Neonatal Sepsis Alters the Excitability of Regular Spiking Cells in the Nucleus of the Solitary Tract in Rats

OBJECTIVE: Sepsis is a leading cause of mortality and morbidity in infants. Although the measures of autonomic dysfunction (e.g. reduced heart rate variability) predict mortality in sepsis, the mechanism of sepsis-induced autonomic dysfunction has remained elusive. The nucleus of the solitary tract hjh(NTS) is a vital structure for the integrated autonomic response to physiological challenges. In the present study we hypothesized that sepsis alters the excitability of NTS neurons in a rat model of neonatal sepsis (14-day old rats). METHODS AND RESULTS: Sepsis was induced by intraperitoneal injection of cecal slurry (CS) in rat neonates. The presence of autonomic dysfunction was confirmed by observing a significant reduction in both short-term and long-term heart rate variably following CS injection. We investigated the effect of polymicrobial sepsis on the electrophysiological properties of the medial NTS neurons using a whole cell patch clamp recording. Our results showed that the resting membrane potential in regular spiking neurons was significantly less polarized in the septic group (-37.6 ± 1.76 mv) when compared with the control group (-54.7 ± 1.73 mv, P < 0.001). The number of spontaneous action potentials in the septic group, was also significantly higher than the control group (P < 0.05). In addition, the frequency and amplitude of the spontaneous excitatory post synaptic potentials (EPSPs) was significantly higher in neurons recorded in the septic group (P < 0.001). Interestingly, regular spiking cells in the CS group exhibited a rebound action potential following hyperpolarization. Injection of depolarizing currents was associated with lower first spike latency and changes in rise slope of action potential (P < 0.001). CONCLUSIONS: We showed that polymicrobial sepsis increases the excitability of regular spiking cells in the medial NTS. These alterations can potentially affect neural coding and thus may contribute to an abnormal homeostatic or allostatic physiological response to sepsis and systemic inflammation

Postnatal development changes in excitatory synaptic activity in the rat locus coeruleus neurons

Glutamatergic synapses are shown to mature during activity and development. In order to further explore how glutamate can change the excitability of noradrenergic neurons of locus coeruleus (LC) and to better understand the involvement of Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors complements across the LC, we investigated developmental changes in their activity during first postnatal weeks. Spontaneous and evoked excitatory postsynaptic currents (sEPSC and eEPSCs) were recorded in neurons of LC slices from 7, 14 and 21 days old rats using the whole cell patch clamp method. Also, the AMPA/NMDA current ratio (A/N) was measured. A pronounced AMPAR and NMDAR components mediated involvement in synaptic transmission were seen from the first postnatal week. Over this period of development, we have demonstrated that AMPA sEPSCs show an increase in frequency without major changes in their amplitude, while NMDA sEPSCs show an increase in frequency with a major change in amplitude. Neither the probability of release nor the AMPA/NMDA ratio was found to change significantly with age. It is concluded that NMDAR activity as well as AMPAR activity may be involved in coerulear excitability and modulatory effect during postnatal development. © 201

Inhibition of orexin receptor 1 contributes to the development of morphine dependence via attenuation of cAMP response element-binding protein and phospholipase Cβ3

Noradrenergic neurons of the locus coeruleus (LC) receive projection from hypothalamus orexinergic neurons and express orexin 1 receptor (Orx1). Orx in the locus coeruleus nucleus is involved in the development of morphine dependence. The downstream signaling of Orx contribution to the development of morphine dependence in LC neurons of morphine-dependent rats was studied. Therefore, we evaluated cyclic adenosine monophosphate (cAMP), cAMP response element-binding protein (CREB) and phospholipase Cβ3 (PLCβ3) levels by the application of immunohistochemistry. Results showed that cAMP, CREB and PLCβ3 levels were suppressed by the application of SB-334867 (as a selective Orx1 antagonist) in morphine-dependent rats. Our results unraveled that Orx1 blockade is involved in the development of morphine dependency through diminution of a variety of intracellular events including the cAMP, CREB and PLCβ3 levels in morphine-dependent rats. Furthermore, the Orx1 blockade could decrease the percentage of tyrosine hydroxylase (TH)+/CREB+ and TH+/PLCβ3+ neurons in LC of morphine-treated rats. It is concluded that the activation of Orx1 in LC nucleus might be involved in some intracellular changes in morphine dependent rats. © 202

Orexin type-1 receptor inhibition in the rat lateral paragigantocellularis nucleus attenuates development of morphine dependence

Orexin neuropeptides are involved in opiate-induced physical dependence and expression of withdrawal signs following drug abstinence. Orexin type-1 receptors (OXR1) are expressed throughout the rostroventrolateral medulla (RVLM), particularly in the lateral paragigantocellularis (LPGi) nucleus. The present study examined whether blocking OXR1 in LPGi region could affect the development of morphine dependence and so behavioral manifestations induced by morphine withdrawal in rats. Male Wistar rats weighing 250�300 g were used. In order to induce drug dependence, morphine was injected subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. Animals were divided into experimental groups in which the orexin type-1 receptor antagonist, SB-334867 (0.2 μl, 3 mM), or its vehicle were injected into the LPGi nucleus for 7 days before each morphine injection. On day 8, naloxone (2.5 mg/kg, i.p.) was administered and morphine withdrawal behaviors were monitored for 25 min. Our results indicated that the inhibition of OXR1 in LPGi nucleus significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. © 2020 Elsevier B.V

Central blockade of orexin type 1 receptors reduces naloxone induced activation of locus coeruleus neurons in morphine dependent rats

Orexin neuropeptides are implicated in the expression of morphine dependence. Locus coeruleus (LC) nucleus is an important brain area involving in the development of withdrawal signs of morphine and contains high expression of orexin type 1 receptors (OX1Rs). Despite extensive considerations, effects of immediate inhibition of OX1Rs by a single dose administration of SB-334867 prior to the naloxone-induced activation of LC neurons remains unknown. Therefore, we examined the direct effects of OX1Rs acute blockade on the neuronal activity of the morphine-dependent rats which underwent naloxone administration. Adult male rats underwent subcutaneous administration of 10 mg/kg morphine (two times/day) for a ten-day period. On the last day of experiment, intra-cerebroventricular administration of 10 μg/μl antagonist of OX1Rs, SB-334867, was performed just before intra-peritoneal injection of 2 mg/kg naloxone. Thereafter, in vivo extracellular single unit recording was employed to evaluate the electrical activity of LC neuronal cells. The outcomes demonstrated that morphine tolerance developed following ten-day of injection. Then, naloxone administration causes hyperactivity of LC neuronal cells, whereas a single dose administration of SB-334867 prior to naloxone prevented the enhanced activity of neurons upon morphine withdrawal. Our findings indicate that increased response of LC neuronal cells to applied naloxone could be prevented by the acute inhibition of the OX1Rs just before the naloxone treatment. © 2021 Elsevier B.V

Effect of Migraine on Economic Status and Quality of Life of Patients

Migraine as one of the most common types of headaches with high intensity and prevalence, affects life significantly. This study was devised to determine the effects of migraine on economic status and life quality of Iranian surffcres.&quot;n&amp;quot;Pain database questionnaire&amp;quot;, prepared by the International Association for the Study of Pain (IASP) in the year 1995, was translated to Farsi. Then we modified it regaiding cultural, geographical and social characteristics of Iran. 65 patients (55 women and 10 men) were recruited form neurology clinic consultants. Those patients who met the International Headache Society. (IHS) criteria for migraine, were interviewed using IASP questionnaire. Pain effects on sleep, marital life, social, recreational and sexual activities, quality and quantity of drug consumption as well as using paraclinic procedures were considered.&quot;nSignificant decrease in sleep duration was seen during pain (7.4 &amp;plusmn; 1.9 h) compared to pain-free conditions (6 &amp;plusmn; 3.7 h) (P &amp;lt; 0.001). The effects of pain on marital life, social, recrealtional and sexual activities during pain were compared with pain-free conditions based on a zero to ten ranking schedule,. Wilcoxone test showed statistically significant (P &amp;lt; 0.02) differences.&quot;nWe concluded that the economic effect of migraine and its impact on patients&apos; quality of life are significant and should be considered in health planning and disease managemen

The effect of methylprednisolone on spatial learning and memory in adult male rats using an experimental model of Alzheimer's disease

Background: The methylprednisolone (MP) is a synthetic glucocorticoid steroid initially developed for its enhanced anti-inflammatory activity. The present study aimed to examine the effect of MP on the spatial learning and memory in an experimental model of Alzheimer's disease in rats. Materials and Methods: Male rats were allocated into five groups: control group lesion group which received electrically-induced lesion (0.5 mA, 3s) in the nucleus basalis magnocellularis (NBM) to create Alzheimer's model sham group (the electrode was impaled into the NBM with no lesion) MP group (lesion+30 mg/kg MP) and saline group (lesion NBM + 0.2 mL saline). After one week, the rats were trained to perform the Y-maze task for five days. The animals were tested for spatial memory one month later. Results: Results showed that the bilateral lesion of NBM impaired the spatial learning compared to the control group (

Direct Facilitatory Role of Paragigantocellularis Neurons in Opiate Withdrawal-Induced Hyperactivity of Rat Locus Coeruleus Neurons: An In Vitro Study.

Studies have shown that following opiate withdrawal, the spontaneous discharge rate of locus coeruleus (LC) neurons remarkably increases. Combination of intrinsic mechanisms with extrinsic excitatory modulations mediates the withdrawal-induced hyperactivity of LC neurons. The nucleus paragigantocellularis (PGi) provides the main excitatory inputs to LC and plays a pivotal role in opiate withdrawal. In the present study the direct facilitatory role of PGi on opiate withdrawal-induced hyperactivity of LC neurons was investigated using a newly developed brain slice, containing both LC and PGi. HRP retrograde neuronal tracing was used to verify the existence of both LC and PGi neurons in the developed slice. The spontaneous discharge rate (SDR), resting membrane potential (RMP) and spontaneous excitatory post-synaptic currents (sEPSCs) were recorded in LC neurons using whole cell patch clamp recording. Results showed that the net SDR and the net RMP of LC neurons in slices containing both LC and PGi neurons are significantly higher than slices lacking intact (uncut) PGi inputs. Also, the frequency of sEPSCs in those LC neurons receiving PGi inputs significantly increased compared to the slices containing no intact PGi inputs. Altogether, our results propose that increase in PGi-mediated excitatory transmission might facilitate the opiate withdrawal-induced hyperactivity of LC neurons

Photomicrograph of a typical OTH brain section.

<p>Photomicrograph shows retrogradely labeled PGi neurons in the rostra1 ventral medulla of a rat which received intra-LC microinjection of HRP (A, left side). Insets illustrate high magnification of LC and PGi regions. Following a single pulse electrical stimulation of PGi, an evoked EPSC was recorded from LC neuron (A, right side). The schematic representation of cutting stage orientation for preparation of OTH brain slices. The tissue block containing LC and PGi were mounted on the wedge-shaped agarose gel with an angle of 50°. The red dashed line shows the cutting direction (B). Picture shows the blade direction and the way through which tissue block was mounted on cutting stage (C). OTH: oblique to horizontal; LC: locus coeruleus; PGi: paragigantocellularis; HRP: horseradish peroxidase; EPSC: excitatory post synaptic current.</p