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.     

Shock-induced hyperalgesia: IV. Generality

Brief-moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, inducing antinociception on the tail-flick test while lowering vocalization thresholds to shock and heat (hyperalgesia) and enhancing fear conditioned by a gridshock unconditioned stimulus (US). This study examined the generality of shock-induced hyperalgesia under a range of conditions and explored parallels to sensitized startle. Reduced vocalization thresholds to shock and antinociception emerged at a similar shock intensity. Severe shocks (3, 25 s, 1.0 mA or 3, 2 s, 3.0 mA) lowered vocalization threshold to shock but increased vocalization and motor thresholds to heat and undermined fear conditioned by a gridshock or a startling tone US. All shock schedules facilitated startle, but only brief-moderate shock inflated fear conditioning. The findings suggest that brief-moderate shock enhances the affective impact of aversive stimuli, whereas severe shocks attenuate pain.     

Perceived self-efficacy and pain control: opioid and nonopioid mechanisms

In this experiment, we tested for opioid and nonopioid mechanisms of pain control through cognitive means and the relation of opioid involvement to perceived coping efficacy. Subjects were taught cognitive methods of pain control, were administered a placebo, or received no intervention. Their pain tolerance was then measured at periodic intervals after they were administered either a saline solution or naloxone, an opiate antagonist that blocks the effects of endogenous opiates. Training in cognitive control strengthened perceived self-efficacy both to withstand and to reduce pain; placebo medication enhanced perceived efficacy to withstand pain but not reductive efficacy; and neither form of perceived self-efficacy changed without any intervention. Regardless of condition, the stronger the perceived self-efficacy to withstand pain, the longer subjects endured mounting pain stimulation. The findings provide evidence that attenuation of the impact of pain stimulation through cognitive control is mediated by both opioid and nonopioid mechanisms. Cognitive copers administered naloxone were less able to tolerate pain stimulation than were their saline counterparts. The stronger the perceived self-efficacy to reduce pain, the greater was the opioid activation. Cognitive copers were also able to achieve some increase in pain tolerance even when opioid mechanisms were blocked by naloxone, which is in keeping with a nonopioid component in cognitive pain control. We found suggestive evidence that placebo medication may also activate some opioid involvement. Because placebos do not impart pain reduction skills, it was perceived self-efficacy to endure pain that predicted degree of opioid activation.     

Activation of the opioid and nonopioid analgesic systems: evidence for a memory hypothesis and against the coulometric hypothesis

It has been suggested that the magnitude and form of hypoalgesia elicited by an aversive event can be predicted from its coulometric product (Intensity X Duration). According to this hypothesis, small products elicit opioid hypoalgesia, and large products elicit nonopioid hypoalgesia. This suggests that increasing the duration of an aversive event should heighten the nonopioid hypoalgesia. Contrary to this prediction, in Experiment 1 I found that increasing the duration of a mild shock attenuated the nonopioid hypoalgesia. In Experiment 2 I tested another implication of the coulometric hypothesis, namely, that mild shocks that have the same coulometric product should elicit equivalent hypoalgesia. The results did not support this prediction. We discuss how these findings are consistent with an alternative theory, the "working memory hypothesis." According to this theory, the representation of an aversive event in working memory elicits hypoalgesia. In Experiment 3 a novel prediction of this theory was tested, namely, that displacing the representation of intense shock from working memory, by following the intense shock with a weak shock "distractor", should attenuate hypoalgesia. The results support this prediction. I conclude by discussing the relation of this work to other findings in the analgesia literature.     

Immunization of opioid analgesia: Effects of prior escapable shock on subsequent shock-induced and morphine-induced antinociception

In Experiment 1, it was shown that experience with escapable foot shock 4 hr prior to a session of 80 inescapable tail shocks prevented the occurrence of an analgesic response normally observed immediately following the tail shock. It has been suggested by J. W. Grau, R. L. Hyson, S. F. Maier, J. Madden, and J. D. Barchas (Science, 1981, 213, 1409–1411) that the analgesia that occurs following this number of inescapable tail shocks is mediated by endogenous opioid systems. To further explore the influence of escapable shock on opiate-mediated analgesia, Experiment 2 examined the effects of prior escapable shock on the long-term analgesia reaction that occurs upon brief exposure to shock 20 hr after morphine administration. Rats were given escapable shock, inescapable shock, or no shock 4 hr prior to a morphine injection. Twenty hours following the injection, all subjects received 5 brief foot shocks and were then immediately given tail-flick analgesia tests. Subjects which received inescapable shock or no shock prior to the morphine injection displayed a significant analgesic response. However, subjects which received escapable shock prior to morphine were not analgesic following brief exposure to shock. Thus, escapable shock seems to directly influence the activation of opioid analgesia systems.     

Selective association in conditioned stress-induced analgesia: functional differences in interoceptive and exteroceptive sensory pathways

Rats were used to determine whether stress-induced analgesia (SIA) can be produced by conditioning with interoceptive stimuli (LiCl) as with exteroceptive stimuli (footshock). SIA was measured using a tail-flick test. As expected, unavoidable footshock as well as conditioning with footshock produced SIA. In contrast, conditioning with LiCl failed to cause SIA. The findings support the notion of functional differences in neural substrates for conditioning by exteroceptive and interoceptive cue.     

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.     

Naloxone and cold-water swim analgesia: Parametric considerations and individual differences

The role of endogenous opioids in the mediation of stress-induced analgesia has been studied using the opiate antagonist naloxone to reduce or eliminate the response. While the analgesic responses following some stressors are reduced by naloxone, other stressors, like cold-water swims, are altered minimally. However, in the case of inescapable foot shock analgesia, the temporal, numerical, and spatial arrangement of the shocks are critical parameters in determining whether naloxone is capable of altering the analgesic state. In assessing parametric variations of naloxone antagonism of cold-water swim analgesia, five experiments were performed. The first experiment showed that naloxone antagonized the analgesic response following a 3.5-min swim in a 15°C bath, but not in baths of 8°C and 2°C. The second experiment demonstrated dose-dependent antagonism of analgesia induced by 2°C swims for 2.5 and 3.5 min; shorter durations failed to increase thresholds. The third experiment indicated that naloxone decreased 2°C, 3.5-min swim analgesia when the pain test occurred 30 min after stress; longer intervals failed to produce analgesia. The fourth experiment showed that the temporal relationship between injections and swims had little bearing on resultant effects. Finally, since it appeared that naloxone decreased analgesia induced by the 2°C, 3.5-min swim in some animals, but not others, the fifth experiment found that the degree of naloxone antagonism was correlated with the magnitude of the analgesic response induced in individual animals. These results are discussed in terms of opioid and nonopioid mechanisms subserving pain inhibition.     

Place avoidance learning and stress-induced analgesia in the attacked mouse: role of endogenous opioids

In this study, mechanisms of pain inhibition (tail-flick test) and memory (place avoidance paradigm) were investigated in attacked, DBA/2 and C57BL/6, mice. During training, exposure of test animals to 10 or 30 bites by an aggressive, isolated ICR mouse situated in the dark half of a bright/dark conditioning box induced a significantly higher social conflict analgesia in DBA than in C57 mice. Naltrexone (0.5 and 2.0 mg/kg) reduced this response in DBA mice that received 30, but not 10, bites and was ineffective in C57 mice. This points to different, opioid versus naltrexone-insensitive nonopioid, analgesic mechanisms. During place choice testing in the same box 24 h later, DBA mice that had received 30, but not 10, bites showed a significant, naltrexone-reversible, avoidance of the attack place. No place avoidance learning was observed in C57 mice. The data provided unequivocal evidence that place avoidance learning was a result of associative conditioning, in that neither pairing nor social conflict per se significantly changed the preference for the dark side seen in experimentally naive DBA mice. Antagonism of place avoidance conditioning was observed regardless of whether testing was carried out in the drugged or undrugged state, excluding possible state-dependent effects as an explanation for the naltrexone-induced impairment. Individual correlational analysis in saline-injected, attacked DBA mice revealed a negative relationship between the analgesic state immediately after training and the avoidance of attack place during testing. In summary, the results suggest strain-dependent analgesic and learning mechanisms and indicate that endogenous opioids released in attacked DBA mice support pain inhibition and modulate the memorization of attack place by their analgesic effects, as well as by mechanisms independent of pain inhibitory systems.     

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.     

Suppression of valid inferences and knowledge structures: the curious effect of producing alternative antecedents on reasoning with causal conditionals

These studies looked at the difficulty that reasoners have in accepting conditional ("If P then Q") major premises that are not necessarily true empirically, as a basis for deductive reasoning. Preliminary results have shown that when reasoners are asked to produce possible alternate antecedents to the major premise ("If A then Q"), they paradoxically tend to deny the modus ponens (MP) inference ("If P is true, then Q is true"). Three studies further explored these results. The first study gave university students paper-and-pencil tests in which instructions to "suppose that the major premise is true" was followed by a request to determine the next number in a sequence, to retrieve information unrelated to the premises, or to retrieve a possible case of "If A then Q." Relative to a control group, reasoners asked to produce an alternative antecedent showed a significant tendency to deny the MP inference, whereas no such tendency was observed for the two other tasks used. A second study compared performance on a condition in which reasoners were asked to produce an alternative antecedent with that when they were given an explicit alternative. Premises used in this study were such that the latter alternative antecedent was also spontaneously produced by over 70% of reasoners. Results showed that the tendency to refuse the MP premise could not be accounted for by the specific nature of the alternative produced. A third study found that the tendency to refuse the MP inference after producing an alternative antecedent was affected by the number of "disabling conditions" (i.e., conditions that allow "P to be true" and "Q to be false") available for the major premise. These results are interpreted as being consistent with a model that supposes that logical reasoning requires selective inhibition of real-world knowledge.     

Naltrexone-reversible pain suppression in the isolated attacking mouse

Fighting pairs of isolated DBA/2 mice showed a significant increase in tail-flick response latencies independent of whether opponents were losing or winning the combat. The effect lasted less than 10 min in both animals. Elevated pain thresholds were also found in isolates that attacked a nonaggressive conspecific, and were prevented by naltrexone (0.2 mg/kg), while a larger dose (1.0 mg/kg) inhibited the attack behavior. A small increase in pain threshold was observed after exposure of isolates to the test box alone, while isolation per se had no effect on baseline tail-flick latencies. The data demonstrate that endogenous pain suppressing systems are activated during attack and suggest that this opioid-mediated antinociception is a correlate of the isolation syndrome, reflecting enhanced arousal of the attacking animal.     

Diazepam-stress interactions in the rat: effects on autoanalgesia and a plus-maze model of anxiety

On six occasions spaced at least a week apart, two groups of rats were subjected to a variety of stressful conditions consisting of a restraint/bright light complex, either alone or in combination with a tail pinch, whole-body inversion, or partial immersion in cold water. One of these groups was injected with diazepam (2.0 mg/kg) 30 min prior to the stressors, while the other group experienced the drug in their home cages the following day. A third group also received the diazepam but was not exposed to the stressors. In three test sessions all animals were injected with either diazepam or saline and were then exposed to a novel stressor: a plus-maze used as a screening device for anxiolytic drugs. This was immediately followed by a tail-flick measure of analgesia. The longest tail-flick latencies, indicating stress-induced analgesia ("autoanalgesia"), were observed in the group that had not been exposed to stress prior to testing. The other two groups exhibited substantially shorter latencies but did not differ from one another, thus showing a "stress inoculation" effect that was uninfluenced by diazepam. In the plus-maze, diazepam tends to increase the amount of time rats will spend in the two exposed arms of the maze relative to the two enclosed arms. This effect was significantly attenuated in the group that had previously experienced the variety of stressors after a diazepam injection, suggesting a learned association between drug and stress that resulted in a diminution of the drug's anxiolytic property.     

Perceived self-efficacy in coping with cognitive stressors and opioid activation

This experiment tested the hypothesis that perceived self-inefficacy in exercising control over cognitive stressors activates endogenous opioid systems. Subjects performed mathematical operations under conditions in which they could exercise full control over the cognitive task demands or in which the cognitive demands strained or exceeded their cognitive capabilities. Subjects with induced high perceived self-efficacy exhibited little stress, whereas those with induced low perceived self-efficacy experienced a high level of stress and autonomic arousal. Subjects were then administered either an inert saline solution or naloxone, an opiate antagonist that blocks the analgesic effects of endogenous opiates, whereupon their level of pain tolerance was measured. The self-efficacious nonstressed subjects gave no evidence of opioid activation. The self-inefficacious stressed subjects were able to withstand increasing amounts of pain stimulation under saline conditions. However, when endogenous opioid mechanisms that control pain were blocked by naloxone, the subjects were unable to bear much pain stimulation. This pattern of changes suggests that the stress-induced analgesia found under the saline condition was mediated by endogenous opioid mechanisms and counteracted by the opiate antagonist.     

How Today’s Shocks Predict Tomorrow’s Leaving

Purpose

This research explores “shocking events” as part of the unfolding model of turnover, extending our understanding of the influence of various types of shocks on future voluntary employee separations.

Design/Methodology/Approach

1536 new hires at a large financial institution reported shocks monthly during their first 8 months at work as well as their job satisfaction and perceptions of marketability. We used event history to estimate the basic distributional properties of the shocks and Cox proportional hazards models to examine the effects of shocks on job satisfaction and turnover over the subsequent year as reported by the organization.

Findings

Organizational shocks generally occur earlier than personal shocks. Further, unexpected shocks have a stronger impact than expected shocks on subsequent turnover. Finally, the effects of organizational shocks on turnover are mediated by job satisfaction, whereas personal shocks have direct effects on turnover.

Implications

Our findings offer evidence for the utility of the shock construct in the unfolding model of turnover and speak to the importance of encouraging managers to monitor shocks on an ongoing basis in order to predict when different types of shocks will occur and their likely influence on turnover.

Originality/Value

Ours is the first study to examine shocks as they occur. This is a contrast to prior studies that relied on retrospective accounts. Thus, we are able to test new hypotheses (e.g., direct effects vs. mediation) that expand the unfolding model of turnover.

     

Mapping from Sound to Meaning: Reduced Lexical Activation in Broca''s Aphasics

Recent studies of lexical access in Broca's aphasics suggest that lexical activation levels are reduced in these patients. The present study compared the performance of Broca's aphasics with that of normal subjects in an auditory semantic priming paradigm. Lexical decision times were measured in response to word targets preceded by an intact semantically related prime word ("cat"-"dog"), by a related prime in which one segment was acoustically altered to produce a poorer phonetic exemplar ("c*at"-"dog"), and by a semantically unrelated prime ("ring"-"dog"). The effects of the locus of the acoustic distortion within the prime word (initial or final position) and the presence of potential lexical competitors ("cat" --> /gaet/versus "coat" --> "goat") were examined. In normal subjects, the acoustic manipulations produce a small, short-lived reduction in semantic facilitation irrespective of the position of the distortion in the prime word or the presence of a voiced lexical competitor. In contrast, Broca's aphasics showed a large and lasting reduction in priming in response to word-initial acoustic distortions, but only a weak effect of word-final distortions on priming. In both phonetic positions, the effect of distortion was greater for prime words with a lexical competitor. These findings are compatible with the claim that Broca's aphasics have reduced lexical activation levels, which may result in a disruption of the bottom-up access of words on the basis of acoustic input as well as increased vulnerability to competition between acoustically similar lexical items.     

Sympathetic nervous system and pain: a clinical reappraisal

The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called "reflex sympathetic dystrophy" (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called "sympathetically maintained pain" (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic-sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied.     

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.     

Context, Cognition, and Common Method Variance: Psychometric and Verbal Protocol Evidence

Researchers continue to debate the importance of (item) context effects, which are often thought to produce inflated percept-percept correlations in organizational self-reports. Using Feldman and Lynch's (1988) theory of self-generated validity, we propose five conditions under which such context effects are most likely to occur and to have an impact on substantive conclusions. The proposed effects are tested with psychometric and verbal protocol data from 208 subjects responding to an organizational justice questionnaire, using a 3 (types of context) by 2 ("think aloud" versus "silent") experimental design. Psychometric results revealed context effects on scale means, reliabilities, and some of the relations between constructs. Respondents' concurrent verbal protocols from the "think aloud" condition provided evidence for the cognitive basis of these effects.