Antinociceptive effect of the agonist of 5-HT1A receptors buspirone in the model of abdominal pain in dogs.

We have demonstrated that activation of 5-HT1A receptors with buspirone promotes visceral analgesia in awake dogs. The administration of 0.035 mg/kg (i.m.) of the drug caused depression of viscero-motor (contraction of the abdominal muscles) and pressor (increase in the heart rate) responses to noxious distension of the large intestine. An increase in the dose to 0.07 and 0.14 mg/kg did not enhance the antinociceptive effect of buspirone but triggered basal tachycardia. The obtained results provide evidence of the inhibitory role of 5-HT1A receptors in modulating visceral pain sensitivity and the possibility of an exciting effect of their activation on the cardiovascular system.

Effects of Millimeter-Wave Electromagnetic Radiation on the Experimental Model of Migraine.

Effects of millimeter-wave electromagnetic radiation (40 GHz frequency, 0.01 mW power) on the spontaneous fi ring of convergent neurons of the spinal trigeminal nucleus and their responses to electrical stimulation of the dura mater were studied in neurophysiological experiments on rats. Irradiation of the area of cutaneous receptive fields of spinal trigeminal nucleus reversibly inhibited both spontaneous discharges and activity induced by electrical stimulation of the dura mater. The second and third exposures to electromagnetic radiation with an interval of 10 min were ineffective. These results suggest that suppression of neuronal excitability in the spinal trigeminal ganglion can be a mechanism of the anti-migraine effects of electromagnetic radiation observed in clinical practice.

[EFFECTS OF 5-HT3-RECEPTOR BLOCKADE ON VISCERAL NOCICEPTIVE NEURONS IN THE VENTROLATERAL RETICULAR FIELD OF THE RAT MEDULLA OBLONGATA].

The caudal ventrolateral medullary reticular formation is the first supraspinal level processing visce- ral nociceptive signals. In experiments on rats reactions of neurons of this zone to nociceptive stimulation of large intestine were examined and effects of selective blockade of 5-HT3-receptors on these reactions were assessed. According to the character or responses to nociceptive colorectal stimulation (CRS) the re- corded medullary cells were divided into three groups - excitated, inhibited and indifferent. Intravenous injection of 5-HT3-antagonist granisetron (1 and 2 mg/kg) as well as local application of the substance on medulla surface (1.25 and 2.5 nmole) suppressed dose-dependently background and evoked discharges of the reticular neurons excited by CRS but did not exert so much expressed influence on the cells inhibited by visceral nociceptive stimulation. Spike activity of the group of neurons indifferent to CRS under simi- lar conditions was of 5-HT3-independent character. The results obtained provide evidence that 5-HT3-re- ceptors mediate the facilitating effect of serotonin on the supraspinal transmission of abdominal nocicep- tive stimulus which, partly at least, is realized through selective activation of visceral nociceptive neurons of the medulla. The blocking of this mechanism may underlie the analgesic effect of 5-HT3-antagonists in a abdominal pain syndromes.

[Effect of migrepin on activity of trigeminal nucleus caudalis neurons].

Neurophysiological experiments on anesthetized rats were used to study the effects of various doses (12.5, 25, 37.5 mg/kg, i.v.) of drug composition migrepin (representing a combination of potassium-2,4-dichlorobenzoate, carbamazepine, and caffeine) on background firing of the trigeminal nucleus caudalis neurons and their responses to electrical stimulation of the dura mater. It was found that migrepin produces direct, dose-dependent inhibitory action on functional activity of TNC neurons. The results confirmed anti-migraine properties of the drug but did not exclude the necessity to study its action in clinical trials.

Involvement of the sacral parasympathetic nucleus in the innervation of the descending colon and rectum in cats.

Studies in anesthetized (urethane, 1.5 g/kg, i.p.) cats using retrograde transport of horseradish peroxidase addressed the locations and morphometric characteristics of neurons in the sacral parasympathetic nucleus of the spinal cord innervating the descending colon and rectum. Marker solution was injected beneath the serous membrane of the study areas of the large intestine. Transcardiac perfusion with fixative solution was performed 48 h later and frontal sections of the sacral segments of the spinal cord were prepared; these were processed by the Mesulam method (1978). The results showed that these areas of the large intestine receive innervation from neurons in the sacral parasympathetic nucleus located in spinal cord segments SI, SII, and SIII. The largest number of labeled cells was seen in segment SII. The neurons of this nucleus innervating the study areas of the large intestine formed two longitudinally distributed group (a lateral and a dorsal), the cells of which differed in terms of size and the orientation of the long axis. The largest number of labeled cells was seen in the lateral group.

Parasympathetic innervation of the initial segments of the large intestine in cats.

The locations and morphometric characteristics of efferent parasympathetic neurons in the dorsal motor nucleus of the vagus nerve and the cruciform parasympathetic nucleus of the spinal cord, innervating the area of the ileocecal sphincter and the ascending and transverse segments of the colon, were studied. Horseradish peroxidase solution was injected beneath the serous membranes of these parts of the intestine in urethane-anesthetized cats. After 48 h, animals were subjected to transcardiac perfusion with a fixative mixture and sections of the medulla oblongata and spinal cord were prepared and processed by the Mesulam method. The results showed that all these parts of the large intestine received parasympathetic innervation from neurons in the ventrolateral part of the dorsal motor nucleus, which were uniform in terms of their morphometric characteristics. The number of neurons of this group sending axons to the ileocecal area was greater than the number of neurons innervating the ascending colon. A second group of neurons, which were smaller cells, was located in the same part of the nucleus and innervated the transverse colon. The transverse colon also received innervation from neurons in the cruciform parasympathetic nucleus of the spinal cord.

[Participation of sacral parasympathetic nucleus in the innervation of the descending colon and the rectum in cats].

The localization and morphometric features of the preganglionic neurons of the spinal sacral parasympathetic nucleus innervating the descending colon and the rectum, were studied in cats, anesthetized with urethane (1.5 g/kg intraperitoneally) using the method of retrograde horseradish peroxidase transport. The solution of the marker was injected under the serosa of the indicated areas of the colon. After 48 h the animals were transcardially perfused with a fixative solution. Frontal sections of the sacral spinal segments were prepared and stained according to M. Mezulam's protocol (1978). It was demonstrated that the indicated areas of the colon were innervated by the neurons of the sacral parasympathetic nucleus, located in SI, SII and SIII segments of the spinal cord. The majority of the labeled cells were observed within SII segment. The neurons of this nucleus, which innervated the indicated areas of the colon, formed two longitudinal groups (lateral and dorsal ones), the cells in which differed by their sizes and longitudinal axis orientation. Most of the labeled cells were detected in the lateral group.

[Localization of the neurons of the amygdala central nucleus projecting to the hypothalamic paraventricular nucleus area].

The aim of this study was to identify, using retrograde axonal transport of horseradish peroxidase in rats, the cells, within distinct divisions of the amygdala central nucleus, innervating hypothalamic paraventricular nucleus area. The labeled cells were found in the ipsilateral amygdala central nucleus in the whole of its rostro-caudal extension. The maximal number of labeled neurons was detected in the middle third of the nucleus, corresponding to the intermediate subnucleus of the central nucleus. Single cells were located in the medial and the lateral subnuclei of the amygdala central nucleus. Labeled neurons of the intermediate subnucleus were represented by the oval cells or the cells of an indefinite form.

[Effect of GABA-positive drugs on the background and superior sagittalis sinus-electrostimulated activity of neurons in the nucleus trigeminalis caudalis of rats].

There is extensive clinical evidence for the high efficacy of GABA-ergic drugs in prophylactic and abortive treatment of migraine and cluster headache, while the mechanisms of anticephalgic drugs action are not clear, in particular, because of insufficient number of investigations on experimental headache models. In this study, the influence of baclofen (i.v.) in doses 2.5, 5, 10, and 15 mg/kg and valproate (i.v.) in doses 25, 50, 100, and 200 mg/kg on the background activity of the trigeminal nucleus caudalis neurons and that evoked by electrical stimulation of the superior sagittalis sinus was investigated in series of acute experiments on rats. It is established, that baclofen and valproate reduce both the background and evoked activity of trigeminal complex neurons in dose-dependent manner, thus determining the role of GABA-A and GABA-B receptors in realization of this effect. These results provide experimental basis for explanation of the clinical efficacy of the GABA-positive drugs in vascular headaches.

The central effects of buspirone on abdominal pain in rats.

BACKGROUND: Buspirone, a partial agonist of the 5-HT1a receptor (5-HT1a R), owing to potential antinociceptive properties may be useful in treatment of abdominal pain in IBS patients. The pain-related effects of buspirone are mediated via the 5-HT1a Rs, specifically located within the ventrolateral medulla (VLM). The most animal studies of the 5-HT1a R involvement in pain control have been carried out with somatic behavioral tests. The 5-HT1a R contribution in visceral pain transmission within the VLM is unclear. The objective of our study was to evaluate the 5-HT1a R contribution in abdominal pain transmission within the VLM. METHODS: Using animal model of abdominal pain (urethane-anaesthetized rats), based on the noxious colorectal distension (CRD) as pain stimulus we studied effects of buspirone (1.0-4.0 mg kg-1 , iv) on the CRD-induced VLM neuron and blood pressure responses as markers of abdominal pain before and after the 5-HT1a R blockade by antagonist, WAY 100,635. RESULTS: The CRD induced a significant increase in VLM neuron activity up to 201.5 ± 18.0% and depressor reactions up to 68 ± 1.8% of baseline. Buspirone (1.0-4.0 mg kg-1 , iv) resulted in an inhibition of the CRD-induced neuron responses which were changed inversely with dose increase and decreased depressor reactions directly with dose increase. These effects were antagonized by intracerebroventricular WAY 100,635. CONCLUSION: Buspirone exerts complex biphasic action on the pain-related VLM neuron activity inversely depending on dose. The final effect of buspirone depends on the functional balance between of activation the pre- and postsynaptic 5-HT1a Rs in mediating pain control networks.

[Parasympathetic innervation of proximal parts of the colon in cat].

The localization and morphometric features of efferent parasympathetic neurons of the vagus dorsal motor nucleus and of the spinal sacral parasympathetic nucleus innervating the area of ileocaecal sphincter, ascending and transverse colon, were investigated. In urethane anaesthetized cats, the solution of horseradish peroxidase was injected under the serosa of the indicated areas of colon. In 48 hours animals were transcardially perfused with a fixative solution. Sections of the medulla oblongata and the sacral spinal cord were stained using Mezulam's technique (1978). It was shown that all the areas of the colon studied received parasympathetic innervation from the neurons of the ventrolateral part of the vagus dorsal motor nucleus, which were uniform according to their morphometric characteristics. The number of neurons in this group, sending their axons to the ileocaecal area, was greater than the number of neurons, innervating ascending colon. Second group of neurons, that was represented by smaller cells, was located in the same part of the nucleus and innervated transverse colon. Transverse colon had an additional parasympathetic supply from the neurons of the spinal sacral parasympathetic nucleus.

[Structural organization of neurons of spinal ganglia innervating the colon].

The localization and morphological features of viscerosensory neurons of sacral spinal ganglia (SSG), innervating the colon, were investigated. In urethane anaesthetized cats, the solution of horseradish peroxidase was injected under the serosa of ascending and descending parts of the colon as well as of the rectum. After 48 hours animals were repeatedly anesthetized and transcardially perfused. Sections of SSG were stained according to Mezulam protocol (1978). All the regions of the colon studied were shown to receive afferent innervation from neurons of SSG SI, SII and SIII. Maximum number of the labeled cells was detected in SSG SII. The intensity of afferent innervation of the colon by the neurons of SSG was found to increase along its length in cranio-caudal direction.

Responses of neurons in the spinal nucleus of the trigeminal nerve to electrical stimulation of the dura mater of the rat brain.

The pathogenesis of migraine is based on the aseptic inflammation of dura mater tissues surrounding the large cranial vessels, such as the superior sagittal sinus. This inflammation develops in conditions of antidromic activation of sensory terminals of the trigeminal nerve and is accompanied by changes in the responses of neurons in the spinal nucleus of the trigeminal nerve to electrical stimulation of the superior sagittal sinus. However, the characteristics of the responses of these neurons to this stimulation have received virtually no study. Experiments on anesthetized rats were performed with recording of the responses of 387 neurons in the spinal nucleus of the trigeminal nerve to electrical stimulation of the superior sagittal sinus. The results showed that the responses of neurons to this stimulation was biphasic, consisting of a short initial phase with a latent period of 7-19 (11.4 +/- 0.17) msec, followed by a longer-lived discharge with a latent period of 20-50 (34.2 +/- 0.8) msec. It is suggested that the first phase reflects orthodromic activation of perivascular A(delta) and C fibers of the trigeminal nerve, while the second phase is associated with activation of meningeal C fibers with low conduction velocities and/or secondary activation of the perivascular sensory endings of the trigeminal nerve by algogenic and vasoactive substances released from them during antidromic activation. These changes seen in animal experiments may serve as an indicator of the efficacy of antimigraine agents.

Intravenous dextromethorphan/quinidine inhibits activity of dura-sensitive spinal trigeminal neurons in rats.

BACKGROUND: Migraine is a chronic neurological disorder characterized by episodes of throbbing headaches. Practically all medications currently used in migraine prophylaxis have a number of substantial disadvantages and use limitations. Therefore, the further search for principally new prophylactic antimigraine agents remains an important task. The objective of our study was to evaluate the effects of a fixed combination of dextromethorphan hydrobromide and quinidine sulphate (DM/Q) on activity of the spinal trigeminal neurons in an electrophysiological model of trigemino-durovascular nociception. METHODS: The study was performed in 15 male Wistar rats, which were anaesthetized with urethane/α-chloralose and paralysed using pipecuronium bromide. The effects of cumulative intravenous infusions of DM/Q (three steps performed 30 min apart, 15/7.5 mg/kg of DM/Q in 0.5 mL of isotonic saline per step) on ongoing and dural electrical stimulation-induced neuronal activities were tested in a group of eight rats over 90 min. Other seven animals received cumulative infusion of equal volumes of saline and served as control. RESULTS: Cumulative administration of DM/Q produced steady suppression of both the ongoing activity of the spinal trigeminal neurons and their responses to electrical stimulation of the dura mater. CONCLUSIONS: It is evident that the observed DM/Q-induced suppression of trigeminal neuron excitability can lead to a reduction in nociceptive transmission from meninges to higher centres of the brain. Since the same mechanism is believed to underlie the pharmacodynamics of many well-known antimigraine drugs, results of the present study enable us to anticipate the potential efficacy of DM/Q in migraine.

Limbic cortical influences to the vagal input neurones of the solitary tract nucleus.

In acute experiments on cats, electrical stimulation of the anterior limbic cortex was shown to modulate activity of vagal input neurones of the nucleus of the tractus solitarius. In the majority of the solitary tract nucleus neurones the responses induced by electrical stimulation of the vagus were depressed by the stimulation of anterior limbic cortex. Under these conditions the patterns of responses or their latency were changed. Our results are discussed with respect to possible mechanisms for cortical control of sensory transmission in the nucleus of the tractus solitarius.

Identification of gastric related neurones in the rat insular cortex.

Location peculiarities of insular neurones implicated in the regulation of gastrointestinal motility have been studied in acute experiments on rats. After microinjection of a horseradish peroxidase solution in a part of the dorsal vagal complex that receive gastric afferent inputs, retrogradely labelled cell bodies are observed in a certain area of the agranular and disgranular insular cortex. Electrical stimulation of the insular cortex area had no significant effect on heart and respiration rate but had evoked gastric tone changes. These results suggest that the insular cortex contains a specific cell group that provides direct output to the bulbar 'gastric' centre and takes part in regulation of gastrointestinal functions.

[Multineuronal characteristics of brain activation during extinction of the effects of indifferent stimuli]. / Mul'inteironal'naia kharakteristika aktivatsii mozga pri ugashenii deistviia indifferentnykh razdrazhitelei.

In chronic experiments on cats, the correlation of multineuronal activity (MNA) in the somatosensory cortex with EEG activation reactions recorded at the same point was studied during the process of extinction. The MNA was discriminated in three amplitude levels and averaged by means of a computer. Three kinds of stimuli were used: electric shocks to the forepaw, sounds and direct stimulation of the midbrain reticular formation. It was found that with repetition of stimuli, the progressive inhibition of the EEG activation correlates with gradual reduction of the level of sharp increase of MNA frequency in response to stimulation, and with shortening of the poststimuli periods of prolonged frequency reduction. A minor part of neuronal populations reacted with a slowing down of the discharge frequency (e. g. to the sound and reticular stimulation). More specific frequency reactions during extinction were recorded at different amplitude levels, depending on the modality and the parameters of the stimuli and on the population type. The changes in multineuronal discharges rate were more diverse and more continuous than the EEG responses. A comparative study of both phenomena reveals only partial coherence between them.

[Changes in the phasic activity of neuron microsystems of the somatosensory cortex of the cat during extinction of activation reactions to unreinforced stimuli]. / Izmeneniia faznoi deiatel'nosti mikrosistem neironov somatosensornoi kory koshki pri ugashenii reaktsii aktivatsii na nepodkrepliaemye stimuly.

In chronic experiments on cats, three-phasic responses of neuronal microsystems in the cortical somatic area I were studied during habituation of the EEG activation reactions. Repeated stimuli of different modalities were used: electrical pulses to the forepaw, sounds, direct stimulation of the mesencephalic RF. Simultaneously with the extinction of EEG activation reactions, the three-phasic responses of the multiunit activity (MUA) also became progressively extinct: the 1st phase of primary excitation--only a little, the 2nd phase (inhibitory)--greatly, as well as the 3rd phase--the phase of secondary excitation (if it existed at the beginning). The MUA responses to all stimuli show that these neuronal microsystems are polysensory. Relatively to the nonspecific activating RF macrosystem, the investigated neuronal microsystems are autonomous because their two functionally opposed response phases--the 1st excitatory and the 2nd inhibitory--occur against the monotonous excitatory background of the EEG activation. But in some way the neuronal microsystems are connected with the RF-system because of the parallel development of the extinction process.

[Correlation between nonspecific and specific excitation in the cat somatosensory cortex during different modalities of stimulation]. / Sootnoshenie mezhdu nespetsificheskim i spetsificheskim vozbuzhdeniem v somatosensornoi kore koshki pri raznomodal'noi stimuliatsii.

Multiunit activity and EEG recorded with the same electrode from the somatosensory cortex in unrestrained cats, were compared. The obviously identical patterns of the EEG activation coincided with different multiunit patterns (acceleration or deceleration of frequency, modification of discharge order) depending on the stimulus modality (somatic, acoustic, direct RF stimulation) and on the foregoing background impulsation. This suggests that the EEG activation, although being basically unspecific, has specific features. The sensory information, apart from the known forms, seems to be coded in the form of diverse modes of functional activity of a neuronal population localized in a brain structure.