Reversal of hyperalgesia by transplantation in lateral hypothalamic lesioned rats

Lateral hypothalamus (LHA) plays a very important role in the modulation of nociceptive behaviour. The stimulation of LHA is known to produce analgesia of both tonic and phasic pain. The present study reports hyperalgesia induced by lateral hypothalamic lesions and the effect of fetal (gestation day 16) hypothalamic transplant on the nociceptive response to phasic thermal noxious stimulation [tail flick latency (TFL)] in LHA lesioned rats. The TFL decreased significantly (12.91 +/- 3.91 sec to 10.51+/- 1.23 sec) following LHA lesion. However, after transplantation, the TFL did not change. This is the first report of a hypothalamic transplant inducing recovery of a nociceptive response.     

Neural tissue transplant in the lateral hypothalamic lesioned rats: functional recovery pattern

Transplantation has come of age as an important investigative tool for studying normal growth and development of the brain tissue. The present study reports the effect of lateral hypothalamic (LHA) lesion and foetal hypothalamic tissue transplantation on the feeding behaviour. In a group of rats, LHA was lesioned bilaterally by passing direct current. Subsequently, in a separate group of rats, foetal hypothalamic tissue was transplanted at the lesioned site. Following LHA lesion, all the rats died of aphagia and adipsia within 7 days, whereas, the rats in whom foetal hypothalamus was transplanted, started taking food and water in small quantities from the first day of transplantation itself. Later, they were able to attain their preoperative values. This recovery of the feeding behaviour following foetal tissue transplantation may be due to the formation of synaptic connections or due to the release of neurotrophic factors.     

Effects of pedunculopontine tegmental nucleus lesions on emotional reactivity and locomotion in rats

Bilateral damage to the pedunculopontine tegmental nucleus (PPTg) has been found to impair several learning tasks; however, it is not clear whether this effect could be at least partially attributable to changes in the rat emotional reactivity and/or spontaneous locomotion. Therefore, the present work has tested the effects of bilateral electrolytic lesions of the PPTg on the behaviour of rats in the elevated plus-maze and the open field test. Because the behaviour of rats in learning and emotional tasks can be sensitive to routine experimental manipulations, we also have tested the effects of brief pre-surgical handling procedures on anxiety-like behaviours and locomotion in both lesioned and control rats. Lesions of the pedunculopontine tegmental nucleus (1). did not have any effects on spontaneous locomotor activity and (2). did not increase emotional reactivity. In fact, there was a slight bias towards a reduction in anxiety-like behaviours in lesioned rats, as evidenced by a significant increase in the number of open arm entries. Pre-surgical handling induced a slight decrease of emotional reactivity and a slight increase of exploratory activity. We conclude that damage to the pedunculopontine tegmental nucleus is not accompanied by either an enhancement of emotional reactivity or by an altered spontaneous locomotion.     

Neuropathic pain is associated with depressive behaviour and induces neuroplasticity in the amygdala of the rat

Chronic pain is associated with the development of affective disorders but the underlying mechanisms are not fully understood. Changes in brain centres implicated in both emotional and pain processing are likely to be critical in the interplay of pain control and affective emotional behaviour. In the present study, we assessed emotional behaviour and performed a structural analysis of the amygdala (AMY) in neuropathic rats after two months of hyperalgesia and allodynia, induced by the spared nerve injury model (SNI). When compared with Sham-controls, SNI animals displayed signs of depressive-like behaviour. In addition, we found an increased amygdalar volume in SNI rats. No alterations were found in the dendritic arborizations of AMY neurons but, surprisingly, the amygdalar hypertrophy was associated with an increased cell proliferation [bromodeoxyuridine (BrdU)-positive cells] in the central (CeA) and basolateral (BLA) amygdaloid nuclei. The phenotypic analysis of the newly-acquired cells revealed that they co-label for neuronal markers (BrdU + NeuN and BrdU + Calbindin), but not for differentiated glial cells (BrdU + glial fibrillary acidic protein).We demonstrate that neuropathic pain promotes generation of new neurons in the AMY. Given the established role of the AMY in emotional behaviour, we propose that these neuroplastic changes might contribute for the development of depressive-like symptoms that are usually present in prolonged pain syndromes in humans.     

Behavioral, immunocytochemical and biochemical studies in rats differing in their sensitivity to pain

The aim of the study was to further explore the anatomical and neurochemical background of differences in response to the conditioned aversive stimuli. The different patterns of behavioral coping strategies (a conditioned freezing response and ultrasonic vocalization) were analyzed in animals differing in their response to the acute painful stimulation, a foot-shock (HS: high sensitivity rats, LS: low sensitivity rats, and MS: medium sensitivity rats, according to their behavior in the flinch-jump pre-test), and correlated with plasma corticosterone levels, expression of c-Fos protein, and distribution of 5-HT innervation, in different brain structures. It was found that HS rats showed significantly more freezing behavior, whereas LS animals vocalized much more intensively. The behavior of LS group (less freezing response and stronger vocalization) was related to activation of prefrontal cortex (PFCX), increased activity of adrenal glands and stronger serotonin immunostaining in the PFCX, in comparison with HS animals. The more passive strategy of coping with the aversive event of HS group was related to increased activity of amygdalar nuclei and some areas of the hippocampus, and stronger 5-HT immunostaining in the baso-lateral nucleus of the amygdala, in comparison with LS rats. The present findings suggest that animals more vulnerable to stress might have innate deficits in the activity of brain systems controlling the hypothalamic-pituitary-adrenal axis that would normally allow them to cope with stressful situations. It appears also that response to pain may determine other patterns of emotional behavior, probably reflecting different activation thresholds of some brain structures controlling anxiety, e.g. prefrontal and secondary motor cortex.     

Effects of bilateral lesions of the central and lateral amygdala on free operant successive discrimination

Male rats received either ibotenic acid (IBO) or sham lesions bilaterally into the central or lateral amygdala or were assigned to an unoperated control group. After the postoperation recovery period all lesioned and unoperated animals were tested for open field behaviour and for the ability to master a free operant successive discrimination. Retention of the discrimination learning was evaluated 48 h later for the original and reversal problem. After the reversal learning retention test the unoperated animals were assigned at random to one unoperated control and two IBO amygdaloid lesioned groups (central and lateral) and these, unoperated and lesioned animals, received additional free operant successive discrimination retraining after the surgery recovery period. Significant lesion effects were found in the emotional indices in the open field test. The lesions significantly impaired the postoperative acquisition of a free operant successive discrimination and its reversal and diminished its retention but did not impair the retention of such a discrimination task acquired before the lesion. The contribution of central and lateral amygdala in open field behaviour and in the major components of a free operant successive discrimination is discussed. In order to know how the amygdala is involved in association of sensorial stimuli with reinforcement we suggest experimental designs controlling the detailed components of such an association.     

The effect of medial hypothalamus lesions on pain control

In the rat, discrete electrolytic lesions located in 6 different parts of the medial hypothalamus (MH) are shown to induce clearcut hyperalgesia. During a time limit of 14 days following the lesions, no other obvious deficits were noticed (in sensory and/or motor functions, affectivity towards conspecifics, food and water intake).Three nociceptive reactions (tail withdrawal, vocalization, vocalization after-discharge) were tested and their thresholds measured following electrical stimulation of the tail.The lesions aimed at the rostral part of the arcuate nucleus, as well as at ventro-medial and dorsomedial nuclei, produced the most profound hyperalgesia.The possible involvement of the endorphinergic and enkephalinergic systems known to be located in the MH is discussed. The relation between the hyperalgesic effects of MH lesions and various structures (limbic areas, descending pain control system, pituitary) is also considered.     

Electrical self-stimulation in the central amygdaloid nucleus after ibotenic acid lesion of the lateral hypothalamus

This experiment was carried out in order to investigate the involvement of lateral hypothalamus (LH) in electrical self-stimulation of the central amygdaloid nucleus (CeA). Adult male Sprague-Dawley rats were bilaterally implanted with a guide cannula situated above each LH and with two electrodes in the CeA. Self-stimulation was subsequently obtained separately from both right and left electrodes. The LH was then lesioned unilaterally by ibotenic acid (IBO) injection. Eight days later, the effect of this unilateral lesion on self-stimulation of the ipsilateral and contralateral CeA was tested. Then the neurons of the remaining non-lesioned LH side were lesioned with IBO and self-stimulation was tested 15 days after the second lesion. Both unilateral as well as bilateral lesions of LH produced a significant decrease in CeA self-stimulation rates but had no significant effect on the reward effectiveness. The unilateral lesions did not produce any modification of the rate-intensity function in the contralateral CeA. This lesion-induced depression in performance was reversed by treatment with phenobarbital. These results provide clear evidence that the rewarding effects of CeA electrical stimulation do not result from the activation of the LH outputs and that the apparent decrease in CeA self-stimulation may result from the LH lesion-induced increase in the frequency of epileptiform manifestations that occur following amygdaloid stimulation.     

Possible involvement of the amydaloid complex in morphine analgesia as studied by electrolytic lesions in rats

The analgesic effects of morphine (5 mg/kg i.p.) were studied in biamygalectomized rats. (1) Using the tail-flick test neither withdrawal latencies nor morphine time-course and efficacy were affected by the lesions. (2) The threshold for vocalization to electrical stimulation of the tail was greatly increased in lesioned rats; however, statistical analysis revealed no significant change in the analgesic efficacy of morphine.     

Egocentric spatial orientation in a water maze by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

The acquisition of a water maze based task requiring egocentric spatial orientation in the absence of distal cues was studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats that received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham-operated control group. Isolated lesions of both the anteromedial prefrontal cortex and the hippocampus were associated with a significantly impaired task acquisition. Both of these individually lesioned groups did, however, eventually demonstrate full functional recovery by reaching the task proficiency of the sham-operated control group. In contrast, the group in which both of these structures had been lesioned failed to demonstrate full functional recovery and was severely and long-lastingly impaired when compared to all other groups. Behavioural challenges in the form of a no-platform session and two reversals of platform position demonstrated that while the sham-operated control group and the group subjected to fimbria-fornix transections in isolation utilized rather pure egocentric orientation strategies, the two prefrontally lesioned groups (and especially the combined lesion group) employed a different set of solution strategies which at least partly relied on a "circling" method. Even in the behaviour of the prefrontally lesioned groups, however, indications of a certain level of cognitive representations of the platform positions were seen. It is concluded that both the prefrontal cortex and the hippocampus contribute to the mediation of egocentric spatial orientation. Furthermore, the hippocampus is a significant and potentially irreplaceable part of the neural substrate of functional recovery of the presently studied task after prefrontal lesions--while the prefrontal cortex may play a similar role with respect to hippocampal lesions.     

Involvement of the basolateral complex and central nucleus of amygdala in the omission effects of different magnitudes of reinforcement

Evidence from appetitive Pavlovian and instrumental conditioning studies suggest that the amygdala is involved in modulation of responses correlated with motivational states, and therefore, to the modulation of processes probably underlying reinforcement omission effects. The present study aimed to clarify whether or not the mechanisms related to reinforcement omission effects of different magnitudes depend on basolateral complex and central nucleus of amygdala. Rats were trained on a fixed-interval 12s with limited hold 6s signaled schedule in which correct responses were always followed by one of two reinforcement magnitudes. Bilateral lesions of the basolateral complex and central nucleus were made after acquisition of stable performance. After postoperative recovery, the training was changed from 100% to 50% reinforcement schedules. The results showed that lesions of the basolateral complex and central nucleus did not eliminate or reduce, but interfere with reinforcement omission effects. The response from rats of both the basolateral complex and central nucleus lesioned group was higher relative to that of the rats of their respective sham-lesioned groups after reinforcement omission. Thus, the lesioned rats were more sensitive to the omission effect. Moreover, the basolateral complex lesions prevented the magnitude effect on reinforcement omission effects. Basolateral complex lesioned rats showed no differential performance following omission of larger and smaller reinforcement magnitude. Thus, the basolateral complex is involved in incentive processes relative to omission of different reinforcement magnitudes. Therefore, it is possible that reinforcement omission effects are modulated by brain circuitry which involves amygdala.     

Differential effects of specific δ and κ opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective δ antagonist naltrindole, and that of the κ antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se, but which prevents the analgesic effect of the δ agonist DTLET (3 mg/kg, i.v.) or the κ agonist U-69, 593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the μ agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the δ antagonist, the paradoxical antinociceptive effect produced by 3 μg/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 ± 9% versus 161 ± 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were87 ± 4% versus 69 ± 5% in the control group). In rats injected with the κ antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 ± 3% versuss 169 ± 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds =70 ± 3% and 65 ± 3%, respectively). Based on these results, the possible role of each receptor subtype in the putative control exerted by endogenous opioid substances on nociceptive messages in pathological conditions is discussed.     

神经营养因子NGF、BDNF对AD模型鼠海马移植的影响

目的:研究神经营养因子NGF、BDNF对AD模型鼠海马移植后行为和形态学变化。方法:24.只AD模型鼠随机分成4组:单纯胚基底前脑细胞悬液移植组(ST组)、含NGF或BDNF胚基底前脑细胞悬液移植组(NGF组)、(BD-NF组)和模型对照组(M组),移植后3月进行行为测试并比较移植区AchE细胞数和纤维密度,运用方差分析和SNK检验进行组间比较。结果:行为测试移植3组明显优于模型M组,含因子组又较ST组效果好(P<0.01),两因子组间差异无显著性(P>0.05);因子组存活细胞数均高于ST组,NGF组细胞数多于BDNF组(P<0.05),纤维密度两组相似(P>0.05)。结论:海马内存活胆碱能神经元能代偿受损胆碱能神经元的功能,改善动物的学习记忆功能;NGF、BDNF均能促进胆碱能神经元存活,增加AchE细胞数目和突起,但BDNF促进神经元突起延伸作用较好,而NGF则对神经元保护作用较强。     

Effects of surgical stress on brain prostaglandin E2 production and on the pituitary-adrenal axis: attenuation by preemptive analgesia and by central amygdala lesion

Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.     

Septal elicitation of hippocampal theta rhythm did not repair cognitive and emotional deficits resulting from vestibular lesions

Bilateral vestibular lesions cause atrophy of the hippocampus in humans and subsequent deficits in spatial memory and the processing of emotional stimuli in both rats and humans. Vestibular lesions also impair hippocampal theta rhythm in rats. The aim of the present study was to investigate whether restoring theta rhythm to the hippocampus of a rat, via stimulation of the medial septum, would repair the deficits caused by vestibular lesions. It was hypothesized that the restoration of theta would repair the deficits and the vestibular rats would exhibit behavior and EEG similar to that of the sham rats. Rats were given either sham surgery or bilateral vestibular deafferentation (BVD) followed in a later operation by electrode implants. Half of the lesioned rats received stimulation. Subjects were tested in open field, elevated T-maze and spatial nonmatching to sample tests. BVD caused a deficit in hippocampal theta rhythm. Stimulation restored theta power at a higher frequency in the vestibular-lesioned rats, however, the stimulation did not repair the cognitive and emotional deficits caused by the lesions. It was concluded that stimulation, at least in the form used here, would not be a viable treatment option for vestibular damaged humans.     

Dual 5-HT mechanisms in basolateral and central nuclei of amygdala in the regulation of the defensive behavior induced by electrical stimulation of the inferior colliculus

Regulatory mechanisms in the basolateral nucleus of the amygdala (BLA) serves as a filter for unconditioned and conditioned aversive information that ascend to higher structures from the brainstem whereas the central nucleus (CeA) is the main output for the resultant defense reaction. We have shown that neural substrates in the inferior colliculus are activated by threatening stimuli of acoustic nature and have important functional links with the amygdala. In this work, we examined the influence of lesions with 5,7-dihydroxytryptamine (5,7-DHT) of these nuclei of amygdala on the aversive responses induced by electrical stimulation of the inferior colliculus. Thus, rats were implanted with an electrode in the CeA of the inferior colliculus for the determination of the thresholds of alertness, freezing and escape responses. Each rat also bore a cannula implanted in the BLA or CeA for injection of 5,7-DHT (8.0 microg/0.8 microl) or its vehicle. The data obtained show that CeA lesions increase the thresholds of aversive responses whereas BLA lesions decrease the thresholds of these responses. From this evidence it is suggested that defensive behavior induced by activation of the neural substrates of aversion in the inferior colliculus seems to depend on the integrity of the amygdala. BLA regulates the input and CeA functions as the output for these aversive states generated at brainstem level. It is likely that aversive information ascending from the inferior colliculus may receive either inhibitory or excitatory influences of 5-HT mechanisms in the BLA or CeA, respectively.     

The effect of pituitary removal on pain regulation in the rat

The effects of hypophysectomy (HX) on pain regulation in basal and in various stressful situations were investigated in the rat. Pain sensitivity was assessed by measuring the thresholds of 3 nociceptive reactions (tail withdrawal, vocalization, vocalization afterdischarge) following electrical stimulation of the tail. The completeness of HX and the integrity of hypothalamus were verified in each HX rat.(1) Baseline pain thresholds were lower in HX rats than in shan-operated animals; (2) naloxone (Nx) hyperalgesia was only slightly altered by HX; (3) different types of stress induced different types of changes in nociception i.e. analgesia or hyperalgesia. The influence of HX varied according to the stress: it increased hyperalgesia, reduced analgesia, or had no effect at all.These results indicate that in the rat: (i) the pituitary participates in the regulation of basal pain sensitivity, probably through analgesic factors; (ii) Nx hyperalgesia results essentially from an antagonism of endogenous opioids originating in the CNS and not in the pituitary; and (iii) the pain regulatory processes engaged in adaptation to stressful stimuli involve the CNS and the pituitary in variable proportions depending upon the nature of the stress.     

Temporally limited role of substantia nigra-central amygdala connections in surprise-induced enhancement of learning

Prediction error plays an important role in modern associative learning theories. For example, the omission of an expected event (surprise) can enhance attention to cues that accompany those omissions, such that subsequent new learning about those cues is more rapid. Many studies from our laboratories have demonstrated that circuitry that includes the amygdala central nucleus (CeA), the cholinergic neurons in the substantia innominata/nucleus basalis region and their innervation of the posterior parietal cortex is critical for this surprise-induced enhancement of attention in learning. We recently showed that midbrain dopamine neurons, known to code prediction error, are also important for surprise-induced enhancement of learning through their interaction with CeA. The present study examined whether in rats the communication between the substantia nigra pars compacta (SNc) and CeA is critical only at the time of surprise, for example to detect prediction error information, or is also needed to maintain and later express that information as enhanced learning. All animals received unilateral CeA lesions and unilateral cannula implants targeting the SNc located contralateral to the lesioned CeA. As the SNc–CeA connections are mainly ipsilateral, inactivating SNc contralateral to the lesioned CeA provided transient blockage of SNc and CeA communication. The results show that SNc–CeA communication is critical for processing prediction error information at the time of surprise, but neither SNc nor SNc–CeA communication is necessary to express that information as enhanced learning later.     

The bidirectional dose-dependent effect of systemic naloxone is also related to the intensity and duration of pain-related disorders: a study in a rat model of peripheral mononeuropathy

In an experimental model of mononeuropathy in the rat, created by 4 ligatures around the sciatic nerve, i.v. naloxone 1 week after surgery induces bidirectional effects (antinociceptive effects at very low doses, hyperalgesic effects with high doses). Using the same nociceptive test (vocalization thresholds to paw pressure), the activity of the same doses of naloxone (3 micrograms/kg, and 1 mg/kg) was investigated 2 weeks after sciatic ligation, when the behavioural pain-related disorders are at a maximum. Three micrograms/kg naloxone produced a significant antinociceptive effect on the lesioned and non-lesioned paw, which was clearly related to the degree as well as to the duration of pain-related signs in the rat. By contrast, the high dose of naloxone did not induce a mean significant effect when tested on either paw; however, it elicited a potent hyperalgesic effect in those rats which had recovered from hyperalgesia at this 2 week time point after the sciatic injury.     

Enhanced detection of nucleus basalis magnocellularis lesion-induced spatial learning deficit in rats by modification of training regimen

Bilateral excitotoxic lesions of the nucleus basalis magnocellularis (NBM) in the rat cause deficits in the water maze, a spatial memory paradigm. Previous investigations aimed at reversing the water maze performance deficit with anticholinesterase treatments have been unable to demonstrate a consistent drug effect due to the relatively good acquisition of the task seen following NBM lesions. The present investigation tested three different water maze training regimens designed to separate the learning curves. F-344 rats received bilateral NBM injections of ibotenic acid; sham-operated rats served as controls. The animals were tested in three groups in the water maze as follows: (1) four trials per day with no intertrial interval (standard paradigm), (2) four trials per day with a 10-minute intertrial interval, and (3) two trials per day with no intertrial interval. Each group was tested in the water maze for five consecutive days, followed by two days of rest, and then tested for an additional five days. The two-trial per day paradigm was more difficult than the standard paradigm for both lesions and controls and yielded the most difference between lesions and controls as compared to the other two testing regimens. The 10-min intertrial interval schedule was more difficult than the standard paradigm for lesioned animals but acquisition was not affected in control rats. These data demonstrate that the nucleus basalis lesions cause a deficit in the water maze task regardless of training parameters. Further, while all rats showed some acquisition of the water maze task, training schedule affected the level of learning of both lesioned and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)