Pavlovian conditioning of pain regulation: Insights from pharmacological conditioning with morphine and naloxone

Biological Psychology North-Holland

41

28 (1989) 41-65

PAVLOVIAN CONDITIONING FROM PHARMACOLOGICAL AND NALOXONE

OF PAIN REGULATION: INSIGHTS CONDITIONING WITH MORPHINE

Janet GREELEY Natronal Drug and Alcohol Research Centre, University 01 New South Wales. Kensington, New South Wales 2033, Australia

1. Introduction Research involving the pharmacological manipulation of responsiveness to pain has contributed significantly to our understanding of how endogenous systems operate to modulate the perception of, and reaction to, pain. In recent years, investigation of the role of Pavlovian conditioning in the manipulation of endogenous pain control systems has become an area of particular interest (e.g., Bolles & Fanselow, 1980; Fanselow & Sigmundi, 1986; Greeley, Poulos & Cappell, in preparation; Rochford & Stewart, 1987). Research on Pavlovian conditioning of responses to drugs has an important role to play in elucidating the adaptive capacity of these systems. Morphine and naloxone are the opioid agents most prominent in the study of pain modulation. Morphine is employed as the prototypical opioid agonist which, at sufficient dosages, induces significant analgesia. In contrast, naloxone is seen as a “pure” opioid antagonist which is capable of blocking the potent analgesic effects of morphine, and can itself induce the contrary effect of hyperalgesia. The phenomenon of conditional tolerance to the analgesic effect of morphine is discussed in the early sections of this paper. Some important methodological and theoretical issues are presented, along with a brief summary of data from the investigation of conditional tolerance to various drug effects. In later sections, findings are presented from recent experiments on Pavlovian conditioning of the nociceptive effects produced by chronic treatment with naloxone. These findings illustrate the adaptive flexibility of endogenous pain control mechanisms. In addition, they have implications for theories of opioid tolerance and dependence. Research into classical conditioning of the effects of morphine dates from early this century. In his early work, Pavlov (1926/1927) described an observation made by Krylov: over repeated injections of morphine in dogs, presentation of the external stimuli that had preceded each injection was sufficient to elicit the symptoms initially produced by the drug (e.g., nausea, profuse salivation and vomiting). So reliable was this phenomenon that Pavlov employed it as a demonstration for students in his lectures. 0301~0511/X9/$3.50

G 1989. Elsevier Science Publishers

B.V. (North-Holland)

42

J. Greelq

/ Paolouian conditioning wth morphine and nuloxone

Lynch, Stein, and Fertziger (1976) provide a thorough review and present a cogent analysis of the changes in theoretical and experimental trends that occurred in the area of morphine conditioning up until the mid-1970s. The present paper discusses some important research questions in Pavlovian conditioning of drug responses that have emerged since that time. The first part of this paper concentrates on the role of Pavlovian conditioning in the development of drug tolerance, in particular, tolerance to morphine-induced analgesia (Siegel, 1975, 1979).

2. Conditioning

and tolerance

Tolerance is a term used in pharmacology to describe the decrease in magnitude of the effect of a fixed dose of a drug over repeated administrations of that dose (Kalant, LeBlanc, & Gibbins, 1971). When tolerance has developed, an increase in dosage is required in order to reinstate the effect produced by the original drug dose. Initially, it was thought that tolerance was mediated entirely by physiological changes which occur as a function of mere exposure to a drug. For example, one physiological explanation of tolerance to morphine suggests that repeated stimulation by morphine suppresses biosynthesis and releases of endogenous opioids which may lead to a loss of opioid receptors (Kalant. Roschlau, & Sellers, 1985). However, researchers found that tolerance could be affected by environmental factors that would have no apparent influence on such psychological events (Adams, Yeh, Woods, & Mitchell, 1969). For example, Mitchell, Woods and their colleagues found that the rate of development of tolerance to the analgesic effect of morphine was influenced by the availability of environmental cues uniquely present at the time of drug administration (Adams et al., 1969; Kayan, Woods, & Mitchell, 1971; Siegel. 1975, p. 499). These findings led researchers to investigate the possibility that Pavlovian conditioning played a role in the development of drug tolerance (Siegel, 1975). The role of Pavlovian conditioning in the development of tolerance to morphine became a major focus of research in the area of conditioning in the mid-1970s (for reviews see Baker & Tiffany, 1985; Siegel, 1978a, 1979, 1983). The notion of conditional tolerance was introduced by Siegel (1975). It describes the phenomenon whereby the reduction or absence of a given drug effect (i.e., tolerance) is evident only in the presence of salient and particular external cues. The concept of conditional tolerance follows from the basic Pavlovian conditioning model. There are four integral elements in the Pavlovian conditioning paradigm: the unconditioned stimulus and response, and the conditioned stimulus and response. The unconditioned stimulus (UCS) is a stimulus or event in the environment of an organism which naturally or unconditionally

J. Greeley / Pavlovian conditioning with morphine and naloxone

43

elicits a particular response from the organism. In the case of the salivary reflex system of the dog, the presence of food in he dog’s mouth elicits salivation. Salivation is the unconditioned response (UCR), a response readily elicited by the UCS. The conditioned stimulus (CS) is a neutral stimulus or event in the environment of an organism that initially does not elicit the UCR (i.e., salivation). Eventually, over repeated pairings of the CS and UCS, the CS becomes an effective elicitor of salivation. The response elicited by the CS is referred to as the conditioned response (CR). Considerable research has been conducted on the role of Pavlovian conditioning in the development and maintenance of drug tolerance (for reviews see Baker & Tiffany, 1985; Kesner & Baker, 1981; Poulos & Hinson, 1984; Siegel, 1978a, 1979, 1983). The capacity to form associations between the pairing of a distinctive set of environmental cues and the administration of a drug has been applied to various drugs and drug effects (e.g., pentobarbital: Cappell, Roach, & Poulos, 1981; chlordiazepoxide: Greeley & Cappell, 1985; haloperidol: Hinson, Poulos, & Thomas, 1982; alcohol: Le, Poulos, & Cappell, 1979; amphetamine: Poulos, Wilkinson, & Cappell, 1981). Like other Pavlovian conditioning paradigms, conditioning preparations which use drugs to produce unconditional effects involve pairing a CS with a UCS. Eventually this pairing instills the CS with response-eliciting properties. In such preparations, the UCS and UCR are produced by the administration of a drug. The measurable effects of a drug can include changes in overt behaviour, such as activity, or physiological changes, such as temperature modulation. The CR eventually elicited may resemble the observed drug effect or be in a direction opposite to the effect initially produced by the drug (Eikelboom & Stewart, 1982; Poulos et al., 1981). A sensitization or increase in drug effect is observed over repeated CS-UCS pairings where the CR is in the same direction as the drug effect (e.g., Hinson & Poulos, 1981). In other instances, there is a reduction in the magnitude of the drug effect over repeated drug administrations. This characterizes the phenomenon of tolerance. Evidence of conditioned tolerance is provided when the reduction in drug effect is observed only in the presence of the CS that has been repeatedly paired with drug administrations. It has been shown that in some cases of conditional tolerance the CR is diametrically opposed to the initial effect of the drug (e.g., Le et al., 1979; Siegel, 1975). It was from such an observation that Siegel (1975) proposed that the acquisition of a drug-opposite or “compensatory” CR was the mechanism underlying the phenomenon of conditional tolerance. 3. Are the CR and UCR opposites? There has been some question as to the appropriate UCS and UCR in conditioning preparations involving

classification of the drug administration

(Eikelboom & Stewart, 1982; Poulos et al., 1981). In his original formulation of the Pavlovian model of tolerance, Siegel (1975) stated that the UCR was the observed drug effect (e.g., analgesia). According to this classification, the observed CR and UCR were in opposite directions (Siegel, 1975, 1979). This finding was at odds with the widely accepted stimulus-substitution view of Pavlovian conditioning in which the CR and UCR are very similar, if not identical (e.g., salivation; Pavlov, 1927). Hence, conditional tolerance was referred to as a “paradoxical” form of conditioning (Eikelboom & Stewart, 1982). More recent formulations of the Pavlovian model of tolerance have questioned this view that the CR and UCR are, in fact, opposites (Eikelboom & Stewart, 1982; Poulos et al., 1981). These analyses have attempted to distinguish between the effect of a drug and the response elicited by that effect. The Eikelboom and Stewart (1982) analysis is a good example of this approach. According to their view, only those changes in behaviour or physiological state which are mediated by the central nervous system (CNS) can be considered bona fide responses. In other words, the initial change in behaviour or state produced by administration of a drug may not reflect a response to the drug. It may be the effect produced by the drug which actually evokes a response by the organism. (This analysis may only be relevant with drugs and effects for which there is a change in response with chronic administration.) For example, the initial analgesia induced by morphine might be the UCS or effect of this drug. There is a reduction in the amount of analgesia induced by a given dose of morphine over repeated administrations of the drug. This reduction in drug effect may reflect the body’s UCR to the analgesic effect of morphine. The Pavlovian model of tolerance described by Siegel (1975) suggests that the acquisition of a drug-opposite response is one mechanism which may explain tolerance. Some researchers have observed that. after conditional tolerance has developed to the initial analgesic effect of morphine, the CR observed is hyperalgesia (Krank, Hinson, & Siegel, 1981; Siegel, 1975). The observation of hyperalgesia in the presence of the CS which has been paired with morphine administration supports the compensatory response model of conditional tolerance. However, if analgesia is the UCS and hyperalgesia the UCR, then the CR is in the same direction as the UCR. According to this analysis, conditional tolerance is similar to other forms of conditioning and not a paradoxical phenomenon.

4. A Pavlovian According environment

analysis

of tolerance

to a Pavlovian that are present

analysis of drug tolerance, neutral cues in the during drug administration come to serve as CSs.

45

J. Greeley / Pavlovran conditioning with morphine and naloxone

These CSs might consist of exteroceptive stimuli such as the features of a distinctive environment; for example, illumination and sound levels (Siegel, 1975), or the injection ritual, or indeed the interoceptive effects of the drug itself (Greeley, Le, Poulos, & Cappell, 1984). The administration of a drug provides the UCS. The UCR is the centrally mediated response elicited by this stimulus. According to the model of conditional tolerance proposed by Siegel (1983), the CR is compensatory to the initial effect of the drug. Hence, the

Table 1 Experimental

reports

on the conditional

control

of tolerance

to the analgesic

effect of morphine

Reference

Dependent measure

Conditional response

Conditional tolerance

Abbott, Melzack, & Leber (1982) Advokat (1980) Advocat (1981) Advocat (1983)

Paw-lick latency Formalin test Tail-flick latency Tail-flick latency Tail-flick latency

No a

Dafters & Bach (1985) Krank (1987)

Vocalization threshold Paw-lick latency Tail-flick latency Paw-lick latency

Yes No Yes Very labile Partial (pellet implant) Yes

Krank, Hinson, & Siegel (1981) LaHoste, Olson, Olson, & Kastin (1980) Paletta & Wagner (1986) Sherman (1979) Sherman, Proctor, & Strub (1982) Siegel (1975) Siegel (1976) Siegel (1977) Siegel, Hinson, & Krank (1978) Siegel, Hinson, & Krank (1981) Siegel, Sherman, & Mitchell (1980) Tiffany, Petrie, Baker, & Dahl (1983) Walter & Riccio (1983)

Tail-flick

No No

Hyperalgesia No Hyperalgesia

latency

Tail-flick Paw-lick

latency

Paw-lick

latency

Paw-lick latency Paw-lick latency Paw-withdrawal threshold Paw-lick latency

Yes Yes

Partial No

Yes

Yes (but not conclusive)

Yes (but not conclusive) Extinction

Hyperalgesia

Yes Yes Yes Yes

Paw-lick

latency

Yes

Paw-lick

latency

Extinction No

Flinch-jump Paw-lick

* Where there is no entry in the column

Yes

latency

labelled

Yes

Conditional

response,

no placebo

test was given.

46

J. Greelqr

/ PaAwun

conditroning

wrth morphine

and nuloxone

summation of a compensatory or drug-opposite CR with the effect unconditionally produced by the drug results in a diminished drug effect or tolerance. A number of experiments on conditional tolerance to morphine have examined tolerance to the analgesic .effect of this drug. A list of these experiments is given in table 1. In a typical conditional tolerance experiment there are two groups - an experimental group and a control group. Both groups receive an equal amount of experience with the conditional stimuli and the drug. For the experimental group, the drug is administered in the presence of CS, (e.g., a distinctive room) while the other group receives the drug in the presence of CS, (e.g., the colony room). Both groups receive saline injections in the presence of the alternate environment. On a test for conditional tolerance both groups are given the same dose of the drug in the presence of CS,. The group that had received prior drug injections in the presence of CS, shows significantly more tolerance to the effects of the drug than does the other group (i.e., the group that received drug injections in CS,). In some experiments a drug-naive control group is also included. These control subjects receive only saline injections in both environments and serve to demonstrate the effects of the drug on a totally drug-naive group while also controlling for potential non-associative effects of the environments on the animals’ response to the drug. If these drug-naive animals respond similarly to drug administration in the presence of both environments then the environments themselves are deemed to be free of non-associative influences on responding. That rats are tolerant only in the environment in which they have previously received morphine injections is evidence of conditional control of tolerance. However, to determine whether the mechanism underlying this tolerance is a compensatory CR. a placebo test must be conducted. In this test all rats in both groups are given an injection of saline in the presence of CS,. According to the Pavlovian model proposed by Siegel (1975) the group which shows conditional tolerance in the presence of the environment that has been paired with drug administrations should show a drug-opposite or compensatory response. The observation of a compensatory CR in the presence of the drug-paired environment is the most compelling evidence in support of this model.

5. Is there a compensatory

CR?

The notion that a compensatory conditional response is the mechanism underlying conditional tolerance (Siegel, 1975) has proved beguiling. It has spawned a considerable amount of research. In experiments on conditional tolerance to the hypothermic effect of alcohol, evidence for compensatory hyperthermia as the CR has been compelling (Crowell, Hinson, & Siegel, 1981;

J. Greeley / Pavlovian conditiomng

with morphine and naloxone

47

Greeley et al., 1984; Le et al., 1979; Mansfield & Cunningham, 1980). However, in the investigation of conditional tolerance to the analgesic effect of morphine, the evidence for the existence of a compensatory hyperalgesic response is less consistent. Although there have been three demonstrations of conditional hyperalgesia following the acquisition of conditional tolerance to morphine-induced analgesia (Krank, 1987; Krank et al., 1981; Siegel, 1975) other researchers have failed to find evidence of a compensatory hyperalgesic CR (Abbott, Melzack, & Leber, 1982; Krank, 1987; Paletta & Wagner, 1986; Tiffany, Petrie, Baker, & Dahl, 1983; Zelman, Tiffany, & Baker, 1984). Partly as a response to these failures to observe hyperalgesia as a compensatory CR, other theories of conditional tolerance to morphine have emerged. Baker and Tiffany (1985) proposed a model of morphine tolerance based on habituation which can be acquired through associative or non-associative processes. Conditional tolerance develops through an associative process of retrieval-generated priming. That is, a CS which has been paired with prior drug administrations is capable of eliciting a representation of the drug-UCS. Retrieval of the drug-UCS prevents processing of the current UCS (i.e., the drug). An underlying premise of this model is taken from Wagner’s (1976) priming model of habituation which states that only those events or stimuli that are surprising or unexpected will initiate “processing”. For this view of tolerance to be accepted it must also be assumed that processing is equivalent to producing a drug effect. Thus, it follows that tolerance is due to a failure to process a drug stimulus which has already been primed. Likewise, non-associative tolerance (i.e., tolerance which is not attributable to conditioning) is due to failure to process the current drug-UCS because the UCS representation has been primed in memory through prior recent presentation of the UCS itself. Baker and Tiffany argue that their model provides a more comprehensive account of tolerance phenomena than does the compensatory response model proposed by Siegel (1975, 1979). One advantage of the habituation model is that a single mechanism (i.e., priming of the drug’s representation in memory) can be used to explain both associative and non-associative tolerance. Although this is a plausible explanation of demonstrations of tolerance, the priming notion has difficulty in accounting for some pieces of data. For example, the notion of associatively generated priming cannot account for findings where compensatory responses have been observed as CRs in cases of conditional tolerance (Hinson & Siegel, 1983-hyperactivity; Krank et al, 1981; Siegel, 1975-hyperalgesia; Siegel, 1978b-hypothermia). A dual-process interpretation of context-specific or conditional tolerance to morphine has been proposed by Paletta and Wagner (1986). This model purports to account for cases of conditional tolerance in which compensatory CRs are observed as well as cases in which they are not evident. According to Paletta and Wagner (1986) “only those response measures in which the

48

J. Greeley / Paolournn condittoning with morphme and nuloxone

drug-elicited UCR also evidences a ‘compensatory phase’ would result in a compensatory CR being acquired during the development of conditional tolerance.” Those cases of conditional tolerance, in which there is no compensatory response, resemble the phenomenon of conditioned diminution of the UCR (Kimble & Ost, 1961). These predictions are based on Wagner’s (1981) Sometimes Opponent Process (SOP) model of associative learning and performance which proposes that conditioned diminution of the UCR typically occurs in conditioning preparations. However, in some instances, a CR is acquired in addition to the diminished processing of a signalled UCS. This CR may either mimic or antagonize the UCR. The dual-process model espoused by Paletta and Wagner (1986) can account for a larger proportion of the existing data than either the compensatory response (Siegel, 1975) or habituation (Baker & Tiffany, 1985) models. It can explain those instances of conditioned tolerance in which compensatory CRs have been observed (e.g., Siegel, 1975. 1978b) as well as those in which no evidence of compensatory responding has been found (e.g.. Tiffany et al.. 1983). According to Wagner (1981), the empirical rule is that the CR will always resemble the secondary response to the UCS. Therefore, only when that secondary response is antagonistic to the measured UCR will the acquisition of a compensatory CR contribute to the development of tolerance. However, this apparent strength of the dual-process interpretation of tolerance may be its major flaw. Because it is not possible to predict with any certainty the nature of the secondary response to a UCS, it is difficult, if not impossible. to determine a priori whether a tolerance preparation will result in the acquisition of a compensatory CR or not. If the nature of the secondary response to the UCS is determined by a test for the elicitation of a CR, then the so-called distinction becomes a logical tautology.

6. Tolerance

as adaptation

It was stated earlier that tolerance was traditionally thought of as a physiological change which occurred as a function of the presence of a drug in the body (Kalant et al., 1971). A notion of tolerance which emphasized the physiological or behavioural effect induced by the drug was proposed by Kalant et al. They introduced an adaptational view of tolerance in which the interaction between the effect produced by a drug and the adaptive response of the organism to that effect were differentiated. Kalant et al. suggested that tolerance be considered an adaptation to a functional disturbance produced within an organism by a drug. For example, reliable perception of and reaction to pain are important factors for survival. If an animal does not respond by avoiding or escaping from a source of painful stimulation, its physical well-being and survival are threatened. Thus, it can be argued that,

J. Greeley / Pavlovian conditromng with morphine und naloxone

49

under certain conditions, the analgesic effect of morphine presents a functional disturbance. The development of tolerance to this effect serves an important biological function of modulating a potentially dangerous set of responses (i.e., failure to avoid or escape from the nociceptive stimulus). In the same way that not perceiving pain can be harmful, being particularly sensitive to pain can also be maladaptive. Situations can arise in which escape from or avoidance of painful stimulation must be delayed. For example, when engaged in territorial combat an animal must be able to delay tending to wounds in order to defend its territory. Under these circumstances it would be useful for an animal to have some mechanism for coping with pain. Since the discovery of the endogenous opioid peptides (Hughes et al., 1975) much research has been conducted on the role of these endogenous substances in the regulation of pain. Numerous studies have demonstrated the capacity to engage endogenous mechanisms to cope with pain. Two major types of pain control systems have been identified: (1) an opioid system which is blocked by naloxone and shows cross-tolerance with morphine; and (2) a non-opioid system which is not influenced by morphine and naloxone in these ways (Drugan, Moye, & Maier, 1982; Lewis, Cannon, & Liebeskind, 1980). The acquisition of tolerance to the analgesic effect of morphine can be viewed as an illustration of how adaptation occurs when an exogenous stimulus acts upon the pain-regulatory system to decrease the perception of pain. It has been shown that tolerance can be modulated by Pavlovian conditioning, a procedure which involves the CNS. This, along with other information, indicates that centrally mediated processes play an important role in adaptive responding in the endogenous pain-regulatory system. Organisms can also adapt to a pharmacological manipulation which increases the perception of pain. Pilcher (1980) showed that tolerance developed to the hyperalgesic effect of naloxone as a result of repeated administrations of naltrexone, a long-acting opioid antagonist. The next section of this paper discusses an apparently paradoxical finding that repeated administration of naloxone results in the development of a significant and long-lasting analgesic effect. The importance of Pavlovian conditioning as a mediating process in the development and maintenance of this analgesic effect will be discussed and some parallels will be made with Pavlovian conditioning of tolerance to morphine-induced analgesia (Siegel, 1975, 1979).

7. Adaptation to the nociceptive effects of naloxone Naloxone is a competitive opioid antagonist; that is, naloxone attaches to opioid receptors, thereby preventing opioid agonists from binding with these receptors to produce a pharmacological effect (Jaffe & Martin, 1980). In the presence of exogenous opioid stimulation, the capacity of naloxone to reverse

50

J. Greelqv / Paulouinn

conditioning

with morphme

and naloxonr

opioid-induced analgesia is profound (Jaffe & Martin, 1980). However, in the absence of stimulation from exogenously applied opioids, the action of naloxone as a nociceptive agent is variable (Sawynok, Pinsky, & LaBella, 1979). Several studies have shown that mute administration of naloxone produced an enhanced nociceptive effect (Coderre & Rollman, 1983; Grevert & Goldstein, 1977; Jacob & Ramabadran, 1978; Jacob, Tremblay, & Colombel, 1974). This hyperalgesic effect of naloxone is thought to be mediated through competitive antagonism of endogenous opioids (Coderre & Rollman, 1983). Relatively few studies have been conducted on the effect of chronic treatment with naloxone. However, studies have shown that after chronic treatment with naloxone, the analgesic effect produced by a dose of morphine was enhanced (Bardo, Miller, & Risner, 1984; Snell, Feller, Bylund, & Harris, 1982; Tang & Collins, 1978). The mechanism through which naloxone acts to enhance subsequent analgesia produced by morphine is not known. It has been suggested that this effect is due to an increase in endogenous opioid receptors. an observed physiological concomitant of chronic treatment with naloxone (Lahti & Collins, 1978). Recall that a reduction in opioid receptors was proposed as a mechanism underlying the development of tolerance to morphine (Kalant et al., 1985). It was argued that an explanation based solely on such a relatively long-lasting change in physiology could not readily account for conditional effects. Likewise, it would seem that an account of enhanced analgesia based on an increase in opioid receptors cannot easily explain research which shows that enhancement of the analgesic effect of morphine by pre-treatment with naloxone can be manipulated by Pavlovian conditioning (Rochford & Stewart, 1987). In recent experiments reported by Rochford and Stewart (1987) rats in the experimental group were given naloxone injections in the presence of a distinctive room and saline injections in the home room. The control group received naloxone and saline injections under reversed environmental conditions. Only those rats receiving naloxone in the presence of the distinctive room showed enhanced analgesia when given an injection of morphine in that room. This finding cannot be explained easily by a structural change such as an increase in numbers of receptors. A dynamic process which can be activated or not, in accordance with the environmental cues present, is required to explain this phenomenon. One such process might be the acquisition of a conditional response, perhaps a compensatory CR. The analgesic response observed after chronic treatment with naloxone might reflect an adaptive response to the hyperalgesic effect produced by acute administration of this drug. If the hyperalgesia produced by naloxone acutely is considered the direct effect of the drug (i.e., the UCS) and the subsequent analgesia an adaptive response of the body to that effect (i.e., to evoke analgesia as the UCR), then an explanation based on the model of conditional tolerance might apply. However, Rochford and Stewart (1987) did not observe

J. Greek-y / Pavlovian conditioning with morphine and nuloxone

51

an acute hyperalgesic effect of naloxone. Alternatively, it might be argued that the analgesic effect observed after chronic treatment with naloxone is a direct effect of naloxone and not a response to acute hyperalgesia. In some studies, analgesia has been observed after acute administration of naloxone (e.g., Pinsky, LaBella, Havlicek, & Dua, 1978; Wu, Martin, Kamerling, & Wettstein, 1983) but this effect was not seen in the experiments by Rochford and Stewart (1987). Given the broad action of naloxone as an opioid antagonist, it seems unlikely that analgesia was a direct effect of the drug in this preparation. A series of studies by Greeley et al. provides commentary on the effect of acute and chronic naloxone administration and on the adaptive capacity of the endogenous opioid system. The effect of varying doses of naloxone on responsiveness to heat stimulation of varying intensities was assessed. Three doses of naloxone (2.5, 5.0 and 10.0 mg/kg) were administered to different groups of rats. Fifteen minutes after drug administration each rat was placed on the heated surface of a hot-plate apparatus and latency to perform the first paw-lick response was monitored. The hot plate was maintained at one of three temperatures (48.5, 49.5, 50.5“ C). The response latency of naloxonetreated groups was compared with that shown by control groups administered saline. Analgesia was not seen following naloxone administration under any of the test conditions. However, a slight though statistically significant hyperalgesia was observed. The dose and temperature parameters at which this hyperalgesic effect was seen were employed in the subsequent conditioning experiments. In accordance with a discriminative conditioning regimen, rats were given repeated injections of naloxone (5 mg/kg) and saline. Fifteen minutes after either drug or saline administrations rats were placed on the heated surface of a hot plate (49.5”C) for a period of 30 s. Naloxone and saline injections were administered to the rats in the presence of distinctively different environments as an integral part of discrimination training. On days when naloxone was given, rats were transported to a distinctive room which was characterized by dim lighting and background music (room CS + ). Rats remained in their home room, which was quiet and brightly lit (room CS-), on days when they received saline injections. All injections were subcutaneous in the back of the neck and administered in the light phase of the 12-hour dark : light cycle. Rats in the experimental group (group NAL) received naloxone and saline injections in a 1 : 2 ratio. The saline control group (group SAL) received the same number of exposures to each of the conditioning environments as did group NAL. However, group SAL received only saline injections in the presence of both environments. The same general procedures were employed in the acquisition phase of all discrimination experiments. The key differences between experiments were in the number of acquisition trials given and the type of testing procedures employed. In brief, the experiments yielded the following findings.

52

J. Greeley / Puolorkn

conditioning

wth

morphine

and naloxone

(1) Although the dose of 5 mg/kg of naloxone had produced a hyperalgesic effect in the initial dose response test, it produced no observable effect on responsiveness to pyretic stimulation in the discrimination experiments. (2) Following repeated administrations of naloxone, however, rats showed the development of an analgesic response. (3) Conditional control of the analgesia that developed over repeated naloxone administrations was established; that is, analgesia was observed following an injection of naloxone, but only in the environment that had been repeatedly paired with prior naloxone administrations. (4) When conditioned subjects were given an injection of saline in the presence of the environment in which naloxone had been administered previously they showed analgesia as the CR. This provided further evidence of conditional control. (5) Analgesia following naloxone administration remained intact unless it was actively extinguished. Thus, the conditioned analgesic response acquired over repeated naloxone trials was subject to extinction. (6) In the presence of the environment which had been paired with naloxone the analgesic effect of morphine was enhanced. This was further evidence of excitatory conditioning, that is, the capacity for the CS to elicit the analgesic CR. However, in the presence of the environment that was unpaired with naloxone morphine analgesia was significantly diminished. This finding was taken as evidence for the acquisition of inhibitory conditioning, or the suppression of conditioned responding by a CS.

8. Naloxone

and endogenous

pain control

systems:

acute and chronic

effects

Fig. 1 shows the changes in response latencies as rats learned to discriminate between the CSs during training. The top panel shows the latencies to perform the first paw-lick response shown by group NAL when given naloxone in the presence of room CS + and when given saline in the presence of room CS - . Note that there is a significant increase in response latency from the first to the last naloxone injection and a significant decrease in response latency across trials in which saline was injected. The lower panel indicates that group SAL showed a decrease in response latency across repeated injections of saline, irrespective of the environment in which these injections were given. The reduction in paw-lick latency which occurs as a function of repeated exposures to the hot plate following saline injections suggests that an adaptive process is taking place in this group, such as habituation to the test apparatus or some underlying change in sensitivity to pyretic stimulation. It has been shown that tolerance develops to the analgesic effect of endogenous opioids

J. Greeley / Pavlovian conditioning with morphine and naloxone

53

Group NAL CSt 2

trials/block CS- 5 trials/block

0

i

i

3

4

i

4

5

TRIAL/BLOCK Group SAL 25.

G 20.

CSt 2 trials/block CS- 5 trials/block

* cst

8

* cs-

f? 15. E 4 510. J.

z 5. -'b a 0

i

i

3

2

j

4

j

TRIAL/BLOCK

Fig. 1. Mean latencies to the first paw-lick response shown by groups NAL and SAL during the acquisition phase of discrimination training. The left-hand panel shows results from the first three trials in the presence of rooms CS + and CS - The right-hand panel shows results from the remaining acquisition trials grouped in blocks.

(unpublished observation cited in Christie & Chesher, 1982). It is possible that rats repeatedly tested on the hot plate acquire such tolerance. There was no evidence in the discrimination experiments conducted by Greeley et al. that naloxone produced a hyperalgesic effect acutely. However, an earlier dose-response test indicated that hyperalgesia did occur. This failure to observe hyperalgesia in the discrimination experiments may have been due to alterations in the test conditions. On the first naloxone trial in the discrimination experiments, rats were given naloxone in the presence of a distinctive, novel environment. This may have affected their response latency initially. Although subtle in its acute action, over a few repeated administra-

54

J. Greeley / Pavlovian conditioning with morphine and ndoxone

tions naloxone produced a significant analgesic effect. This analgesic effect was quite robust and in a direction opposite to that anticipated from a drug classified as a “pure” opioid antagonist. The perception of, and reaction to, pain are regulated by complex processes (Stimmel, 1983). Through various pharmacological and physiological manipulations the existence of at least two types of endogenous pain control systems, opioid and non-opioid (Mayer, 1983; Watkins & Mayer, 1982) has been established. One theory of endogenous pain regulation asserts that there is a reciprocally inhibitory relationship between the endogenous opioid and nonopioid analgesic systems. According to this theory, if one system is suppressed, the other is activated (Kirchgessner, Bodnar, & Pasternak, 1982). It is possible that the analgesic response that developed over repeated naloxone administrations in the present experiments was due to such an effect. If naloxone blocked analgesic activity in the endogenous opioid system during drug trials, the endogenous non-opioid system may have been triggered into action. The data of Rochford and Stewart (1987) suggest that a non-opioid mechanism underlies the analgesic effect of naloxone. It has been shown that chronic treatment with naloxone results in an increase in endogenous opioid receptors (Bardo et al., 1984; Lahti & Collins, 1978). An alternative explanation of the analgesic effect induced by chronic administration of naloxone might be that the increase in numbers of receptors superseded the effectiveness of the administered dose of naloxone to block activation by endogenous opioids. However, this explanation cannot easily account for the failure to see endogenously induced analgesia in the environment where saline was administered to naloxone-experienced rats. Research with humans experiencing post-operative pain has demonstrated that naloxone produces dose-dependent bimodal effects on nociception (Levine, Gordon, & Fields, 1979). Levine et al. showed that low doses of naloxone produced analgesia, whereas higher doses produced hyperalgesic effects. These authors suggest that low doses of naloxone may stimulate the release of endogenous opioids, while blocking only some of the effects of these substances at various types of opioid receptors. However, the doses of 5 and 10 mg/kg of naloxone administered to rats in the experiments by Greeley et al. and by Rochford and Stewart (1987) could hardly be considered low, when doses as low as 0.4 mg completely block the effects of high doses of exogenous opioids in humans. Specific endogenous opioid peptides have different binding affinities for different opioid receptor sites. The various exogenous and endogenous opioid ligands produce different effects at these different receptors (Kalant et al., 1985). Research with specific opioid agonists (i.e., opioid agents which attach specifically to one type of opioid receptor) has shown that stimulation of both mu and kappa receptors produces analgesia (Jaffe & Martin, 1980). It is also known that naloxone has a greater binding affinity for mu than for kappa

J. Gree1e.v / Pavlovian conditioning with morphine and nnloxone

55

sites. Morphine, although not as specific in action as some opioid agonists, produces its analgesic effect mainly through stimulation of mu receptors (Jaffe & Martin, 1980). Therefore, it is possible that the analgesic effect observed in the environment paired with naloxone administration could be mediated via endogenous opioid action on another opioid receptor (perhaps kappa). However, these assertions are speculative since no specific manipulations were employed here to ascertain the nature of the acquired analgesic response.

9. Pavlovian control of naloxone-induced

analgesia

The analgesic effect of naloxone was observed only in the presence of the environment in which naloxone had been repeatedly administered. On a test, a group of naloxone-experienced rats were given their usual dose of 5 mg/kg of naloxone in the presence of room CS - . They responded with a mean paw-lick latency similar to that shown by saline-treated control subjects. Furthermore, when a group of naloxone-experienced rats was given saline in the presence of room CS + , the place where they had previously received only naloxone injections, they showed evidence of a conditionally elicited analgesic response (see fig. 2). It was stated previously that the environmental specificity of this analgesic effect cannot be attributed to an up-regulation of receptors alone. A dynamic process is needed: one which can be turned on and off within a short period of time. Not only was environment-specific elicitation of the CR (analgesia) observed, but also its extinction (i.e., gradual diminution of the CR upon

SAL c_l

.

g > c_l

lo-

L5 2

-

..e

“u “J 5.

za 0

cst cs-

pJ

r

!YJ-JOM

T

cst cs-

Fig. 2. Mean latencies (f SE,,,) to the first paw-lick response shown on a placebo test for elicitation of a conditional response. All subjects received an injection of saline in the presence of either room CS + or room CS -

J. Greeley / Paolov~an conditionmg

56

20

-

0.

NAL

EXT

SAL

cs

CONTROL

Fig. 3. Mean latencies conditioned analgesia.

with morphine and ~&nxme

cs

cs-

(i SE,) to the first paw-lick response shown on the test for extinction of Groups NAL/Ext and NAL/control received naloxone (5 mg/kg) and the saline control groups received saline.

withdrawal of the UCS). Prior to the extinction phase of training groups NAL and SAL were each subdivided into two groups. Subjects in the subgroups of group NAL were matched for performance during acquisition. During the extinction phase, group NAL/Ext received repeated exposures to room CS + , where they were now given an injection of saline in place of the usual naloxone dose. Group NAL/control received repeated exposures to room CS - , where saline was administered as usual. Both groups were tested on the hot plate 15 min after receiving an injection. The subjects from group SAL were treated similarly, half receiving repeated saline trials in the presence of room CS + and half in the presence of room CS - When, once again, groups NAL/Ext and NAL/control were administered a dose of naloxone in the presence of room CS + , only group NAL/control showed an analgesic response (see fig. 3). Group NAL/Ext showed a significant decrease in response latency from pre-extinction levels. It might be argued that maintenance of the analgesic response in group NAL/control is attributable to a novelty effect because room CS + had become unfamiliar after the extended period of absence from that room during the extinction phase. However, that the saline control group which had been absent from room CS + did not differ in response latency from its counterpart argues against this interpretation. Clearly, the analgesic effect observed after discrimination training with naloxone could not be attributed to mere repeated exposures to the drug. The effect was observed only in the environment where naloxone had been repeatedly administered. In addition, the CR dissipated only when extinction trials were carried out in the presence of environmental cues which had acquired the capacity to elicit the CR. Once again, an explanation based on a tonic physiological change such as the up-regulation of opioid receptors by

J. Greeley / Pavlovian conditioning with morphine und naloxone

57

chronic naloxone treatment cannot account for these findings. Research on receptor up-regulation suggests that these receptors dissipate over a period of days following termination of naloxone treatment (Bardo et al., 1984). Naloxone treatment was terminated for the drug-experienced control group at the beginning of the extinction phase of training, yet this group did not show a dissipation in the analgesic response to naloxone at the end of this period, which lasted approximately 6 weeks. These results on conditional control of analgesia agree with numerous reports on conditional control of other manipulations that affect the pain system. For example, a CS that has been paired with a stressor such as shock can elicit analgesia (e.g., Watkins, Cobelli, & Mayer, 1982). Conditional tolerance to morphine-induced analgesia (e.g., Siegel, 1975, 1976, 1977) is a further demonstration of associative control of endogenous pain regulation. The precise physiological mechanisms by which these changes in responsiveness to pain are produced are unknown. However, these data provide a pattern of results that suggests tremendous adaptive flexibility within the regulatory system for pain. At one level, conditional control of naloxone-induced analgesia might be viewed as the mirror image of conditional control of morphine tolerance. Numerous reports of the conditional control of tolerance to morphine-induced analgesia have been documented (see table 1). Within the morphine tolerance preparation, the acute effect of morphine is one of analgesia. Over repeated administrations of this drug there is a significant reduction in this initial effect. The acquired CR, when one is observed, is hyperalgesia, a response opposite in direction to the drug’s acute effect. In contrast, the acute effect of naloxone is thought to be hyperalgesia. Over repeated dosing with naloxone, a marked analgesic response appeared. This analgesic response was evident both when naloxone was administered and when a placebo was administered in the drug-paired environment. While the acquisition of conditioned hyperalgesia is thought to underlie the development of tolerance to morphine, the function of the analgesic response acquired over repeated naloxone administrations is not as clear. Although naloxone did not reliably produce hyperalgesia, neither did it elicit analgesia acutely. It produced no observable acute effect on nociception in the experiments conducted by Greeiey et al. Therefore, from an adaptive perspective, it is difficult to determine the significance of the acquired analgesic response. The influence of Pavlovian conditioning upon the acquired analgesic effect of naloxone was investigated further in a test for conditioned inhibition. The discrimination design employed in the experiments by Greeley et al. has been used in more traditional conditioning preparations to train conditioned inhibition (e.g., Hearst & Franklin, 1977). The CS which is explicitly unpaired with the UCS becomes the inhibitory stimulus. One procedure commonly used to test for the presence of conditioned inhibition is the summation test. In this

58

J. Greeley / Pavlovian conditioning with morphine and naloxone

T

ROOMcsFig. 4. Mean latencies (k SE,) were administered a 5-mg/kg

to the first paw-lick response in groups NAL and SAL ;when they dose of morphine in the presence of either room CS+ or room cs-.

procedure, the excitatory CS is presented in combination with the putative conditioned inhibitor, and the level of excitatory responding is measured. If the conditioned inhibitor is effective, the level of conditioned excitatory responding is diminished below that shown by an appropriate control group. A modification of the typical summation test was employed to test for conditioned inhibition following discrimination training with naloxone in the experiments by Greeley and her colleagues. In this test, a UCS was given in the presence of the inhibitory CS (i.e., room CS - ). Rochford and Stewart (1987) showed that when morphine was given in the presence of an excitatory CS for naloxone, there was an enhanced analgesic effect. There was an apparent summation of the conditioned analgesic response, acquired over repeated naloxone trials, with the unconditional analgesic effect of morphine. Greeley et al. reasoned that if room CS - functioned as a conditioned inhibitor, then the elicitation of analgesia should be inhibited in the presence of that environment. This was the case. Fig. 4 shows the results of a test in which morphine was administered to two groups of rats from group NAL; one group was given morphine in the presence of room CS + , where naloxone had been administered previously, and the other in the presence of the putative inhibitory CS, room CS - . The open bars show the response of saline control groups tested in the two environments. Group NAL showed a significant analgesic response relative to the control group when given morphine in the presence of room CS + . This finding supported the results found by Rochford and Stewart (1987). The rats that had experience with naloxone were, however, hyperalgesic relative to controls, when given morphine in the presence of room CS - . Relative to the drug-naive control group, the rats from group NAL were tolerant to the analgesic effect of morphine. This

J. Greeley / Pavlovian conditioning with morphine and naloxone

59

result provided compelling evidence for the presence of conditioned inhibition. It further demonstrated the considerable adaptive flexibility of the endogenous pain regulatory system.

10. Conclusions

and implications

The functional significance of the acquisition of an analgesic response over repeated naloxone injections is not immediately apparent. It is also not clear whether this analgesic effect is mediated by changes in the endogenous opioid system or some other non-opioid analgesic system. However, it can be argued that the observation that rats pre-treated with naloxone showed tolerance to the analgesic effect of morphine in the presence of the inhibitory CS strongly suggests involvement of the endogenous opioid system. In early training trials (see fig. 1) it can be seen that when rats experienced with naloxone were given saline their response latencies after saline were longer than those shown by drug-naive control subjects. This increase in response latency may have indicated a generalization of responding from naloxone trials. It is plausible that this initial increased latency belied a release of endogenous opioids. The reduction of this response latency over subsequent saline trials may have reflected the acquisition of tolerance to endogenous opioids. Thus, on the test for conditioned inhibition those rats tolerant to endogenous opioids in the presence of room CS - showed cross-tolerance with morphine. The perception and modulation of pain by endogenous pain control systems are complex processes. Not only can they be influenced by manipulations at a direct physiological level, such as the administration of a drug, but also by higher-level processes in the CNS, such as those involved in associative learning. At a behavioural level, the findings of Greeley et al. demonstrate the plasticity of endogenous pain regulatory mechanisms. This is illustrated in the observation of opposite and symmetrical effects on responsiveness to pain in the presence of excitatory and inhibitory conditional stimuli. Investigation of the interaction between learning and biological functioning of endogenous pain control systems can provide interesting methods for assessing the physiological mechanisms which underlie pain regulation. The recent work of Rochford and Stewart (1987) and of Greeley et al. also exemplifies how Pavlovian principles can be used to explain certain types of drug interactions. For example, prior experience with one drug may influence the effect produced by other drugs administered subsequently (cf. Hinson & Rhijnsburger, 1984). These results may have important implications for the use of multiple drugs in medical treatment as well as for the investigation of poly-drug abuse. For example, it might be possible to enhance the analgesic effect of opioid agonists by prior treatment with an opioid antagonist. In the case of poly-drug abuse, it may be that experience with one drug (e.g., alcohol)

60

J. Greelqy / Paolovian conditiomng

with morphine and naloxone

affects the impact of another, opposite-acting drug (e.g., cocaine) differentially, depending upon the circumstances surrounding administration. For example, in the presence of cues predictive of alcohol consumption, cocaine may have greater stimulant action than in the absence of those cues. In the treatment of opioid abusers with naltrexone, there may be a danger of overdose if heroin is administered after naltrexone treatment has been discontinued. 11. Conditioning and drug dependence Drug tolerance is thought to result from adaptation to drug-induced changes in physiological states and behaviour. One model that has been proposed to explain these adaptive changes is the acquisition of compensatory or drug-opposite responding through Pavlovian conditioning (Siegel, 1983). The elicitation of compensatory responses while a drug is in the body acts to counteract the drug’s effect and will result in tolerance (i.e., a reduction in the of these responses in the observed drug effect). However, the occurrence absence of drug administration might be perceived as withdrawal, a defining feature of physical dependence. It has been postulated that the elicitation of withdrawal-like symptoms in the presence of environmental stimuli previously associated with drug-taking may result in “craving”, which, in turn. mediates further drug-taking. Extinction of these conditionally elicited “withdrawal symptoms” has been proposed as an important consideration in the effective treatment of drug dependence (Wikler, 1980). The results from the experiments in which naloxone was employed as the “UCS” indicate that it is possible to establish conditional responses which mimic the effects of opioids. It is possible that these responses may effectively counteract the responses elicited in withdrawal. It would seem more efficacious to acquire a response opposite to that which is thought to promote “craving” than to simply extinguish that response. If opioid-like responses other than analgesia can be induced by naloxone, then it may be possible to effectively prevent the occurrence of their opposite counterparts in withdrawal through conditioning. Wikler (1980) has recommended the use of naltrexone (a long-acting opioid antagonist) in the treatment of opioid dependence to facilitate extinction. According to Wikler’s view, in the presence of naltrexone, opioid administration will be devoid of its reinforcing effects. Through repeated failed attempts to get high on opioids while under naltrexone, extinction of cue-elicited craving should occur as well as extinction of drug-acquisitive and drug-taking behaviours. The work of Greeley et al. suggests a further benefit of antagonist treatment ~ the possible acquisition of responses which may counteract withdrawal. Other evidence which supports this hypothesis comes from experiments in

J. Greeley / Pavlovran conditioning with morphine and naloxone

61

which naloxone and naltrexone have been used to facilitate withdrawal from methadone (Charney et al., 1982; Riordan & Kleber, 1980). The withdrawal syndrome which accompanies abstinence from long-term methadone use encompasses an extended period of discomfort. It is the length of this syndrome rather than its intensity that often leads to resumption of opioid use. Clinical studies have shown that the withdrawal period induced by abstinence from methadone can be decreased by chronic administration of naloxone or naltrexone (Charney et al., 1982; Riordan & Kleber, 1980). Although the intensity of the symptoms may be increased, the period over which they occur is significantly reduced. Concomitant administration of the a-adrenergic agonist clonidine alleviates some of the withdrawal symptoms without provoking dependence itself. The faster recovery under antagonist-precipitated withdrawal suggests that naloxone or naltrexone may enhance recovery of the endogenous systems which have been inhibited by repeated opioid administration. In addition to facilitating extinction of conditionally acquired responses, opioid antagonists may elicit their own adapative responses which counter the withdrawal syndrome and enhance recovery to a drug-free, withdrawal-free state.

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Kiordan,

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H.D. (1980). Rapid

opiate

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