Conditioning processes contribute to severity of naloxone-precipitated withdrawal from acute opioid dependence

Abstract

Rationale: Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal, when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine results in further increases in naloxone potency, and prior work has shown that this progressive shift in naloxone potency requires repeated naloxone experience under some but not all experimental conditions. Objective: The current study sought to further characterize the experimental conditions that support naloxone experience-dependent and experience-independent potentiation of precipitated suppression of operant responding in morphine pretreated rats, and to assess more directly whether conditioning mechanisms may contribute to the former process. Methods: Rats trained on an FR15 schedule for food received a total of five vehicle or morphine injections (5.6 mg/kg SC) at 4, 8, or 22 h prior to an operant session in which a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Separate groups of animals at each interval between morphine and naloxone received cumulative naloxone dosing after all morphine pretreatments (NAL all days) or after just the first and last morphine pretreatment (NAL first/last). Additional groups of rats at the 4 h MOR-NAL interval received most of their naloxone cumulative dose-effect experience in either the home cage or in the operant context with levers retracted. Results: Vehicle-pretreated (Morphine-naive) rats showed little change in the naloxone dose-effect function even after five cumulative dose-effect determinations. With a single morphine pretreatment, naloxone potency was increased at 4 or 8 h post-morphine, but not at 22 h. With repeated morphine treatment, all MOR-NAL intervals resulted in significant shifts in naloxone potency across treatment days even when naloxone was administered only after the first and last morphine pretreatment. However, much greater shifts in naloxone potency were observed at 4-h and 8-h intervals when naloxone was administered on all treatment days. At the 22 h MOR-NAL interval, there was no further potentiation in naloxone potency with additional naloxone experience provided on the intermediate days. Finally, when the repeated naloxone experience occurred in the home cage at the 4-h interval, naloxone potency was identical to that seen after limited naloxone experience (NAL first/last), and significantly less than naloxone potency in groups receiving repeated naloxone experience in the operant context. Conclusions: The results suggest that conditioned withdrawal mechanisms may play a significant role in the initial development of opioid dependence.

Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner

“…In fact, disrupting the former also weakens the latter. This outcome has important implications for developing therapeutic strategies to treat or prevent addiction, and in line with previous literature, underscores the importance of context and cue-dependent conditioning in eliciting morphine dependence and motivational withdrawal (24)(25)(26)(27).…”

Conditioned Withdrawal Drives Heroin Consumption and Decreases Reward Sensitivity

“…This observation likely reflects a progressive increase in the magnitude of the conditioned withdrawal effect with repeated cue-withdrawal pairings (Schulteis et al, 2004;Kenny and Markou, 2005). Most importantly, on the test day, withdrawal-associated cues elevated reward thresholds and provoked significant increases in heroin consumption in 23 h rats.…”

Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems

“…B, Percentage of change from baseline ICSS thresholds Ϯ SEM in morphine-dependent unpaired rats injected with saline instead of naloxone during conditioning sessions. dependent rats was increased significantly when naloxone was administered in a specific environment (Schulteis et al, 2004), suggesting that contextual cues may potentiate withdrawal. Overall, these data suggest the possibility that, as discrete and contextual stimuli become paired repeatedly with nicotine withdrawal in human smokers, the magnitude of withdrawal-induced reward deficit may become progressively greater, potentially contributing more and more to the persistence of the tobacco habit.…”