Intra-Administration Associations and Withdrawal Symptoms: Morphine-Elicited Morphine Withdrawal.

On the basis of a conditioning analysis, some drug "withdrawal symptoms" are conditional responses elicited by stimuli paired with the drug effect. Prior demonstrations of conditional elicitation of withdrawal symptoms evaluated the role of environmental cues; however, pharmacological cues also typically signal a drug effect. Within each administration, early drug onset cues (DOCs) may become associated with the later, larger drug effect (intra-administration associations). This experiment evaluated the contribution of intra-administration associations to withdrawal symptoms. The results indicated that (a) 5 mg/kg morphine elicited behavioral and thermic withdrawal symptoms in rats previously injected on a number of occasions with 50 mg/kg morphine and that (b) DOC-elicited withdrawal symptoms are not a sensitized response to the opiate but rather an associative phenomenon. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of cholecystokinin in conditional compensatory responding and morphine tolerance in rats.

As elaborated in the conditioning analysis of tolerance, cues present at the time of drug administration become associated with the drug effect. A particularly salient cue that may become associated with the drug effect is the pharmacological drug-onset cue inherent to drug administration. Drug-associated cues contribute to tolerance by eliciting a conditional compensatory response that attenuates the drug effect. For example, the early drug effect, having been paired with the subsequent larger drug effect, may elicit the release of antiopioid peptides that counter opioid effects. The role of a putative antiopioid peptide, cholecystokinin-8 (CCK), in the associative mechanisms of opiate tolerance was evaluated. The results of these experiments suggest that a CCK2 receptor antagonist attenuates both the expression of opiate tolerance and the conditional compensatory response hypothesized to mediate such tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats.

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anticipatory hyperexcitability and tolerance to the narcotizing effect of morphine in the rat.

Examined the role of Pavlovian conditioning in tolerance to the narcotizing effect of a high dose of morphine in 32 male albino Sprague-Dawley rats. Initially, 2 groups received 9 injections of morphine (40 mg/kg), and 2 groups received 9 injections of saline. One group administered each substance was injected in 1 of 2 distinctive environments: the animal colony or a distinctive room. Subsequently, Ss in all groups received 5 morphine injections in the distinctive room. Analyses of videotape records of postinjection behavior indicated that Ss tested in the presence of the usual predrug cues were more tolerant to the narcotizing effect of morphine than Ss tested with cues different from those previously associated with morphine. In addition, Ss tested with the usual predrug cues exhibited more anticipatory "hyperexcitable" behavior than Ss tested in the absence of the usual predrug cues. Results provide further evidence that compensatory pharmacological conditional responses partially mediate tolerance and suggest that these drug-anticipatory responses contribute to so-called "withdrawal symptoms." (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of formalin-induced pain in morphine tolerance, withdrawal, and reward.

The effect of a commonly used experimental pain-induction procedure (formalin injection into a hindpaw site) on morphine tolerance, withdrawal, and reward was examined in rats. Results suggest that the effects of morphine are different in the organism that is experiencing pain at the time it receives the drug than in the organism that is pain free. The presence of pain at the time of each morphine administration decreased analgesic tolerance, decreased naloxone-precipitated withdrawal, and enhanced the rewarding effect of the opiate. These findings, together with those of previous studies, suggest that theories of opiate tolerance, withdrawal, and reward should incorporate the effects of pain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Applying laboratory research: Drug anticipation and the treatment of drug addiction.

Basic research concerning drug tolerance and withdrawal may inform clinical practice, and vice versa. Three areas that integrate the work of the laboratory and the clinic are discussed: (a) drug overdose, (b) cue exposure treatment of addiction, and (c) pharmacological treatment of withdrawal symptoms. The areas are related in that they indicate the contribution of drug-paired cues to the effects of addictive drugs and the role of Pavlovian conditioning of drug effects in drug tolerance and withdrawal symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Narp regulates long-term aversive effects of morphine withdrawal.

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the Nature of the Intra-Administration Unconditioned Stimulus: Comment on McDonald and Siegel (2004).

R. V. McDonald and S. Siegel (see record 2004-10475-001) present convincing evidence that a small dose of morphine (5 mg/kg) may elicit withdrawal signs in rats previously injected on a number of occasions with a large dose of morphine (50 mg/kg), thus suggesting that intra-administration associations may be involved in drug withdrawal. This finding is important for basic and applied researchers studying drug reward mechanisms. Although R. V. McDonald and S. Siegel point out that the morphine conditional stimulus (CS) and unconditioned stimulus (US) making up the intra-administration association differ in onset and magnitude, the author of this comment argues that the CS and US may also differ in terms of pharmacologic activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disentangling the Sources of Opioid Withdrawal Responses: Comment on McDonald and Siegel (2004).

R. V. McDonald and S. Siegel (see record 2004-10475-001) present new evidence for the idea that opioid drug-opposite responses can become conditioned to cues of initial drug onset and that they could, therefore, play a role in the development of tolerance of some drug effects and a role in the elicitation of withdrawal-like symptoms in cases in which addicted individuals are exposed to small doses of the drug they normally consume. In this comment, some puzzling features of the data are discussed, and alternative explanations are suggested. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurobiology of withdrawal motivation: Evidence for two separate aversive effects produced in morphine-naive versus morphine-dependent rats by both naloxone and spontaneous withdrawal.

In drug-naive rats, the rewarding effects of morphine are blocked by lesions of the tegmental pedunculopontine nucleus (TPP), but not by neuroleptics. In dependent rats (chronically treated with morphine), morphine reward is blocked by neuroleptics, but not by TPP lesions. Just as this activation of opiate receptors in naive vs dependent rats produces different mechanisms of reward, this study concludes that reduced opioid activity on these opiate receptors produces different mechanisms of aversion. Neuroleptics blocked the conditioned place aversions produced by naloxone and spontaneous withdrawal in morphine dependent, but not naive, rats, without attenuating the somatic withdrawal syndrome induced by naloxone in dependent rats. The researchers suggest that the aversive effects of endogenous opioid withdrawal in naive rats are mediated by different neural substrates than the aversive effects of exogenous opioid withdrawal in dependent rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Different effects of opiate withdrawal on dopamine turnover, uptake, and release in the striatum and nucleus accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.     

"Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats": Correction.

Reports an error in the original article by J. E. Kelsey and S. R. Arnold (Behavioral Neuroscience, 1994[Dec], Vol 108[6], 1119–2127). On pages 1121 and 1122, the artwork for Figures 1 and 2 was reversed; the figure captions are correct. In the last line of the author note, on page 1119, the e-mail address should read as follows: jkelsey@bates.edu. (The following abstract of this article originally appeared in record 1995-12607-001.) Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal.… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence from rats that morphine tolerance is a learned response.

Proposed that the direct analgesic effect of morphine becomes attenuated over the course of successive administrations of the narcotic by a conditioned, compensatory, hyperalgesic response elicited by the administration procedure, the net result being analgesic tolerance. This proposal was tested in 3 experiments with a total of 41 male Wistar-derived rats using the "hot plate" analgesia assessment situation. The proposed conditioning view of tolerance was supported by several findings: (a) It was necessary to have reliable environmental cues predicting the systemic effects of morphine if tolerance was to be observed. (b) A hyperalgesic conditioned response could be observed in morphine-tolerant Ss when drug administration cues were followed by a placebo. (c) Merely by repeatedly presenting environmental cues previously associated with morphine (but now presented with a placebo), morphine tolerance could be extinguished. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

State dependent learning and morphine tolerance.

On the basis of a Pavlovian conditioning analysis of morphine tolerance, cues signaling the systemic effects of morphine come to elicit conditional pharmacological responses that attenuate the effect of the drug. Experiments were conducted to evaluate the relevance of this analysis to recent reports that morphine-experienced rats, anesthetized with pentobarbital prior to a final test injection of morphine, do not display the analgesic tolerance seen in nonanesthetized rats. It was hypothesized that such pentobarbital blockage of morphine tolerance represents an instance of state-dependent learning: the barbiturate alters predrug cues so that the final, barbiturate-signaled morphine administration is presented in the context of different signals than those accompanying pretest administrations of the opiate. Results of the present experiments confirmed the finding that pentobarbital interferes with the expression of morphine tolerance in rats that had not previously received barbiturate-opiate pairings. In addition, the results supported the state-dependency interpretation of this interference: Rats that had pretest administrations of morphine signaled by pentobarbital, as well as the test administration, displayed substantial morphine tolerance. Moreover, if pretest morphine administrations were signaled by pentobarbital, omission of the barbiturate cue on the test session attenuated tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Motivational control of heroin seeking by conditioned stimuli associated with withdrawal and heroin taking by rats.

The authors investigated the impact of conditioned withdrawal on drug seeking by training rats to work for a heroin infusion on a seeking-taking schedule, which required responding on a seeking lever in order to gain the opportunity to self-administer the drug by a single response on a taking lever. Following the establishment of opiate dependence, a conditioned stimulus (CS) that had been previously paired with naloxone-precipitated withdrawal suppressed heroin seeking in extinction. However, when the rats had prior experience of heroin taking in the presence of the withdrawal CS, drug seeking was elevated in the presence of this stimulus. The authors conclude that the conditioned motivation of drug seeking in withdrawal depends on previous association of the CS with drug taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pavlovian psychopharmacology: The associative basis of tolerance.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intraadministration associations: Conditional hyperalgesia elicited by morphine onset cues.

There is evidence that exteroceptive cues associated with drug administration elicit conditional compensatory responding (e.g., hyperalgesia in organisms with a history of morphine administration). Recently it has become apparent that, within each administration, interoceptive early-drug onset cues (DOCs) may become associated with the later, larger drug effect (intraadministration associations). The present experiments evaluated DOC-elicited conditional hyperalgesia in rats intravenously infused with morphine. The results indicated that DOC-elicited hyperalgesia contributes to tolerance to the analgesic effect of morphine, and such DOC-elicited hyperalgesia is an associative phenomenon, rather than a sensitized response to the opiate. The findings suggest that associative analyses of tolerance should acknowledge the conditional responding elicited by DOCs, and extinction-based addiction treatments should incorporate extinction of DOC-elicited conditional responding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Procedures that produce context-specific tolerance to morphine in rats also produce context-specific withdrawal.

Rats previously injected with morphine in the presence of a distinct environment (paired animals) were more tolerant to the analgesic effects of morphine in that environment than were rats previously injected with morphine in another environment (unpaired animals). When injected with saline instead of morphine in the distinct environment, paired animals were more reactive to pain (hyperalgesic) than unpaired animals, but no more reactive to pain than animals never given morphine. More important, the paired animals also exhibited more withdrawal symptoms (wet dog shakes, genital licking, circling, rearing, and defecation) during abstinence and naltrexone-precipitated withdrawal in the distinct environment than did the unpaired and saline animals. Thus, procedures that are capable of providing context-specific opiate tolerance are also capable pf producing context-specific opiate withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clonidine antagonizes the aversive effects of opiate withdrawal and the rewarding effects of morphine only in opiate withdrawn rats.

The researchers asked whether clonidine, an α?-noradrenergic agonist, would block selectively the motivational effects of opiate withdrawal and whether clonidine's effects would respect the boundary between nondeprived and deprived motivational states. In a place conditioning paradigm, clonidine (0.05 mg/kg ip) blocked the rewarding effects of morphine in opiate-withdrawn rats (as well as the aversive properties of withdrawal itself), but did not affect morphine place preferences (2 and 20 mg/kg) in drug-naive rats. Furthermore, clonidine blocked the acquisition of morphine (15 mg/kg), but not LiCI (15 mg/kg), conditioned taste aversions in water-deprived rats. The results suggest that the motivational system activated in deprived animals includes dopaminergic and noradrenergic components that are in series with each other. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Extinction of tolerance to the analgesic effect of morphine: Intracerebroventricular administration and effects of stress.

Previous research demonstrated that tolerance to the analgesic effect of morphine in rats is attenuated by administrations of a placebo in the context of drug-associated cues. Such apparent extinction of tolerance has been interpreted as support for a Pavlovian conditioning model of tolerance. Recently, it has been suggested that these findings are attributable to stress, induced during placebo sessions and augmenting the analgesic effect of morphine (rather than to Pavlovian extinction). Our results indicate that placebo sessions actually attenuate tolerance by extinguishing the association between predrug cues and the systemic effects of the drug. In addition, the results indicate that conditioning contributes to analgesic tolerance when morphine is administered intracerebroventricularly, which suggests that conditional alterations within the central nervous system mediate such tolerance. This contrasts with alternative suggestions that conditional alterations in drug distribution or metabolism mediate the effects of conditioning manipulations on tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)