Dennis D. Kelly

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.

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.

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.

Stress-induced analgesia: Time course of pain reflex alterations following cold water swims

Recent reports indicate that rats acutely stressed by inescapable footshock, rotation, restraint, or injections of hypertonic saline display increased tail-flick latencies. The present study parametrically analyzed the time course of analgesia following exposure to another stressor, a brief, forced cold water swim, by means of three nociceptive reflex tests. Rats acutely subjected to a cold water (2°C) swim for 3.5 min displayed significantly elevated tail-pinch and flinch-jump thresholds for up to 60 min; no change was noted in similarly treated warm water (28°C) controls. Tail-flick withdrawal latencies to radiant heat stimuli exhibited similar, but more enduring, increases, lasting up to 120 min. These results demonstrate that reactivity to three different nociceptive reflex modalities, electric shock, heat, and pressure, can be altered by acute exposure to a stressor.

Opiate and non-opiate mechanisms of stress-induced analgesia: Cross-tolerance between stressors

Abstract Acute exposure to severe stressors induce profound analgesia. Repeated exposures to the same stressors esult in adaptation in much the same way that repeated administration of opiates results in tolerance. The present study investigated whether two qualitatively different stressors, cold-water swims (CWS) and injections of 2-deoxy-D-glucose (2-DG) share common pain-inhibitory mechanisms by determining whether cross-tolerance developed to their analgesic effects. Cross-tolerance was also examined between 2-DG and morphine. Flinch-jump thresholds were determined in six groups of six rats each. Analgesia was observed 30 min following acute exposure to CWS (2°C for 3.5 min), 2-DG (350 mg/kg) and morphine (10 mg/kg), but not following placebo injections or warm water swims. Chronic exposure to all three analgesic treatments resulted in tolerance and adaptation. Complete and reciprocal cross-tolerance developed between the analgesia induced by CWS and by DG. Complete cross-tolerance to 2-DG analgesia also developed in morphine-tolerant rats, but only partial cross-tolerance to morphine analgesia developed in 2-DG adapted rats. These results support the concept that stressful events induce analgesia through specific activation of an intrinsic pain-inhibitory system which has both opiate and non-opiate branches.

Part VIII. Psychopharmacological and Biological Effects Of Opioid Peptides In Animals: 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.

Dissociation of cold-water swin and morphine analgesia in Brattleboro rats with diabetes insipidus

Abstract The present study examined whether vasopressin mediated the analgesic response to morphine and cold-water stress by comparing the analgesic responses of homozygous Brattleboro rats with diabetes insipidus with those of normal rats of the same strain of similar weight. Brattleboro rats exhibited hypersensitive responses to foot shock which were brought back to within normal limits by systemic administration of arginine vasopressin and desamino-D-arginine vasopressin. While Brattleboro rats failed to display an analgesic response to cold-water swim stress, they displayed a normal analgesic response to morphine. These results provide further evidence for dissociation of pain-inhibitory mechanisms into opioid and non-opioid components, and suggests that vasopressin might be involved in the elucidation of the latter component.

Biphasic alterations of nociceptive thresholds induced by food deprivation

Acute exposure to such stressful events as inescapable footshock, rotation, or cold-water swims produces a transient analgesia. The physiological effects of food deprivation resemble those of an environmental stressor, in that corticosterone levels increase during food restriction and fall following meals. The present study investigated whether food deprivation, like other stressors, would produce a transient analgesia. Flinch-jump thresholds of 16 rats, maintained on a 14-h-light/10-h-dark cycle, were tested twice daily for 4 baseline, 3 food-deprivation, and 2 recovery days. Deprivation was initiated for eight animals at the beginning of the dark cycle (p.m. group), and for eight animals at the end of the dark cycle (a.m. group). Nociceptive thresholds of the p.m. group increased after 12 h of deprivation and decreased after 36 and 60 h. Thresholds of the a.m. group were increased for up to 36 h of deprivation and decreased after 72 h. Thresholds were higher after the dark cycle on the 1st deprivation day, and lower on the 3rd deprivation day, indicating an important circadian rhythmicity. Changes in weight, water intake, or activity levels could not account for the nociceptive alterations. These results provide further support for the contention that initial exposure to severe environmental stressful events produces a transient analgesia.

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.

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.