Effects of the Nucleus Raphe Magnus Stimulation on Nociceptive Neurons of the Rat Caudal Ventrolateral Medulla in Normal Conditions and after Intestinal Inflammation

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Abstract

The nucleus raphe magnus (RMg) is a key structure of the endogenous antinociceptive system, the activity of which is regulated by serotonin 5-HT1A receptors. A recipient of the RMg descending projections is the caudal ventrolateral medulla (cVLM) - the first supraspinal center for processing visceral and somatic pain signals. Intestinal pathology is known to cause persistent functional alterations in the RMg, which are associated with the development of visceral and somatic hyperalgesia. Presumably, a consequence of the alterations may be changes in the RMg modulating effects on cVLM nociceptive activity. However, the specific neuronal and molecular mechanisms underlying such influence in normal conditions, as well as their changes in pathology remain unexplored. The aim of our neurophysiological experiments performed in anesthetized adult male Wistar rats was to compare the effects of RMg electrical stimulation on the activity of cVLM neurons evoked by visceral (colorectal distension, CRD) and somatic (tail squeezing) pain stimulations that occur in normal conditions and after intestinal inflammation (colitis), with an assessment of the contribution to these processes of the supraspinal 5-HT1A receptor activation with intracerebroventricular buspirone. It has been shown that RMg can exert an inhibitory effect on both non-selective and differential responses of the cVLM neurons to diverse pain stimuli, causing a weakening of excitatory neuronal ractions and an increase in inhibitory responses to CRD while inhibiting both types of reactions to tail squeezing. The RMg-evoked suppression of nociceptive excitation in the caudal medullary neurons is enhanced under activation of supraspinal 5-HT1A receptors by buspirone. It has been established that in postcolitis period the RMg inhibitory action on different populations of cVLM neurons are significantly diminished, indicating an impairment of the nucleus’ antinociceptive function. In these conditions, the RMg descending influence loses its 5-HT1A receptor-dependent component. The changes described may contribute to the supraspinal mechanisms underlying pathogenesis of post-inflammatory abdominal pain and comorbid somatic hyperalgesia.

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About the authors

B. M. Sushkevich

Pavlov Institute of Physiology of the Russian Academy of Sciences

Author for correspondence.
Email: lyubashinaoa@infran.ru
Russian Federation, Saint Petersburg

I. B. Sivachenko

Pavlov Institute of Physiology of the Russian Academy of Sciences

Email: lyubashinaoa@infran.ru
Russian Federation, Saint Petersburg

O. A. Lyubashina

Pavlov Institute of Physiology of the Russian Academy of Sciences

Email: lyubashinaoa@infran.ru
Russian Federation, Saint Petersburg

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2. Fig. 1. Localisation of neuron registration sites in the caudal ventrolateral reticular area of the medulla oblongata in healthy (dark symbols) and colitis-transfused (light symbols) rats (a) and the area of electrical stimulation of the large suture nucleus in all animals (b). In (a), each symbol corresponds to the localisation of several neurons studied. Slice diagrams are adapted from the standard atlas of the rat brain [45]

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3. Fig. 2. Examples of responses of neurons of the caudal ventrolateral reticular area of the medulla oblongata belonging to visceral (a, b), somatic (c, d) and general (e, f) nociceptive types to painful colorectal distension and squeezing of the tail. On (a - f), at the top are native recordings of impulse activity, at the bottom are the corresponding frequency histograms with a bin of 1 s. On the abscissa axis is time in seconds, on the ordinate axis is frequency of discharges (spikes/s). Horizontal segments - time of action of stimuli

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4. Fig. 3. Examples of excitatory (a, b) and inhibitory (c - f) responses of nociceptive neurons of the caudal ventrolateral reticular area of the medulla oblongata to painful colorectal distension (CRD) and tail squeeze (ST) initially (a, c, e) and after electrical stimulation of the large suture nucleus (b, d, f). On (a - f), native recordings are at the top and corresponding frequency histograms with a 1 s bin are below. On the abscissa axis is time in seconds, on the ordinate axis is frequency of discharges (spikes/s). Horizontal segments - time of action of painful stimuli. Arrow - electrical stimulation of the large suture nucleus (RMg)

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5. Fig. 4. Amplitude of responses of neurons of the caudal ventrolateral reticular area of the medulla oblongata belonging to visceral (a, b), somatic (c, d) and general (e, f) nociceptive types, to painful colorectal distension (CRD) and tail squeeze (Tail) baseline (CRD or Tail) and after pre-electrical stimulation of the large suture nucleus (RMg+CRD or RMg+Tail) in healthy (Control) and colitis-treated (Postcolitis) rats. On the ordinate axis is the response in % of the background activity level. On (a - f), the upper and lower boundaries of each rectangle are the first and third quartiles (25th and 75th percentiles, respectively), the horizontal line inside is the median (50th percentile), the ends of the segments are the 10th and 90th percentiles, and the rhombuses are individual values in the sample. Significant differences compared to the corresponding value before electrical stimulation: # - p < 0.05, ## - p < 0.01, ### - p < 0.001, paired Wilcoxon test. Significant differences compared to the corresponding value in the control group: * - p < 0.05, ** - p < 0.01, *** - p < 0.001, Mann-Whitney-Wilcoxon test

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6. Fig. 5. Effects of electrical stimulation of the great suture nucleus on excitation of neurons of the caudal ventrolateral reticular area of the medulla oblongata, evoked by painful colorectal distension (CRD) and tail squeeze (ST), after intracerebroventricular injection of the 5-HT1A receptor agonist buspirone in amounts of 0.3 and 1 μg in healthy (a, c) and colitis-treated (b, d) rats. On the abscissa axis, time before (0) and after injection in min. On the ordinate axis - response in % of the background activity level. On (a - d), the upper and lower corners of each rhombus are the first and third quartiles (25th and 75th percentiles, respectively), the horizontal line inside is the median (50th percentile), and the ends of the segments are the 10th and 90th percentiles. Significant changes compared to the corresponding baseline: # p < 0.05, ## p < 0.01 and ### p < 0.001, paired Wilcoxon test. Significant differences compared to saline injection: * p < 0.05, Mann-Whitney-Wilcoxon test. Significance of changes is given taking into account the Bonferroni correction

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