Stress-induced analgesia: neural and hormonal determinants.

Extensive evidence has indicated that distinct neural systems specifically designed to inhibit sensitivity to painful stimuli exist. Recent advances suggest that the endorphins, enkephalins and the opiate receptor interact with a descending serotonergic bulbospinal system to mediate the analgesic responses to opiates and electrical stimulation. In assessing the evolutionary and behavioral significance of this pain-inhibitory system, several laboratories discovered that acute exposure to a wide variety of stressful events results in a transient analgesia. Chronic exposure to a number of these stressors results in adaptation of the analgesic response. The purpose of this review is to identify and characterize the mechanisms by which these stressors activate pain-inhibition. The relationship of stress-induced analgesia to each of the following is reviewed: (a) the role of endorphins, enkephalins and the opiate receptor; (b) the role of the descending serotonergic bulbospinal system; (c) the role of the pituitary gland; and (d) the role of hypothalamic mechanisms. Data will be discussed in terms of "opiate" and "non-opiate" pain-inhibitory mechanisms, in which some stressors act through the former and other stressors act through the latter.

Chlordiazepoxide antinociception: cross-tolerance with opiates and with stress.

Chlordiazepoxide (CDP) has been previously shown to possess antinociceptive properties that are resistant, except at high doses, to the opiate antagonist naloxone. The present study evaluated whether CDP's antinociceptive effects were subject to tolerance following repeated injections and whether cross-tolerance might develop between the antinociceptive action of CDP and that of either morphine or cold water swins. CDP increased flinch-jump thresholds following acute administration and exhibited tolerance following repeated injections. Neither morphine-tolerant nor cold water swim-adapted rats displayed an antinociceptive effect when tested with CDP. On the other hand, chronic pretreatment with CDP attenuated the antinociceptive effects of cold water swims, but did not produce any clear effect upon morphine analgesia.

The role of endorphins in stress-induced analgesia.

We have seen that exposure of an organism to any of a wide range of stressful situations can induce alterations in sensitivity to pain that outlast the exposure. Not all stressors induce analgesia; among those that do not are some that produce maximal elevations in plasma beta-endorphin, ACTH, and adrenal corticosteroids. Some examples of SIA are sensitive to opiate receptor blockade by naloxone, but others are not. Hypophysectomy produces a similarly uneven profile of effects across different stressors. This diversity has often been interpreted as evidence for the existence of an array of pain inhibitory systems, with differing physiological properties and activated by different stressors. However, it might also suggest that stressors can prompt a variety of behavioral changes, many of which can be interpreted as analgesia if a pain reflex test is employed as the dependent measure.

Sister chromatid exchanges induced by behavioral stress.

Rats subjected to swim stress showed a doubling of sister chromatid exchange (SCE) level. In a second experiment, the generality of SCE induction by behavioral stressors was tested by exposing rats to either swim, white noise, or either continuous or intermittent inescapable footshock stress. The induction of SCEs, although to differing degrees, by qualitatively different stressors, demonstrates that this is a general phenomenon of stress. There may be a cellular genetic basis for some of the effects of stress.

Elevations in nociceptive thresholds following locus coeruleus lesions.

Serotonin depletion or lesions of the midbrain dorsal raphe nuclei attenuate both morphine-produced and stimulation-produced analgesia. In contrast, norepinephrine depletion enhances both types of analgesia. To extend these findings, the effects of destruction of the noradrenergic locus coeruleus (LC) upon nociceptive flinch-jump thresholds were investigated. after four preoperative baseline sessions, lesions were placed in the LC bilaterally and nociceptive thresholds were determined for up to five weeks postoperatively. The lesions were localized by monoamine histofluorescence procedures together with conventional histological staining techniques. In 9 of 13 animals, the LC or its ascending dorsal noradrenergic bundle sustained either bilateral or unilateral damage, evidenced by green fluorescent back-up caudal to the lesions. Eight of these animals demonstrated significantly increased jump thresholds. In the remaining four animals, both lesions spared the LC and nociceptive thresholds were either unchanged or significantly decreased. In three of the four, raphe damage was noted, evidenced by yellow fluorescent back-up. The results suggest apparently contrasting roles of norepinephrine and serotonin in nociception.

Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation.

In three experiments, the locus of tail stimulation in the tailflick assay was found to be an important parameter in determining morphine action. Rats were intravenously infused (Experiment I), injected with morphine subcutaneously (Experiment II), or implanted subcutaneously with morphine pellets (Experiment III). Analgesia was evaluated periodically following drug administration using the tailflick test and 3 adjacent 1 in. tail areas. In all three experiments, the distal tail section was more sensitive to the analgesic effects of morphine than more proximal sections. In Experiments I and III, tolerance to the effects of morphine developed more slowly at the distal tail location. These results indicate that the locus of stimulation in the tailflick assay can profoundly affect the development of analgesia and tolerance to morphine.

Characterization of pituitary mediation of stress-induced antinociception in rats.

Antinociception, induced by continuous cold-water swims (CCWS) and certain parameters of inescapable foot shock, is reduced in hypophysectomized rats receiving supplements of corticosterone and l-thyroxine. To assess which lobe of the pituitary gland is involved in this effect, the first experiment compared the effects of total hypophysectomy and posterior lobectomy in supplemented rats upon CCWS antinociception on the tail-flick and jump tests and upon continuous inescapable foot shock antinociception on the tail-flick test. Total hypophysectomy, but not posterior lobectomy, significantly reduced CCWS antinociception on both tests in supplemented rats relative to sham surgery. Both total and posterior hypophysectomy either reduced or potentiated foot shock antinociception as functions of shock intensity or duration of exposure in supplemented rats. To assess whether hormonal supplementation is necessary for the observed effects, the second experiment examined CCWS antinociception in sham-operated and hypophysectomized rats that received either no hormonal supplements or corticosterone and/or l-thyroxine. These regimens failed to alter CCWS antinociception in sham-operated rats. Treatment of hypophysectomized rats with corticosterone and l-thyroxine either separately or together significantly reduced CCWS antinociception. In contrast, if hypophysectomized rats did not receive supplements, CCWS antinociception was significantly potentiated relative to sham-operated controls. These effects could not be attributed to treatment-induced changes in either body weight or CCWS hypothermia. These data suggest that the anterior lobe of the pituitary gland and adrenal cortex are involved in the mediation and/or maintenance of CCWS antinociception.

Analgesia induced by cold-water stress: attenuation following hypophysectomy.

In addition to the well-known activation of the pituitary-adrenal axis, acute exposure to severe stressors includes a temporary analgesia in rats. Thus, the present study investigates whether the pituitary was involved in the mediation of analgesia induced by severe cold-water swim (CWS) stress. Flinch-jump thresholds were measured 30 min following 3.5-min swims in water temperatures ranging from 2-35 degrees C. Compared with untreated normal rats, hypophysectomized rats, receiving corticosterone and thyroxin, displayed significantly less CWS-induced analgesia, while similarly-supplemented normal rats exhibited significantly more CWS-induced analgesia. In a second experiment, operant liminal escape pain thresholds were determined following acute and chronic CWS. Whereas normal rats exhibited profound analgesia following the initial swims, the hypophysectomized rats never displayed any CWS-induced operant escape shifts. Stress-induced alterations in general activity levels and/or thermoregulation were shown to be unrelated to the diminished effectiveness of CNS to produce analgesia in hypophysectomized rats. These data imply that the pituitary is involved in the mediation of CWS-induced analgesia.

Potentiation of cold swim stress analgesia in rats by diazepam.

It was hypothesized that diazepam (DZP) would attenuate the analgesia produced by cold swim stress because of its anxiolytic and biochemical anti-stress properties. In fact, it had the opposite effect. Administered alone, neither DZP nor its vehicle affected the nociceptive thresholds of rats, as assessed by a flinch-jump test. In combination with cold swim stress, DZP elevated nociceptive thresholds significantly more than did the stressor alone. This was true whether DZP was injected before or after exposure to the stressor, or whether or not DZP administration was acute or chronic.

2-Deoxy-D-glucose analgesia: influences of opiate and non-opiate factors.

Acute administration of 2-deoxy-D-glucose (2-DG), an antimetabolic glucose analogue induces a powerful analgesia which adapts following repeated administration. 2-DG analgesia displays significant cross-tolerance with morphine, and like morphine analgesia, is potentiated in hypophysectomized rats. The present study examined further the role of opiates in 2-DG analgesia by examining whether the opiate antagonist, naloxone, would affect 2-DG analgesia, and whether ineffective doses of 2-DG and morphine would interact in a synergistic fashion to induce analgesia. Nociceptive thresholds were measured by the flinch-jump test. Naloxone doses of 1, 5, 10 and 20 mg/kg were all ineffective in reducing significantly 2-DG (600 mg/kg) induced pain threshold elevations. Naloxone failed to attenuate 2-DG (350 mg/kg) analgesia whether administered before or after the 2-DG injection. On the other hand, simultaneous administration of sub-analgesic doses of 2-DG (200 mg/kg) and morphine (2.5 mg/kg) summated to produce significant analgesia. This, 2-DG analgesia is similar to opiates in its tolerant and summative actions, yet dissimilar in that naloxone is ineffective in reversing its effects.

Stress-produced analgesia and morphine-produced analgesia: lack of cross-tolerance.

Animals exposed to cold-water swims, rotation, inescapable shocks, abrupt food deprivation and other stressors display temporary analgesia. Since repeated exposures result in adaptation of this analgesia in much the same way that repeated administration of opiates results in tolerance, the possibility of cross-tolerance between cold-water stress-induced and morphine-induced analgesia was investigated. Flinch-jump thresholds were determined in ten experimental groups of six rats each. Three groups showed dose-dependent analgesia following single injections of morphine at 5, 10 and 15 mg/kg, respectively. A fourth group, subjected to a single cold-water swim at 2 degrees C for 3.5 min, displayed analgesia comparable to that produced by 10 mg/kg of morphine. Groups subjected either to 14 daily cold-water swims or to 14 daily morphine injections at 10 mg/kg showed normal thresholds on the 14th day indicating that adaptation and tolerance had developed, respectively. The cross-over groups were exposed to either 13 days of could-water swims followed by morphine or the reverse arrangement. Both groups showed profound analgesia instead of cross-tolerance, suggesting that a non-opiate neural mechanism may mediate stress-induced analgesia.

Differential effects of hypophysectomy upon analgesia induced by two glucoprivic stressors and morphine.

Pain threshold elevations induced in rats following acute exposure to stressful cold-water swims and to inescapable foot shocks are significantly attenuated by hypophysectomy. The present study investigated the effects of hypophysectomy upon the dose-dependent and time-dependent analgesia induced by morphine and by the glucoprivic agents, 2-deoxy-D-glucose (2-DG) and insulin. Two reflex pain tests, the tail-pinch and the flinch-jump were employed. In normal rats, insulin induced prolonged (180 min) analgesia at doses of 16 U/kg on the tail-pinch test and 256 U/kg on the flinch-jump test. However, the same agents induced small and brief pain threshold elevations in hypophysectomized animals. By contrast, though 2-DG increased both measures in both groups, its effects were more marked in hypophysectomized rats. Hypophysectomized rats also exhibited a potentiated analgesic effect on both tests following high doses of morphine. On the other hand, low doses of morphine transiently increased tail-pinch thresholds in normal, but not hypophysectomized subjects. These data provide further evidence of multiple pain-inhibitory mechanisms in which the pituitary plays a complex, but integral part.

Dose-dependent reductions by naloxone of analgesia induced by cold-water stress.

Animals exposed to cold-water swims, rotation, or inexcapable shocks, display analgesia comparable to that of 10 mg/kg of morphine. The present study investigated whether a narcotic antagonist would eliminate analgesia induced by cold-water swims. In one group of 12 rats, naloxone at 0, 1, 5, 10 and 20 mg/kg was administered at weekly intervals immediately preceding forced cold-water swims (2 degrees C for 3.5 min) and alterations in flinch-jump thresholds were determined 30 min thereafter. In a second group of six rats, the effects of the same dose range of naloxone were determined upon normal flinch-jump thresholds. Naloxone dose-dependently attenuated the cold-water swim-induced analgesia up to a maximal reduction of 50% at 20 mg/kg. In contrast, all doses of naloxone had no effects upon normal flinch-jump thresholds. Since low doses of naloxone completely abolish morphine-induced analgesia, the present data suggest that the analgesia induced by stress is not identical to that of opiates.

Reversal of stress-induced analgesia by apomorphine, but not by amphetamine.

Acute exposure to severe stressors induce profound analgesia as well as depleting catecholamine levels. The present study examined whether d-amphetamine and apomorphine, agents which increase catecholamine availability, would alter the analgesic effectiveness of cold-water swims (CWS) and 2-deoxy-D-glucose (2-DG) as measured by an operant liminal escape procedure. Two groups of 10 rats each were tested to determine alterations in liminal escape threshold functions following amphetamine at doses of 0.25, 0.5, 1, 2 mg/kg and following apomorphine at doses of 0.025, 0.05, 0.1, 0.2 mg/kg. Half of the amphetamine and half of the apomorphine groups were tested across their respective dose ranges for the drug effects upon CWS analgesia. The remaining animals in each group received 2-DG (600 mg/kg IP) alone followed by 2-DG paired with each stimulant dose. No dose of amphetamine or apomorphine alone altered escape thresholds. While amphetamine produced slight potentiations of 2-DG analgesia at the two low doses, apomorphine at the 0.05 and 0.1 mg/kg doses returned CWS and 2-DG analgesia to within normal placebo values. These results provide indirect evidence for a role for brain norepinephrine and dopamine in stress-induced analgesia, and these data are discussed with respect to catecholamine involvement in pain-inhibitory processes.

2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds.

Acute exposure to many environmental stressors induces significant analgesia. The present study examined whether 2-deoxy-D-glucose (2-DG), an antimetabolic glucose analogue, which induces glucoprivation and peripheral sympatho-adrenal discharge, would also produce analgesia as measured by either an operant liminal escape or a reflex tail-pinch procedure. In the liminal escape paradigm, 9 rats were tested at weekly intervals in 6 randomly selected testing conditions: 30 min pre-test injections of four 2-DG doses (100, 225, 350 and 700 mg/kg, IP) and 180 min pre-test injections of the 2 higher doses. Moderate analgesia occurred at the lower 2-DG doses 30 min after injection, while profound analgesia occurred at the higher doses. After 180 min, only the 700 mg/kg 2-DG dose produced moderate analgesia, which was further enhanced by food deprivation. Rats tested in the tail-pinch paradigm displayed a similar dose-dependent analgesia course. These results demonstrate that 2-DG decreases nociceptive sensitivity, possibly through stress-induced activation of an intrinsic pain-inhibitory system.

Two unlike patterns of random-ratio responding associated with different eating habits in rhesus monkeys.

Four rhesus monkeys were exposed to an identical series of schedules that specified a uniform probability of reinforcement for every response. As probability was lowered slowly in 10 steps of 20 sessions each from 1.0 through 0.01, two distinct patterns of responding emerged. Two subjects showed high, pause-free response rates that increased with each successive reduction in reinforcement probability. The other two showed consistent post-reinforcement pausing at all probabilities, including 1.0, and substantially lower response rates that peaked at the moderate probability values of 0.04 and 0.03. This low-rate pattern was found to be correlated with a pre-experimental preference in the two subjects for mouthing and chewing food pellets one at a time, while the former high-rate, pause-free pattern was linked to a long-standing habit of "pouch feeding" in the other monkeys. These idiosyncratic collateral behaviors that differentiated the schedule performances appeared neither superstitious in origin, nor useful in the case of the low-rate monkeys.

Enhancement of conditioned autonomic responses in monkey when preshock signals occasion operant suppression.

Classical pairings of a sound stilulus with shock elicited larger magnitude and more rapidly conditioned autonomic responses when subjects were responding on variable-interval schedules for food than when they were eating freely available food. The difference was not attributable to changes in control values of heart rate and blood pressure, or to alterations in motor activity, but appeared related to operant suppression.

Suppression of random-ratio and acceleration of temporally spaced responding by the same prereward stimulus in monkeys.

A 1-min tone and light signal that preceded two free pellets of food suppressed the random-ratio responding of four rhesus monkeys, but accelerated the same subjects' responding on a differential-reinforcement-of-low-rate schedule in separate sessions. Both schedule-specific interactions occurred during the first presentations of the signal that previously had been paired with food outside the operant sessions. Thus, neither effect was adventitiously produced. In two subjects, both the direction and magnitude of the prereward change in differential-reinforcement-of-low-rate responding appeared related to baseline response rates: the more rapid the baseline responding, the less was the acceleration during the signal. Suppression and acceleration did not appear as dichotomous effects with separate parameters, but as related effects at least partly determined by the characteristics of the baseline operant performance.

Long-term prereward suppression in monkeys unaccompanied by cardiovascular conditioning.

In Experiment I, a 3-min tone that preceded a free pellet of food suppressed variable-interval performances maintained by the same type of pellets, but failed to elicit conditioned changes in the heart rates and blood pressures of two rhesus monkeys. Initially severe, the prereward suppression became temporally discriminated to progressively later portions of the tone, and was maintained at an attenuated level for over four months. The suppression was apparently not caused by interfering autonomic respondents, nor was it superstitiously conditioned, since 21 of the initial 25 tone-food pairings took place outside of baseline sessions. In Experiment II, a 1-min light, paired with four free pellets of food, suppressed the variable-interval responding of a second pair of similarly trained monkeys. An interresponse-time analysis showed that in one subject, mild prereward suppression of responding developed through two stages. On early trials, response rate slowed by 10% throughout the prefood interval. On later trials, the animal suppressed by pausing for a like portion of the interval, most often near the end, but otherwise responded normally during the prefood signal.

A student nurse intervenes to foster grandfather/grandchild bonding.

This article describes the important role played by a student nurse in assisting a new grandparent bond with his granddaughter. This grandfather had been a noncustodial parent to his daughter, and as such, was anxious about his new role. The increasing numbers of noncustodial parents becoming grandparents presents a new problem facing nurses in helping a family meet their new members. The opportunity for grandparent/grandchild bonding may be enhanced by nurses who are sensitive to the less-than-perfect relationship that might exist between a noncustodial parent and the adult child. These grandparents may need encouragement to find their place in the life of the new child.