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.     

The aftereffects of ventriloquism: are they sound-frequency specific?

Exposing different sense modalities (like sight, hearing or touch) to repeated simultaneous but spatially discordant stimulations generally causes recalibration of localization processes in one or both of the involved modalities, which is manifested through aftereffects. These provide opportunities for determining the extent of the changes induced by the exposure. Taking the so-called ventriloquism situation, in which synchronized sounds and light flashes are delivered in different locations, we examine if auditory recalibration produced by exposing tones of one frequency to attraction by discordant light flashes generalizes to different frequencies. Contrary to an earlier report, generalization was obtained across two octaves. This result did not depend on which modality attention was forced on through catch trials during exposure. Implications concerning the functional site of recalibration are briefly 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.     

Audiovisual tau effect

This study investigated how spatial intervals between successive visual flashes are influenced by the temporal intervals between auditory pure tones presented concurrently with the flashes. Three successive visual flashes defined two spatial intervals with different extents as well as two equal temporal intervals. The onsets of the first and third tones were temporally aligned with those of the first and third flashes, while the onset of the second tone was temporally offset to that of the second visual flash, resulting in shorter or longer temporal intervals between pairs of tones. Observers judged which of the first or second spatial intervals between flashes was shorter. The results showed that the shorter temporal interval between tones caused underestimation of the spatial interval between flashes. On the other hand, stimuli without the first and third tones did not result in underestimation of spatial intervals between flashes. These results indicate an audiovisual tau effect, which is triggered by a constant velocity assumption applied to moving objects defined by more than one modality.     

Opiate antagonists and long-term analgesic reaction induced by inescapable shock in rats

Five experiments examined the influence of opiate antagonists on both the short-term analgesic reaction resulting 30 min after exposure to inescapable shock and the long-term analgesic reaction resulting after reexposure to shock 24 hr after inescapable shock exposure. Experiment 1 showed that the long-term analgesic reaction could be reduced by administration of naltrexone prior to exposure to inescapable tail shock. Experiment 2 showed that the reduction in the long-term analgesic reaction produced by naltrexone was dose-dependent. Experiment 3 showed that the long-term analgesic reaction could also be reduced by administration of naltrexone prior to reexposure to shock. Experiment 4 showed that the long-term analgesic reaction could be reduced by administration of large dose of naloxone prior to reexposure to shock. Experiment 5 showed that the short-term analgesic reaction was reduced by naltrexone administered prior to inescapable shock. Some implications of these results for the biochemical substrates of both learned helplessness and stress-induced analgesia are discussed.     

Multi- and unisensory visual flash illusions

The role of stimulus structure in multisensory and unisensory interactions was examined. When a flash (17 ms) was accompanied by multiple tones (each 7 ms, SOA < or =100 ms) multiple flashes were reported, and this effect has been suggested to reflect the role of stimulus continuity in multisensory interactions. In experiments 1 and 2 we examined if stimulus continuity would affect concurrently presented stimuli. When a relatively longer flash (317 ms) was accompanied by multiple tones (each 7 ms), observers reported perceiving multiple flashes. In experiment 3 we tested whether a flash presented near fixation would induce an illusory flash further in the periphery. One flash (17 ms) presented 5 degrees below fixation was reported as multiple flashes if presented with two flashes (each 17 ms, SOA =100 ms) 2 degrees above fixation. The extent to which these data support a phenomenological continuity principle and whether this principle applies to unisensory perception is discussed.     

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.     

Long delay learning in the T-maze

Rats were trained to go to one side of a T-maze with delays of reward lasting 1, 20, or 60 min in Expt 1 and 1 or 60 min in Expt 2. Mediation by secondary reward was prevented by administering the same delay treatment regardless of whether the response was correct or incorrect: after a response, the rat was removed from the choice alley and placed in its home cage to spend the delay. Feedback for the response was given in the startbox after the delay interval ended. The rats learned and there were no significant differences in performance among groups trained with different delays. These results had been expected on the basis of Revusky's (1971) hypothesis that removal of the rat from the learning situation to spend the delay elsewhere facilitates long delay learning by reducing associative interference. In Expt 3, this notion was tested explicitly by varying the amount of a 2-min delay to be spent in the experimental situation. Different groups of rats were left in the choice alley after the response for 0, 15, or 60 sec; then the rats were removed to spend the remainder of the 2-min delay in the home cage As predicted, the level of performance decreased as the length of time in the choice alley was increased.     

Spatial grouping resolves ambiguity to drive temporal recalibration

Cross-modal temporal recalibration describes a shift in the point of subjective simultaneity (PSS) between 2 events following repeated exposure to asynchronous cross-modal inputs--the adaptors. Previous research suggested that audiovisual recalibration is insensitive to the spatial relationship between the adaptors. Here we show that audiovisual recalibration can be driven by cross-modal spatial grouping. Twelve participants adapted to alternating trains of lights and tones. Spatial position was manipulated, with alternating sequences of a light then a tone, or a tone then a light, presented on either side of fixation (e.g., left tone--left light--right tone--right light, etc.). As the events were evenly spaced in time, in the absence of spatial-based grouping it would be unclear if tones were leading or lagging lights. However, any grouping of spatially colocalized cross-modal events would result in an unambiguous sense of temporal order. We found that adapting to these stimuli caused the PSS between subsequent lights and tones to shift toward the temporal relationship implied by spatial-based grouping. These data therefore show that temporal recalibration is facilitated by spatial grouping.     

The aftereffects of ventriloquism: patterns of spatial generalization

We examined how visual recalibration of apparent sound location obtained at a particular location generalizes to untrained locations. Participants pointed toward the origin of tone bursts scattered along the azimuth, before and after repeated exposure to bursts in one particular location, synchronized with point flashes of light a constant distance to their left/right. Adapter tones were presented straight ahead in Experiment 1, and in the left or right periphery in Experiment 2. With both arrangements, different generalization patterns were obtained on the visual distractor's side of the auditory adapter and onthe opposite side. On the distractor side, recalibration generalized following a descending gradient; practically no generalization was observed on the other side. This dependence of generalization patterns on the direction of the discordance imposed during adaptation has not been reported before, perhaps because the experimental designs in use did not allow its observation.     

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.     

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.     

Context extinction following conditioning with delayed reward enhances subsequent instrumental responding

In Experiment 1, delayed reward generated low response rates relative to immediate reward delivered with the same frequency. Lister rats exposed to delayed reward subsequently responded at a higher rate in extinction if they received nonreinforced exposure to the conditioning context after instrumental training and prior to test, compared with animals that received home cage exposure. In Experiment 2, a signaled delay of reinforcement resulted in higher rates than an unsignaled delay. Nonreinforced exposure to the conditioning context elevated response rate for subjects in the unsignaled condition relative to a home cage group, but had no effect on response rates for subjects that had received the signaled delay. In Experiment 3, following an unsignaled reinforcement delay, groups receiving either no event or signaled food in the context responded faster in extinction than groups receiving no context exposure or unsignaled food.     

Stop—reaction time and the internal clock

In astop-reaction-time (stop-RT) task, a subject is presented with a regular, isochronous sequence of brief signals separated by a constant time interval, orstimulus onset asynchrony (SOA). His/her task is to press a response key as fast as possible when the sequence stops. As the sequence unfolds, an internal representation of the SOA duration builds up. Stop-RT is assumed to be triggered when aninternal clock, operating as an “alarm clock,” reaches a time criterion. Criterion setting is contingent upon variability in the SOA’s internal representation. In Experiment 1A, stop-RT was measured for isochronous sequences of brief tones, light flashes, and also sequences of tones and flashes presented in regular alternation (tone-light-tone…). Stop-RT was a linear function of SOA duration (ranging from 250 to 1,000 msec), regardless of modality, supporting a “central-clock” hypothesis. On the other hand, taken together, the results of Experiments 1A, 1B, 2, and 3 suggest that no internal representation of thebimodal (tone-light) SOA of alternating sequences builds up. Indeed, an alternating sequence is physically equivalent to two interlaced isochronous subsequences, one auditory and one visual. So,two internal representations, one for the auditory (tone-tone) and one for the visual (light-light) SOA, could build up, andtwo time criteria running “in parallel” could thus support stop-RT. To provide a critical test of parallel timing, stop-RT was measured for bimodal 5∶3 polyrhythms formed by the superposition of auditory and visual isochronous sequences that haddifferent SOA durations (Experiment 4). Parallel timing accounted for a large proportion of variance in polyrhythmic stop-RT data. Overall findings can be accounted for by assuming a functional architecture of an internal clock in which pulses emitted by acentral pacemaker are available in parallel with twomodality-specific switch-accumulator “timing modules.”     

Long lasting increase in nociceptive threshold induced in mice by forced swimming: involvement of an endorphinergic mechanism

Mice submitted to forced swimming session(s) displayed a long lasting modification in their nociceptive threshold, assessed through their jump latency from a hot plate (55 degrees C). Thus two forced swimming sessions (6 min each, 8h apart), in water at 33 degrees C, increased by about 50% the jump latency when the hot plate test was performed 14 hours, 3 days or 6 days thereafter. The water temperature (16 degrees C vs 33 degrees C) had no critical influence in this respect. To be clearly effective (at 33 degrees C) the swimming session had to be performed twice (when performed only once it was irregularly effective); it apparently culminated for a 6 min duration, since its effectiveness was not significantly increased by extending the swimming time to 12 min or 18 min. Performing 2 forced swimming sessions (6 min each, 8h apart), 5 consecutive days, resulted in a suppression of the increase in jump latency in the hot plate test. The two forced swimming episodes-induced analgesia was prevented by the s.c. administration of diazepam (from 0.125 mg/kg) or morphine (from 5 mg/kg) or scopolamine (1 mg/kg) before each forced swimming episode. Morphine (7.5 mg/kg) was uneffective to prevent the induction of two forced swimming episodes-induced analgesia when it was administered immediately after each forced swimming session. Finally this analgesia was dose dependently reversed by naloxone (ID(50) = 0.14 mg/kg, s.c., 30 min before the hot plate test). It is hypothesized that the handling of mice immediately before the hot plate test induces the remembrance of the stress induced by previous forced swimming episodes, triggering a fear reaction which increases the nociceptive threshold.     

Is binocular fusion of "cortical yellow" an illusion, contingent upon abstraction of coherent sensory information from the two eyes?

This research on the binocular fusion of phenomenal yellow, given red-filtered flashes of light in one eye and green-filtered flashes of light in the other, directly compared the effects of wider-bandwidth and narrow-bandwidth filtering. 20 male college students with normal stereopsis, Mage = 19.3 yr., SD = 2.2, were tested for the binocular perception of flashing yellow sensations given wider-bandwidth versus narrow-bandwidth filtering of light flashes which, monocularly, were experienced as red sensations in one eye and as green sensations in the other. When 3 wide-bandwidth tests for binocular yellow fusion were alternated with 3 narrow-bandwidth tests, simultaneous flashes of red-filtered light in one eye and green-filtered light in the other were binocularly perceived as yellowish on 25% of the wide-bandwidth tests (SD = 40%)--as yellow on 8% of the tests, orange on 12% of the tests, yellow-green on 5% of the tests-and were binocularly perceived as yellowish on 0% of the narrow-bandwidth tests. When wider-bandwidth and narrow-bandwidth testing were separated spatially and conducted contemporaneously, the red-filtered flashes in one eye and green-filtered flashes in the other were binocularly experienced as yellowish sensations by 80% of all participants under wider-bandwidth conditions--as yellow by 55%, orange by 10%, yellow-green by 15%--and as yellowish sensations by 0% of the participants under narrow-bandwidth conditions.     

Pigeons flexibly time or count on cue

In Experiment 1, pigeons were presented with a sequence of light flashes and cued to peck a key for reward either after a fixed time or after a fixed number of flashes. Curves that showed the rate of key pecking over time within trials indicated that peak rates of response were reached near the fixed time on timing-cued trials and near the fixed number of flashes on counting-cued trials. In Experiment 2, the key cue was shifted from timing to counting or from counting to timing midway through a trial. The peak times reached after the cue change indicated that pigeons kept track of time while cued to count but did not count while cued to time. These findings suggest a basic asymmetry in the dual-mode model of timing and counting.     

Chronic exposure to a novel odor increases pups' vocalizations, maternal care, and alters dopaminergic functioning in developing mice

This study was designed to assess the stress effect of manipulation of the olfactory environment in developing mice. In a first experiment it was found that mouse pups could be stressed (as measured by an increase in ultrasonic calls) by removing the litter from the dam for 15 min/day for the first 14 days of life and exposing them to a novel odor (clean bedding). This stress procedure also produced a long-term modification in maternal behavior. The stress response (ultrasounds) and the modification of maternal behavior were prevented by providing the litter with home cage bedding during maternal separation. In a second experiment it was demonstrated that early stress influenced apomorphine-induced wall climbing behavior in 15-day-old mice, suggesting stress-induced alterations in the dopaminergic system. Pups exposed to clean bedding during infancy exhibited more wall climbing behavior than pups never separated from the mother. Moreover, preventing the early stress response during mother-offspring separation, by providing pups with home cage bedding, eliminated the increase in apomorphine-induced wall climbing. Taken together these results suggest that olfactory cues are decisive in characterizing stressful situations inducing both immediate and long-lasting effects in mouse pups.     

On cross-modal similarity: auditory-visual interactions in speeded discrimination

A series of four experiments explored how cross-modal similarities between sensory attributes in vision and hearing reveal themselves in speeded, two-stimulus discrimination. When subjects responded differentially to stimuli on one modality, speed and accuracy of response were greater on trials accompanied by informationally irrelevant "matching" versus "mismatching" stimuli from the other modality. Cross-modal interactions appeared in (a) responses to dim/bright lights and to dark/light colors accompanied by low-pitched/high-pitched tones; (b) responses to low-pitched/high-pitched tones accompanied by dim/bright lights or by dark/light colors; (c) responses to dim/bright lights, but not to dark/light colors, accompanied by soft/loud sounds; and (d) responses to rounded/sharp forms accompanied by low-pitched/high-pitched tones. These results concur with findings on cross-modal perception, synesthesia, and synesthetic metaphor, which reveal similarities between pitch and brightness, pitch and lightness, loudness and brightness, and pitch and form. The cross-modal interactions in response speed and accuracy may take place at a sensory/perceptual level of processing or after sensory stimuli are encoded semantically.     

Pigeons presented with sequences of light flashes use behavior to count but not to time

On randomly ordered trials, pigeons were presented with either a blue or a white key that flashed red for 200 ms at a fast (2 flashes/s), medium (1 flash/s), or slow (0.5 flashes/s) rate. The blue key signaled a fixed-interval (FI) schedule in which the first response after 20 s was reinforced, and the white key signaled a fixed-number (FN) schedule in which the first response after 20 flashes was reinforced. In Experiments 1 and 2, pigeons showed depressed responding to the flash on FI-cued trials and accelerated responding to the flash on FN-cued trials. When the response key was periodically blacked out in Experiments 3 and 4, counting but not timing was eliminated.