Aversive conditioning in the rat: effects of a benzodiazepine and of an opioid agonist and antagonist on conditioned hypoalgesia and fear.

Hypoalgesia and fear co-occurred in rats trained on a heated floor and tested for their latencies to paw lick on that floor and to step down onto a nonheated floor. These responses were extinguished, suggesting a mediation by aversive conditioning processes. A benzodiazepine impaired the acquisition of aversive conditioning, but it did not attenuate the expression of conditioned hypoalgesia. The opioid agonist morphine also impaired acquisition across a range of drug doses and variations in hypoalgesic tolerance, whereas the opioid antagonist naloxone facilitated acquisition. The results are discussed in terms of the perceptual-defensive-recuperative (Fanselow, 1986) and working memory (Grau, 1987) models of the mechanisms for the co-occurrence of conditioned hypoalgesia and fear.     

Naloxone-induced hypoalgesia: Effects of heat, cold and novelty

Experiment 1 confirmed that pairings of the opioid antagonist naloxone and a heated floor served to induce and then to maintain a conditioned hypoalgesia in rats. Experiments 2a and b demonstrated that this was not specific to some property of the heated floor: pairings of the drug and a cold floor (a) resulted in conditioned hypoalgesia and (b) maintained the hypoalgesia provoked by pairings of the drug with a heated floor. Experiments 3a and 4 showed that pairings of naloxone with the non-heated floor of the apparatus provoked hypoalgesia and provided evidence that this was due to the drug's disruption of a familiarization process. Experiment 3b revealed that pairings of naloxone with the non-heated floor maintained the hypoalgesia induced by pairings of the drug with a heated one. The results were interpreted to mean that naloxone interacts selectively with a stressor so as to maintain or enhance its aversive properties.     

Some effects of exposure to a heat stressor upon the rat's subsequent reactions to that stressor

In six experiments, rats were placed on a heated plate on two occasions (test and retest), and the latencies with which they licked their paws were taken as an index of their sensitivity to nociceptive stimulation. Experiment 1 provided evidence that rats were selectively analgesic on retest depending upon the intensity of the heat experienced on the initial test. Experiment 2 showed that this analgesia was recruited rapidly and was long-lasting, as it was observed when retest was scheduled as early as 0.2 and as late as 48 h after the initial exposure to the hot-plate. Experiment 3 documented a role for conditioning processes, as this analgesia was removed by an extinction-like procedure conducted between test and retest. Experiments 4 and 5 provided evidence for a non-opioid mechanism of pain control, because the analgesia was not diminished by the opioid antagonist, naloxone, nor by a history of morphine injections. These experiments also revealed that the analgesia observed on retest was enhanced and reduced when rats were given naloxone and morphine, respectively, on the initial test. Finally, Experiment 6 showed that the analgesia on retest summated with that produced by morphine. The results were taken to mean that the hot-plate assay for analgesia can itself activate endogenous mechanisms of pain control, and some speculations were offered as to how this occurred.     

Effects of an infusion of morphine into the accumbens nucleus upon acquisition of hypoalgesic and fear responses in rats exposed to a heat stressor

Four experiments examined the effects of an infusion of morphine into the accumbens nucleus upon the aversive conditioning that can occur in rats exposed to the heated floor of a hot-plate apparatus. An infusion of morphine into the accumbens nucleus but not into the caudoputamen or into the prefrontal cortex impaired the acquisition of a conditioned hypoalgesic (Experiment 1) and fear (Experiment 4) response. This impairment was dose-dependent (Experiment 2) and mediated by opioid receptors in the accumbens nucleus, because it was removed by a systemic (Experiment 3a) or by an accumbal (Experiment 3b) infusion of naloxone. The results were attributed to an antagonism between the reinforcement process for aversive conditioning and the appetitive properties of an accumbal infusion of morphine.     

Some effects of the opioid antagonist, naloxone, upon the rat's reactions to a heat stressor

Eight experiments examined the apparently paradoxical analgesia that accrues when rats are repeatedly injected with an opiate antagonist, naloxone, and exposed to a heat stressor. Experiments 1 and 2 showed that such pairings came to enhance in a dose-dependent manner the latencies with which rats paw-licked in response to the stressor. Experiment 3 demonstrated that the latencies to paw-lick in saline-treated rats decreased with increases in the intensity of the heat, indicating that naloxone had not provoked long latencies to paw-lick by increasing the functional intensity of the stressor. Experiment 4 documented a role for conditioning processes in recruiting the naloxone-induced analgesia. Experiment 5 showed that the analgesic effect was due to the pairings of the drug and the heat stressor, as a history of exposure to naloxone in a distinctive environment did not render the animals analgesic when challenged with the drug and the stressor. Experiments 6 and 7 provided evidence that the conditioned analgesia that accrued from drug-stressor pairings was non-opioid in nature, as the analgesia was observed in morphine-tolerant rats and was not reversed by an administration of naloxone in advance of exposure to the conditioning context. Experiment 8 demonstrated that the administration of morphine in the context previously associated with naloxone-stressor pairings provoked a superanalgesia. Although analgesic on the paw-lick assay, naloxone-treated subjects did not appear to be insensitive to the heat or impaired motorically, as they persistently reared with short latencies. The results were discussed in terms of the collateral inhibition model of the endogenous pain control system, and some speculations were offered concerning the relation between paw-licking and rearing.     

Changes in pain reactivity induced by unconditioned and conditioned excitatory and inhibitory stimuli

In three experiments we investigated the effects of aversive-conditioning components on the reactivity of rats to pain. After training in Experiment 1 with a discrete conditioned stimulus (CS) for a shock unconditioned stimulus (US), different groups were exposed to the CS, US, CS/Us compound, just the training context, or none of those immediately prior to a hot-plate test assessing the latency of a paw-lick response. Relative to no exposure and context alone, the CS produced a shorter latency--that is, an apparent sensitization effect--whereas the US produced a longer latency--that is, a hypoalgesic effect--that was actually augmented by the CS/US compound. Furthermore, whereas the US-induced hypoalgesia was unaffected by the opiate antagonist, naloxone, hypoalgesia produced by the CS/US compound was appreciably decremented by the drug. Experiment 2 showed the same effects with parameters more typical of conditioning research. Experiment 3 compared signals for the presence (CS+) and absence (CS-) of the US. The CS- did not itself affect pain reactivity, but in inhibited the effects of the CS+, US, and CS+/US compound. Collectively, the results suggest that a CS+sensitizes the animal to imminent events and also potentiates an opioid reaction that supplants the less effective nonopioid hypoalgesia induced by the US. In contrast, a CS- functions as a general moderator of excitation, inhibiting both sensitization and hypoalgesic effects, whether opioid or nonopioid.     

Defeat-induced hypoalgesia in the rat: effects of conditioned odors, naltrexone, and extinction

In Experiment 1, male rats were either defeated as a colony intruder by alpha conspecifics or had no defeat experience, and 24 hr later they were given a paw injection of formalin prior to observational tests with or without alpha-colony odors. The combination of defeat and tests with these odors produced conditioned hypoalgesia (i.e., a suppression in paw licking) and freezing. In Experiment 2, defeated rats were given either an injection of naltrexone or saline prior to defeat and 24 hr later prior to testing. An injection of naltrexone prior to defeat increased freezing during defeat and later testing. In contrast, naltrexone during testing did not affect freezing but significantly reduced hypoalgesia. In Experiment 3, a 12-hr exposure session with alpha-colony odors extinguished hypoalgesia in previously defeated rats. These findings are discussed in terms of associative, opioid/nonopioid, and adaptive evolutionary processes.     

Associative morphine tolerance in the rat: examinations of compensatory responding and cross-tolerance with stress-induced analgesia

The results of three experiments designed to examine the processes subserving associative tolerance to morphine's analgesic effects, as assessed by the tail-flick test, are reported. The experiments indicated that associative tolerance in male Holtzman rats was not subserved by conditioned compensatory responses but was cross-tolerant with an apparently nonopioid form of stress-induced analgesia (SIA). Experiment 1 showed that rats tested for morphine analgesia in a distinctive context that had been paired previously with morphine injections (5 mg/kg) were more tolerant than animals that had had this context explicitly unpaired with a series of morphine injections or animals that were drug-naive. There was no evidence of a conditioned compensatory response of hyperalgesia in animals given a saline injection in the presence of environmental stimuli that had been previously paired with morphine, even under test conditions designed to minimize the possibility of floor effects that might have obscured the detection of drug-compensatory hyperalgesia. Experiment 2 demonstrated that the footshock procedures used for stress induction produced an SIA that was not attenuated by naloxone (10 mg/kg). Experiment 3 replicated the associative tolerance phenomenon of Experiment 1 and again failed to find evidence of conditioned compensatory responses. It was found that animals exposed to footshock in the context that had been associated with morphine administration developed significantly less SIA than control animals. The relevance of these findings for associative models of drug tolerance is discussed.     

Effects of naloxone on acquisition and extinction of jump-up avoidance behavior in rats

Two experiments were carried out to assess the effects of the opioid antagonist, naloxone, on the acquisition and extinction of shock avoidance by rats in the jump-up apparatus. In Experiment 1 naloxone pretreatment facilitated acquisition but had no effect on extinction of avoidance behavior. In the second experiment the effect of naloxone on acquisition was replicated and in addition, it was shown that naloxone enhanced freezing when a response prevention or flooding procedure was introduced. Again naloxone failed to alter the course of extinction, nor did it interact with the effects of flooding which, by itself, facilitated extinction. The results suggest that naloxone's effects are limited to increasing the functional intensity of the US, and provide further support for the dissociation between extinction of avoidance behavior and other indices of fear.     

Latent inhibition and conditioning after preexposure to the training context

Experiment 1, using the conditioned suppression technique with rats, showed that the retardation of learning produced by prior exposure to a stimulus (latent inhibition) was more marked in subjects given an initial phase of preexposure to the training context. This effect was confirmed and extended in Experiment 2 in which an appetitive conditioning procedure was used. Experiments 3 and 4, again using conditioned suppression, found no effect of preexposure to the context on the acquisition of suppression when training was given with a novel stimulus, either immediately after preexposure or after a delay; but context preexposure was again found to be effective when exposure to the to-be-conditioned stimulus was given in the delay interval between context preexposure and conditioning. The implications of these findings for accounts of the role of contextual factors in latent inhibition are discussed.     

Shock signals and the development of stress-induced analgesia

We report five experiments in which we investigated the effects of "feedback signals" on the pattern of hypoalgesia produced by inescapable shocks. A 5-s lights-out stimulus coincident with shock termination had no effect on the naltrexone-insensitive (nonopioid) hypoalgesia, which occurred after 10 inescapable shocks, but completely blocked the naltrexone-sensitive (opioid) hypoalgesia, which followed 100 inescapable shocks. The stimulus prevented the development of the opioid hypoalgesia rather than merely masking its measurement. This effect did not depend on the use of lights-out as the stimulus but did depend on the temporal relation between the stimulus and shock. Stimuli immediately preceding or simultaneous with shock had no effect. Surprisingly, stimuli randomly related to shock also blocked the opioid hypoalgesia. Simultaneous measurement of both hypoalgesia and fear conditioned to contextual cues revealed that the level of fear did not predict the blockade of hypoalgesia. Different backward groups received different temporal gaps between shock termination and the signal. An interval between 2.5 s and 7.5 s eliminated the effect of the signal on fear, but 12.5-17.5 s were required to eliminate the effect of the signal on hypoalgesia. The opioid hypoalgesia blocking power of the random stimulus was entirely attributable to those stimuli occurring within 15 s of the termination of the preceding shock. The implications of these results for the explanation of stimulus feedback effects and for stress-induced analgesia are discussed.     

Reinforcement of wheel running in BALB/c mice: role of motor activity and endogenous opioids

The authors investigated the effect of the opioid antagonist naloxone on wheel-running behavior in Balb/c mice. Naloxone delayed the acquisition of wheel-running behavior, but did not reduce the expression of this behavior once acquired. Delayed acquisition was not likely a result of reduced locomotor activity, as naloxone-treated mice did not exhibit reduced wheel running after the behavior was acquired, and they performed normally on the rotarod test. However, naloxone-blocked conditioned place preference for a novel compartment paired previously with wheel running, suggesting that naloxone may delay wheel-running acquisition by blocking the rewarding or reinforcing effects of the behavior. These results suggest that the endogenous opioid system mediates the initial reinforcing effects of wheel running that are important in acquisition of the behavior.     

Tail-pinch hyperalgesia and analgesia: Test-specific opioid and nonopioid actions

Reactivity to noxious stimuli in rats is altered following acute exposure to tail-pinch. However, while our laboratory has reported that tail-pinch produces hyperalgesia as measured by the flinch-jump test and attenuates analgesic responses following morphine and cold-water swims, others have found that tail-pinch elicits an opioid-sensitive analgesia on the hot plate test and a nonopioid-sensitive analgesia on the writhing test. The first experiment of the present study examined whether tail-pinch altered responses on two somatic pain tests and showed that tail-pinch significantly decreased both jump thresholds and tail-flick latencies. In assessing whether tail-pinch hyperalgesia on the jump test was mediated by endogenous opioids, the second experiment indicated that low (0.1 and 0.5 mg/kg) doses of naloxone eliminated tail-pinch hyperalgesia by selectively lowering control thresholds and a high (10 mg/kg) dose of naloxone eliminated tail-pinch hyperalgesia by selectively increasing thresholds following tail-pinch. Further, the third experiment showed that morphine-tolerant rats (10 mg/kg morphine daily over 14 days) did not exhibit tail-pinch hyperalgesia on the 15th day, an effect attributable to a selective lowering of control thresholds. The fourth experiment was a direct replication of the observation that tail-pinch produces analgesia on the writhing test which is not antagonized by naloxone. These results demonstrate that the pain test employed and the amount of prior tail-pinch experience are critical variables in determining the direction of tail-pinch effects upon pain perception in rats.     

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance

Rats administered 5 mg/kg morphine SO4, through subcutaneously implanted catheters, during each of several daily sessions in an open field showed a progressive increase in locomotor activity measured in the open field prior to each morphine administration. Since the increases in activity were not observed in rats given morphine in a different environment (home cage) and saline in the open field, it is concluded that the increases were due to conditioning. In addition, the increases in activity were retained over a 7-day rest period; they were also produced when a second opiate (5 microgram/kg etorphine HCl) was substituted for morphine, were not seen when 2 mg/kg naloxone HCl (ip) was administered during treatment, and were present in rats showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose-response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs. .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. The discussion deals with the relation of conditioning and morphine tolerance, the question of whether the unconditioned stimulus of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other stimuli that are reinforcing.     

The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat

The role of the N-methyl-D-aspartate (NMDA) receptor in Pavlovian conditioning of hypoalgesic responses in the hotplate apparatus was examined using the non-competitive NMDA antagonist MK-801. Either MK-801 or saline were administered before the training phase, test phase, or both, and MK-801 disrupted the acquisition and extinction but not the expression of conditioned hypoalgesic responses. All rats received counterbalanced injections of both MK-801 and saline after the training phase, therefore the learning decrements could not be attributed to a delayed, non-specific action of the drug. MK-801 did not augment paw-lick latencies on either the training or test days, indicating that its behavioural effects are not due to alterations in nociceptive sensitivity or motor performance. Similarly, MK-801's effects upon acquisition and extinction could not be attributed to state-dependent generalization decrement or impairments in processing of the hot-plate apparatus cues during training, as rats displayed normal hypoalgesic responses when tested with MK-801, and MK-801-treated animals displayed normal habituation of novelty-induced hypoalgesia in the hot-plate apparatus. These data suggest that the NMDA receptor system is involved in the acquisition and extinction, but not the expression of conditioned hypoalgesia and parallels the effects of NMDA receptor antagonists on the acquisition and expression of long-term potentiation (LTP) both in vitro and in vivo. It is plausible that an endogenous NMDA-mediated form of LTP plays a vital role in the acquisition and storage of aversive representations mediating conditioned hypoalgesic responses.     

吗啡对不同距离条件下大鼠信号追踪和目标追踪的影响

条件刺激短暂呈现并消失后, 奖赏立即呈现, 多次匹配后诱导出动物对条件刺激(信号追踪)或奖赏呈现装置如食盒(目标追踪)的接近。条件刺激与食盒间的距离是影响信号/目标追踪反应和损害联结学习的重要变量, 成瘾药物能够增加奖赏的诱因动机, 进而增加个体的奖赏寻求行为。距离能否通过损害联结学习而减弱成瘾药物的动机放大作用尚未见到报道。本实验采用autoshaping模型, 考察8、30和60 cm距离条件下吗啡处理对大鼠信号追踪和目标追踪的影响。结果发现：(1)信号追踪随距离增加而减少, 目标追踪对距离不敏感。(2)急性吗啡处理减少8、30和60 cm条件下信号追踪而增加8和60 cm条件下目标追踪, 慢性吗啡处理在8和30 cm条件下减少信号追踪增加目标追踪; 消退检测中, 吗啡前暴露减少8和60 cm条件下信号追踪而增加60 cm条件下目标追踪。(3)辨别反转学习中, 吗啡前暴露使30和60 cm条件下的大鼠偏爱旧信号、辨别力受损, 减少8、30和60 cm条件下大鼠对新信号的接触。这些结果提示, 距离较少影响吗啡的信号追踪抑制作用和目标追踪增强效应, 而易化吗啡前暴露对反转学习的损害。说明距离是易化成瘾药物对联结学习不利影响而非反转其动机放大作用的重要因素。     

Effects of post-trial administration of naloxone and beta-endorphin on shock-induced fighting in rats

To study the involvement of endogenous opioid peptides in the development of shock-induced fighting, naloxone (2 mg/kg) or beta-endorphin (10 micrograms/kg) was administered subcutaneously immediately after the session and during nine consecutive daily sessions to rats repeatedly exposed to electric shocks. beta-Endorphin blocked the development of shock-induced fighting while naloxone facilitated it but only when shock-induced fighting occurred at a low rate. The effects of beta-endorphin were time dependent since when beta-endorphin was injected 90 min after the shock session instead of immediately after, its impairing effect disappeared. In addition, naloxone blocked the impairment produced by beta-endorphin. Differential postsession treatment of each member of pairs of rats with naloxone and beta-endorphin resulted in a higher probability of rats treated with naloxone to be dominant over rats treated with beta-endorphin in the test situation. These results are discussed in relation with the possible involvement of endogenous opioids in the modulation of the physiological consequences of defensive behavioral responses to shock.     

Temporally graded,context-specific retrograde amnesia and its alleviation by context preexposure: effects of postconditioning exposures to morphine in the rat

Five experiments studied retrograde impairments in Pavlovian fear conditioning following prolonged exposure to the opioid receptor agonist morphine. Injections of morphine commencing 1-7 days but not 14 days after conditioning produced amnesia for that conditioning episode. This amnesia was (a) selective such that morphine impaired freezing to the conditioning context but not to the auditory conditioned stimulus, (b) independent of the interval between the last injection of morphine and test, and (c) accompanied by a failure of contextual discrimination. Context preexposure protected context conditioning and discrimination from the amnestic effects of morphine. These results show that retrograde deficits in contextual fear conditioning are mediated by failures to consolidate a contextual representation.     

Interaction of Pavlovian conditioning with a zero operant contingency: chronic exposure to signaled inescapable shock maintains learned helplessness effects

In four experiments we used triads, consisting of escapable-shock (ES), yoked inescapable-shock (IS), and no-shock (NS) rats, to investigate the effect of the interaction between Pavlovian contingencies and a zero operant contingency (i.e., uncontrollability) upon subsequent shock-escape acquisition in the shuttle box. After exposure to 50 signals and shocks per session for nine sessions, interference with shuttle box escape acquisition for IS rats was a monotonically increasing function of the percentage of signal-shock pairings during training (Experiment 1), with 50% pairings producing little or no impairment. Without regard to signaling, ES rats performed as well as NS rats. Experiment 2 demonstrated that our training and test conditions led to substantial and equal impairment in IS rats preexposed for one session to 100% or 50% signal-shock pairings or to unsignaled shocks. In Experiment 3, chronic exposure to 100% signaled inescapable shocks resulted in impairment only if the signal (light) was present during the shuttle box test. The continuous presence of the signal during the test contrasted with its discrete (5-s) presentation during training and suggested that an antagonistic physiological reaction rather than a specific competing motor response had been conditioned. Experiment 4 provided evidence for possible conditioned opioid mediation by demonstrating contemporaneous stress-induced analgesia and shock-escape impairment in IS rats chronically exposed to 100%, but not to 50%, signal-shock pairings, and the elimination of both analgesia and escape interference by the opiate antagonist naltrexone. Thus, chronic exposure to uncontrollable shocks appears to maintain the impairment produced by acute exposure only if the shocks are adequately signaled.     

吗啡行为及条件性行为敏感化效应及其个体差异

目的：考察吗啡处理下,大鼠行为敏感化及条件性行为敏感化效应及其个体差异性表现。方法：根据大鼠在初次抵达的新颖环境中水平活动量的高低,将大鼠划分为高反应大鼠（High responder, HR）和低反应大鼠（Low responder, LR）,应用自动监测大鼠活动箱,分别考察HR和LR大鼠在行为及条件性行为敏感化效应表达上的差异。结果：（1）连续5天吗啡给药,LR大鼠活动量显著升高,HR大鼠无此效应;（2）条件测试日（第6天）,给药与环境匹配大鼠,活动量较给药与环境非匹配组动物和对照组动物显著为高;此效应在HR和LR大鼠同时存在;（3）从给予吗啡到给予盐水,发现LR大鼠活动量显著下降,而HR大鼠活动量无显著改变。结论：在连续给药下,LR大鼠较HR大鼠,在行为敏感化效应的形成中,具有更为显著的效应,此效应为LR动物对吗啡更高的药物效应,而非条件效应所致,同时HR和LR大鼠都可以对吗啡条件性线索产生应答,产生条件性行为敏感化效应。