ASSESMENT OF ANTI-NOCICEPTIVE ACTIONS OF ADIPOSE-DERIVED MESEMCHYMAL STEM CELLS IN EXPERIMENTAL PERIPHERAL NEUROPATHIC PAIN

Objective. To estimate an anti-nociceptive and regenerative potential of adipose-derived mesenchymal stem cells in experimental post-traumatic neuropathy in rats. Methods. Neuropathic pain was induced by axotomy technique in rat left hind paw (Wistar rats (n=113)). The respective group of subjects received ADMSCs dose of 1×10⁶ cells/kg and 2×10⁶ cells/kg into the site of sciatic nerve injury at 2 regimens: single (7^th day post-surgery) and twice (7^th and 14^th day post-surgery). Nociceptive responses, as well as histological changes of sciatic nerve and perineural tissue were assessed in dynamics. Results. Sciatic nerve axotomy led to a significant increase of mechanical nociceptive sensitivity of ipsilateral hind paw by 7^th day, as well as to fibrotic changes of peri- and epineural areas of damaged nerve fibers and to denervation of surrounding muscle tissue and fascia. Local administration of ADMSCs effectively abolished mechanical hyperalgesia by 14^th day after first injection at all regimens tested. Among tested regimens, the most pronounced anti-nociceptive and regenerative effects were induced by single injection of ADMSCs (1×10⁶ cells/kg). As the dose and frequency of ADMSCs administration elevated, their reparative and anti-inflammatory properties reduced. Conclusion. Obtained results testify anti-nociceptive potential of ADMSCs and feasibility of its further investigation on the experimental models of neuropathy. What this paper adds For the first time the impact of different regimen of allogenic adipose-derived mesenchymal stem cells (ADMSCs) transplantation on nociceptive sensitivity and microstructure changes of sciatic nerve in rats with peripheral neuropathy has been studied. Allogenic transplantation of mesenchymal stem cells at a dose of 1×10⁶ cells/kg has been found out to exhibit the most powerful anti-nociceptive and regenerative effects with a single local injection confirmed by algometry and histological study.

Endothelial dysfunction and features of nociceptive sensitivity in patients with microvascular angina

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): фГБ ОУ ВО СЗГМУ им. И.И. Мечникова Introduction. The pathogenesis of microvascular angina pectoris (MVA) is not completely clear to the end, some authors consider the violation of pain (nociceptive) sensitivity to be an important cause of this disease. The purpose of this study was to study the perception of pain and serum endothelin-1 in patients with MVA. Materials and methods. The criteria for inclusion in the group with MVA (49 patients): chest pain, positive stress test, unchanged coronary artery according to coronary angiography, the presence of a violation of myocardial perfusion and a decrease in the coronary reserve according to the positron emission tomography (PET) of the myocardium in rest, with a sample with adenosine and a cold test. Pain in the chest was noted in all 49 patients. Assessment of the nature of the pain syndrome was carried out using a 10-point visual-analogue scale (VAS), verbal rank scale (VRS). All subjects underwent a study of the functional activity of nociceptive and antinociceptive systems using the nociceptive flexor reflex method on the Nicolet VikingSelect expert class equipment, the pain threshold (Pb), the threshold of the reflex (Pr), and ratio coefficient (Pb / Pr), which in healthy people is approximately 0.9-1.0. The content of endothelin-1 in the serum of peripheral blood was determined by the method of enzyme immunoassay using test systems "Endotelin 1-21" (the normal values are up to 0.26 fmol / l) Fresh samples immediately after collection of blood were placed on ice and centrifuged during the day. Results. The intensity of pain in the usual attacks in patients with MVA according to the VAS data (5.51 ± 0.2) in most cases was moderate and none of the subjects reached the maximum possible values. According to VRS, moderate pain was described by 60% of patients with MVA, strong - 34.3%.In the study of NFR in patients with MVA, the group as a whole showed a decrease in the pain threshold, the threshold of the reflex, and the ratio coefficient (Pb / Pr) as compared with normal values. In the MVA group, Pb was equal to 9.5 ± 0.58 mA; Pr = 12.1 ± 0.58 mA; Pb / Pr = 0.78 ± 0.02. When studying the level of endothelin-1 in patients with MVA the level of this peptide was raised to 2.9 ± 0.82 fmol / l. According to the correlation analysis between endothelin-1 and the parameters of NFR, an inverse correlation was observed: between endothelin-1 and pain threshold (r = -0.4; p <0.01); between the level of endothelin-1 and the ratio coefficient of PB / PR (r = -0.9; p <0.01). Based on the results of the correlation analysis of the pain intensity index on the VAS scale and endothelin-1 level in patients with MVA, a significant relationship was found (r = 0.6, p <0.01) Conclusions. In patients with MVA, a decrease in the pain threshold and an elevated level of endothelin-1 were found. Thus, the severity of endothelial dysfunction in patients with MVA was interrelated with the process of perception of pain.

Effects of GABAB receptor activation on excitability of IB4-positive maxillary trigeminal ganglion neurons: Possible involvement of TREK2 activation

IB4-positive maxillary trigeminal ganglion (TG) neurons are a subtype of afferent neurons involving nociception in orofacial regions, and excitability of these neurons is associated with orofacial nociceptive sensitivity. TREK-2 channel is a member of two-pore domain potassium (K2P) channel family mediating leak K+ currents. It has been shown previously that TREK-2 channel activity can be enhanced following GABAB receptor activation, leading to a reduction of cortical neuron excitability. In the present study, we have characterized TREK-2 channel expression on maxillary TG neurons and investigated the effect of the GABAB agonist baclofen on electrophysiological properties of small-sized maxillary TG neurons of rats. We show with immunohistochemistry that TREK-2 channels are predominantly expressed in small-sized IB4-positive maxillary TG neurons. Patch-clamp recordings on neurons in ex vivo TG preparations show that baclofen hyperpolarizes resting membrane potentials, increases outward leak currents, and decreases input resistances in IB4-positive maxillary TG neurons. Moreover, baclofen significantly reduces action potential (AP) firing in IB4-positive maxillary TG neurons. In contrast, baclofen shows no significant effect on electrophysiological properties of small-sized nociceptive-like and non-nociceptive-like maxillary trigeminal neurons that are IB4-negatve. Our results suggest that TREK-2 channel activity can be enhanced by baclofen, leading to reduced excitability of IB4-positive maxillary TG neurons. This finding provides new insights into the role of TREK-2 and GABAB receptors in controlling nociceptive sensitivity in orofacial regions, which may have therapeutic implications.

Quantifying individual nociceptive sensitivity to optimise analgesic trials in infants

Despite the high burden of pain experienced by hospitalised infants there are few analgesics with proven efficacy. Testing analgesics in infants is experimentally and ethically challenging and minimising the number of infants required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in infant’s responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in baseline nociceptive sensitivity which can be used to improve the design of analgesic trials in infants. The paradigm is developed and tested across four studies using clinical, experimental and simulated data (99 infants). We provide evidence of the efficacy of both gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in infants.

REACTION OF MOLLUSCSHELIX ALBESCENSFOR LOW INTENSITY ELECTROMAGNETIC RADIATION EFFECTS OF EXTREMELY HIGH FREQUENCY

The effect of low-intensity EMR EHFon the parameters of nociceptive sensitivity of molluscs Helix albescens. It is shown that EMR EHF has a pronounced antinociceptive effect in the regulation mechanisms of which the importance played by opioid system, whose role at different stages of the impact of EMR EHF varies

Listening to your gut: immune challenge to the gut sensitizes body wall nociception in the caterpillar Manduca sexta

Immune–nociceptor connections are found in animals across phyla. Local inflammation and/or damage results in increased nociceptive sensitivity of the affected area. However, in mammals, immune responses far from peripheral nociceptors, such as immune responses in the gut, produce a general increase in peripheral nociceptive sensitivity. This phenomenon has not, to our knowledge, been found in other animal groups. We found that consuming heat-killed pathogens reduced the tactile force needed to induce a defensive strike in the caterpillar Manduca sexta . This increase in the nociceptive sensitivity of the body wall is probably part of the reconfiguration of behaviour and physiology that occurs during an immune response (e.g. sickness behaviour). This increase may help enhance anti-predator behaviour as molecular resources are shifted towards the immune system. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.