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Biomedical subjects

S F Maier

Publications and source records attributed to S F Maier.

At least 127 records · Page 7Linked to original sources
PubMed1992

Kappa opiate receptors mediate tail-shock induced antinociception at spinal levels.

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Analysis of Variance↗
PubMed1992

Delta opiate receptors mediate tail-shock induced antinociception at supraspinal levels.

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The preceding companion paper and the present work were aimed at identifying the neuroanatomical loci at which opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 8 experiments included in the present paper examined the effect of microinjecting either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist) either into the third ventricle or over the frontal cortex. Taken together, these experiments demonstrate that the late (80-100 shock) opiate analgesia is mediated by delta opiate receptors located within subcortical structures rostral to the 4th ventricle. No evidence for supraspinal opiate involvement in the early (2 shock) opiate analgesia was found.

Analysis of Variance↗
PubMed1992

Cholecystokinin antianalgesia: safety cues abolish morphine analgesia.

Environmental stimuli that signal the occurrence of aversive or dangerous events activate endogenous opiate analgesia systems. Signals for safety (the nonoccurrence of aversive events) produce the opposite and inhibit environmentally produced analgesia. Stimuli that signal safety are now shown to abolish the analgesic effect of morphine, even when morphine is applied directly to spinal cord. Further, this antiopiate effect occurs because the environmental stimulus leads to release of the neuropeptide cholecystokinin in the spinal cord. This process may contribute to the regulation of pain and the development of opiate tolerance.

Analgesia↗
PubMed1992

Total plasma cholesterol levels of rats are increased following only three sessions of tailshock.

Male Sprague-Dawley rats were maintained for three weeks on one of three different diets. Two of the diets were high-cholesterol, high-fat, while the third was standard laboratory chow. Animals from each group were then given either daily 2 hr sessions of tailshock for three days, or left in their home cage. Blood samples were taken from all subjects prior to stress, and again immediately after the third stress session. Sera were separated and analyzed for total plasma cholesterol. Results indicate that total plasma cholesterol was increased in the stressed animals maintained on standard lab chow. Stressed animals in the two high cholesterol diet groups showed no cholesterol increase relative to their respective dietary controls.

Animals↗
PubMed1992

Specific changes in lymphocyte subpopulations: a potential mechanism for stress-induced immunomodulation.

The mechanisms by which stressors alter immune function are not well understood. One hypothesis for stress-induced immunomodulation is that since immune responses require cooperation of different cell types, stress-induced shifts in cell populations might affect an organism's ability to mount an immune response. We sought to determine if inescapable shock (IS) could alter lymphocyte subpopulations and if so, whether this could be a mechanism for shock-induced immunomodulation. Our results suggest that IS produces changes in lymphocyte subpopulations and that these shifts could be responsible for modulation of in vivo antibody production. Exposure to IS resulted in an increase in the percent of CD4+ mesenteric lymphocytes and a decrease in the percent of CD8+ mesenteric lymphocytes when examined immediately after the cessation of IS. The stressor reduced antibody production to antigen processed at the altered mesenteric nodes, but did not alter antibody production to antigen processed at other sites. No measurable shifts were found in other compartments examined. The changes in CD4+ and CD8+ mesenteric lymphocytes resulted in an increased CD4+/CD8+ ratio that persisted for 1-24 h after stressor termination, becoming absent 48 h after IS termination. The stress-induced reduction in antibody production occurred only when antigen was given immediately prior to but not when antigen was given 48 h post stress. These findings suggest that the effects of a stressor could be specific to the manner in which the antigen enters the body, and that the stress-induced decrease in antibody production could be due to altered lymphocyte subpopulations as reflected by an increased CD4+/CD8+ ratio.

Animals↗
PubMed1990

Adinazolam both prevents and reverses the long-term reduction of daily activity produced by inescapable shock.

The behavioral consequences of exposure to stressors such as inescapable shock are usually quite transitory if testing is conducted in an environment different from that in which the stressor was administered. Daily running activity is an exception in that it remains depressed for several weeks following experience with inescapable shock. In the present experiments we found the administration of the triazolbenzodiazepine adinazolam able to both reduce this long-term activity reduction produced by inescapable shock when acutely administered before the inescapable shock, and to reverse the effect when chronically administered after the inescapable shock. Classic 1,4-benzodiazepines such as diazepam have been able to prevent such effects when acutely administered before inescapable shock, but cannot reverse these effects when provided after the inescapable shock. Conversely, classic antidepressants such as desipramine have been unable to prevent these behavioral effects when given before inescapable shock in acute form, but can reverse the effects with chronic administration following the inescapable shock. Our observations that adinazolam can both prevent and reverse the effects of inescapable shock are consistent with reports that this agent has both anxiolytic and antidepressant effects in clinical use.

Animals↗
PubMed1990

Diazepam modulation of stress-induced analgesia depends on the type of analgesia.

Factors that determine the impact of diazepam on the hypoalgesia produced by electric shocks were investigated. Tailshocks (1, 5, & 20) were followed by an initial hypoalgesia, lasting 2-4 min, that was unaffected by prior administration of diazepam. This hypoalgesic reaction was followed by a second hypoalgesia if subjects were allowed to remain in the shock environment during testing, and this reaction was reduced or eliminated by prior diazepam. If subjects were removed from the shock situation, this second reaction did not occur. In contrast, 80 shocks were followed by a single hypoalgesia that was sensitive to blockade by diazepam throughout its entire course and was not affected by removing subjects from the shock environment. These results have implications for the perceptual-defensive-recuperative, working memory, and unconditioned response-learned helplessness interpretations of shock-produced analgesia.

Animals↗
PubMed1990

Role of fear in mediating shuttle escape learning deficit produced by inescapable shock.

The relation between the shuttlebox escape deficit produced by prior inescapable shock (IS) and fear during shuttlebox testing as assessed by freezing was investigated in rats. IS rats learned to escape poorly and were more fearful than either escapably shocked subjects or controls, both before and after receiving shock in the shuttlebox. However, fear and poor escape performance did not covary with the manipulation of variables designed to modulate the amount of fear and the occurrence of the escape deficit. A 72-hr interval between IS and testing eliminated the escape deficit but did not reduce preshock freezing. Diazepam before testing reduced both preshock and postshock fear in the shuttlebox but had no effect on the escape deficit. Naltrexone had no effect on fear but eliminated the escape deficit. This independence of outcomes suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects.

Animals↗
PubMed1989

D2 dopamine receptors in the rat prefrontal cortex: characterization and alteration by stress.

D2 dopamine (DA) receptors were characterized in the medial prefrontal cortex (MPFC) of the rat by employing radioligand binding techniques which greatly reduced [3H]spiperone binding to filters, S2 serotonin receptors and spirodecanone sites. Competition studies suggested that the MPFC contains a higher proportion of D2 [high] receptors than does the striatum. The IC50 values of DA receptor antagonists in assays of MPFC tissue were correlated with their antipsychotic potencies. Stress (footshock or tailshock) increased the density of MPFC D2 dopamine receptors and decreased their affinity for [3H]spiperone. These changes were delayed in onset, being present at 27 h but not at 3 h after exposure to stress. The binding assay detected the changes when it was performed at pH 7.9 but not when the pH was reduced to 6.2. D2 dopamine receptors in the striatum and nucleus accumbens were not affected by stress.

Animals↗
PubMed1989

Reduced serum antibodies associated with social defeat in rats.

Many studies have linked various physical stressors with changes in immune function. The present experiment examined the effect of a social stressor, defeat associated with territorial defense, on serum antibodies to a specific protein, keyhole limpet hemocyanin (KLH). Pairs of male rats formed colonies and experimental rats were intruders. Experimental animals were immunized with KLH prior to exposures to territorially defensive colonies. Control animals were placed into colonies but separated from residents by a Plexiglas barrier. Behavioral measures, including number of bites and total time spent in submissive postures, were taken for colony-intruder interactions. Serum antibody levels were determined from blood samples taken one, two, and three weeks following immunization. Experimental animals had significantly less serum antibodies to KLH than did controls. Within the experimental group, total time spent in submissive postures at week one was significantly correlated with serum antibody levels, such that animals spending the most time in submission had lower antibody levels. Total bites correlated only slightly with antibody levels. The correlation between submission and serum antibody levels increased when the bites factor was partialled out. A stressful social encounter may thus affect immune function in a manner independent of the influence of physical (nociceptive) stressors.

Aggression↗
PubMed1989

Determinants of the nature of environmentally induced hypoalgesia.

Factors that determine whether naltrexone and pentobarbital anesthesia block the hypoalgesia produced by electric shock were investigated. The number of shocks delivered, the time since the last shock, and whether the subject is removed from the shock environment for testing were all found to be critical. One shock was followed by an initial hypoalgesia that was reversed by naltrexone but was not affected by pentobarbital. Moreover, this initial hypoalgesia was not eliminated by removing the subject from the shock apparatus. When testing was conducted in the shock context, this early hypoalgesia was followed by a hypoalgesia that was still reversed by naltrexone but differed from the early response in that it was eliminated by pentobarbital anesthesia. This second hypoalgesia did not occur when testing was conducted after removing the animal from the shock apparatus. Five shocks were also followed by two separable responses. Here the first response was also not reduced by pentobarbital, but it was not blocked by naltrexone. This initial response was also not prevented by removal from the shock context, but, again, the second response did not occur after removal. The pattern after 80 shocks was quite different. Here the hypoalgesic response did not appear to change in character across the 10 min of testing or with removal from the shock apparatus. The response persisted for 10 min in the shock context or after removal and was blocked by both naltrexone and pentobarbital throughout its entire duration. These results reconcile findings from different laboratories and bear on a number of theoretical models of stress-induced hypoalgesia.

Analgesia↗
PubMed1988

Monoamine neurotransmitters and metabolites during the estrous cycle, pregnancy, and the postpartum period.

A wide variety of behavioral changes in the female rat have been associated with the estrous cycle, pregnancy, and the postpartum period and their accompanying hormonal fluctuations. Since monoamine systems have been implicated in the control of these behaviors, the present study examined the tissue concentrations of norepinephrine (NE), dopamine (DA), and serotonin (5HT) and their primary metabolites dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5HIAA) in the anterior cerebral cortex, hippocampus, and cerebellum during the estrous cycle, late pregnancy, and the early postpartum period. Results show no significant differences in neurotransmitter or metabolite levels during the estrous cycle in any of the three brain regions examined. However, profound differences were observed between samples from late pregnancy, early postpartum, and the estrous cycle. In general, NE and 5HT levels in all three brain regions fell from normal values during late pregnancy and rose in the early postpartum period; levels of their metabolites rose in postpartum samples. Conversely, DA levels were elevated in late pregnancy and depressed in the early postpartum period in anterior cortex, while DOPAC levels were depressed in both late pregnancy and the early postpartum period. The finding of changes in monoamine metabolism associated with pregnancy and its termination could be important in understanding the increased susceptibility to affective illness in women during the postpartum period.

Animals↗
PubMed1988

Long-term effects of inescapable stress on daily running activity and antagonism by desipramine.

The behavioral consequences of exposure to stressors such as inescapable shock are usually transitory if testing is conducted in an environment different from that in which the stressor was administered. The behaviors tested have generally been motivated by discrete stimuli in the environment (e.g., activity in reaction to shock) or have been part of homeostatic regulatory mechanisms (e.g., eating). Here we investigated the effects of inescapable shock on a behavior that is not so tightly tied to motivating and reinforcing conditions, daily activity in a familiar home cage/running wheel environment. Rats lived in the wheel environment for 44-85 days before treatment. Inescapable shock produced only a transient reduction of water intake and body weight, but daily running was depressed for 14-42 days (the maximum period studied) depending on the conditions. This long-term effect on activity occurred despite the fact that shock was administered in an environment very different from the animal's home running wheel environment. The activity reduction was reversed by desipramine in a dose dependent fashion. Indeed, the activity of inescapably shocked animals treated with the optimum dose of desipramine exceeded that of control animals undergoing neither stress nor drug treatment. The maximum effect of desipramine required 7 days of treatment. Desipramine did not affect the activity of control subjects.

Animals↗
PubMed1988

Suppression of specific antibody production by inescapable shock: stability under varying conditions.

The effect of exposure to uncontrollable shock on the production of antibodies to a novel antigen, keyhole limpet hemocyanin (KLH), was studied in adult male Sprague-Dawley rats. Groups of rats were tested under one of four experimental conditions which included testing during either the light or dark portions of their light cycles and following either one or three daily exposures to tail shock. Control subjects were immunized with KLH in the absence of shock exposure during either the light or dark phases of their light cycle. A tertiary (memory) response was evoked 60 days following the initial immunization sequence in all animals in the absence of a shock exposure. Blood samples were obtained from the tip of the tail at the time of each immunization and at 1-week intervals for 3 weeks following immunizations. Specific IgG antibodies to KLH were determined by an enzyme-linked immunosorbent assay (ELISA). All animals exposed to shock showed reduced levels of IgG antibodies to KLH regardless of the experimental conditions of shock exposure. Antibody levels were highest among animals immunized during the dark phase of their cycle for both control and shocked animals. Antibody production to a novel antigen appears to be a robust and sensitive measure for studies of modulation of immunity by behavioral factors.

Animals↗
PubMed1988

The estrous cycle and estrogen modulate stress-induced analgesia.

In this article we investigate the impact of estrous cycle, ovariectomy, and estrogen replacement on both opioid and nonopioid stress-induced analgesia. Stage of estrous strongly influenced analgesia. Diestrus females exhibited the typical male pattern produced by the analgesia inducing procedures used--strong nonopioid analgesia following 10-20 tailshocks, and strong opioid analgesia following 80-100 tailshocks. In these experiments the nonopioid analgesia was slightly attenuated during estrus, but the opioid analgesia was markedly reduced. The role of estrogen in producing these changes was studied with estrogen replacement in ovariectomized subjects. Ovariectomy only slightly altered nonopioid analgesia but eliminated opioid analgesia, which suggests that some estrogen might be necessary to maintain the integrity of the system(s) underlying opioid analgesia. Estrogen administration restored opioid analgesia, but further estrogen suppressed opioid analgesia, duplicating the estrus pattern. It did not suppress nonopioid analgesia. Opioid analgesia was enhanced 102 hr after estrogen replacement, thus duplicating the diestrus pattern. Estrogen thus appears to be responsible for the impact of estrous cycle on opioid but not on nonopioid analgesia. These results suggest that ovarian hormones may modulate the impact of stressors on endogenous pain inhibition and other stress-responsive systems.

Animals↗
PubMed1988

Inescapable shock and attention to internal versus external cues in a water discrimination escape task.

In these experiments we examined discrimination learning in a water escape task following exposure to escapable, yoked inescapable, or no electric shock. Inescapable shock did not have an effect on swim speeds in any of the experiments. Inescapable shock interfered with the acquisition of a position (left-right) discrimination when an irrelevant brightness cue (black and white stimuli) was present. However, inescapable shock did not affect the acquisition of the position discrimination when the irrelevant brightness cue was removed. Inescapably shocked subjects showed facilitated learning relative to escapably shocked and nonshocked subjects when the brightness cue was included as a relevant cue. These data may resolve discrepancies between studies that did, and did not, find inescapable shock to interfere with the acquisition of discriminations. Moreover, they point to attentional processes as one locus of the cognitive changes produced by inescapable shock and suggest that exposure to inescapable shock biases attention away from "internal" response-related cues toward "external" cues.

Animals↗
PubMed1987

Shock signals and the development of stress-induced analgesia.

We report five experiments in which we investigated the effects of "feedback signals" on the pattern of hypoalgesia produced by inescapable shocks. A 5-s lights-out stimulus coincident with shock termination had no effect on the naltrexone-insensitive (nonopioid) hypoalgesia, which occurred after 10 inescapable shocks, but completely blocked the naltrexone-sensitive (opioid) hypoalgesia, which followed 100 inescapable shocks. The stimulus prevented the development of the opioid hypoalgesia rather than merely masking its measurement. This effect did not depend on the use of lights-out as the stimulus but did depend on the temporal relation between the stimulus and shock. Stimuli immediately preceding or simultaneous with shock had no effect. Surprisingly, stimuli randomly related to shock also blocked the opioid hypoalgesia. Simultaneous measurement of both hypoalgesia and fear conditioned to contextual cues revealed that the level of fear did not predict the blockade of hypoalgesia. Different backward groups received different temporal gaps between shock termination and the signal. An interval between 2.5 s and 7.5 s eliminated the effect of the signal on fear, but 12.5-17.5 s were required to eliminate the effect of the signal on hypoalgesia. The opioid hypoalgesia blocking power of the random stimulus was entirely attributable to those stimuli occurring within 15 s of the termination of the preceding shock. The implications of these results for the explanation of stimulus feedback effects and for stress-induced analgesia are discussed.

Animals↗