Pain Mechanisms Research Articles

Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats.

Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism in bone cancer pain have not been fully explored. Methods: Bone cancer pain model was created by implanting walker 256 mammary gland carcinoma into right tibia bone cavity. Primary cultured spinal neurons were used for in vitro evaluation. FLIPR, western-blot, immunofluorescence, and Co-IP were used to detect cell signaling pathway. Results: Our results indicated that spinal dopamine D1 receptor (D1DR) and spinal dopamine D2 receptor (D2DR) could form heteromers in TCI rats, and antagonizing spinal D1DR and D2DR reduced heteromers formation and alleviated TCI-induced bone cancer pain. Further results indicated that D1DR or D2DR antagonist induced antinociception in TCI rats could be reversed by D1DR, D2DR, and D1/D2DR heteromer agonists. And Gq, IP3, and PLC inhibitors also attenuated TCI-induced bone cancer pain. In vitro results indicated that D1DR or D2DR antagonist decreased the Ca2+ oscillations upregulated by D1DR, D2DR, and D1/D2DR heteromer agonists in activated primary cultured spinal neurons. Moreover, inhibition of D1/D2DR heteromers induced antinociception in TCI rats was partially mediated by the CaMKII and MAPKs pathway. In addition, a natural compound levo-Corydalmine (l-CDL), could inhibit D1/D2DR heteromers and attenuate bone cancer pain. Results: Inhibition of spinal D1/D2DR heteromers via l-CDL decreases excitability in spinal neurons, which might present new therapeutic strategy for bone cancer pain.

Long-term plasticity of NMDA GluN2B (NR2B) receptor in anterior cingulate cortical synapses.

The anterior cingulate cortex (ACC) is a key cortical area for pain perception, emotional fear and anxiety. Cortical excitation is thought to be the major mechanism for chronic pain and its related emotional disorders such as anxiety and depression. GluN2B (or called NR2B) containing NMDA receptors play critical roles for such excitation. Not only does the activation of GluN2B contributes to the induction of the postsynaptic form of LTP (post-LTP), long-term upregulation of GluN2B subunits through tyrosine phosphorylation were also detected after peripheral injury. In addition, it has been reported that presynaptic NMDA receptors may contribute to the modulation of the release of glutamate from presynaptic terminals in the ACC. It is believed that inhibiting subtypes of NMDA receptors and/or downstream signaling proteins may serve as a novel therapeutic mechanism for future treatment of chronic pain, anxiety, and depression.

Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study.

It is well known that there are significant differences in the prevalence of chronic pain between males and females. Human and animal imaging studies have shown that chronic pain profoundly alters the structure and function of brain regions. However, there is limited research on the sex-specific mechanisms underlying the brain plasticity and adaptive changes associated with chronic pain. In this article, we conducted a multimodal study to evaluate how nerve injury-induced chronic pain affects the brain. Male and female Sprague-Dawley (SD) rats with spared nerve injury (SNI) model underwent resting-state functional magnetic resonance imaging (rs-fMRI) (male sham group: n = 18; male SNI group: n = 18; female sham group: n = 20; female SNI group: n = 18) and magnetic resonance diffusion tensor imaging (DTI) (male sham group: n = 23; male SNI group: n = 21; female sham group: n = 20; female SNI group: n = 21) scanning. ICA method, Fractional amplitude of low-frequency fluctuations (fALFF), immunofluorescence staining, and graph theory analysis was utilized to extract the rs-fMRI changes of brain regions of each group. Using SNI model, which promotes long-lasting mechanical allodynia, we found that neuropathic pain deeply modified the intrinsic organization of the brain functional network in male and female rats (main effect of operation: F = 298.449, P < 0.001). 64 independent components (ICs) in the brain were divided and assigned to 16 systems. In male rats, we observed significant alterations in the microstructure of the hippocampal cornu ammonis 1 and cornu ammonis 2 (CA1/CA2) region, as indicated by increased mean diffusivity (MD) (CA1_L: P = 0.02; CA1_R: P = 0.031; CA2_L: P = 0.035; CA2_R: P = 0.015) and radial diffusivity (RD) (CA1_L: P = 0.028; CA1_R: P = 0.033; CA2_L: P = 0.037; CA2_R: P = 0.038) values, along with enhanced activating transcription factor 3 (ATF3) expression. Conversely, in female rats, we found significant increases in the fractional amplitude of low frequency fluctuations (fALFF) value within the hippocampal dentate gyrus (DG) (F = 5.419, P = 0.023), accompanied by elevated c-Fos signal (F = 6.269, P = 0.031). Furthermore, graph theory analysis revealed notable differences in the small-world network of the hippocampal system in female rats, characterized by reduced small-world attributes and increased inter-nodal transmission efficiency. Our study indicates sex differences in structural and functional alterations in the hippocampal system in rats under chronic pain conditions. The results suggest that the hippocampus system plays an important role in the different mechanisms of chronic pain in different sexes. These findings provide reliable insights to explore the complex mechanisms underlying sex differences in chronic pain.

Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats.

Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.

Mechanisms of ocular surface pain

Ocular pain is evoked upon activation of a small number of nociceptive neurons located at the trigeminal ganglion whose peripheral projections profusely innervate the cornea and conjunctiva. In healthy conditions, nerve impulse activity originated at peripheral nerve endings of these primary sensory neurons in response to noxious or potentially noxious stimuli acting on the ocular surface travels centrally and reaches second‐order neurons located at the trigeminal brain stem complex. In turn, these brainstem neurons send their axons to the contralateral posterior thalamic nuclei, where the third neurons along the ocular nociceptive pathway are found. Thalamic neurons send their axons to the primary somatosensory area of the brain cortex and, after brain cortex processing if this sensory inflow, nociceptive pain sensation is experienced.The activity of ocular nociceptor neurons is modified under inflammation. Inflammatory mediators released at the ocular surface increase the excitability of the nerve terminals. As a result, the impulse response of primary nociceptor neurons to noxious stimuli is increased, which constitutes the basis of hyperalgesia and leads to pain and other sensations such as gritty eyes, foreign body sensation, etc. experienced under ocular inflammation.After a lesion (including surgery) or disease that affects any nerve or neuron of the ocular somatosensory pathway, the activity and connectivity of the neurons involved in ocular pain is altered, sometimes permanently. The excitability of damaged neurons is long‐lasting increased, leading to ocular dysesthesia and development of neuropathic pain referred to the eye.(Supported by PID2020‐115934RB‐I00 from DOI: MCIN/AEI/10.13039/50110001103, and CIPROM/2021/48 from the Generalitat Valenciana, Spain)

Cancer Pain Management with Traditional Chinese Medicine: Current Status and Future Perspectives.

Cancer pain, especially the moderate-to-severe pain experienced by patients with advanced cancer, is still one of the most challenging clinical problems. The current mainstream pharmacological treatment for cancer pain involves applying opioid medications and other pain-killing drugs. However, analgesic drugs have many adverse effects such as addiction, tolerance, and other formidable clinical and social issues. Thus, finding a new therapeutic approach to treat cancer pain is essential. Traditional Chinese medicine (TCM) has been increasingly applied in clinical practice because of its good efficacy and few side effects. However, its mechanisms of action in treating pain are still under investigation. The most important mechanism of cancer pain is that a large amount of pain-causing substances are secreted from cancer cells and promote their growth and invasion. The physical and chemical stimulations of these substances exist along with the cancer growth, leading to constantly increased pain sensation. Whether cancer pain can be alleviated by inhibiting cancer cells from releasing the substances and changing the microenvironment around the cancer mass, or even by eliminating pain-causing substances, is largely unknown. Based on TCM theory, this study reported that the aforementioned approach could effectively manage different cancer pains by tonifying qi, clearing and activating channels and meridians, and strengthening body resistance. The TCM therapies activate blood circulation, remove blood stasis, and nourish the heart. Commonly used Chinese herbal drugs include Corydalis yanhusuo, Angelica dahurica, and Ligusticum chuanxiong. Instead of using conventional analgesics to reduce pain, we should focus on using TCM modalities to alleviate cancer pain and increase the quality of life in patients suffering from cancer pain. TCM should provide us with a new strategy for managing cancer pain.

Interactive effects of pain and arousal state on heart rate and cortical activity in the mouse anterior cingulate and somatosensory cortices

Sensory disconnection is a hallmark of sleep, yet the cortex retains some ability to process sensory information. Acute noxious stimulation during sleep increases the heart rate and the likelihood of awakening, indicating that certain mechanisms for pain sensing and processing remain active. However, processing of somatosensory information, including pain, during sleep remains underexplored. To assess somatosensation in natural sleep, we simultaneously recorded heart rate and local field potentials in the anterior cingulate (ACC) and somatosensory (S1) cortices of naïve, adult male mice, while applying noxious and non-noxious stimuli to their hind paws throughout their sleep-wake cycle. Noxious stimuli evoked stronger heart rate increases in both wake and non-rapid eye movement sleep (NREMS), and resulted in larger awakening probability in NREMS, as compared to non-noxious stimulation, suggesting differential processing of noxious and non-noxious information during sleep. Somatosensory information differentially reached S1 and ACC in sleep, eliciting complex transient and sustained responses in the delta, alpha, and gamma frequency bands as well as somatosensory evoked potentials. These dynamics depended on sleep state, the behavioral response to the stimulation and stimulation intensity (non-noxious vs. noxious). Furthermore, we found a correlation of the heart rate with the gamma band in S1 in the absence of a reaction in wake and sleep for noxious stimulation. These findings confirm that somatosensory information, including nociception, is sensed and processed during sleep even in the absence of a behavioral response.

Electroencephalography-based biological and functional characteristics of spinal cord injury patients with neuropathic pain and numbness.

To identify potential treatment targets for spinal cord injury (SCI)-related neuropathic pain (NP) by analysing the differences in electroencephalogram (EEG) and brain network connections among SCI patients with NP or numbness. The EEG signals during rest, as well as left- and right-hand and feet motor imagination (MI), were recorded. The power spectral density (PSD) of the θ (4-8 Hz), α (8-12 Hz), and β (13-30 Hz) bands was calculated by applying Continuous Wavelet Transform (CWT) and Modified S-transform (MST) to the data. We used 21 electrodes as network nodes and performed statistical measurements of the phase synchronisation between two brain regions using a phase-locking value, which captures nonlinear phase synchronisation. The specificity of the MST algorithm was higher than that of the CWT. Widespread non-lateralised event-related synchronization was observed in both groups during the left- and right-hand MI. The PWP (patients with pain) group had lower θ and α bands PSD values in multiple channels of regions including the frontal, premotor, motor, and temporal regions compared with the PWN (patients with numbness) group (all p < 0.05), but higher β band PSD values in multiple channels of regions including the frontal, premotor, motor, and parietal region compared with the PWN group (all p < 0.05). During left-hand and feet MI, in the lower frequency bands (θ and α bands), the brain network connections of the PWP group were significantly weaker than the PWN group except for the frontal region. Conversely, in the higher frequency bands (β band), the brain network connections of the PWP group were significantly stronger in all regions than the PWN group. The differences in the power of EEG and network connectivity in the frontal, premotor, motor, and temporal regions are potential biological and functional characteristics that can be used to distinguish NP from numbness. The differences in brain network connections between the two groups suggest that the distinct mechanisms for pain and numbness.

Insight in perception of pain in sports – selected aspects

Purpose: Research in recent decades has shed light on the neurophysiological mechanisms of pain, which not only has an information and warning function, but is also considered an important diagnostic factor. The results of various studies indicate that physical activity, especially at moderate intensity, modulates the intensity of perceived pain and generally leads to its reduction.The aim of this study was to characterize in depth the effects of physical activity on pain perception, in particular to deepen the knowledge of the direct and indirect effects of recurrent repetitive injuries on pain perception and modulation of the activity of the endogenous antinociceptive system.Methods: This article reviews the current state of knowledge on the effects of physical activity and injury on pain perception and the role of the endogenous analgesic system in pain modulation.Results: Both excessive physical effort and a lack of physical activity are factors that increase the risk of pain. Physical activity, especially training in athletes, exerts loads on the locomotor system structures and by means of the nociceptive system signalises potential hazards through pain. At the same time, these very same loads trigger the processes activating the endogenous analgesia systems. In the case of intense and prolonged physical activity, these systems are subject to adaptation as well as exhaustion. Conclusions: For athletes and amateur athletes, knowledge about pain has a practical dimension, enabling conscious, knowledge-based monitoring of applied loads and control of the body's condition. Gaining knowledge about pain in sports can be of great practical importance in the in the training process, during the competition but above all the prevention of injuries. The intensity and quality of pain, although these are subjective feelings, can be defined and analyzed in clinical practice and in research conducted on physically active people, using established procedures and appropriate tests.

20-HETE mediated TRPV1 activation drives allokinesis via MrgprA3+ neurons in chronic dermatitis.

Rationale: Noxious stimuli are often perceived as itchy in patients with chronic dermatitis (CD); however, itch and pain mechanisms of CD are not known. Methods: TRPV1 involvement in CD was analyzed using a SADBE induced CD-like mouse model, and several loss- and gain-of-function mouse models. Trigeminal TRPV1 channel and MrgprA3+ neuron functions were analyzed by calcium imaging and whole-cell patch-clamp recordings. Lesional CD-like skin from mice were analyzed by unbiased metabolomic analysis. 20-HETE availability in human and mouse skin were determined by LC/MS and ELISA. And finally, HET0016, a selective 20-HETE synthase inhibitor, was used to evaluate if blocking skin TRPV1 activation alleviates CD-associated chronic itch or pain. Results: While normally a pain inducing chemical, capsaicin induced both itch and pain in mice with CD condition. DREADD silencing of MrgprA3+ primary sensory neurons in these mice selectively decreased capsaicin induced scratching, but not pain-related wiping behavior. In the mice with CD condition, MrgprA3+ neurons showed elevated ERK phosphorylation. Further experiments showed that MrgprA3+ neurons from MrgprA3;Braf mice, which have constitutively active BRAF in MrgprA3+ neurons, were significantly more excitable and responded more strongly to capsaicin. Importantly, capsaicin induced both itch and pain in MrgprA3;Braf mice in an MrgprA3+ neuron dependent manner. Finally, the arachidonic acid metabolite 20-HETE, which can activate TRPV1, was significantly elevated in the lesional skin of mice and patients with CD. Treatment with the selective 20-HETE synthase inhibitor HET0016 alleviated itch in mice with CD condition. Conclusion: Our results demonstrate that 20-HETE activates TRPV1 channels on sensitized MrgprA3+ neurons, and induces allokinesis in lesional CD skin. Blockade of 20-HETE synthesis or silencing of TRPV1-MrgprA3+ neuron signaling offers promising therapeutic strategies for alleviating CD-associated chronic itch.

Australian healthcare professionals' beliefs and practice behaviours in management of chronic pelvic pain: a cross-sectional survey.

Background Chronic pelvic pain (CPP) is a common and debilitating condition, and sufferers present to healthcare professionals with variable complex symptoms and co-morbidities. This study aimed to investigate the current beliefs and practice behaviours of healthcare professionals towards the management of CPP in Australian females. Methods We distributed an online survey to Australian healthcare professionals. Participants were questioned regarding their beliefs, the importance of various contributing factors and assessment variables, and their management preferences for two CPP vignettes. Demographic information and responses were analysed with descriptive statistics. Results Complete data were obtained and analysed from 446 respondents including gynaecologists (n =75), general practitioners (GPs) (n =184) and physiotherapists (n =187). Most of the respondents were female (88.1%), with male (11.7%) and other (0.2%) making up a smaller representation. Physiotherapists rated themselves higher in understanding mechanisms of CPP (64.7% very good to excellent) compared to gynaecologists (41.3%) and GPs (22.8%). Physiotherapists also reported higher levels of confidence in managing patients with CPP (57.8% quite or extremely confident) compared to 41.3% of gynaecologists and 22.3% of GPs who reported being quite or extremely confident. All three professions rated patient's beliefs (89.8%), nervous system sensitisation (85.7%), stress/anxiety/depression (91.9%), fear avoidance (83.3%), history of sexual/emotional/physical abuse (94.1%) and pelvic floor muscle function (85.0%) as very/extremely important factors in the development of chronic pelvic pain. Most gynaecologists (71.0%) and GPs (70.2%) always referred for pelvic ultrasound during assessment. Physiotherapists assessed goal setting (88.8%) and screened for patients' beliefs (80.9%) more often than gynaecologists (30.4% and 39.1% respectively) and GPs (46.5% and 29.0% respectively). Conclusions All three groups of healthcare professionals demonstrated a good understanding of pain mechanisms and incorporated a biopsychosocial and multidisciplinary approach to management of females with chronic pelvic pain. However, both gynaecologists and GPs were less confident in their understanding of and management of CPP, and less likely to consider patient beliefs and goals. The findings of this online survey may assist in the provision of more targeted education to further improve management of this condition.

Characterization of the neuropathic pain component contributing to myalgia in patients with myotonic dystrophy type 1 and 2.

Chronic muscle pain is common in myotonic dystrophies (DM). Little is known about its pathophysiology. We aimed to investigate the characteristics of the neuropathic pain component contributing contributes to the pathogenesis of chronic pain in DM. Twenty-one DM1 and 32 DM2 patients completed pain questionnaires (Brief pain inventory-BPI, PAIN-DETECT, pain disability index-PDI) and underwent neurological examination, nerve conduction studies (NCS), quantitative sensory testing (QST, dorsum of the right hand and right thigh) and skin biopsy to determine the intraepidermal nerve fiber density (IENFD, distal and proximal site of lower extremity). NCS and QST results at the thigh were compared to 27 healthy controls and IENFD and QST at the dorsum of the hand to published reference values. The sensory profile of DM2 patients was characterized by a loss in thermal and mechanical detection, while DM1 patients showed reduced mechanical and heat pain thresholds and higher mechanical pain sensitivity. Both DM groups showed pressure hyperalgesia. IENFD was reduced in 63% of DM1 patients and 50% of DM2. The slightly higher pain interference and disability found in DM2 was rather due to age difference than disease. Similar pain mechanisms likely occur in both DM1 and DM2, even though a tendency toward more pain sensitivity was observed in DM1 and more sensory loss in DM2. Both QST and reduced IENFD highlight the presence of peripheral nerve damage in DM. This must be considered for the best pain management strategies.

Chronic pain management in fibromyalgia: the INTEGRO (INTEGRated Psychotherapeutic InterventiOn) protocol and its application on two case studies.

To present an innovative integrated manualized psychotherapeutic intervention for fibromyalgia (FM) based on cognitive and behavioral therapy, acceptance and commitment therapy, and somatic experiential techniques (namely the INTEGRated Psychotherapeutic InterventiOn, INTEGRO) and illustrate its application on two case studies. INTEGRO is composed of 12 individual sessions. The main objectives of the intervention were psychoeducation of chronic pain mechanisms, understanding the role of cognitive and emotional variables in one's pain perception, teaching patient-tailored skills to increase pain awareness and its management, and learning how to live with pain experience. A 57-year-old woman (patient A) and a 26-year-old woman (patient B) with FM have been selected to describe their care pathways connected to the INTEGRO protocol. Data related to assessment variables and clinical processes have been reported, focusing on the mechanisms that contribute to the maintenance (i.e., avoidance or overcompensation) of chronic pain in FM, on the role of patients' naïf theories, and on the implications that all these aspects may have on the burden related to pain management. Both patients showed a reduction in FM burden and an increase in self-efficacy in pain management: patient A reported an improvement in emotional regulation ability; patient B showed a decrease in pain interference in work activities and on emotional dimension. Examining each phase of the clinical protocol through the lens of its clinical application, the paper provides insights into the relationship among crucial psychosocial mechanisms, pain perception, management in FM treatment, and how all these aspects have been dealt with during psychotherapeutic treatment.

MOLECULAR MECHANISMS OF NOCICEPTION IN CHRONIC PROSTATITIS

Introduction. The need to understand the pathophysiology of prostatitis is determined by its prevalence, usually chronic progressive course, significant impact on quality of life, fertility and sexuality. The modern arsenal of medicines allows us to achieve a clinically significant effect. Along with this, non-pharmacological methods are widely used to increase the effectiveness of treatment. However, despite significant successes in the treatment of prostatitis, the problems of insufficient efficiency remain unsolved by modern urology, and it is extremely difficult to help these patients. Understanding the pathophysiology of the disease has always been the key to successful diagnosis and treatment. That is why it is important to determine the mechanisms of development of painful manifestations of prostatitis.&#x0D; The aim. To describe the main molecular mechanisms of tissue damage reception, in particular of the prostate gland, which are perceived as pain sensations.&#x0D; Materials and methods. An evaluation of modern literature devoted to the mechanisms of creation of nerve impulses due to damage and inflammation of the prostate gland was carried out. The search was conducted in the MEDLINE and databases of the National Library of Ukraine named after V.I. Vernadsky.&#x0D; Results. The main molecular mechanisms of nociception in chronic prostatitis have been determined. A review of modern literature devoted to the study of pain mechanisms as a biologically significant signal of damage at the molecular level of reception is presented. Attention is focused on the features of nociception in prostatitis, its connection with the production of inflammatory mediators, possible mechanisms of hyperalgesia and allodynia.&#x0D; As a result of stress and tissue damage, the production and release of inflammatory mediators such as interleukins, interferon, prostaglandins, bradykinin, adenosine triphosphate, protons and nerve growth factor increase. These mediators activate pain receptors located on nerve endings and are ion channels of various types: transient receptor potential, acid, purinergic, and potassium ion leak channels.&#x0D; Conclusions. The presented literature data describe the mechanisms of nociception, hyperalgesia and allodynia in chronic prostatitis, the understanding of which can be the basis for the development of new methods of diagnosis and treatment.

Fatigue can influence the development of late-onset pain in post-COVID-19 syndrome: An observational study.

Late-onset pain is frequent following COVID-19, and many pathogenetic mechanisms have been proposed. Identifying the main features of patients may help in designing tailored rehabilitative interventions. We enrolled post-COVID-19 patients with an increase in pain intensity of two points on the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) at 52 weeks compared to the pre-COVID-19 condition. All subjects were retrospectively monitored at 12, 26, and 52 weeks. A specific pain assessment was performed to determine the characteristics and mechanisms of pain. Catastrophizing, kinesiophobia, and other psychological symptoms were evaluated. The pressure pain threshold (PPT) and temporal summation (TS) were measured and compared in age- and sex-matched healthy controls to analyse pain characteristics. A total of 67 patients were recruited, with 20 of them presenting an increase in pain at 52 weeks. Subjects of the two subgroups were similar in demographic and clinical characteristics at baseline; significant differences in fatigue, anxiety, mobility, ability to perform daily activities, and general health perception were recorded at 26 weeks. Fatigue significantly predicted pain onset (β = 0.54, p = 0.002). Sixteen different body regions were identified as painful, with a pain intensity of 6.0 ± 1.9. Most of the samples did not show neuropathic or nociplastic mechanisms. No differences in PPT and TS were recorded between patients and healthy controls. Almost one out of three patients hospitalized for COVID-19 developed pain 1 year later, and fatigue seems responsible for chronicity. An overlapping of conditions may explain late-onset post-COVID-19 pain, and a comprehensive approach must be considered for patient management. Late-onset pain is frequent in post-COVID-19 syndrome and an overlapping of different mechanisms seems to be responsible for its development. Among many predisposing factors, fatigue in the months before seems to be one of the primary causes of pain one year following infection and its management may help to identify new strategies for prevention and treatment of late-onset pain.

Sex differences in the association between smoking and central sensitization: A cross-sectional study.

Despite the acknowledged interconnection between smoking and pain, research on the relationship between smoking and central sensitization (CS) is scarce; this pain mechanism has attracted recent research attention. Considering potential sex differences, this cross-sectional study aimed to investigate the association between smoking and CS. Overall, 415 adult participants from an outpatient clinic underwent evaluation. The analysis focused on determining the relationship between smoking status and CS by differentiating between sexes. Data were collected on smoking presence or absence (independent variable) and CS (dependent variable) for each sex, with age, education level, drinking history, depression, and anxiety as covariates. CS was evaluated using the Central Sensitization Inventory. Following a descriptive analysis of the study population's characteristics, logistic regression analysis was employed to assess the relationships. The average participant age was 42.3 years, with 59% being women. Among women, a significant association was found between smoking status and higher CS severity (AOR=3.21; 95% CI 1.29-7.99, p<0.01), after accounting for confounding variables. Conversely, no significant association was observed for men (AOR=1.50; 95% CI 0.63-3.60, p=0.36). Interaction by sex on the relationship between smoking and CS was not statistically significant (p=0.23). This study suggests a potential association between smoking and CS in women, whereas no conclusive relationship was observed among men. These findings indicate the necessity of considering CS when examining the relationship between smoking and pain.

Peripheral neural mechanism of visceral pain and acupoint sensitization in 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis model mice.

To explore the neural mechanism of visceral pain and related somatic (acupoints) sensitization by using in vivo calcium imaging of dorsal root ganglia (DRG) neurons. Eight BALB/c mice were randomly divided into control and model groups, with 4 mice in each group. The colitis model was induced by colorectal perfusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) once daily for 7 days. Mice of the control group received colorectal perfusion of normal saline once daily for 7 days. The location and area of the somatic neurogenic inflammation (cutaneous exudation of Evans blue ［EB］) of the 2 groups of mice were observed after intravenous injection of EB. For pain behavioral tests, sixteen C57BL/6J mice were randomly divided into control and model groups, with 8 mice in each group, and a Von Frey filament was used to stimulate the referred somatic reactive regions in colitis mice, and the number of avoidance and paw withdraw reaction within 10 tests was recorded. For in vivo DRG calcium imaging tests, 24 Pirt-GCaMP6s transgenic mice were randomly and equally divided into control group and colitis model group. The responses of the neurons in L6 or L4 DRG to colorectal distension (CRD), lower back brushing, or mechanical stimulation at the hindpaw were observed using confocal fluorescence microscope. Compared with the control group, the area of EB exudation spot in the hindpaw and lower back regions was increased in the colitis model group (P<0.05), and the avoidance or paw withdraw numbers induced by Von Frey stimulation at the lower back and hindpaw were increased (P<0.01, P<0.05), indicating that colitis induced regional skin (acupoints) sensitization in the lower back and hindpaw regions. Compared with the control group, the percentage of L6 DRG neurons activated by 60 mm Hg CRD in the colitis model mice were apparently increased (P<0.01), the activated neurons mainly involved the medium-sized DRG neurons (P<0.01). In Pirt-GCaMP6s transgenic mice, following brushing the skin of the receptive field (lower back) of L6 DRG neurons, the fluorescence intensity of the brushing-activated DRG neurons and small, medium and large-sized neurons were significantly higher in the colitis model group than those in the control group (P<0.001, P<0.01, P<0.05). After brushing and clamping the skin of the right hindpaw (receptive field of L4 DRG neurons), the percentages of the activated L4 DRG neurons were obviously higher in the colitis model group than those in the control group (P<0.01, P<0.05), while there were no significant changes in the proportion of small, medium and large-sized neurons between the control and colitis model groups. Colitis may lead to body surface sensitization at the same and adjacent neuro-segments as well as to an increase of the number and activity of the responsive lumbar DRG neurons, among which the L6 DRG neurons at the same neuro-segment as the rectum colon showed an increase in the number of responders and intensity of calcium fluorescence signal while L4 DRG neurons at the level adjacent to the rectum colon showed an increase in the number of responders, suggesting that there may be different mechanisms of peripheral neural sensitization.

Molecular mechanisms of pain in acute pancreatitis: recent basic research advances and therapeutic implications.

Although severe abdominal pain is the main symptom of acute pancreatitis, its mechanisms are poorly understood. An emerging body of literature evidence indicates that neurogenic inflammation might play a major role in modulating the perception of pain from the pancreas. Neurogenic inflammation is the result of a crosstalk between injured pancreatic tissue and activated neurons, which leads to an auto-amplification loop between inflammation and pain during the progression of acute pancreatitis. In this review, we summarize recent findings on the role of neuropeptides, ion channels, and the endocannabinoid system in acute pancreatitis-related pain. We also highlight potential therapeutic strategies that could be applied for managing severe pain in this disease.

UNLOCKING PAIN MANAGEMENT FOR PEOPLE LIVING WITH DEMENTIA: AN INTERVENTION TO BE TAILORED

Abstract Effective pain management for persons living with dementia (PLWD) is critical to quality of life and could be achieve through rehabilitative care. However, it’s not well understood how physical therapists (PTs) and occupational therapists (OTs) develop and deliver treatment plans for PLWD, as most pain studies and evidence-based guidelines explicitly exclude those with cognitive impairment. In this qualitative descriptive study, we explored clinicians’ perceptions of pain management in PLWD as recommended by available guidelines. Semi-structured virtual interviews of 6 PTs and 4 OTs from 4 outpatient facilities were all female, with an average age of 36.7 (SD 8.78) years and an average clinical experience of 7.01 (SD 4.81) years. We analyzed transcripts using conventional content analysis and identified a consistent theme that rehabilitative-based interventions for pain management among PLWD need to be “carefully tailored.” Clinicians explained that the plan of care they designed for PLWD need to be tailored to the patient’s underlying pain mechanism, physical function, and comorbidities that can affect their participation in therapy, to avoid activities that exacerbate pain symptoms, and take into consideration the extent of memory loss that the person is experiencing and their preferences. This study highlights the important factors practicing clinicians take into consideration when developing rehabilitative programs to manage pain among PLWD. These findings can guide the updating of current pain management guidelines so they are more inclusive and tailored to PLWD.

Inhibition of aquaporin-4 and its subcellular localization attenuates below-level central neuropathic pain by regulating astrocyte activation in a rat spinal cord injury model

The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the upregulation of astrocytic aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly upregulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocyte activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of the AQP4 channel and perivascular localization in the SDH. Targeted inhibition of AQP4 subcellular localization with trifluoperazine effectively diminished astrocyte activation in vitro and further ablated astrocyte activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerge as a promising agent to prevent chronic CNP after SCI.