Orexin-1 Receptor Antagonist SB-334867 Enhances Formalin-Induced Nociceptive Behaviors in Adult Male Rats.

Background: Orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. Neurons that produce orexin are scattered mediolaterally within the Dorsomedial Hypothalamus (DMH) and the lateral hypothalamus. In the current research, we assessed the impact of prolonged application of the antagonist of Orexin Receptor 1 (OXR1) on nociceptive behaviors in adult male rats. Methods: Sixteen Wistar rats received subcutaneous (s.c.) injections of the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle repetitively from Postnatal Day 1 (PND1)-PND30. On the 30th day following the final application of the OXR1 antagonist formalin-provoked pain was evaluated by injecting formalin. Results: Administration of the OXR1 antagonist in the long-term augmented the formalin-provoked nociceptive behaviors in interphase and phase II of the formalin-induced pain. Conclusion: Current results showed that the continued inhibiting OXR1 might be implicated in formalin-induced nociceptive behaviors. Therefore, the present study highlighted the effect of orexin on analgesia.

Contribution of the intra-hippocampal orexin system in the regulation of restraint stress response to pain-related behaviors in the formalin test.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.

Heterosynaptic plasticity-induced modulation of synapses.

Plasticity is a common feature of synapses that is stated in different ways and occurs through several mechanisms. The regular action of the brain needs to be balanced in several neuronal and synaptic features, one of which is synaptic plasticity. The different homeostatic processes, including the balance between excitation/inhibition or homeostasis of synaptic weights at the single-neuron level, may obtain this. Homosynaptic Hebbian-type plasticity causes associative alterations of synapses. Both homosynaptic and heterosynaptic plasticity characterize the corresponding aspects of adjustable synapses, and both are essential for the regular action of neural systems and their plastic synapses.In this review, we will compare homo- and heterosynaptic plasticity and the main factors affecting the direction of plastic changes. This review paper will also discuss the diverse functions of the different kinds of heterosynaptic plasticity and their properties. We argue that a complementary system of heterosynaptic plasticity demonstrates an essential cellular constituent for homeostatic modulation of synaptic weights and neuronal activity.

The Implication of Hypocretin in Drug Abuse and Arousal in the Brain Stem.

Hypocretin (orexin, Hcrt) neurons located in the lateral hypothalamus (LH) project widely into the brain and are thus responsible for the physiological action of the hypocretin complex. Hypocretin is involved in both arousal and addiction, and brainstem areas such as the locus coeruleus (LC), paragigantocellularis (PGi), and dorsal raphe (DR) contribute to these functions. In the present review, we focus on the effect of Hcrt on drug abuse and arousal in the brainstem.

Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches.

Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and antiplatelet effects. It is commonly used for its cardiovascular benefits and is prescribed as secondary prophylaxis after a heart attack. Furthermore, low-dose, long-term ASA is used to reduce the risk of heart attack and stroke in individuals without prior cardiovascular disease. Acetylsalicylic acid acts as a non-selective inhibitor of cyclooxygenase (COX), which inhibits the synthesis of prostaglandins and prevents pro-inflammatory cytokines. Findings suggest that targeting cytokines and growth factors could be a potential therapeutic strategy for reducing neuroinflammation and slowing down the progression of dementia. Additionally, prostaglandins contribute to synaptic plasticity and can act as retrograde messengers in synapses. Research has implicated COX-1, one of the isoforms of the enzyme, in neuroinflammation and neurodegenerative disorders. The inhibition of COX-1 might potentially prevent impairments in working memory and reduce neuroinflammation caused by beta-amyloid proteins in some conditions, such as Alzheimer's disease (AD). Cyclooxygenase-2, an inducible form of the enzyme, is expressed in cortical and hippocampal neurons and is associated with long-term synaptic plasticity. The inhibition or knockout of COX-2 has been shown to decrease long-term potentiation, a process involved in memory formation. Studies have also demonstrated that the administration of COX-2 inhibitors impairs cognitive function and memory acquisition and recall in animal models. There remains a debate regarding the effects of aspirin on dementia and cognitive decline. Although some studies suggest a possible protective effect of non-steroidal anti-inflammatory drugs, including aspirin, against the development of AD, others have shown inconsistent evidence. This review provides an overview of the effects of ASA or its active metabolite salicylate on learning, memory, and synaptic plasticity.

A Review of the Physiological Role of Hypocretin in the Ventral Tegmental Area in Reward and Drug Dependence.

Orexin (OX, hypocretin: HCRT) as a neuropeptide is produced in a distinct population of neurons in the posterior lateral hypothalamus (LH). OX neurons implicate in reward function. OX makes a main input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. OX, through OX receptors (OXR1, OXR2) activates VTA dopamine (DA) neurons. VTA neurons are involved in reward processing and motivation. In this review, we will discuss the OX effect on addiction through VTA activation and related areas of the brain.

Preventive impacts of vitamin C on memory damage caused by unpredictable chronic mild stress in relation to biochemical parameters in the hippocampus of male rats.

The present study focused on examining the impact of vitamin C (Vit C) administration on the function of memory and the status of oxidative stress (OS) in the hippocampal area of the brain using an unpredictable chronic mild stress (UCMS) model in rats. To this end, 50 male Wistar rats (11-12 weeks of age at the start of the study) were assigned to five groups of six animals, including control, UCMS, UCMS + Vit C 50 mg/Kg, UCMS + Vit C 100 mg/Kg, and UCMS + Vit C 400 mg/Kg. The animals received daily intraperitoneal injections of Vit C at a certain time (9 am) before the initiation of a stressor. UCMS, including a progression of typical stressors, was applied for four weeks. Subsequently, using the passive avoidance (PA) and Morris water maze (MWM) tests were performed to investigate learning and memory. Eventually, hippocampal tissues were evaluated in terms of OS criteria. The results revealed that the latency to enter the dark chamber (P < 0. 01 and P < 0.05, PA test) and the time spent in the target quadrant (P < 0.0001, MWM test) were shorter in the UCMS group, while latency to discover the platform was longer (P < 0.05 and P < 0.001, MWM test) compared to the control group. However, UCMS decreased the content of thiol (P < 0.0001), as well as the activities of catalase (P < 0.0001) and superoxide dismutase (P < 0.0001), whereas the concentration of malondialdehyde (P < 0.01) increased in the hippocampal region of the brain in comparison to the control group. Interestingly, Vit C treatment reversed the mentioned effects of UCMS. Therefore, the latency to enter the dark chamber (P < 0. 05 and P < 0.01,1 and 24 h after the shock, PA test, UCMS + Vit C 400) and the time spent in the target quadrant (P < 0. 01 and P < 0.05, MWM test, UCMS + Vit C 400 and UCMS + Vit C 100, respectively) were longer in the UCMS + Vit C groups. Moreover, Vit C increased the content of thiol (P < 0.05, UCMS + Vit C 400), as well as the activity of catalase (P < 0.001, UCMS + Vit C 400) and superoxide dismutase (P < 0.0001, UCMS + Vit C 400, UCMS + Vit C 100), whereas the concentration of malondialdehyde (P < 0. 05 and P < 0.01, UCMS + Vit C 100, UCMS + Vit C 400) decreased in the hippocampal region of the brain in comparison to the UCMS group. Overall, these results suggest that Vit C could reverse UCMS-induced learning and memory impairment possibly through the modulation of brain OS.Key points Memory and learning impairments were induced by unpredictable chronic mild stress (UCMS)Vitamin C could prevent cognitive impairments caused by UCMS in rats by attenuation of oxidative stress in the brain.

Comparative investigation of analgesic tolerance to taurine, sodium salicylate and morphine: Involvement of peripheral muscarinic receptors.

Nowadays various analgesic medications are used for the management of acute and chronic pain. Among these opioid and non-steroidal anti-inflammatory drugs stand in the first line of therapy, however, prolonged administration of these substance is generally challenged by development of analgesic tolerance in patients. Therefore, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. In this respect, Taurine, a free amino acid, has been shown to induce significant analgesia at both spinal and peripheral levels through cholinergic mechanisms. In the present study, we used hot-plate analgesic test to investigate how taurine either as a single medication or in combination with sodium salicylate and morphine may affect both acute response to pain and development of analgesic tolerance. The effect of taurine was also tested on morphine withdrawal syndrome. Hyoscine butyl bromide was used to assess the role of muscarinic receptors in taurine-mediated effects. Finally, biochemical assay was done to reveal how the activity of brain acetylcholinesterase may change in relation with muscarinic receptor activity. Results indicated that acute administration of taurine-sodium salicylate combination causes more potent analgesia compared to the use of tau (but not SS alone) and this seems to be mediated via activity of muscarinic receptors in peripheral nervous system. Furthermore, the effect of this combination undergoes less analgesic tolerance during time. Combination of taurine and morphine is an effective strategy to attenuate both morphine analgesic tolerance and dependence and this also seems to depend on activity of muscarinic receptors, however through differential cellular mechanisms.

The genetic factors contributing to the risk of cleft lip-cleft palate and their clinical utility.

Cleft lip and cleft palate (CL/P) are among the most common congenital malformations in neonates and have syndromic or nonsyndromic forms. Nonsyndromic forms of malformation are being reported to be associated with chromosomal DNA modification by teratogenic exposure and to complex genetic contributions of multiple genes. Syndromic forms are shown to be related to chromosomal aberrations or monogenic diseases. There is a growing body of data illustrating the association of several genes with risk of developing this malformation, including genetic defects in T-box transcription factor-22 (TBX22), interferon regulatory factor-6 (IRF6), and poliovirus receptor-like-1 (PVRL1), responsible for X-linked cleft palate, cleft lip/palate-ectodermal dysplasia syndrome, and Van der Woude and popliteal pterygium syndromes, respectively. Genetic variants in MTR, PCYT1A, ASS1, SLC 25A13, GSTM1, GSTT1, SUMO1 BHMT1, and BHMT2 are being reported to be linked with CL/P risk. The etiology of nonsyndromic CLP is still remained to be unknown, although mutations in candidate genes have been found. Here, we provide an overview about the potential variants to be associated with CL/P for identification of the relative risk of CLP with respect to the basis of genetic background and environmental factors (e.g., dietary factors, alcohol use).

PPARγ activation improved learning and memory and attenuated oxidative stress in the hippocampus and cortex of aged rats.

Oxidative stress has an important role in brain aging and its consequences include cognitive decline and physiological disorders. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been suggested to decrease oxidative stress. In the current research, the effect of PPARγ activation by pioglitazone(Pio) on learning, memory and oxidative stress was evaluated in aged rats. The rats were divided into five groups. In the Control group, vehicle (saline-diluted dimethyl sulfoxide (DMSO)) and saline were injected instead of Pio and scopolamine (Sco), respectively. In the Sco group, the vehicle was injected instead of Pio and the rats were injected by Sco 30 min before the behavioral tests. In the Sco-Pio 10, Sco-Pio 20, and Sco-Pio 30 groups, 10, 20, and 30 mg/kg Pio was injected and finally, the rats were injected with Sco 30 min before the behavioral tests. Morris water mater maze(MWM) and passive avoidance(PA) tests were carried out, and finally, the hippocampus and cortex were removed for biochemical assessments. The results showed that the highest dose of Pio decreased the traveling time and distance during 5 days of learning and increased the time and distance in the target area on the probe day of MWM. The highest dose of Pio also prolonged the delay time for entering the dark and total time spent in the light while decreasing the total time spent in and the number of entries into the dark in PA test. Pio especially, in the medium and highest doses, decreased MDA while increasing thiol, superoxide dismutase, and catalase in the hippocampus and cortex. It is concluded that PPARγ activation by Pio as an agonist improved learning and memory in aged rats probably by attenuating oxidative stress in the hippocampus and cortex.

Neural correlates and potential targets for the contribution of orexin to addiction in cortical and subcortical areas.

The orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. This variety of functions can be described by a united function for orexins in translating states of heightened motivation, for example during physiological requirement states or following exposure to reward opportunities, into planned goal-directed behaviors. An addicted state is characterized by robust activation of orexin neurons from the environment, which triggers downstream circuits to facilitate behavior directed towards obtaining the drug. Two orexin receptors 1 (OX1R) and 2 (OX2R) are widely distributed in the brain. Here, we will introduce and describe the cortical and subcortical brain areas involved in addictive-like behaviors and the impact of orexin on addiction.

The Role of 5-HT1A Receptors and Neuronal Nitric Oxide Synthase in a Seizur Induced Kindling Model in Rats.

BACKGROUND AND OBJECTIVE: Dentate gyrus (DG) has a high density of 5-HT1A receptors. It has neural nitric oxide synthase (nNOS), which is involved in neural excitability. The purpose of this study was to investigate the role of 5-HT1A receptors and nNOS of DG in perforant path kindling model of epilepsy. MATERIAL AND METHODS: To achieve this purpose, a receptor antagonist (WAY100635, 0.1 mg/kg, intracerebroventricular, i.c.v) and neuronal nitric oxide synthase inhibitor (7-NI, 15 mg/kg, intraperitoneal, i.p.) were injected during kindling aquisition. Adult male Wistar rats (280 ± 20 g) were used in this study Animals were kindled through the daily administration of brief electrical stimulations (10 stimulations per day) to the perforant pathway. Field potential recordings were performed for 20 min in DG beforehand. Additionally, glial fibrillary acidic protein (GFAP) expression rate in the DG was determined using immunohistochemistry as a highly specific marker for glia. RESULTS: WAY100635 (0.1 mg/kg) significantly attenuated the kindling threshold compared to the kindled + vehicle group (P < 0.001). The co-administration of WAY100635 with 7-NI, exerted a significant anticonvulsive effect. Furthermore, the slope of field Excitatory Post Synaptic Potentials (fEPSP) at the end of 10 days in the kindled + 7-NI + WAY100635 group was significantly lower than in the kindled + vehicle group (P < 0.001). Furthermore, immunohistochemistry showed that the density of GAFP+ cells in the kindled + 7-NI + WAY100635 group was significantly higher than in the kindled + vehicle group (P < 0.001). CONCLUSION: Our data demonstrate that antagonists of 5-HT1A receptors have proconvulsive effects and that astrocyte cells are involved in this process, while nNOS has an inhibitory effect on neuronal excitability.

Addiction-induced plasticity in underlying neural circuits.

Synaptic plasticity, the substrate for learning, has been established in neural reward circuits and might involve in the learning of addictive behaviors. Long-term exposure to addictive drugs caused long-lasting memories of the drug experience. The main clinical problem that involves the persistence of addiction is a relapse that is resulted from the exposure to cues of the drug experience. Persistent forms of synaptic plasticity are associated with some of the behavioral effects of addictive drugs. Here, we present the underlying mechanisms of plasticity induced by different brain reward circuitry. Therefore, we focus on the collected evidence that drugs of abuse can disturb synaptic plasticity in the main brain circuits of addiction. Prevention of these drug-induced synaptic modifications may be helpful in the treatment of this problem of society.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats.

AIM OF THE STUDY: In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats. MATERIALS AND METHODS: Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection. RESULTS: Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain. CONCLUSIONS: Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor.

OBJECTIVES: Phytocannabinoids beyond the Δ9-tetrahy-drocannabinol have shown anticonvulsive effects. Also, alkylamides from Echinacea purpurea have been proved as cannabinomimetics. We examined the effect of the hydroalcoholic root extract of E. purpurea on pentylenetetrazol (PTZ)-induced tonic-clonic seizures and kindling model of epileptogenesis and the involvement of CB2 receptors as the mediator of this effect. METHODS: Male Wistar rats (200 ± 20 g) were used. Single intraperitoneal (i.p.) injection of PTZ (80 mg/kg) was used to induce tonic-clonic seizures. The kindling model of epileptogenesis was induced by daily injections of PTZ (37 mg/kg; i.p. for 15 days). Latency and duration of the stages were monitored for analysis. The hydroalcoholic root extract of E. purpurea was injected (i.p.) 20 min before seizure induction at the doses of 10, 50, 100 and 200 mg/kg. CB2 receptor antagonist SR144528 was injected (0.1 mg/kg; i.p.) 20 min before the Echinacea injection. RESULTS: In the tonic-clonic model, pretreatment with E. purpurea at the doses of 100 and 200 mg/kg significantly increased latencies to S2-S6, while it significantly decreased S6 duration and mortality rate. SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly prevented the effects of the extract on S4-S6 latencies. In the kindling model, E. purpurea at the doses of 100 and 200 mg/kg significantly delayed epileptogenesis and decreased mortality rate, while SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly blocked this effect of the extract. CONCLUSIONS: These findings revealed the anticonvulsive and antiepileptogenesis effects of the E. purpurea root extract, which can be mediated by CB2 receptors.

Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity.

Cyclooxygenase (COX) plays a critical role in synaptic plasticity. Therefore, long-term administration of acetylsalicylic acid (ASA) and its main metabolite, salicylate, as a COX inhibitor may impair synaptic plasticity and subsequently memory formation. Although different studies have tried to explain the effects of ASA and sodium salicylate (SS) on learning and memory, the results are contradictory and the mechanisms are not exactly known. The present study was designed to investigate the effects of long-term low-dose (equivalent to prophylactic dose) and short-term high-dose (equivalent to analgesic dose) administration of ASA and SS respectively, on spatial learning and memory and hippocampal synaptic plasticity. Animals were treated with a low dose of ASA (2 mg/ml solvated in drinking water, 6 weeks) or a high dose of SS, a metabolite of ASA, (300 mg/kg, 3 days, twice-daily, i.p). Spatial memory and synaptic plasticity were assessed by water maze performance and in vivo field potential recording from CA1, respectively. Animals treated with ASA but not SS showed a significant increase in escape latency and distance moved. Furthermore, in the probe test, animals treated with both drugs spent less time in the target quadrant zone. The paired-pulse ratio (PPR) at 20-ms inter-pulse intervals (IPI) as an index of short-term plasticity in both treated groups was significantly higher than of the control group. Interestingly, none of the administered drugs affected long-term potentiation (LTP). These data suggested that long-term inhibition of COX disrupted memory acquisition and retrieval. Interestingly, cognitive impairments happened along with short-term but not long-term synaptic plasticity disturbance.

Effects of aqueous extract of Hyssopus officinalis on seizures induced by pentylenetetrazole and hippocampus mRNA level of iNOS in rats.

OBJECTIVE: We examined the effectiveness of Hyssopus officinalis (hyssop) aqueous extract on pentylenetetrazole (PTZ)-induced acute seizures and the hippocampus iNOS (inducible nitric oxide synthases) gene expression as a potential mediator of the effects. MATERIALS AND METHODS: Adult male Wistar rats were used. Tonic-clonic seizures were induced by intraperitoneal (i.p.) injection of PTZ (80 mg/kg) then behavioral profile during 30 min was characterized by stages defined as seizure scores. Hyssop extract were prepared and injected (i.p.) 15 minutes before the seizure induction at three doses 50, 100 and 200 mg/kg. Experimental groups were as below: (1) saline+PTZ (n=5); (2) Hyssop 50mg/kg+PTZ (n=10); (3) Hyssop 100mg/kg+PTZ (n=10); (4) Hyssop 200 mg/kg+PTZ (n=8). Two hours after the experimental procedure, all animals were decapitated, brain was removed and right hippocampus was quickly dissected. After total RNA extraction and cDNA synthesis quantitative PCR were used for gene expression of iNOS. RESULTS: Our results showed significant increase (p<0.05) in latency to reach stages 5 and 6 of tonic-clonic seizure at dose 100 mg/kg hyssop extract. In addition, this dose caused significant increase in the gene expression of iNOS in the hippocampus. CONCLUSION: It seems a 100 mg/kg dose of hyssop extract might have anticonvulsant effects. However, these anticonvulsant effects might not occur through the iNOS gene expression.

Long-term potentiation enhancing effect of epileptic insult in the CA1 area is dependent on prior-application of primed-burst stimulation.

Herein field recordings were utilized to test the effects of a transient period of pentylenetetrazol (PTZ) treatment on theta-burst long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses as well as RT-PCR was used to investigate the effects of the combination of the pharmacological treatment and the theta-burst LTP induction on the expression of NMDA subunit mRNA in hippocampal slices. The slope of field excitatory postsynaptic potential (fEPSP) was unaffected while the population spike amplitude and area were increased by a transient period of PTZ treatment (3 mM, 10 min). After a theta burst, a brief PTZ exposure can lead to an enhancement of LTP as documented by fEPSP recording. The effect can be blocked by a selective NMDA receptor antagonist DL-AP5. An increase in the expression of GluN2B and GluN2A subunit mRNAs was also shown due to the combined treatment. The results indicate that the combined treatment increases the degree of NMDA-dependent LTP and are in accord with literature data on the subunit alterations of the hippocampal NMDA receptors. Moreover, our experimental paradigm can be used as a new approach to study the relevance of LTP-like phenomena and epileptic mechanisms.

Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons.

The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti-nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity.

Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats.

Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. It is known that greater regularity in a complex system could indicate uncoupling of the system's components. The present study aimed to test the hypothesis that impaired responsiveness of cardiac pacemaker to autonomic nervous system may lead to uncoupling of the cardiovascular regulatory mechanisms during systemic inflammation. Systemic inflammation was induced by intraperitoneal injection of endotoxin (lipopolysaccharide, 1 mg/kg) in rats. Cardiovascular signals were recorded in conscious animals using a telemetric system. Heart rate dynamics was analyzed using Poincaré plot, and cardiac cycle regularity was assessed by sample entropy analysis. Spontaneously beating atria were isolated, and chronotropic responsiveness to adrenergic and cholinergic stimulation was assessed using standard organ bath. Sample entropy decreased significantly 4 h after endotoxin injection in conscious rats. Vagal modulation of cardiac cycle (as assessed by Poincaré plot) also exhibited a significant reduction in endotoxemic rats. Acute endotoxin challenge was associated with a significant hyporesponsiveness of isolated spontaneously beating atria to cholinergic stimulation. The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin-treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation.