[Peripheral neurostimulation in headache treatment]. / Perifericheskaia neirostimuliatsiia v terapii golovnykh bolei.

According to rough estimates, at least one third of the population in developed countries suffers, to varying degrees, from certain forms of primary headache, the modern pharmacotherapy of which is not always effective and has a number of limitations. The non-pharmacological treatment of headache can be an alternative to the prescription of pharmacological agents and the only possible assistance option for patients developing drug-resistant cephalalgias. This review describes various methods of electrical neuromodulation that are used for the management of primary headaches. The authors provide information on current stages in implementation of implantable and non-invasive equipment into clinical practice, which makes possible electrical stimulations of peripheral nerves and of the sphenopalatine ganglion, as well as allows transcranial magnetic stimulation. Also the appearance and usage of portable electrical devices available on the world market are described, and mechanisms that can underlie anticephalgic action of neuromodulation therapy are discussed. Special attention is paid to the methods that are applied for electrostimulation of the vagus nerve and occipital nerves.

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.

The 5-HT4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla.

Activation of the serotonin type 4 (5-HT4) receptors has been reported to improve abdominal pain in patients with functional gastrointestinal disorders and reduce visceral nociception in animal models. Earlier studies have proposed that 5-HT4 agonist can produce visceral analgesia by acting at the supraspinal level, but the underlying neuronal mechanisms remain unclear. The caudal ventrolateral medulla (CVLM) is the first site for processing of visceral nociceptive signals ascending via spinal pathways and an important component of the endogenous pain modulatory system. Therefore, the objective of the present study was to examine whether activation of 5-HT4 receptors can affect the visceral pain-related neurons in the CVLM. In urethane-anesthetized adult male Wistar rats, we evaluated the effects of a 5-HT4 receptor agonist, BIMU8 on ongoing firing of the CVLM neurons and their excitatory responses to noxious colorectal distension (CRD, 80mmHg). The drug's effect was also tested on blood pressure reactions induced by CRD-a general physiological measure of visceral nociception. Intravenous administration of BIMU8 (0.5, 1 or 2mg/kg) produced dose-dependent suppression of both the ongoing and CRD-evoked activities of the CVLM neurons and simultaneously attenuated the depressor hemodynamic reaction to CRD. The compound's inhibitory effect was almost completely eliminated by intracerebroventricular pretreatment with GR113808, a selective 5-HT4 antagonist, indicating the preferential involvement of supraspinal 5-HT4 receptors. Results indicate that visceral nociceptive transmission through the caudal medulla is negatively modulated by descending 5-HT4-dependent mechanisms. These findings can contribute to a deeper understanding of supraspinal processing of pain signals from the abdomen.

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.

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.

Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats.

Vagus nerve stimulation (VNS) is an approved antiepileptic and antidepressant treatment, which has recently shown promise as a therapy for drug-resistant primary headaches. Specific neurobiological mechanisms underlying its anticephalgic action are not elucidated, partly because of the deficiency of research-related findings. The spinal trigeminal nucleus (STN) plays a prominent role in pathophysiology of headaches by modulating pain transmission from intracranial structures to higher centers of the brain. To determine whether vagal stimulation may affect trigeminovascular nociception, we investigated the effects of VNS on the STN neuronal activity in the animal model of headache. In anesthetized rats the spike activity of the STN neurons with convergent orofacial and meningeal inputs was monitored, and the changes in neuronal responses to electrical stimulation of the dura mater under preconditioning or under continuous electrical stimulation of the left cervical vagus nerve were studied. Preconditioning vagal afferent stimulation (200-ms train of pulses at 30 Hz applied before each dural stimulus) did not produce substantial changes in the STN spike activity. However, continuous VNS with frequency of 10 Hz in 48% of cases significantly suppressed trigeminal neuronal responses to dural electrical stimulation. In line with the decrease in evoked activity, the VNS-induced depression of ongoing neuronal firing was observed. Although the inhibitory effect was prevailing, 29.5% of STN neurons were facilitated by VNS, whereas 22.5% were unresponsive to the stimulation. These results provide an evidence of VNS-induced modulation of trigeminovascular nociception, and therefore contribute to a deeper understanding of neurophysiological mechanisms underlying effects of vagal stimulation in chronic drug-resistant headaches.

Effects of stimulation of the insular cortex on execution of the antrofundal reflex in conscious dogs.

Neuroanatomical studies demonstrated the existence of direct descending projections from the insular cortex to the area of the solitary tract nucleus responsible for mediating the vagovagal reflexes of the proximal part of the gastrointestinal tract. These studies provided grounds for suggesting that one of the mechanisms mediating the influences of the insular cortex on stomach function may be modulation of its vagovagal reflex reactions, one of which is the antrofundal inhibitory reflex. Experiments on conscious dogs were performed to study the effects of electrical stimulation of the insular cortex on execution of the antrofundal gastric reflex in conditions of intermittent gastrointestinal tract activity during fasting. Stretching of the walls of the antral segment of the stomach during the active period of intermittent gastric activity led to suppression of contractions in the fundal segment. Electrical stimulation of the insular cortex was found to prolong this reflex reaction. Thus, one result of activation of the insular area of the cortex is enhancement of the inhibitory vagovagal gastric reflexes, in all probability occurring as a result of modulation of neurotransmission in the vagovagal reflex arc system.

Location of neurons in the central nucleus of the amygdaloid body projecting to the paraventricular nucleus of the hypothalamus.

Experiments were performed on rats using retrograde axonal transport of horseradish peroxidase with the aim of identifying cells in the individual structures of the central nucleus of the amygdaloid body (CNAB) innervating the paraventricular nucleus of the hypothalamus. Labeled cells were seen in the ipsilateral CNAB throughout its rostrocaudal extent. The largest number of labeled neurons was seen in the middle third of the nucleus in the area corresponding to the intermediate subnucleus of the CNAB. Occasional cells were located in the medial and lateral subnuclei of the CNAB. Labeled neurons in the intermediate subnucleus were oval cells or cells of indeterminate shape.

NO-Dependent mechanisms of amygdalofugal modulation of hypothalamic autonomic neurons.

Neurophysiological and histochemical experiments on rats were performed to study the effects of the central nucleus of the amygdala on the activity of cells in various areas of the hypothalamus. Electrical stimulation of the medial part of the nucleus evoked marked excitatory reactions in neurons in the medial part of the paraventricular nucleus of the hypothalamus and the rostral part of the lateral hypothalamic area. Intravenous administration of N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) led to increases in evoked neuron responses. A series of histochemical studies following activation of the central nucleus demonstrated increases in the quantity and optical densities of NADP diaphorase (NADP-d)-positive neurons in the parvocellular zone of the paraventricular nucleus of the hypothalamus and the medial part of the lateral hypothalamic area. The activity of nitroergic cells in the ventrolateral part of the lateral hypothalamic area was suppressed in these conditions. These mechanisms may underlie the amygdalofugal modulation of the autonomic functions of the hypothalamus.

Possible mechanisms of involvement of the amygdaloid complex in the control of gastric motor function.

Electrophysiological and neuroanatomical experiments on Wistar rats were performed to study the mechanisms of the modulatory influences of the amygdaloid nuclei on reflex motor activity in the stomach. Electrical stimulation of the central nucleus was accompanied by reproducible changes in the ongoing motor activity of the stomach in activity evoked by activation of the vagovagal reflex arc. The most marked, and predominantly inhibitory, effects were seen in response to stimulation of the medial part of the nucleus. Microinjections of the anterograde neuron marker Phaseolus vulgaris leucoagglutinin (PHA-L) into the central nucleus of the amygdala revealed the existence of direct descending projections from its dorsomedial part to the area containing cells of the vagosolitary complex, associated with performance of the vagovagal reflexes of the stomach. Electrical stimulation of this part of the central nucleus led to changes in neuron responses in the bulbar "gastric" center evoked by stimulation of the vagus nerve. These features may underlie one of the mechanisms of the amygdalar modulation of the reflex activity of the stomach.

Vagal stimulation modifies parameters of heterochromatin in the nuclei of vagosolitary complex neurons of medulla oblongata in rats.

New data were obtained on modification of heterochromatin parameters in the nuclei of medulla oblongata neurons in Wistar rats after stimulation of the vagus nerve: decrease in the area of heterochromatin regions and redistribution of chromocenters within the neuronal nuclear system. It was concluded that realization of the viscero-visceral reflex is associated with rearrangement of chromatin in neurons involved in transmission of the corresponding information.