Does selective destruction of the vagal afferent inflow facilitate or reduce the development of fever?

Secondary afferent neurons in the (i) rostral commissural nucleus tractus solitarii (NTS) or (ii) caudal NTS in rats were destroyed with kainate. Lipopolysaccharide (3 mg/kg i.p.) in (i) led to a rise in colonic temperature (Tc) and random changes in the tail-flick reflex (TFR) latency. In (ii), lipopolysaccharide was not accompanied by fever, but induced a sustained hypoalgesia. In subdiaphragmatically vagotomized rats (iii) lipopolysaccharide failed to change Tc and TFR. Structural alterations in NTS and other brainstem nuclei in (iii) were electron microscopically visualized. The changes in the responses to lipopolysaccharide in the three groups may be related to degenerative events in the brainstem nuclei

Capsaicin-sensitive area in the ventral surface of the rat medulla

Capsaicin sensitive structures were found near the ventral surface of the medulla, at the exit of hypoglossal nerve roots in acute experiments on rats. Injection of 5-50 nl 0.01% capsaicin to the rostral region of the capsaicin-sensitive area was accompanied by the increase of arterial pressure and heart rate while injection to the caudal region provoked the decrease of these parameters. By the end of the 2nd week, rostral and caudal ventrolateral medulla showed asymmetric distribution of NADPH-d-positive cells, suggesting involvement of nitric oxide in the neurochemical rearrangements within the brainstem

Are the capsaicin-sensitive structures of ventral medulla involved in the temperature response to endotoxin in rats?

In chronic experiments on rats pretreated with bilateral microinjection of 25 nl 1% capsaicin to the caudal ventrolateral medulla under ketamine-xylazine-acepromazine anesthesia, an enhancement of the temperature response to intraperitoneal application of 3 μg/kg E. coli lipopolysaccharide as compared to animals who received vehicle to the caudal ventrolateral medulla was found. This is indicative of the involvement of the capsaicin-sensitive bulbar structures in thermoregulatory processes during endotoxemi

Role of the dorsomedial and ventrolateral medulla in the regulation of pain sensitivity in the endotoxemic organism

This study compared the physiological and morphological effects of vagus nerve transection to the chemical destruction of its central projections. Subdiaphragmatic vagotomy disturbed nociception and body temperature regulation during endotoxemia. Micro-injections of glutamate or vanilloid receptor agonists in toxic concentrations into the nucleus tractus solitarii (NTS) and the caudal ventrolateral medulla (CVLM) lead to the similar effect. Both types of intervention – vagotomy, and central microinjections – were followed by structural alterations in NTS and CVLM, which was visualized by the electron microscopy. The results suggest involvement of NTS and CVLM neurons in the regulation of nociceptive threshold during the acute phase reaction to endotoxins

EFFECT OF KETAMINE ON THE EXCITABILITY OF DORSAL RAPHE NEURONS

The non-competitive NMDA antagonist ketamine is an old drug that traditionally has been used as an anesthetic with unique properties dissociative anesthesia. More recently, it has been repeatedly shown that a single dose of ketamine is able to quickly relieve major depressive symptoms (including suicidal thoughts) in severely affected patients. This effect appears to be transient (the effect lasts less than one week), robust and reproducible, although several questions on its clinical use remain to be addressed. We therefore propose to test the hypothesis that ketamine and/or its metabolites acutely enhance serotoninergic (5HT) transmission by either modulating afferent synaptic transmission onto serotonin neurons of the dorsal raphe or changing their intrinsic excitability. We set out to directly test this hypothesis using whole-cell patch clamp recordings in brainstem slices from juvenile (P21-P30) rats. We used a conventional bicarbonate-based Ringer and a KCl-based intrapipette solution. This allowed us to discriminate presumed 5HT from non-5HT neurons. 5HT neurons were identified as cells generating an outward current > 30 pA in voltage clamp at -60 mV during superfusion of 100 nM of the 5HT1A agonist 8-OH-DPAT (calculated EK was = -93 mV). We first tested Ketamine’s effect on sEPSCs by using 10µM gabazine and 1 µM CGP55845. We found that 10 µM racemic ketamine increase the AMPA EPSCs in terms of amplitude and frequency in the half of 5HT recorded neurons (N total = 18).This effect was not observed in the case of non-5HT recorded neurons (N = 6). The same effect was observed by the racemate of its metabolite 2,6 hydroxynorketamine (HNK). In current clamp recordings, both ketamine and HNK increased the firing of 5HT neurons in whole-cell recordings when AMPA, NMDA, GABAA and GABAB receptors were blocked. In conclusion, ketamine and its metabolite HNK robustly enhance AMPA EPSCs onto a subgroup of pharmacologically identified 5HT neurons. It remains to be determined whether this subgroup projects to specific targets, given that subpopulations of DR 5HT neurons have been shown to have specific and non-overlapping projections (Ren et al., Cell 175, 472-487, 2018)

Effet de l'amphétamine sur les neurones de l'aire tegmental ventrale des rats

Amphetamine (AMPH) is an addictive psychostimulant targeting the dopamine system. But its effect on the neurons of this system is still unclear. Here, we studied the effects of amphetamine on the firing rate of dopamine (DA) and non-dopamine neurons of the ventral tegmental area, a key structure in the reward circuit, of awake rats. Using wireless neural probes to investigate the electrical activity of the neurons in freely moving rats, we observed that acute injection of AMPH is followed by a decrease of firing rate of most of registered DA units. The remaining population of DA units either increased or did not significantly change their activity. At the same time, AMPH stimulated the locomotor activity and induced a stereotypic behavior. (FR) L'amphétamine (AMPH) est un psychostimulant addictif visant le système dopaminergique. Cependant, ses effets sur les neurones de ce système sont nébuleux. Nous étudions les effets de l'AMPH sur la fréquence de décharge des neurones dopaminergiques et non dopaminergique de l'aire tegmentale ventrale, une structure clef du circuit de la récompense, de rats éveillés. En utilisant un système d'électrodes sans fil pour étudier l'activité électrique des neurones de rats libres de leurs mouvements, nous avons observer que l'injection aiguë d'AMPH est suivie d'une diminution de la fréquence de décharge de la majorité des neurones dopaminergiques enregistrés. Le reste des neurones dopaminergique présentaient une activité augmentée ou qui ne subissait pas de changement significatif. En même temps, l'AMPh stimule l'activité locomotrice et induit un comportement stéréotypé

Ketamine selectively enhances AMPA neurotransmission onto a subgroup of identified serotoninergic neurons of the rat dorsal raphe

It has been shown repeatedly that the old drug ketamine is able to induce a rapid (within hours to days) antidepressant effect in otherwise treatment-resistant depressive patients. Despite many preclinical studies, the exact mechanism and precise site of action of ketamine is a matter of debate. Because an hypoactivity of brain dorsal raphe nucleus (DRN) serotonergic neurons has been strongly associated with the pathophysiology of depressive disorders, we tested the hypothesis that ketamine may rapidly enhance the activity of these neurons in a brain slice model. In a first step, we examined whether the drug and one of its possibly important metabolites, hydroxynorketamine (HNK) may alter the excitatory synaptic drive onto these neurons

Effect of electrode morphology on the frquency spectrum of local field potentials in the rat ventral tegmental area

Implantable microelectrode arrays for chronic neural recordings receive an attention by a number of research groups investigating ensemble spike activity and local field potentials. Due to that interest, various types of arrays have been developed. In the present study we compared the LFP signals recorded from the ventral tegmental area (VTA) of freely moving male Wistar rats using the two types of arrays: microelectrode microwire arrays, and silicon-based planar probes. Our choice was based on the difference in the geometry of these two array types. The microwire electrodes have a three-dimensional recording surface around their tips. This allows them to receive the signal from the diverse brain regions. In contrast, the electrode contacts of the planar probe are patterned on one side of the silicon shaft (often named top-side, in contrast to the other, back-side). This configuration mainly allows registering the signal from the top-side of the shaft, while the signal from the back-side gets attenuated. Microwire arrays used in this study consisted of 8 sharpened platinum iridium wires, coated with parylene-C, except for the tip allowing the recording (Alpha Omega GmbH, Israel). Planar probes (ATLAS Neuroengineering, Belgium) had 16 iridium oxide electrode contacts implemented in the 4 silicon shafts, 4 electrode contacts per shaft. The recording was performed using a wireless system (W-Basic-System, Multi Channel Systems MCS GmbH, Germany). The probes were implanted in two orientations: top-side facing the midline, and top-side facing the lateral plane of the brain. For verification of the recording area the rats were anaesthetized and perfused with 4% paraformaldehyde containing 1 % of Gadovist. The brains were removed from the skull and placed in Fomblin for MRI scanning (9.4 Tesla MRI DirectDrive VNMRS, Agilent Technologies, Palo Alto, CA). Frequency spectra of LFP recorded by the microwire arrays, and by the planar probes oriented to the lateral plane of the brain contained a prominent peak in the theta range (6-8 Hz). In contrast, the signal registered using the planar probes oriented to the midline lacked such a peak and was more heterogeneous. We attribute the observed difference to the geometry of the recording platforms

Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus

Nitric oxide is thought to control transmitter release and neuronal activity in the spinal dorsal horn and the spinal trigeminal nucleus, where nociceptive information from extra- and intracranial tissues is processed. Extracellular impulse activity was recorded from neurons in the rat spinal trigeminal nucleus with afferent input from the cranial dura mater. In contrast to the inactive isomer D-NAME, infusion of the nitric oxide synthase inhibitor L-NAME (20 mg/kg) significantly reduced neuronal activity and increased systemic blood pressure. It is concluded that nitric oxide production contributes to the ongoing activity of sensitized neurons in the spinal trigeminal nucleus. The results suggest that nitric oxide may be involved in the generation and maintenance of primary headaches such as migraine