Antinociceptive System Research Articles

Scratch-collapse test in reflex cervical-elbow syndrome

The scratch-collapse test was proposed in 2008 to detect the level of compression of the ulnar and median nerves in tunnel lesions. Further study of this phenomenon has shown that weakness of the shoulder external rotators occurs in nerve lesions at other levels as well. The scratch-collapse test was studied in 155 patients (mean age 45 years) with unilateral reflex cervical-elbow syndrome, with complaints of different localization. The scratch-collapse test was positive in all patients on the affected side. The localization of the trigger zone depended on the patient’s complaints and was established experimentally. Short-term kneading of the trapezius muscle or voluntary contraction of the forearm muscles on the side of the lesion was used to prove the reflex nature of the cervico-elbow syndrome, resulting in complete recovery of triceps or extensor strength of the first and third finger. In the course of the study, suppression of the scratch-collapse test in reflex cervico-elbow syndrome with proprioceptive stimulation was found. In confirmed carpal tunnel and cubital tunnel syndromes, the phenomenon of suppression of the scratch-collapse test was also observed in response to proprioceptive stimulation. The scratch-collapse test and reflex cervical-elbow syndrome have a common mechanism of occurrence, which is based on the protective reaction of the body in the form of a nociceptive shortening reflex. The scratch-collapse test at skin irritation over the site of nerve injury can be considered as a subthreshold physiologic nociceptive reflex. Based on the theory of prognostic action of the nociceptive system, cervicolumbar reflex syndrome is a pathologic nociceptive reflex. Scratchcollapse test suppression phenomenon and recovery of muscle strength in reflexive cervical-elbow syndrome after shortterm kneading of the trapezius muscle are the result of activation of the antinociceptive system in response to proprioceptive stimulation. This suppression phenomenon can be used for the treatment of reflex cervical lockjaw syndrome.

ИГЛОРЕФЛЕКСОТЕРАПИЯ В КОМПЛЕКСНОЙ МЕДИЦИНСКОЙ РЕАБИЛИТАЦИИ ПРИ ФАНТОМНОМ БОЛЕВОМ СИНДРОМЕ

Background. Phantom limb pain is a common complaint after lower limb amputation, which can be defined as discomfort or pain in the missing part of the limb. According to the literature, the frequency of phantom pain syndrome ranges from 42.2 to 78.8% of all cases, while the registered prevalence is 45-85% [1, 2]. The task of acupuncture is to provide general soothing, analgesic and decongestant effects, improve neurovascular regulation, activate the endocrine antinociceptive system, collateral circulation, eliminate foci of peripheral pain impulses, reduce hypoxic tissue changes, optimize the overall reactivity of the body, normalize the functional state of the central nervous system. Purpose. The purpose is to review the literature on acupuncture in complex medical rehabilitation for phantom pain syndrome. Materials and methods. A method of collecting and analyzing published information on the use of acupuncture in complex medical rehabilitation for phantom limb pain was chosen for this article. Results. A literature review on the use of acupuncture in complex medical rehabilitation for phantom pain syndrome is presented. Conclusion. Acupuncture refers to the evolving methods of exposure, which is based on ancient traditions, but also in modern conditions has proven its flexibility, safety, and ability to effectively solve new modern problems.

Selective opioid agonist Taphalgin® as a component of postoperative analgesia in various surgical areas: “NIKITA” observational multicenter study

Introduction. The role of peptides in antinociceptive system regulation has became a subject of interest for scientists worldwide. The first registered peptide analgesic tyrosyl-D-arginyl-phenylalanyl-glycinamide acetate which currently can be used in clinical practice was developed in Russia under the name Taphalgin® (PharmFirma “Sotex”, Russia). The effectiveness and safety of this pharmaceutical in postoperative pain management was evaluated in the all-Russia multicenter prospective observation program NICITA (Non-interventional Clinical Trial of Taphalgin ®).Aim. To analyze the effectiveness and safety of Taphalgin® in postoperative pain management in various surgical fields.Materials and methods. The observational program NICITA included 887 patients including patients with malignant tumors of various locations from 15 study centers in different Russian cities. All patients underwent surgical interventions in various anatomical areas under general, regional and combination anesthesia. The principal scheme of postoperative pain management was based on the multimodal approach which included peptide opioid agonist alongside acetaminophen, cyclooxygenase inhibitors in combination with regional anesthesia or without it. The study also included patients who underwent small-volume surgeries, and pain was managed through Taphalgin® monotherapy with subsequent switch to cyclooxygenase inhibitors. The primary endpoint of the NICITA observational program was response to therapy after the first Taphalgin® administration. Decreased pain syndrome per the numerical rating scale 15–60 min after subcutaneous injection and maintenance of analgesic effect 3 h later were considered treatment response. The secondary endpoints included mean time to analgesia start after administration of the 1st single drug dose (in min), duration of effect, types and frequency of adverse reactions including serious in the central nervous system, pulmonary system, gastrointestinal tract developed during the observational program, as well as patient and research physician satisfaction with pain management. To evaluate the significance of pain intensity change at rest and in motion in time, analysis of variance with repeat measurements was used; for pairwise comparison of two time periods, Student’s t-test for dependent samples was used. The differences were considered significant at p = 0.05.Results. Statistically significant decrease in pain intensity in the total patient group was observed 15 minutes after Taphalgin® administration; it reached its minimum 40 min after the injection (р <0.05). The percentage of patients responding to analgesic therapy with Taphalgin® was 96.5 %. During administration of the drug, insignificant decrease (10–15 mmHg) in arterial blood pressure (1.7 % of cases) and vertigo (1 % of cases) were observed. In some patients, several adverse reactions were observed. Satisfaction with analgesic effect of Taphalgin® was relatively high both in patients and research physicians.Conclusion. Taphalgin® has pronounced analgesic effect and is effective for pain management after surgical interventions of various volumes and injury level. The use of this drug is associated with low rate of adverse reactions and absence of pulmonary depression characterizing opioid agonists. Therefore, Taphalgin® can be recommended for clinical use for postoperative pain management after various types of surgical interventions.

Collaborative action between noradrenergic and serotoninergic systems in peripheral antinociception in mice

Collaborative action between noradrenergic and serotoninergic systems in peripheral antinociception in mice

Features of pain sensitivity during premedication with xenon in patients before outpatient dental interventions

BACKGROUND: Premedication in outpatient dental interventions normalizes pain sensitivity and emotional state of patients. Inhalation of xenon-oxygen mixture can be an effective means for it. AIM: To study the effect of xenon premedication on pain sensitivity in patients with outpatient dental interventions. MATERIALS AND METHODS: Twenty patients were studied. Emotional and personal characteristics of patients were determined using the Eysenck test, Spielberger–Khanin personal anxiety scale, and hospital scale of anxiety and depression. Pain sensitivity was assessed using pain thresholds and somatosensory evoked potentials of the brain before and after inhalation of xenon-oxygen mixture at a concentration of 30/70 for 3 minutes. RESULTS: According to the results of psychological testing, all examined patients were characterized by a stable psychological sphere and predominantly lowered anxiety and constituted a group with insignificantly different emotional and personal characteristics. Before inhalation, pain sensitivity in patients varied significantly. After inhalation, multidirectional changes in pain sensitivity occurred, which were expressed in a decrease and an increase in pain sensitivity thresholds and the degree of activation of brain structures. CONCLUSION: Preoperative stress can both exacerbate and reduce pain sensitivity in patients. The use of inhalation of a xenon-oxygen mixture at a concentration of 30/70 for 3 minutes as a premedication causes multidirectional changes in the sensitivity of tissues and organs in the maxillofacial region in patients before outpatient dental interventions, which may be caused by a change in the activity of endogenous antinociceptive (analgesic) system.

Pathological Turbulence of the Heart Rhythm and Activation of the Antinociceptive System as Predictors of the Complicated Course of Silent Myocardial Ischemia in Patients with Post Infarction Cardiosclerosis According to the Data of Long-term Observation

To date, the issues of evaluating the course of silent myocardial ischemia (SMI) after a myocardial infarction (MI) taking into account risk factors (RF), evaluating the pathological turbulence of the heart rhythm, the state of activation of the body’s antinociceptive system, which necessitates an in-depth study of this pathology, remain unresolved, as well as new differentiated approaches to the treatment and rehabilitation of the modern category of patients. The objective: to analyze the features of the SMI course in patients with post-infarction cardiosclerosis depending on the RF. Identification of the interdependence between the degree of activation of the sympathoadrenal system and the features of the SMI course in patients with post-infarction cardiosclerosis, as well as the prognostic value for assessing the severity of the course of the disease. Materials and methods. The research was performed on the basis of the Ivano-Frankivsk Regional Clinical Cardiology Center (Ukraine). 154 patients with a silent form of coronary artery disease, which occurred in people with post-infarction cardiosclerosis, were examined. The diagnostic criteria were: episodes of SMI verified with the help of HM ECG and a test with dosed physical load. Results. Significant deviation of the ST segment which was detected during Holter monitoring of the ECG (HM ECG) in patients with SMI episodes does not mean that the absence of pain sensations in the presence of efferent nociceptive stimulation is a sign of the absence of ischemia and does not indicate an easier course of SMI compared to clinically manifest forms of CHD. The average concentration of β-endorphins in patients with lipid metabolism disorders was 4.01±0.02 ng/ml, in the presence of diabetes mellitus this indicator was equal to 4.68±0.03 ng/ml (р<0.01), and in persons with concomitant arterial hypertension it was 4.91±0.02 ng/ml (р<0.05). In subjects with two or more RFs, the similar indicator was the highest and amounted to 5.73±0.03 ng/ml (р<0.01). The point-biserial correlation coefficient was equal to 0.61 (р<0.05), which indicates a sufficiently high probability of the influence of the processes of activation of the antinociceptive system on the risk of myocardial infarction and unstable angina. Conclusions. It has been proven that the presence of postinfarction cardiosclerosis, type 2 diabetes mellitus, dyslipidemia, and arterial hypertension should be considered as factors that increase the risk of complications of coronary artery disease in patients with SMI. In the painless form of CHD, there is a probable increase in β-endorphins in the blood, which indicates the presence of pronounced afferent nociceptive stimulation, the intensity of which depends on the degree of myocardial ischemia. It has been proven that an increase of β-endorphins levels is associated with an increase in the risk of a complicated course of coronary heart disease in patients with silent myocardial ischemia. The presence in patients with SMI of myocardial ischemia, pathological turbulence of the heart rhythm, and activation of the antinociceptive system are extremely important for understanding the main links of the course of SMI and make it possible to base the approach to the therapy of such patients on a differentiated system algorithm that takes into account the discrepancy between the clinical manifestations of the disease and its real impact on coronary perfusion and the condition of the vascular wall.

Медико-социальные особенности хронических болевых синдромов у детей и подростков

ABSTRACT INTRODUCTION. A review of the social, psychological and medical issues of chronic pain syndromes in children and adolescents. The impact of chronic pain on daily activity, academic performance and morbidity in adulthood in this category of patients is analyzed. MATERIAL AND METHODS. A systematic search was conducted on the RSCI and PubMed database for the period from 2000 to 2023 on the topic of chronic pain syndromes in children and adolescents, which yielded 761 matches on key features, of which we analyzed 24 sources. DISCUSSION. The review presents information according to which, in the pathogenesis of chronic pain syndromes in children and adolescents, a significant role is given to both the characteristics of the antinociceptive system and socio-psychological aspects. The main factors involved in the formation of chronic pain syndromes are presented. CONCLUSION. Chronic pain in children and adolescents has its own medical, psychological and social characteristics, which affect not only the current state of health, but also has a significant impact on later life. KEYWORDS: children, adolescents, chronic pain, medicalization of pain, depression

Dopamine antinociceptive system

The article presents modern views on structure and functioning of dopaminergic structures of the brain and spinal cord and their role in mechanisms of antinociception, formation, and chronification of different pain syndrome types. The paper provides a detailed description of analgesic effects of various dopamine receptors in the structures of the CNS (the spinal cord, ventral tegmental area, periaqueductal gray, corpus striatum, nucleus accumbens, hypothalamus, and medial prefrontal cortex) which function as the dopaminergic antinociceptive system. The results of numerous investigations carried out on models of neuropathic pain syndrome have shown that D2 dopamine receptors possess the greatest analgesic activity. Their antinociceptive mechanism of action is effectuated at the level of substantia gelatinosa of the spinal cord and cerebral dopaminergic structures. D1‑like receptors have lower analgesic activity and different mechanisms of action depending on localization within the brain. High availability of D2/D3 receptors in corpus striatum is indicative of a low synaptic level of endogenous dopamine and leads to reduction of pain perception threshold. On the contrary, low availability of D2/D3 receptors results in the increase of pain perception threshold. The dopaminergic antinociceptive system is characterized by a modulating effect on other neurotransmitter systems participating in nociception and antinociception. An important mechanism of antinociception of dopaminergic structures is connected with superadditivity and synergism of D2 receptors with opioid receptors. Proven participation of dopaminergic structures in pain perception and analgesia demonstrates a potential possible application of D2‑receptors agonists as an adjuvant method for achieving a greater effect in therapeutic multimodal schemes of analgesia.

Cannabidiol Decreases Neuropathic Pain in Mice by Release of Opioid Peptides

Background: More than 100 phytocannabinoids have already been identified present in varying percentages of composition in the various plants of the genus Cannabis, including cannabidiol (CBD). Some evidences have demonstrated the effectiveness of CBD in treating neuropathic pain. We evaluated the participation of the opioid system in peripheral antinociception induced by the administration of CBD in the face of neuropathic pain induced by constriction of the sciatic nerve. Methods: Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mice paw. All drugs were administered by intraplantar injections in the right hind paw of mice. Results: Bestatin, an inhibitor of the enzyme aminopeptidase N, which degrades opioid peptides, potentiated the antinociceptive effect of the lowest administered dose of CBD (5 μg/paw). The antinociceptive effect of CBD was reversed by the administration of naloxone, a non-selective antagonist for opioid receptor. The selective antagonist for μ opioid receptor, clocinnamox, reversed the antinociceptive effect of CBD. Naltrindole, a selective antagonist for δ opioid receptors, and nor-binaltorphymine, a selective antagonist for κ opioid receptors, partially reversed the antinociception induced by CBD. Conclusions: Our data suggest the participation of the opioid system in CBD-induced peripheral antinociception in the model of neuropathic pain induced by sciatic nerve constriction in mice. Keywords: Cannabidiol; Neuropathic Pain; Peripheral Antinociception; Opioid System

Modern concepts of treatment of phantom limb pain

Phantom limb pain is a specific entity of neuropathic pain that develops in 30%85% of patients with amputated limbs and leads to considerable worsening of the quality of life. The number of such cases increases during military conflicts. It can be caused by a traumatic amputation due to mine blast injury, peculiarities of provided medical assistance, and the special psychological state of casualties being in extremely stressful situations at the moment of wounding. Phantom limb pain development is accompanied by multiple functional and structural changes at different levels of the peripheral and central nervous systems. As a result, different theories of pathogenesis are proposed. However, at present, no final opinion concerns mechanisms of phantom limb pain development. Although different versions of drug and non-drug therapy have been suggested, none of them turned out to be universal and fully effective. Many medications were found to be linked to phantom limb pain pathogenesis; however, even first-line therapy drugs (non-steroidal anti-inflammatory drugs, tricyclic antidepressants, narcotic analgesics, and anticonvulsants) often fail to provide adequate analgesia. Long-term prescription of narcotic analgesics is at risk of the development of addictive disorders. Surgical interventions have not demonstrated their effectiveness as well. Thus, their use is justified only in the case of ineffective conservative treatment. Poor efficacy of conventional concepts of phantom limb pain treatment led to the use of new means such as botulinum toxin therapy, non-drug methods (psychotherapy, mirror therapy, biological feedback, virtual reality, acupuncture, massage, hypnosis, etc.). Thus, the search for original methods based on the development and introduction of new drug therapy schemes is imperative. A possible solution to this problem is not only creating absolutely new non-opioid analgesics but also using adjuvant therapeutic means in the multimodality schemes of analgesia. The latter promotes neurotransmission in the antinociceptive system and potentiates the effect of traditional analgesics.

Pathogenetic mechanisms of periodic pain in women

A study was made of the prevalence and severity of pain syndromes in women with premenstrual syndrome in the dynamics of the menstrual cycle. 96 patients suffering from premenstrual syndrome and 78 healthy women were examined. Both a high association of pain syndromes with premenstrual syndrome and a signifcant decrease in pain thresholds were revealed, which indicates insuffcient activity of the antinociceptive system in this category of patients.

ИССЛЕДОВАНИЕ ГЕМАТОТОКСИЧНОСТИ НОВЫХ ПРОИЗВОДНЫХ КОНДЕНСИРОВАННЫХ 3-АМИНОТИЕНО[2,3-b]ПИРИДИНОВ И 1,4-ДИГИДРОПИРИДИНОВ С ВЫСОКОЙ АНАЛЬГЕТИЧЕСКОЙ АКТИВНОСТЬЮ

Pain is a significant problem in medicine today. More than 70% of diseases are accompanied by acute or chronic pain syndrome. According to the World Health Organization, pain syndromes are one of the most common reasons for seeking medical care, accounting for up to 40% of registered cases. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed around 500 million times every year. However, many patients with chronic pain rely on over-the-counter medications. Among the NSAIDs prescribed in clinical practice, hematotoxicity is a common adverse reaction. Objective: To assess changes in blood parameters in rats after a two-week administration of the most commonly used clinically NSAIDs and new derivatives of the 3-aminothieno[2,3-b]pyridine and 1,4-dihydronicotinamide series with the most pronounced analgesic activity. Methods: Ten low molecular weight ligands were chosen after screening various ligands. These ligands are capable of interacting with receptors and enzymes that are involved in the antinociceptive system. They contain fragments of 3-aminothieno[2,3-b]pyridine and 1,4-dihydronicotinamide. Samples with laboratory codes AZ023, AZ169, AZ213, AZ257, AZ729, AZ383, AZ331, AZ420, AU04271, AU04288 were selected for the experiment. Among them, AZ383, AZ331, AZ023, and AZ420 were chosen. The study involved 36 white male rats weighing between 250-280 g. Blood was collected via the femoral vein and analyzed using standard methods for erythrocyte, leukocyte, platelet, hemoglobin, and erythrocyte sedimentation rate (ESR) levels. Results: According to experimental studies, unlike the reference drug, the compounds studied do not cause leukopenia. In addition, only a tendency to decrease the number of platelets was detected for compounds AZ023, AZ331, and AZ383 with pronounced analgesic and anti-inflammatory activity, which requires additional research. Conclusion: Studies conducted on the safety of using derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines have shown promising results for further preclinical development. These derivatives can become highly effective and safe agents for alleviating pain and inflammation of various origins and severity in the future. Keywords: Blood test, hematotoxicity, pain syndrome, analgesic activity, thienopyridines, 1,4-dihydropyridine

FMRI Findings in Cortical Brain Networks Interactions in Migraine Following Repetitive Transcranial Magnetic Stimulation.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is one of the high-potential non-pharmacological methods for migraine treatment. The purpose of this study is to define the neuroimaging markers associated with rTMS therapy in patients with migraine based on data from functional MRI (fMRI).Materials and MethodsA total of 19 patients with episodic migraine without aura underwent a 5-day course of rTMS of the fronto-temporo-parietal junction bilaterally, at 10 Hz frequency and 60% of motor threshold response of 900 pulses. Resting-state functional MRI (1.5 T) and a battery of tests were carried out for each patient to clarify their diagnosis, qualitative and quantitative characteristics of pain, and associated affective symptoms. Changes in functional connectivity (FC) in the brain's neural networks before and after the treatment were identified through independent components analysis.ResultsOver the course of therapy, we observed an increase in FC of the default mode network within it, with pain system components and with structures of the visual network. We also noted a decrease in FC of the salience network with sensorimotor and visual networks, as well as an increase in FC of the visual network. Besides, we identified 5 patients who did not have a positive response to one rTMS course after the first week of treatment according to the clinical scales results, presumably because of an increasing trend of depressive symptoms and neuroimaging criteria for depressive disorder.ConclusionsOur results show that a 5-day course of rTMS significantly alters the connectivity of brain networks associated with pain and antinociceptive brain systems in about 70% of cases, which may shed light on the neural mechanisms underlying migraine treatment with rTMS.

Change in the second exteroceptive suppression period of the temporalis muscle during erenumab treatment.

Comparative studies on the second exteroceptive suppression period (ES2) of the masseter or temporalis muscle in migraineurs and controls have provided conflicting results. As the interneurons responsible for ES2 are probably close to the trigeminal nucleus caudalis and receive afferents also from the anti-nociceptive system, the study of ES2 could provide information on neural circuits involved in migraine pathophysiology. The aim of this observational, pilot study was to assess whether erenumab treatment may affect the exteroceptive suppression reflex of the temporalis muscle activity in migraineurs. The exteroceptive suppression reflex of the temporalis muscle activity was previously studied in a small case series of three chronic female migraineurs and after 4 months of beneficial erenumab treatment, administered according to current clinical indications. There was a statistically significant decrease in ES2 latency (p-value 0.039) and duration (p-value 0.030) after treatment. The change observed in the temporalis ES2 during erenumab treatment indicates that ES2 may play some kind of role as a neurophysiological marker and that this monoclonal antibody can modulate the brainstem circuits involved in migraine pathophysiology, at least indirectly. Further studies are required to confirm this intriguing hypothesis.

The analgesic effect of localized vibration: a systematic review. Part 1: the neurophysiological basis.

The analgesic action of localized vibration (LV), which is used in rehabilitation medicine to treat various clinical conditions, is usually attributed to spinal gate control, but is actually more complex. The aim of this review is: 1) to provide neurophysiological insights into the mechanisms underlying the ways in which afferent activity set up by LV induces analgesia through interactions with the nociceptive system throughout the nervous system; 2) to give a broader vision of the different effects induced by LV, some of them still related to basic science speculation. The Medline, EMBASE, AMED, Cochrane Library, CINAHL, Web of Science and ROAD databases were searched for animal and human neurophysiological and neurohormonal studies related to the direct effects of LV on nociceptive transmission and pain perception and were supplemented by published books and theses. The spinal gate control mechanism through Aβ-fibers activation seems to be the most effective antinociceptive system activated by LV at frequencies between 100 and 250 Hz (high-frequency LV [HF-LV]) when applied in the same segment as the pain. A gating effect can be obtained also when it is applied contralaterally to the painful site or to adjacent dermatomes. Kinesthetic illusions of movement induced by HF-LV may induce a stronger analgesic effect. Activation of C-mechanoreceptors induced by a massage-like LV of low frequency and low intensity may interfere with pain through the activation of the limbic system. This action does not involve any gating mechanism. Frequency is more important than intensity as different frequencies induce activity in different cortical and cerebellar areas; these activations may be related to plastic cortical changes tentatively reversing pain-related maladaptive disorganization. Distraction/shift of attention or cortisol-mediated stress-induced analgesia are not involved in LV analgesic action in humans for both LF and HF. The release of opioidergic neuropeptides (analgesia not reversed by naloxone) as well as a reduction in substance P in the CSF does not seem to play a major role in the HF-LV action. Decrease in calcitonin and TRPV1 expression in the trigeminal ganglia in animals has been induced by HF-LV but the role of LF-LV is not completely deciphered. Both high and low LV induce the release of oxytocin, which may induce antinociceptive responses in animals and contribute to controlling pain in humans. Although many aspects of LV-induced pain alleviation deserve more in-depth basic and translational studies, there are sound neurophysiological reasons for using LV in the therapeutic armamentarium of pain control. Laboratory animal and human data indicate that LV relieves pain not only by acting on the spinal gate, but also at higher levels of the nervous system.

Cognitive Reserve as a Protective Factor of Mental Health in Middle-Aged Adults Affected by Chronic Pain.

Chronic pain is associated with worse mental health and cognitive impairment, which can be a cause or a consequence of brain structure and function alterations, e.g., maladaptive plasticity, antinociceptive system dysregulation. Cognitive reserve reflects the effectiveness of the internal connections of the brain and it has been shown to be a protective factor in brain damage, slowing cognitive aging or reducing the risk of mental health disorders. The current study explored the impact of chronic pain on psychosocial factors, mental health, and cognition. Furthermore, we aimed to examine the role of cognitive reserve in the relationship between mental health and chronic pain clinical characteristics in middle-aged adults. The study group consisted of 477 volunteers from the Barcelona Brain Health Initiative who completed online surveys on pain, mental health, cognitive reserve, and psychosocial factors (sleep and quality of life). We described the differences in sociodemographic data, psychosocial factors, mental health, and self-perceived cognitive impairment, and neuropsychological assessment, between participants reporting pain compared with those without pain, as well as the main characteristics of the chronic pain group. Finally, to study the role of cognitive reserve in the modulation of the relationship between chronic pain and mental health, we compared variables between subgroups of participants with high/low pain intensity and cognitive reserve. The results showed that chronic pain was reported by 45.5% of middle-aged adults. Our results revealed that participants with chronic pain were older and had worse health status than people without pain. The presence of chronic pain affected working memory, mental health, and daily life activities. Moreover, cognitive reserve moderated the influence of pain intensity on mental health, resulting in less mental health affection in people suffering from high pain intensity with high cognitive reserve. In conclusion, the construct of the cognitive reserve could explain differential susceptibility between chronic pain and its mental health association and be a powerful tool in chronic pain assessment and treatment, principally due to its modifiable nature.

Involvement of A5/A7 noradrenergic neurons and B2 serotonergic neurons in nociceptive processing: a fiber photometry study.

In the central nervous system, the A6 noradrenaline (NA) and the B3 serotonin (5-HT) cell groups are well-recognized players in the descending antinociceptive system, while other NA/5-HT cell groups are not well characterized. A5/A7 NA and B2 5-HT cells project to the spinal horn and form descending pathways. We recorded G-CaMP6 green fluorescence signal intensities in the A5/A7 NA and the B2 5-HT cell groups of awake mice in response to acute tail pinch stimuli, acute heat stimuli, and in the context of a non-noxious control test, using fiber photometry with a calcium imaging system. We first introduced G-CaMP6 in the A5/A7 NA or B2 5-HT neuronal soma, using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamine β-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus (AAV-TetO(3G)-G-CaMP6). After confirming the specific expression patterns of G-CaMP6, we recorded G-CaMP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli. G-CaMP6 fluorescence intensity in the A5, A7, and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after, it returned to baseline fluorescence intensity. This was not observed in the non-noxious control test. The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B2 5-HT neurons but the non-noxious stimuli do not. The present study suggests that A5/A7 NA or B2 5-HT neurons play important roles in nociceptive processing in the central nervous system. We suggest that A5/A7/B2 neurons may be new therapeutic targets. All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University (MD17105) on February 22, 2018.

Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain.

The subgenual anterior cingulate cortex (sgACC) is a key node of the descending antinociceptive system with sex differences in its functional connectivity (FC). We previously reported that, in a male-prevalent chronic pain condition, sgACC FC is abnormal in women but not in men. This raises the possibility that, within a sex, sgACC FC may be either protective or represent a vulnerability to develop a sex-dominant chronic pain condition. The aim of this study was to characterize sgACC FC in a female-dominant chronic pain condition, carpal tunnel syndrome (CTS), to investigate whether sgACC abnormalities are a common feature in women with chronic pain or unique to individuals with pain conditions that are more prevalent in the opposite sex. We used fMRI to determine the resting state FC of the sgACC in healthy controls (HCs, n = 25, 18 women; 7 men) and people with CTS before (n = 25, 18 women; 7 men) and after (n = 17, 13 women; 4 men) successful surgical treatment. We found reduced sgACC FC with the medial pre-frontal cortex (mPFC) and temporal lobe in CTS compared with HCs. The group-level sgACC-mPFC FC abnormality was driven by men with CTS, while women with CTS did not have sgACC FC abnormalities compared with healthy women. We also found that age and sex influenced sgACC FC in both CTS and HCs, with women showing greater FC with bilateral frontal poles and men showing greater FC with the parietal operculum. After surgery, there was reduced sgACC FC with the orbitofrontal cortex, striatum, and premotor areas and increased FC with the posterior insula and precuneus compared with pre-op scans. Abnormally reduced sgACC-mPFC FC in men but not women with a female-prevalent chronic pain condition suggests pain-related sgACC abnormalities may not be specific to women but rather to individuals who develop chronic pain conditions that are more dominant in the opposite sex. Our data suggest the sgACC plays a role in chronic pain in a sex-specific manner, and its communication with other regions of the dynamic pain connectome undergoes plasticity following pain-relieving treatment, supporting it as a potential therapeutic target for neuromodulation in chronic pain.

Sleep disorders in acute and chronic pain

Pain is one of the leading causes of decline in quality of life. When pain syndromes occur, a person may experience unpleasant sensory sensations and concomitant disorders, which can lead to pain aggravation and sleep disturbances. According to experimental studies, increased pain sensation with reduced sleep duration occurs due to opioid, serotonergic, noradrenergic, and dopaminergic antinociceptive systems dysfunction. In clinical practice, a reduction in sleep duration is usually associated with insomnia, which is the most common sleep disorder. In pain syndromes, insomnia occurs in 53–90% of patients (for comparison: in the general population – in 7.4%). Non-pharmacological (cognitive-behavioral therapy) and pharmacological approaches are used in insomnia treatment. Some medications (amitriptyline, mirtazapine, trazodone, gabapentin, pregabalin) have both hypnotic and analgesic effects, which allows to use them for pain syndromes with sleep disturbances. It has been shown that the correction of sleep disorders can reduce the severity and frequency of pain.

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

Abstract 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.