concerns the fact that in order to achieve a significantlevel of tolerance,subjects in group MS20 were given 3 more acquisitiontreatments than subjects in groups MS5 and MS10 prior to the test. While acknowledging this confoundingfactor, we believe that it is still reasonable to interpret the data as supportingthe predictionsof the dual-processmodel. After all, the data shows that group MS20 had acquired less associativetolerance than the other groups despite having greater opportunity (more drug treatments)to do so. Tolerance retention. Figure 2 shows the extent of toleranceretention following a 28 day drug-free period in a neutral environment (colony room) for groups MS5 and MS20. The columns representmean hotplate latencies on the last of the 3 morphine sessionswhich followed the context-specificitytest (baseline),snd on the retention test (test) for groups MS5 and MS20, expressed as a percentage of the initial latency. Again, scores from both drug-environmentconditionshave been combined since this factor was found not to be significant,@(1,26)=4.g by Anova. The figure suggests that a loss of tolerance (increasein latency) occurred over the 28-day m-free period in both groups and, more importantly, that the loss was greater in the high dose/short ID1 subjects (group MS20) than This was confirmed statistiin the low dose/long ID1 subjects (group MS5 cally by a significantmain effect of Dose . nificsnt interactionof Dose and Baseline vs Test factors
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c
100 110
i
90
J!j
HabituationModel of Morphine Tolerance
1903
+
80 10 60 50 40
1255
PIG. 2 Pre- and Post-retentionlatencies (+ 1 SEM) The main effect of Baseline VE Test was also significant B (1,26)=17.86, Subsequent tests for simple main effect showed that the increase in latencies between the baseline and test sessions just reached significance <.Q$J and was highly significantfor group for Group MS5 ,$(1,14)=4.79, MS20 ~(1,12)=11.89, p <.OO5f . pc.oog.
Discussion In general the results provide support for the dual-processhabituationmodel. As predicted, the degree of associative tolerance, indexed by susceptibility to a context-specificitytest, was greater in subjects receiving low doses end long IDI's during tolerance developmentthan in subjects receiving high doses and short IDI's. This was expected since, according to the model, low doses administeredinfrequentlyare less likely to result in maintained activation of drug representationsthrow self-generatedpriming, drug presentationswill therefore be surprising and more likely to be associatedwith concurrent contextual stimuli. The fact that no differencewas found between groups MS5 and MS10 may simply reflect the fact that the dose and ID1 parameters experienced by these groups were not sufficientlydifferent from each other to generate different asymptotic levels of associative tolerance.Siegel!3Pavlovian model of tolerance does not address non-associativetolerance at all and therefore has little to say regarding the kind of interactionbetween dos&I peremeters end drug signals found here. In addition, a straightforwardconditioning approach requires that the magnitude of CR's and the UCS (drug dose) be positively related. The present results stsnd in direct contrast to this prediction. second prediction of the habituationmodel which was examined in the experiment concerned the retention of tolerance over a drug-free period. It was argued earlier that if tolerance is acquired non-associativelyit will only be manifest on a retention test if a representationof the drug has been primed in memory by a recent prior dose (self-generatedpriming). If tolerance is The
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vol. 42, No. 19, 1988
acquired associatively,it is only necessery that the retention test be administered in the same drug-pairedcontext in which tolerancewas acquired, since the drug representationwill be primed by the contextualcues (associativelygenerated priming). As it is unlikely that significantself-generatedpriming could survive the 28-dey drug-free period used in the present experiment,it follows that the level of tolerence seen on the retention test will be proportional to the degree that it was associatively-acquired.This wes confirmed by the data. Tolerance retention was greater in subjects who had shown a hi level of associativetolerance on the context-specificitytest (group MS5$” than in subjectswho had shown a non-significantlevel (group MS2O). This finding confirms previous reports of the importanceof signalledas opposed to unsignallea drug presentationin producing long-term retention of tolerance (15,16), but in addition suggests that the mere presence of distinctivecontextualcues is not sufficient. It is also necessary that the drug dose and frequency peremetersused in acquisitionare such as to favour associativeas opposed to non-associativemeohanisms. The findings concerning the acquisitionof tolerance in the present study are certainly in accord with the habituationmodel, although in this case it is difficult to generate clear predictions. As argued previously,frequent high doses of drug favour non-associativetolerancemechanisms; infrequentlow doses favour associativemeohanisms. Thus, manipulationsof dose end frequency parameters will have opposite effects on associativeana non-associativetolerance. It is probable then, that the presence of distinctivecontextualcues paired with drug in the present experiment,by allowing associativemechanisms to operate, will weaken the predicted positive correlationbetween tolerance and dose/frequencyfound in unsignelleaprocedures (10,17). In fact our results suggest that associativemechanisms dominated the tolerance acquisitionprocess since tolerancewas acquired more rapidly in low dose/long ID1 subjects than in high dose/short ID1 subjects. This result is in accord with other published data showing that drug signaJ.sexert greater effects on tolerance at low rather then high doses (17,18),and at long rather than short lDI@s (ly), although only the latter study examined the rate of tolerance development. In the other papers, tolerance tests were conducted only after tolersncelevels were asymptotic. Again these results are difficult to reconcile with a Pavlovian analysis of tolerance since associativestrength normally increaseswith increases in magnitude of the UCS (i.e. increases in dose). It may be felt that the absence of augmented acquisitionin DRUG-DE groups relative to DRUGHC groups is problematicfor the dual-processhabituation model. We do not share this view since it implies that only DE is capable of forming an associationwith the drug state, whilst HC is associativelyneutral. This is not the case. It is not the absolute salience of discriminative stimuli that determines their associativepower but their discriminabilityfrom each other. The HC cues sre able to sot as potent discriminativestimuli precisely because they are contrastedwith another set of very different cues (arisingfrom DE), and from which they differ in terms of their relationshipto the drugged state. Indeed, where fully balanced designs have been used, with DRUGHC and DRUGDE grcups receiving tests in either the drug or no-drug environment, context-specificeffects occur irrespectiveof the acquisitionenvironment (22). One issue raised by our results requires further discussion. It may be argued that the apparent absence of associativetolerance in the high dose/short ID1 &roup (m20), as indicatedby the absence of a response to the context-speoifioity test, was due to over-shadowingof the contextualstimuli by interoceptive drug cues, which would be expected to feature more prominantlyunder high dose conditions. While there is evidence that interoceptivedrug cues may pley a role in associativetolerance (20) and that over-shadowingcan be a factor in trenssituationaltolerance (IT), we do not believe that this played a major role in the present experimentfor two reasons. First, if associative
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1905
tolerance development to interoceptivecues in group MS20 was significantly strong to overshadow contextual cues on the context-specificitytest, it is hard to understand why it did not produce faster tolerance developmentin the tolerance acquisitionphase. It will be remembered that group MS20 required additional drug treatments to achieve a significantlevel of tolerence at all. Second, associativetolerance to interoceptivecues in group MS20 cannot explain the pattern of results observed on the retention test. Group MS20 showed less tolerance retention than group MS5 despite experiencinginteroceptive drug cues on that test that they had experiencedduring acquisition.Clearly, further work is required to elucidate the relative contributionsof exteroceptive end interoceptivecueing, end to determine the relative importanceof dose and IDI factors to associativeand non-associativetolerance. Finally, although the present results favour an habituationenalysis in preference to a Pavlwisn analysis of morphine analgesic tolerance, it is possible that with other response systems and other drugs, both analyses may be appropriate. A recent study suggests that classically-conditioned compensatory responses (CCR's)may contribute to associativetolerance in situationswhere the -elicited UR also exhibits a "oompensatoryl@ second phase (21). In this study, two responses to morphine were studied which showed different patterns of URss: tail-flick analgesia,which was found to consist only of a monophasic hypoalgesia,and aotivity, which was found to consist of a biphasti OR, with an initial hypoactivitybeing followed by a secondaryhyperactivity phase. In support of the dual-processmodel suggested, tolerance occurred in both measures but evidence of a CCR was found only in the activity measure. Acknowledgement This research was supported by a grant from the Scottish Home and Health Depsrtment, Grant No. K/MRS/SO/C826. References 1.
2. :: 5. ;: 8. 9. 10.
11. 12. 13. 14. 15. 16. 17.
W.H. ADAMS, S.Y. YE& L.A. WOODS end C.L. MITCHELL, J. P~Eu% Eb% The%, 168, 251-257 (1969). s. KAYAN, L.A. WOODS, end C.L. FHTCBELL, Eur. J. phiurn.&, 333-339 (19691 S. SIEGEL, J. Comp. Fhysiol. Psychol. 2, 498-506 (1975). S. SIEGEL, J. Ezp. Psych: Ani.Behav. Proc. 2, 1-13 (1977). R.I. DAFTER& M. HETHERINGTONend H. MoCARTNEY, Qu.J. Exp.Psch. 35, l-11 (1983). M.T. BARD0 and R,A. RTJGBES,Ph#xn.Bioohem.Behav. l0, 481-485 (1979). G.J. LaHOSTE, R.D. OLSON G.A. OLSON and A,J, KASTIN, Pharm.Biochem.and Behav. 3, 799-SO4 (1980). JOE. SHERMAN, Learning and Motivation,l0, 383-418 (1979). S.T. TIFFANY snd T.B. BAKER, J. Camp. Physiol. Psych. 2, 747-762 (1981). S,F. SEAMAN, in F.R. Brush and J.B. 0vermier (eds.),Affeot, conditioning and cognition: essays on the determinantsof behavior, 249-262 Hillsdale NJ: Erlbaum (1985). T.B. BBgER end S.T. TIFFANY, Psych. Rev. j2, 78-108 (1985). A.R. WAGNER. In: A. Dickinson and B.A. Boakes (Eds.) Mechanisms of learning and motivation,Hillsdale NJ: Erlbaum, 53-82 (1979). R.I. DAFl!ERSand L. BACH, Psychopharmacology, g, 101-106 (1985). S. KAYAN, R.K. FERGUSON and C.L. MITCHELL, J.Phsrm.Exp.Ther.185, 300-306 (1973). S. KAYAN and C.L. MITCRELL, Arch.Internat.Pharmacodynemie, s, 407-414 (1972). R.P. KESNER end T,B. BAKER. In: J.L. Martinez, R.A. Jensen, R.B. Messing, H. Rigter and J.L. McGaugh (Eds.). Eudogenouspeptides and learning and memory processes, New York: Academic Press, 479-518 (1981). T.B. BAKER end S.T. TlFFANY. cited in: T.B. Baker and S.T. Tiffany, Psych. Rev. 92, 78-10s (1985).
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18. 19. 20. 2, . 22.
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R,E, HINSON and S, SIEGEL, Behav. Neurosci,2, 759-767 (1983). R.P, KESNER and D.G. COOK. Behax. Neurosci,41, 4-12 (1983). J. GREZLEFf,I,'&A.D. C.X. POULOS and R. CAPPFZL. Psychophamn,5, 159-162 (1984). M,S. PALETTA and A.R. WAGNER. Behav. Neurosci,100, 611-623 (1986). C.R. CROWELL, R.E. HINSON and S. SIM;EL. Psyohopharm.,11, 51-4 (1981).