Lesions of the lateral parabrachial nucleus block the aversive motivational effects of both morphine and morphine withdrawal but spare morphine's discriminative properties

This study examined if the aversive properties of morphine, the aversive properties of morphine withdrawal, and the discriminative properties of morphine are mediated by common neurobiological substrates. Lesions of the lateral parabrachial nucleus, which blocked the aversive properties of morphine in the conditioned taste aversion paradigm, also blocked the acquisition of conditioned place aversions to environments paired with the aversive properties of morphine withdrawal in morphine-dependent rats. When morphine and saline were used as cues in a discrimination task, however, both sham-operated and lesioned rats were able to solve the task.     

Clonidine antagonizes the aversive effects of opiate withdrawal and the rewarding effects of morphine only in opiate withdrawn rats.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 In a place conditioning paradigm, clonidine (0.05 mg/kg ip) blocked the rewarding effects of morphine in opiate-withdrawn rats (as well as the aversive properties of withdrawal itself), but did not affect morphine place preferences (2 and 20 mg/kg) in drug-naive rats.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)     

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)     

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)     

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)     

The parabrachial nucleus: A brain stem substrate critical for mediating the aversive motivational effects of morphine.

Bilateral ibotenic acid lesions of the lateral, but not the medial, parabrachial nucleus (PBN) blocked conditioned taste aversion (CTA) induced by morphine but not conditioned place preference induced by morphine. The same lateral PBN lesions also blocked conditioned place aversion produced by low intraperitoneal doses of morphine (shown to produce aversion, instead of preference, due to a restricted action on gut opiate receptors). Lateral PBN lesions did not block CTA produced by LiCl. Cerebral peduncle lesions that destroyed the direct descending projections from the visceral cortex to the PBN did not block CTA induced by morphine, nor did ibotenic acid lesions of the tegmental pedunculopontine nuclei (shown to block place preference produced by even high morphine doses). It is suggested that the lateral PBN is a critical link in the neural pathway carrying the aversive motivational effects of opiates from the gut into the CNS, independent of the neural pathway carrying the rewarding motivational effects of morphine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clonidine blocks acquisition but not expression of conditioned opiate withdrawal in rats

Previous studies in rodents have reported that clonidine, an alpha 2-adrenergic receptor agonist, attenuated conditioned aversions to naloxone-precipitated opiate withdrawal when administered prior to each withdrawal conditioning episode. The current study was designed to determine whether clonidine could modify the expression of previously established conditioned place aversions and conditioned suppression of operant responding. Dose- and time-dependent effects of clonidine on activity and suppression of operant responding for food identified appropriate treatment parameters for subsequent studies in which rats rendered dependent on opiates through implantation of morphine pellets were tested for: (1) conditioned place aversion; and (2) conditioned suppression of operant responding for food (fixed ratio-15 schedule), in a paradigm wherein rats received four pairings of naloxone with a distinct tone and odor stimulus. Clonidine dose-dependently blocked the acquisition of both conditioned behaviors when administered prior to naloxone on each conditioning trial, but was ineffective in blocking the expression of these conditioned withdrawal signs when administered prior to the test session.     

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: Apparent tolerance is overshadowing.

Drug-naive, but not morphine-dependent, rats preferred places paired with morphine (2 mg/kg) over unfamiliar neutral places. Both drug-naive and morphine-dependent rats preferred places paired with higher doses of morphine (20 mg/kg) over unfamiliar places. Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the conditioned place preferences produced by both 2 and 20 mg/kg morphine in drug-naive rats but not the preferences produced by 20 mg/kg morphine in dependent rats. When morphine-dependent animals received withdrawal-alleviating doses of morphine (20 mg/kg) 3.5 hrs before pairing one environment with 2 mg/kg morphine, they showed morphine-conditioned place preferences that were abolished by TPP lesions. The apparent behavioral tolerance to the TPP-mediated rewarding effects may have resulted from overshadowing by separate withdrawal-related motivational mechanisms. (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": 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)     

The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: Evidence for the reward comparison hypothesis.

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (UCS), an appetitive UCS, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive UCS (LiCl), a known reinforcing UCS (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to uncontrollable stress alters withdrawal from morphine.

Examined the influence of the controllability/uncontrollability of shock as a stressor on the severity of subsequent morphine withdrawal in 2 experiments with 84 male Holtzman rats. In Exp I (36 Ss), Ss that received 2 daily sessions of 80 yoked-inescapable shocks, in contrast to those given 80 escapable shocks or restrained without shock, showed an enhanced series of correlated withdrawal behaviors (i.e., mouthing, teeth chattering, head/body shakes) 24 hrs later when injected with morphine sulfate (5 mg/kg) followed by a naloxone HCl (5 mg/kg) challenge. In Exp II (48 Ss), this finding was replicated with escape-yoked-restrained Ss given saline injections during the pretreatment phase, but the impact that inescapable shock had on later precipitated withdrawal was completely blocked when Ss were administered naltrexone HCl (14 mg/kg) before each shock session. Findings are discussed in terms of the capability of inescapable shock to activate an endogenous opiate system, thereby leading to a sensitization of release or receptor processes that could protentiate later morphine withdrawal. (56 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the effects of morphine and immobilization stress on discrimination performance of rats.

Compared the effects of morphine and immobilization stress (IMS) on performance of 24 male Sprague-Dawley rats in discrete-trial, 2-choice discrimination tasks. In Exps I and II, 2 shocks of different intensities were discriminative stimuli (DSs) for choices in a T-maze. In Exps III and IV, responses were right and left leverpresses in an operant chamber, where correct responses were signaled by either shocks of different intensities (shock discrimination task) or by the position of a brief light flash (light discrimination task). In Exp I, both 70-min IMS and 5 mg/kg morphine induced greater disruptions in trials in which the higher shock was the DS and there were no significant differences between treatments. However, in Exp II, only the effects of morphine were blocked by 10 mg/kg naltrexone. In Exp III, the effects of IMS and morphine were not selective with respect to shock level in the shock discrimination task, nor were they task (shock vs light) selective. The effect of morphine was significantly greater than the effect of IMS in both tasks. Exp IV indicated that effects induced by actual alterations in the intensities of the DS shocks did not mimic those induced by either morphine or IMS but that abrupt decreases in the duration of the DS lights induced effects similar to those of morphine. Results indicate that (a) different mechanisms mediate the effects of IMS and morphine and (b) many of their behavioral effects in shock discrimination tasks are due to dissociative processes rather than alterations in perceived shock intensity. (52 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ontogeny of morphine withdrawal in the rat.

The present studies examined behavioral changes during precipitated morphine withdrawal in 7- to 42-day-old rat pups. One group of rats was injected with morphine sulfate (10.0 mg/kg) twice daily for 6.5 days. Another group of 7-day-old rats received a lower dose of morphine (3.0 mg/kg). Controls were saline injected or untreated litters (7-day-old pups only). On Day 7, a target pup was injected with saline or naltrexone (0.3–20.0 mg/kg). Preweaning pups were observed in a warm chamber with the litter. Forty-two-day-old rats were tested individually. Morphine-treated pups tested with naltrexone showed significant alterations in behavior that varied at different ages. For example, rolling, stretching, and head and paw moves were observed at the younger ages, whereas burrowing, diarrhea, jumps, teeth chatter, and wet dog shakes occurred in the older rats. These data indicate that morphine-abstinent rats demonstrate withdrawal signs that are within the developmental repertoire of the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative properties of morphine that modulate associations between tastes and lithium chloride.

Wistar rats learned to withhold consumption of a target solution when morphine preceded presentation of the target solution and lithium chloride (LiCl) and to consume the same target solution when saline preceded the presentation of the solution. After this serial feature discrimination training, morphine did not block the formation of a Pavlovian association between saccharin and LiCl but did suppress consumption of familiar tap water. After Pavlovian conditioning, morphine blocked the formation of an association between saccharin and LiCl but did not suppress consumption of a familiar tap water solution. The roles of morphine and saline can be interchanged. It appears that the morphine discriminative stimulus is calling up a representation of neither the conditioned stimulus nor the unconditioned stimulus alone, but rather a modified representation of some aspect of their association. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tegmental pedunculopontine glutamate and GABA-B synapses mediate morphine reward.

The tegmental pedunculopontine nucleus (TPP) of the midbrain is critical in mediating the acute rewarding effects of opiates. However, the circuitry and neurochemistry underlying this effect has not been determined. Here we identify TPP receptors and cell types involved in systemic morphine reward and suggest an anatomical and neurochemical model for reward in the TPP. Simple hypothetical anatomical models for serial cell arrangements and receptors in the TPP were proposed and predictions of behavioral outcome (reward or no reward) then were made, based on the administration of agonists and antagonists directly into the TPP of rats. We report that TPP-administered NMDA produced rewarding effects, although GABA agonists and antagonists had no motivational effects on their own. However, the NMDA receptor antagonist AP-7 and the GABA-B receptor antagonist saclofen, while having no motivational effects on their own, blocked systemic morphine reward as measured by conditioned place preference. These results provide positive evidence for GABA-B and glutamate synapses in the TPP, which mediates systemic morphine reward and suggest that a serial pathway for morphine reward in the TPP is unlikely. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of yohimbine on the development of morphine dependence in the rat: lack of involvement of cortical beta-adrenoceptor modifications

The alpha-2 receptor antagonist yohimbine has been previously shown to prevent the development of morphine dependence in a rat behavioral model. This study was directed to clarify the mechanism of this interaction, which is presently unknown. Since upregulation of cortical beta-adrenoceptors has been suggested to be involved in morphine withdrawal, we have tested the possible correlation between receptor density and withdrawal behaviors in the presence of yohimbine. Sprague-Dawley male rats received a s.c. suspension of morphine (300 mg/kg) or the vehicle. Animals received saline or yohimbine (4 mg/kg, IP) 24, 28, 48 and 52 h after morphine and finally naloxone (1 mg/kg i.p) at 72 h; the subsequent signs of withdrawal (mainly wet-dog shakes and escape attempts) were recorded and the cerebral cortex dissected to study [3H]-CGP 12177 binding. Morphine-treated animals displayed a marked withdrawal behavior together with beta-adrenoceptor upregulation; nevertheless, these effects were not correlated. As expected, yohimbine prevented morphine withdrawal behavior but did not reverse the beta-adrenoceptor upregulation induced by the opiate. These results confirm previous evidence against the involvement of beta-adrenoceptor upregulation on morphine withdrawal behaviors and also permit to discard beta-adrenoceptor regulation as the neurochemical basis of the antiwithdrawal effect of yohimbine. The possible contribution of some other neurochemical effects of yohimbine are discussed to explain the inhibition of morphine dependence by that drug.     

The role of dopamine in withdrawal jumping in morphine dependent rats

The role of dopamine (DA) in precipitated withdrawal jumping was studied in morphine dependent rats. Pretreatment with various dopaminergic agonists induced a dose-dependent increase in naloxone induced jumping. Pimocide totally blocked the facilitatory effect of piribedil while naloxone induced jumping was not dose-dependently decreased. Biochemical measurements revealed that during precipitated withdrawal the level of DA was elevated and the accumulation of 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) after probenecid as well as the level of 3-methoxytyramine in the striatum was reduced. Unilateral inactivation of the caudate by local injection of KCl induced contralateral circling during withdrawal. Additional systemic haloperidol pretreatment did not change the direction of circling while additional apomorphine pretreatment changed the direction to ipsilateral and increased the circling rate highly. These latter as well as the biochemical findings strongly suggest an inhibition of striatal DA-mechanisms during withdrawal. The apparent contradiction of these findings to the above finding showing a facilitatroy role of DA-agonists on jumping is discussed.     

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)     

Effects of morphine in rats withdrawn from repeated nifedipine administration

The effects of withdrawal from repeated nifedipine treatment on morphine-induced analgesia, hyperthermia and catalepsy as well as on cerebral [3H]nitrendipine binding and on morphine-induced changes in striatal and limbic dopamine and 5-hydroxytryptamine metabolism were studied in rats. Repeated administration of nifedipine (5 mg/kg i.p., twice daily for 14 days) decreased [3H]nitrendipine binding in several brain areas of the rats at 24 h after the last dose but did not change the nociceptive response or rectal temperature of the animals. Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment. However, withdrawal from repeated nifedipine treatment failed to affect either the hyperthermia induced by this dose of morphine or the catalepsy and the elevation of dopamine or 5-hydroxytryptamine metabolites induced by 15 mg/kg of morphine. Taken together, these data show that withdrawal from repeated treatment with dihydropyridine calcium channel antagonists selectively reduces the effects of opioids on the nociceptive response.