The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance

According to a model of morphine tolerance, which emphasizes Pavlovian conditioning principles, tolerance results from an association between predrug environmental cues and the systemic effects of the drug. To assess this model, groups of rats were administered morphine on either three or nine occasions, with a complex environmental stimulus either paired or not paired with each injection. Control groups had equivalent experience with the environmental cue and injection procedure, but the injected substance was physiological saline. Subsequently, the analgesic effect of the opiate was tested in all subjects following administration of the drug in conjunction with the environmental cue. As expected on the basis of the conditioning model of tolerance, subjects with a pretest history of paired morphine administrations displayed analgesic tolerance, but subjects with a pretest history of unpaired administration displayed no evidence of such tolerance. The results suggest that prior demonstrations that the display of morphine tolerance is specific to the drug administration environment may be readily interpreted by a conditioning analysis of tolerance.     

Therapy and immunization of long-term analgesia in rats

Three experiments are reported which examine the effects of experience with escapable shock either subsequent to (Experiment 1) or prior to (Experiments 2 and 3) a session of inescapable shock on the subsequently produced long-term analgesic reaction in rats. Experment 1 demonstrated that experience with escapable shock 4 hr after a session of inescapable tail shock completely reverses the analgesic response that is normally observed 24 hr later upon reexposure to shock. The escapability of the shock was shown to be the important factor in reversing the analgesic reaction, since subjects given inescapable shock in amounts equivalent to escape subjects exhibited no reduction in analgesia. Experiment 2 showed that experience with escapable shock 4 hr prior to a session of inescapable tail shock could also completely eliminate the long-term analgesic reaction. Experiment 3 replicated the results of Experiment 2, but employed a different escape task and temporal parameters in order to extend the generality of the findings, and to more closely match the procedures employed in behavioral experiments reported by J. L. Williams and S. F. Maier (Journal of Experimental Psychology: Animal Behavior Processes, 1977, 3, 240–253). The implications of these results for the areas of pain control and learned helplessness were discussed.     

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.     

Pain complaint and muscle soreness associated with high-voltage electrical stimulation: effect of ramp time

The purpose of this study was to determine the effects of ramp time on subjects' perception of discomfort/pain and muscle soreness associated with high-voltage electrical stimulation. 31 female students were randomly assigned to three treatment groups, each of which was assigned a different ramp time (1.0, 3.5, and 5.0 sec.). The subjects' wrist and finger flexors were stimulated with ElectroStim 180-2 unit using the bipolar electrode arrangement. During the stimulation, the subjects rated their experience of discomfort/pain at the threshold of sensory stimulation, the threshold of motor stimulation, and maximum tolerance of painful stimulation. The session was terminated after 10 tetanic isometric contractions. The subjects were instructed to rate their soreness, 24- and 36-hr. poststimulation using a 10-point ratio scale. A significant F ratio was noted for discomfort/pain perceptual levels but not for ramp time. Scheffé's post hoc analysis showed that the discomfort increased as the current intensity was increased. The F ratio for ramp time and time frame (24- and 36-hr. poststimulation) was not statistically significant for the ratings of muscle soreness. The findings suggest that the patients's complaint of pain and muscle soreness associated with high-voltage electrical stimulation is not affected by the rate of rise of current.     

EMG biofeedback training, relaxation training, and placebo for the relief of chronic back pain

24 patients with chronic low back pain were randomly assigned to three treatment conditions: EMG biofeedback, relaxation training, and a placebo condition. Patients were seen for eight sessions and were evaluated before Session 1 and after Session 8. Eight analyses of covariance which were adjusted for age and pretest scores were computed on the final scores to find which variables could detect significant difference between treatments. Age was included as a covariate because the differences in age between conditions were significant. Four variables with significant and nearly significant differences were chosen for analysis. The second set of analyses identified the nature of the differences among the three conditions. These included a priori planned comparisons among conditions, and paired t tests. Relaxation-trained subjects were significantly superior to subjects in the placebo condition, in decreasing pain during the function test, increasing relaxation, and decreasing Upper Trapezius EMG. They were superior to EMG Biofeedback training in increasing reported activity. Both Relaxation and EMG trained subjects were able to reduce Upper Trapezius EMG by Session 8. Relaxation-trained subjects showed significant change on eight of the 14 possible comparisons for each treatment condition. EMG biofeedback training showed significant favorable results in only one condition; the placebo condition showed no significant results. Relaxation training gave better results in reducing EMG and pain, and in increasing relaxation and activity than either EMG biofeedback alone or a placebo condition.     

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.     

Dextroamphetamine and placebo practice effects on selective attention in hyperactive children

Three groups of three boys referred to a hospital study unit for evaluation of hyperactive behavior were tested on a classification task involving selective attention while on either dextroamphetamine (D) or placebo (P). In two sessions, groups had D first, P second (DP), or PD, or PP. Amphetamine reduces response times in general and reduces interference due to orthogonally varying irrelevant information. Practice while on placebo improves performance in a subsequent placebo session. Practice while on amphetamine does not, however, improve performance in the subsequent session on placebo. Assessment of the extent of the drug-state-related practice effect is necessary for evaluation of long-term benefits of dextroamphetamine therapy in these children.Thanks go to Ramona Roberts for assistance in running subjects. The University of Maryland Computer Science Center provided the computer facilities for data analysis.     

Response patterns and cardiovascular effects during response sequence acquisition by humans.

The effects of temporal delays imposed between successive responses and of vitamin C administration were examined on the acquisition of response sequences and on cardiovascular reactivity during sequence acquisition. Thirteen adult subjects (6 female, 7 male), in good health, gave written consent prior to participating in 12 weekly 45-min sessions. Points, exchanged for money after each session, were presented when subjects completed 15-response sequences on a touch-sensitive three-response keypad. A position counter increased from 0 to 14 as subjects emitted correct responses in the sequence. Four novel 15-response sequences were presented each session. No delays were imposed between successive responses during the acquisition of one sequence; delays were imposed immediately following each response during the acquisition of a second sequence, thereby delaying response feedback; delays were imposed following feedback during acquisition of a third sequence, resulting in the removal of the stimulus correlated with sequence position; and, as a control condition, delays were imposed following feedback, but stimuli correlated with sequence position were reinstated prior to the next response during acquisition of a fourth sequence. Subjects were exposed to one of two delay durations (0.2 and 0.5 or 0.5 and 1.0 s) each session, and delay durations alternated every session. During Weeks 5 to 8, subjects received 3 grams of vitamin C per day, whereas during Weeks 1 to 4 and 9 to 12, subjects received placebo under single-blind conditions. All subjects acquired the sequences, as evidenced by decreasing percentages of incorrect responses across trials. When temporal delays were imposed between successive responses during sequence acquisition, acquisition efficiency was enhanced. Examination of response latencies suggested that the status of preceding responses (i.e., correct or incorrect) rather than the status of the position counter influenced subsequent responding. Cardiovascular effects were inversely related to the length of the temporal delay. Neither cardiovascular reactivity or sequence acquisition were related to vitamin C administration.     

Evidence from rats that morphine tolerance is a learned response.

It is 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. Using the "hot plate" analgesia assessment situation with rats, this conditioning view of tolerance is supported by several findings: (a) It is necessary to have reliable environmental cues predicting the systemic effects of morphine if tolerance is to be observed, (b) a hyperalgesic conditioned response may be observed in morphine-tolerant subjects when drug administration cues are followed by a placebo, and (c) merely by repeatedly presenting environmental cues previously associated with morphine (but now presented with a placebo), morphine tolerance can be extinguished.     

Magnitude estimates of cold pressor pain: effects of suggestions, cognitive strategy, and tolerance

Pain magnitude when subjects immersed an arm in ice water was assessed by means of a magnitude estimation procedure during baseline and posttest sessions. Before the posttest session, subjects either received or did not receive an analgesic suggestion. Best-fit functions were linear, though power fits were also good. Analgesic suggestions had no effect on the rate of change in pain intensity. When subjects were classified as copers or catastrophizers on the basis of written testimony, pain intensity increased more rapidly for catastrophizers than for copers during the posttest session but not during the baseline session. Subjects who kept their arm immersed for more than 240 s were classified as high in tolerance. High-tolerance subjects experienced a slower rate of growth in pain intensity than low-tolerance subjects. Theoretical implications of the results are discussed.     

Rapid induction of specific associative behavioral memory by stimulation of the nucleus basalis in the rat

Hypothesized circuitry enabling behavioral memory formation can be tested by its direct activation in the absence of normal experience. Neuromodulation via the cortical release of acetylcholine by the nucleus basalis (NB) is hypothesized to be sufficient to induce specific, associative behavioral memory. Previously, we found that tone paired with stimulation of the nucleus basalis (NBs) for 3000 trials over 15 days induced such memory, supporting the hypothesis. However, as standard associative memory can be established much more rapidly, we asked whether NB-induced memory develops rapidly. Adult male Sprague-Dawley rats, trained and tested in the same calm, waking state, were divided into Paired (n=5) and control (n=4) groups, each of which received a single session of 200 trials of an 8.0 kHz conditioned stimulus (CS) either paired with NBs or with unpaired presentation of NBs. Respiration, cardiac activity, and evoked potentials in the primary auditory cortex (ACx) were recorded. Memory and its degree of specificity were assessed 24 h later by presenting tones of various frequencies (1-15 kHz) in the absence of NBs to yield behavioral frequency generalization gradients. Behavioral responses to test tones consisted of interruption of ongoing respiration and changes in heart rate. Post-training behavioral generalization gradients exhibited response peaks centered on the CS frequency for the Paired group alone. Tone evoked potentials from the ACx also developed CS-specific plasticity. The findings indicate that NB induction of specific behavioral associative memory, like normal memory, can develop rapidly and is accompanied by specific cortical plasticity, supporting the view that NB engagement during normal learning produces memory.     

Interactions between perinatal and neonatal associative learning defined by contiguous olfactory and tactile stimulation

Tactile stimulation of the neonate, as performed by the mother during and after delivery, has been described as an effective unconditioned stimulus during early ontogeny (Leon, 1987; Ronca & Alberts, 1994). The present experiments examined the interaction between perinatal and neonatal learning determined by the explicit association between alcohol odor and vigorous body stimulation of the perinatal organism. In Experiment 1, rat fetuses were exposed to either alcohol or saline 10 min prior to cesarean delivery. The alcohol administration procedure here employed was sufficient to provide sensory contamination of the amniotic fluid but avoid fetal alcohol intoxication. Pups in the two prenatal treatments later experienced the smell of alcohol, tactile stimulation, or both stimuli explicitly paired or unpaired. Other postnatal groups were composed of pups that had no explicit experience with either experimental stimulus. Pups subjected to alcohol odor in utero displayed more overall motor activity in response to that odor than saline controls. The increased motor responses were further potentiated in pups that experienced additional postnatal alcohol odor paired with tactile stimulation. In Experiment 2, pups were exposed to alcohol in the amniotic fluid 10 or 30 min prior to birth. As previously demonstrated the memory acquired in utero appears highly dependent upon contingency between exposure to this particular scent and delivery procedures. Pups in both prenatal treatment groups were then exposed to alcohol odor paired or unpaired with tactile stimulation. Some control animals received no further experience with either stimuli. Those pups exposed to alcohol odor paired with tactile stimulation both pre- and postnatally later showed maximum motor activity elicited by the odor of alcohol. The results support the notion of fetal associative learning comprising alcohol's chemosensory cues and behaviorally activating stimuli. Furthermore, the conditioned response under analysis is potentiated whenever neonates are reexposed to contingent presentations of the elements that defined the original associative memory.     

A novel radiant heat test for assessing pain threshold in human subjects: Measurement stability

New methodologies to assess analgesic response in humans are needed to better integrate preclinical and clinical data. In the present study we examined the test-retest stability of an innovative radiant heat methodology compared with an electrical stimulation methodology. For the radiant heat task, a modified rodent tail flick apparatus was used. The latency for finger withdrawal was recorded. For the electrical stimulation tasks, subjects placed two fingers on two electrodes from which they received a brief series of increasingly intense electrical stimulations. Maximum stimulus intensity (in milliamps) delivered was recorded. On each of 4 test days, the subjects received five test trials with a 10-min interval between trials. All the subjects were tested twice on each apparatus in a counterbalanced design. Finger withdrawal latencies for the radiant heat task did not differ significantly across test trials or test days. Finger withdrawal scores for electrical stimulation increased significantly across test trials as well as test days. These data show that the radiant heat method generates consistent latencies across trials and days, whereas shock produces trends over time. The radiant heat task, which is convenient to operate and inexpensive to build, appears promising as a reliable test of pain threshold in humans.     

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.     

Drive level and cue utilization in a free operant situation with albino rats

Summary Albino rats under either a daily high (2 gms) or moderate (12 gms) food deprivation condition were presented stimuli at the termination of reinforced fixed ratio bar press response chains. Within each drive group, half the animals received a session of brief light-off stimuli accompanied by reinforcement followed by a session of a buzzer and light-off compound stimuli paired with reinforcement. The remaining animals had the buzzer first paired with reinforcement and then the compound stimulus paired with reinforcement. Each stimulus element was tested for its respective control of nonreinforced food-cup approach behavior. These tests demonstrated that the buzzer cue blocked and overshadowed control of approach behavior of the light-off cue. In animals that received the initial light-off conditioning session, overshadowing by the buzzer of the light-off stimulus was less strong in high than moderate drive animals. These results were discussed in terms of Kamin's (1969) findings and Easterbrook's (1959) arousal-cue utilization hypothesis.The present study was supported by a grant given to the senior author from the National Research Council of Canada (APA 7450). The findings of the single stimulus control groups were also presented as a paper in modified form to the Canadian Psychological Association at its annual meeting, 1974, Windsor, Ontario, Canada.     

Trait predictors of placebo responses in itch

This study investigated trait predictors of placebo responses in the context of inflammatory skin reactions. This was a randomized, cross-over, experimental study using a deceptive placebo protocol. A healthy sample of volunteers (N = 48) completed online personality measures, then attended two laboratory sessions in which short-term inflammatory skin reactions were induced. One was a control session and the other the ‘treatment’ session in which a placebo cream was administered with the suggestion of a reduced skin reaction. A placebo response was defined as smaller skin reactions in control vs. treatment sessions. The traits ego resiliency and neuroticism were selected as possible predictors of placebo responses. Traits were selected in consideration of the two-faceted transactional model of placebo responsiveness and in light of empirical and psychometric considerations ego resiliency emerged as a consistent predictor of placebo responses in itch (p < .05). This is the first study to identify trait predictors of placebo responses in inflammatory skin reactions. Ego resiliency may typify greater placebo responsiveness; however, this may only be in certain contexts. Matching treatment approaches to bio-behavioural response tendencies may be useful clinically if the placebo component of traditional treatments can be enhanced.     

The Neural Bases of Placebo Effects in Pain

Abstract— Placebo effects are beneficial effects of treatment caused not by the biological action of the treatment but by one's response to the treatment process itself. One possible mechanism of placebo treatments is that they create positive expectations, which change one's appraisal of the situation and may thereby shape sensory and emotional processing. Recent brain-imaging evidence suggests that placebo-induced expectations of analgesia increase activity in the prefrontal cortex in anticipation of pain and decrease the brain's response to painful stimulation. These findings suggest that placebo treatments can alter experience, not just alter what participants are willing to report about pain. To the extent that they involve neural systems mediating expectancy and appraisal, placebo effects in pain may share common circuitry with placebo effects in depression, Parkinson's disease, and other disorders.     

Endogenous cortisol level interacts with noradrenergic activation in the human amygdala

Animal studies show that high cortisol levels exert their effect on stressful task performance via modulation of the amygdala. Availability of noradrenaline in this brain region appears to be a critical prerequisite for this effect. This relationship between noradrenaline and cortisol is explained by an animal model where the amygdala constitutes a crucial region for this interaction. In humans this model has not been extensively tested so far. In a previously reported study human subjects (aged 20.93+/-2.38) were scanned using fMRI when watching sets of emotional and neutral pictures after taking the beta-adrenergic antagonist propranolol or placebo. Stimulus sets consisted of 92 pictures, divided in four emotional categories that ranged from neutral scenes of domestic objects (CAT1) to extremely negative scenes of mutilation or accidents (CAT4). Confrontation with arousing emotional pictures, accompanied by increased noradrenaline levels, evoked increased amygdala activation under placebo but not under betablocker condition. This new and additional analysis of this data set was carried out to determine the effect of differential endogenous cortisol levels on amygdala activation. Cortisol levels during scanning were determined using salivary samples and subjects were post hoc divided in a High (n=14) and Low cortisol group (n=14). When subjects were watching emotional stimuli, presumably associated with enhanced noradrenaline (NA) levels, amygdala activation was contrasted between the two cortisol groups. We hypothesized that emotional stimuli would elicit more amygdala activation in the High than in the Low cortisol group. Here we demonstrate indeed a significant interaction effect of the endogenous cortisol level with increasing activation in the amygdala under placebo but not under betablocker condition, thereby extending the rodent based model of a synergistic effect of the two stress hormones to the human.     

Effects of retention intervals on the magnitude of optokinetic rotation-induced taste aversions.

This study investigated the effects of different retention intervals on the magnitude of optokinetic rotation-induced conditioned taste aversions in humans. Two experiments were conducted. In Exp. 1, 20 subjects were divided into two groups, a CS-UCS group in which drinking soybean milk was paired with optokinetic rotation-induced gastric illness and a CS-Only group in which drinking soybean milk was not paired with optokinetic rotation. Analysis indicated that two days after pairing soybean milk drinking with optokinetic rotation, the subjects in the CS-UCS group had significantly reduced palatability ratings of soybean milk and lower consumption of soybean milk than those in the CS-Only group. In Exp. 2, 40 subjects were divided into four CS-UCS groups with 1-day, 3-day, 5 day, and 10-day retention intervals between the session of pairing soybean milk with optokinetic rotation and the session of retasting soybean milk. Analysis yielded no significant differences among four groups on palatability of soybean milk and consumption of soybean milk in the retasting session. It is concluded that optokinetic rotation is an effective unconditioned stimulus for conditioned taste aversions formation and that the aversion has a retention period of at least 10 days.     

Anger management style and emotional reactivity to noxious stimuli among chronic pain patients and healthy controls: the role of endogenous opioids.

OBJECTIVE: Previous work suggests that elevated trait anger-out exacerbates pain responses in part through endogenous opioid dysfunction. The authors examined whether this opioid dysfunction affects not only perceived pain intensity, but also emotional responses to being hurt. DESIGN: 79 chronic low back pain (LBP) patients and 46 healthy controls received opioid blockade (8 mg naloxone i.v.) and placebo in randomized, counterbalanced order in separate sessions. During each session, participants sequentially experienced finger pressure pain and ischemic forearm pain tasks, with emotional state assessed at baseline and postpain. MAIN OUTCOME MEASURES: Blockade effects indexing opioid modulation of emotional reactivity were derived by subtracting placebo from blockade condition emotional reactivity. RESULTS: Significant Participant Type x Anger-Out interactions on blockade effects indicated that in LBP participants but not in controls, greater anger-out was associated with deficient opioid modulation of anxiety, anger, and fear reactivity to noxious stimulation. Across participant types, greater anger-in was associated with impaired opioid modulation of anxiety and fear reactivity. Anger-in opioid effects were partially due to overlap with general negative affect. CONCLUSIONS: Opioid dysfunction associated with trait anger-out may affect not only perceived pain intensity, but also pain-related suffering in individuals with chronic pain conditions. Implications for understanding the health effects of anger management styles are discussed.