Potentiation of foot shock analgesia by thyrotropin releasing hormone

Thyrotropin releasing hormone (TRH) interacts with both opioid and non-opioid systems in mediating hypothermic, hypoactive, cataleptic, respiratory and analgesic effects. While TRH neither antagonizes opioid analgesia nor alters pain thresholds itself, it blocks neurotensin analgesia. Different forms of pain-inhibition in rats can be activated by selectively altering the parameters of shock: while analgesia induced by 20 inescapable tail-shocks is not reversed by naltrexone, exposure to 60 or 80 shocks does elicit naltrexone-reversible analgesia. The first experiment examined whether intracerebroventricular administration of TRH (0, 10, or 50 micrograms) would alter the elevations in tail-flick latencies in rats induced by 20 or 80 foot shocks and found that TRH significantly lengthened the duration and magnitude of analgesia induced by 20 and 80 foot shocks in a dose-dependent manner. The second experiment extended these findings to the writhing test, a visceral pain test. While the number and duration of writhes of vehicle-treated rats exposed to 80 foot shocks failed to differ from baseline values. TRH (50 micrograms)-treated rats exposed to 80 foot shocks displayed significant decreases in the number and duration of writhes. The third experiment indicated that the differential effects of naltrexone upon analgesia induced by 20 or 80 tail shocks were not apparent when foot shocks were employed, precluding a definitive statement that TRH may be involved in the modulation of both opioid and non-opioid forms of analgesia.     

beta-Endorphin controls vasopressin release during foot shock-induced stress in the rat

This study tested the possibility that beta-endorphin is involved in the regulation of vasopressin release during stress induced by inescapable electric foot shock. To this end, a specific anti-beta-endorphin antiserum or a control serum lacking the specific anti-beta-endorphin antibodies was administered to male rats. Plasma vasopressin concentrations, measured by radioimmunoassay, were not affected by brief foot shock stress in control rats, but were raised significantly by the stress in animals which had received an intracerebroventricular (i.c.v.) injection of the anti-beta-endorphin antiserum. In contrast, when the same volume of the anti-beta-endorphin antiserum was injected into a tail vein, foot shock stress produced only a slight effect on vasopressin release. I.c.v. injection of the antiserum changed neither basal nociceptive threshold nor stress-induced analgesia as revealed by the tail-flick latency. Vasopressin release induced by an osmotic stimulus was not influenced by the anti-beta-endorphin antiserum given i.c.v. The opiate antagonist naloxone or the glucocorticoid dexamethasone raised plasma vasopressin concentration in stressed rats which had received the control serum (i.c.v.); however, after i.c.v. injection of the anti-beta-endorphin antiserum neither naloxone nor dexamethasone elevated the plasma vasopressin concentration beyond the level reached by the anti-beta-endorphin antiserum (i.c.v.) alone. These results suggest that beta-endorphin inhibits the release of vasopressin during foot shock-induced stress in the rat.     

Startle responses to electric shocks: measurement of shock sensitivity and effects of morphine, buspirone and brain lesions

The present study developed a new protocol to assess shock sensitivity in rats. Male Wistar rats were subjected to footshock stimuli ranging from 0 to 1.6 mA (0.1 s) in a startle apparatus and startle responses elicited by shocks were measured. Acoustic stimuli (95, 105, or 115 dB) were dispersed within the shock series serving as a control measurement of motor performance. Results indicated that the magnitude of shock startle responses significantly increased with the shock intensity in a linear trend. Morphine (8.0 mg/kg) and buspirone (1.0, 2.5, or 5.0 mg/kg), both of which possessing analgesic effects, depressed shock startle but had no such effect on acoustic startle. The effect of morphine was readily reversed by pretreatment of naloxone (1.0 mg/kg). To investigate the neural basis underlying this response, radio-frequency lesions of various structures implicated in processing of nociceptive or aversive information were undertaken. Lesions of the ventroposterior thalamic nucleus, insular cortex, or amygdala decreased startle reactivity to electric shocks but not to acoustic stimuli. Lesions of the anterior cingulate gyrus or medial prefrontal cortex, while altered the reactivity to acoustic stimuli, had no effect on the shock-elicited startle. These results suggested that the amplitude of startle in response to electric shocks provide a quantitative measurement of shock sensitivity within an extended range of stimulus intensities. Performing this response may engage the the central nociceptive pathway.     

Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum

Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress.     

Effects of nicotine and dietary salt on a learned blood pressure response in Dahl-S rats

We examined the effects of chronic nicotine exposure and dietary salt on the arterial blood pressure (BP) changes learned in response to an acute behavioral stress in the Dahl salt-sensitive rat. Four groups were tested: low salt + vehicle; low salt + nicotine; high salt + vehicle; and high salt + nicotine. Rats were fed a low-salt (0.08% NaCl) or a high-salt (8% NaCl) diet for 4 wk; 2.4 mg. kg(-1). day(-1) nicotine or vehicle was given via an implanted osmotic minipump for the last 2 wk. All rats were conditioned by following one tone (CS+) with a 0.5-s tail shock; another tone (CS-) was never followed by shock. CS+ in low salt + vehicle and high salt + vehicle-treated rats evoked an initial arterial BP increase (C(1)), a component of the startle response, and an ensuing, smaller, but more sustained, pressor response (C(2)), which is acquired with training. In these rats, both C(1) and C(2) evoked by CS- were significantly smaller than those to CS+, demonstrating that these groups discriminated between the two tests. Conversely, although the low salt + nicotine-treated rats had both the C(1) and C(2) components of the conditional arterial pressure response, they did not discriminate between CS+ and CS-. Finally, the high salt + nicotine group failed to both discriminate between tones and acquire (i.e., learn) the C(2) response. The unconditional response to shock did not differ between groups. We conclude that combined exposure to high salt and to nicotine inhibits the salt-sensitive animal's acquisition of a learned conditional BP response, perhaps because nicotine acts preferentially on those central processes required for associative learning versus those involved in orientating to external stimuli.     

Opiate-like effects of electroconvulsive shock in rats: A differential effect of naloxone on nociceptive measures

Electroconvulsive shock (ECS) in rats produced a generalized seizure which was followed by an opiate-like catalepsy and an increase in hot-plate escape latencies. Preinjection of naloxone, at doses of 3.0 and 10.0 mg/Kg, significantly diminished the ECS-induced increase in hot-plate latencies. Paradoxically, simultaneous measurement of tail-flick latencies in these same rats demonstrated opiate-$\text{agonist}$ effects of naloxone. The cataleptic effects of ECS were demonstrated to be opiate-like by evaluating righting reflexes, grid responses, and haloperidol effects. Colonic temperatures were also measured in all animals. These data, collectively discussed relative to affective and reflexive components of nociceptive behaviors, support the hypothesis that selective endorphin systems are activated by ECS. Moreover, these observations suggest consideration of a role for endorphin systems in the therapeutic mechanisms of electroconvulsive therapy (ECT) in man.     

Learned helplessness in the rat: effect of response topography in a within-subject design

Three experiments investigated learned helplessness in rats manipulating response topography within-subject and different intervals between treatment and tests among groups. In Experiment 1, rats previously exposed to inescapable shocks were tested under an escape contingency where either jumping or nose poking was required to terminate shocks; tests were run either 1, 14 or 28 days after treatment. Most rats failed to jump, as expected, but learned to nose poke, regardless of the interval between treatment and tests and order of testing. The same results were observed in male and female rats from a different laboratory (Experiment 2) and despite increased exposure to the escape contingencies using a within-subject design (Experiment 3). Furthermore, no evidence of helplessness reversal was observed, since animals failed to jump even after having learned to nose-poke in a previous test session. These results are not consistent with a learned helplessness hypothesis, which claims that shock (un)controllability is the key variable responsible for the effect. They are nonetheless consistent with the view that inescapable shocks enhance control by irrelevant features of the relationship between the environment and behavior.     

Endotoxin shock: prevented by naloxone in intact but not hypophysectomized rats

Previous studies established that naloxone reverses hypotension in endotoxin, hemorrhagic, and spinal shock. We studied endotoxin shock in hypophysectomized (Hx) rats, which have little circulating beta-endorphin. Hx or intact rats received surgically implanted jugular catheters for drug injection and aortic catheters for arterial blood pressure (MAP) recording. On the second day after implantation, rats were pretreated with either naloxone or saline. Two minutes later each rat received endotoxin. Following endotoxin, all rats showed a brief biphasic hypertensive-hypotensive response followed by stabilization of MAP near baseline. Within 20 min, all Hx rats, regardless of pretreatment, and the saline-treated intact rats, showed progressive hypotension (P less than 0.005). Only the naloxone-pretreated intact rats maintained a stable MAP. Plasma endorphin measured at 20 min was undetectable in Hx rats in contrast to intact rats (P less than 0.001); plasma corticosterone levels were likewise suppressed in the Hx rats (P less than 0.01). Thus (1) naloxone protected only the rats with an intact pituitary-adrenal-sympathetic system, and (2) pituitary endorphin is not required to generate endotoxin shock in hypophysectomized rats.     

Effects of diazepam and stress on lung inflammatory response in OVA-sensitized rats

The influence of stress and diazepam treatment on airway inflammation was investigated in ovalbumin (OVA)-sensitized rats. Animals were injected with OVA plus aluminum hydroxide intraperitoneally (day 0) and boosted with OVA subcutaneously (day 7). From the first to 13th day after sensitization, rats were treated with diazepam, and 1 h later they were placed in a shuttle box where they received 50 mild escapable foot shocks/day preceded by a sound signal (S). Response during the warning (S) canceled shock delivery and terminated the S. On day 14, rats were submitted to a single session of 50 inescapable foot shocks preceded by S and then were challenged with OVA. High levels of stress were detected in shocked animals, manifested as ultrasonic vocalizations. Morphometric analysis of stressed animals revealed a significant increase in both edema and lymphomononucleated cells in airways compared with controls. Diazepam treatment reduced edema in stressed and nonstressed rats. No differences were found in polymorphonucleated cell infiltration. Diazepam treatment reduced lymphomononucleated cell infiltration in stressed animals. These data suggest that stress and diazepam treatment play relevant roles in edema and lymphomononucleated airway inflammation in OVA-sensitized rats.     

The selective role of the nucleus raphe magnus in the mechanisms of analgesia in electrocutaneous pain stimulation, cold stress and the action of morphine

Inhibition of the analgetic activity of systemic morphine and inescapable foot shock in certain moments of the experiment was shown on rats subjected to electrolytic destruction of nucleus raphe magnus. Cold swim stress increased analgesia as compared to the control animals. It is concluded that this formation of the brain is selectively and dynamically involved in mechanisms of various types of analgesia.     

Synaptic proteome changes in mouse brain regions upon auditory discrimination learning

Changes in synaptic efficacy underlying learning and memory processes are assumed to be associated with alterations of the protein composition of synapses. Here, we performed a quantitative proteomic screen to monitor changes in the synaptic proteome of four brain areas (auditory cortex, frontal cortex, hippocampus striatum) during auditory learning. Mice were trained in a shuttle box GO/NO-GO paradigm to discriminate between rising and falling frequency modulated tones to avoid mild electric foot shock. Control-treated mice received corresponding numbers of either the tones or the foot shocks. Six hours and 24 h later, the composition of a fraction enriched in synaptic cytomatrix-associated proteins was compared to that obtained from na?ve mice by quantitative mass spectrometry. In the synaptic protein fraction obtained from trained mice, the average percentage (±SEM) of downregulated proteins (59.9 ± 0.5%) exceeded that of upregulated proteins (23.5 ± 0.8%) in the brain regions studied. This effect was significantly smaller in foot shock (42.7 ± 0.6% down, 40.7 ± 1.0% up) and tone controls (43.9 ± 1.0% down, 39.7 ± 0.9% up). These data suggest that learning processes initially induce removal and/or degradation of proteins from presynaptic and postsynaptic cytoskeletal matrices before these structures can acquire a new, postlearning organisation. In silico analysis points to a general role of insulin-like signalling in this process.     

慢性动脉血压监测模型在惊恐条件反射中的应用

目的：探索一种新的、可靠的模型,用于惊恐条件反射的相关研究。方法：通过使用条件刺激(声音)和非条件刺激(足部电击)相结合的方法,可使动物对条件刺激产生惊恐反应。同时对动脉血压进行长期监测并测定利多卡因阻断杏仁基底外侧核群前后的血压变化。结果：该惊恐条件反射建立后(需经4d训练),单独给予动物条件刺激即可引起血压明显升高。我们将它作为条件反射已形成的标志。此时,用利多卡因阻断杏仁基底外侧核群的作用,单独给予动物条件刺激不再引起血压明显升高。结论：慢性动脉血压监测模型在惊恐条件反射的研究中是一种可靠的动物模型。     

Human β-endorphin: Development of tolerance and behavioral activity in rats

Human β-endorphin produced a potent antinociceptive response as estimated by the tail-flick test in rats after intraventricular injection. On a molar basis, the peptide was 21 times more potent than morphine and in addition, the peptide produced morphine-like catatonia and hypothermia. These responses were blocked by naloxone. Repeated injections of the peptide induced tolerance to analgesic response, catatonia and hypothermia. Cross tolerance to morphine was also observed.     

Startle responding and context conditioning. Naloxone pretreatment and stimulus intensity

The possibility that acoustic startle stimuli could support a conditional response (freezing) to contextual stimuli was investigated. Rats were exposed to three acoustic startle stimuli on the first day, and one on the second day. On day 1, 20 rats received naloxone pretreatment and another 20 received saline (placebo) pretreatment. Half of each group received a high-intensity acoustic stimulus, the other half a low-intensity acoustic stimulus. Both the higher stimulus intensity and the naloxone pretreatment led to greater freezing behavior during the 3-minute test period before the single startle stimulus on day 2. These findings support the notion that increased actual or perceived intensity of the acoustic startle stimulus increases conditioning to contextual stimuli as indexed by freezing behavior.     

Progesterone restores stress induced inhibition of estrous behavior in rat

Exposure to a stressor (mild electrical shocks to foot, five times per episode, at 1800, 1830, 1900 and 1930 hrs of proestrus) coinciding with period of pre-ovulatory progesterone secretion in rats abolished estrous behavior as shown by the absence of lordosis response and a significant increase in rejection quotient compared to controls. These rats did not show spermatozoa in the vaginal smear next day morning in contrast to their presence in controls. On the other hand, rats treated with progesterone (a single injection, 500 microg in 0.1 ml olive oil at 1800 hr of proestrus) prior to exposure to stressor showed normal estrous behavior, as shown by significantly lower rejection quotient than rats exposed to stress alone, lordosis quotient similar to controls and presence of spermatozoa in the vaginal smear next day. The results, albeit indirectly, to the best of our knowledge, first time indicate that stress induced impaired steroidogenesis leads to suppression of estrous behavior.     

Effects of apomorphine on the expression of learned helplessness behavior

Dopaminergic system and its D1 as well as D2 receptors are involved in the modulation of emotional behavior. This experiment investigated the role of dopaminergic activity in the inescapable stress-induced learned helplessness, a widely used depression animal model, by using the pharmacological manipulation through the apomorphine (APO), an agonist for D1 and D2 receptors, and sulpiride (SUL), a selective D2 antagonist. Male Sprague Dawley rats were used and tested in a shuttle box. In the day-1 session, the rats received a 10-trial (1 min/trial) inescapable stressor: a 3 sec conditioned stimulus (CS; 75 db sound and 250 lux red light) followed by a 10 sec unconditioned stimulus (UCS; electrical foot shock, 0.5 mA). In the day-2 session, a 15-trial active avoidance test, 3 sec CS followed by UCS, was performed 30 min after the administration of APO (0, 0.05, 0.5, 1, and 5 mg/kg, i.p.). The number of failures was counted and the UCS was stopped when the rats did not escape after 15 sec UCS. The results showed that APO at the dosage of 0.5 mg/kg had a tendency to enhance the avoidance behavior. In contrast, the treatment of higher dose of APO, 1 and 5 mg/kg, reduced the number of escape but increased the number of failure. Pretreatment of SUL (5 mg/kg, i.p.), 10 min before 1 mg/kg of APO, significantly enhanced the failure behavior. The present data suggest that the activity of D2 receptor may be associated with the adaptive or protective role in the prevention of escape deficits after exposure to inescapable stress. However, the excessive stimulation of D1 receptor may participate in the failure of coping behavior leading to learned helplessness and therefore in the pathophysiological mechanisms underling the development of depression.     

The startle response during whiplash: a protective or harmful response?

Whiplash injuries are common following rear-end collisions. During such collisions, initially relaxed occupants exhibit brisk, stereotypical muscle responses consisting of postural and startle responses that may contribute to the injury. Using prestimulus inhibition, we sought to determine if the startle response elicited during a rear-end collision contributes to head stabilization or represents a potentially harmful overreaction of the body. Three experiments were performed. In the first two experiments, two groups of 14 subjects were exposed to loud tones (124 dB) preceded by prestimulus tones at either four interstimulus intervals (100-1,000 ms) or five prestimulus intensities (80-124 dB). On the basis of the results of the first two experiments, 20 subjects were exposed to a simulated rear-end collision (peak sled acceleration = 2 g; speed change = 0.75 m/s) preceded by one of the following: no prestimulus tone, a weak tone (85 dB), or a loud tone (105 dB). The prestimulus tones were presented 250 ms before sled acceleration onset. The loud prestimulus tone decreased the amplitude of the sternocleidomastoid (16%) and cervical paraspinal (29%) muscles, and key peak kinematics: head retraction (17%), horizontal head acceleration (23%), and head angular acceleration in extension (23%). No changes in muscle amplitude or kinematics occurred for the weak prestimulus. The reduced muscle and kinematic responses observed with loud tones suggest that the startle response represents an overreaction that increases the kinematics in a way that potentially increases the forces and strains in the neck tissues. We propose that minimizing this overreaction during a car collision may decrease the risk of whiplash injuries.     

Differential effects of chronic escapable versus inescapable stress on male syrian hamster (Mesocricetus auratus) reproductive behavior

Stress decreases sexual activity, but it is uncertain which aspects of stress are detrimental to reproduction. This study used an escapable/inescapable stress paradigm to attempt to dissociate physical from psychological components of stress, and assess each component's impact on reproductive behavior in the male Syrian hamster (Mesocricetus auratus). Two experiments were completed using this protocol where two animals receive the same physical stressor (an electric footshock) but differ in the psychological aspect of control. One group (executive) could terminate the shock for themselves as well as a second group (yoked) by pressing a bar. Experiment 1 demonstrated a significant increase in plasma glucocorticoids at the end of a single 90-min stress session with no difference in glucocorticoid levels between the executive and yoked groups at any time point. Experiment 2 quantified male reproductive behavior prior to and immediately following 12 days of escapable or inescapable stress in executive, yoked, and no-stress control hamsters (n = 12/group). Repeated-measures analysis of variance revealed a number of significant changes in reproductive behavior before and after stress in the three treatment groups. The most striking difference was a decrease in hit rate observed only in the animals that could not control their stress (yoked group). Hit rate in the executive males that received the exact same physical stressor but could terminate the shock by pressing a bar was nearly identical to control animals that never received any foot shock. Therefore, we conclude that coping or control can ameliorate the negative effects of stress on male reproductive behavior.     

Effects of Cold Pressor Stress on the Human Startle Response

Both emotion and attention are known to influence the startle response. Stress influences emotion and attention, but the impact of stress on the human startle response remains unclear. We used an established physiological stressor, the Cold Pressor Test (CPT), to induce stress in a non-clinical human sample (24 student participants) in a within-subjects design. Autonomic (heart rate and skin conductance) and somatic (eye blink) responses to acoustic startle probes were measured during a pre-stress baseline, during a three minutes stress intervention, and during the subsequent recovery period. Startle skin conductance and heart rate responses were facilitated during stress. Compared to baseline, startle eye blink responses were not affected during the intervention but were diminished afterwards. These data describe a new and unique startle response pattern during stress: facilitation of autonomic stress responses but no such facilitation of somatic startle eye blink responses. The absence of an effect of stress on startle eye blink responsiveness may illustrate the importance of guaranteeing uninterrupted visual input during periods of stress.     

Rats’ (Rattus norvegicus) temporal discrimination of brief auditory stimuli: How does it compare with that of humans (Homo sapiens) and zebra finches (Taeniopygia guttata)?

The present study with rats replicated an experiment on the ability of zebra finches and humans to discriminate among brief auditory stimuli (see Weisman et al., 1999, Experiment 2). We trained rats with 27 3-kHz tones that varied in duration from 10 ms to 1420 ms. Reinforcement was contingent on responding (approaching the food well) to the nine medium-durations range tones (56-255 ms) but not to the nine short-durations range (10-46 ms) or long-durations range tones (309-1420 ms). Rats also received post-discrimination transfer tests with 2 kHz and 4 kHz tones that varied over the same durations as the 3 kHz tones. Rats acquired the temporal discrimination to a slightly lower level of accuracy than seen in finches or humans by Weisman et al. (1999). We tested for transfer of the temporal discrimination to find that rats, similar to humans (data from Weisman et al., 1999), transferred to untrained 2-kHz and 4-kHz tones at levels approaching accuracy to that achieved to the trained 3-kHz tone. By contrast, zebra finches (data from Weisman et al., 1999) failed to transfer their discrimination to the trained tone. We conclude that (a) rats discriminate among tone durations at least as well as they do among auditory frequencies and (b) rats like humans, but unlike finches, are insensitive to absolute pitch in their temporal discrimination.