Papers: 5 Mar 2022 - 11 Mar 2022

Arthroscopic knee surgery remains a common treatment for symptomatic knee osteoarthritis, including for degenerative meniscal tears, despite guidelines strongly recommending against its use. This Cochrane Review is an update of a non-Cochrane systematic review published in 2017.

Psychological trauma is typically accompanied by physical pain, and posttraumatic stress disorder (PTSD) often co-occurs with chronic pain. Clinical reports suggest that pain after trauma may be part of a re-experiencing symptomatology. Classical conditioning can underlie visual re-experiencing since intrusions can occur as conditioned responses (CRs) to trauma-related cues. If individuals also experience pain to cues previously paired with, but not anymore inflicting nociceptive stimulation (CSs), conditioning could also explain re-experiencing of pain. Sixty-five participants underwent classical conditioning, where painful electrocutaneous stimulation and aversive film-clips served as unconditioned stimuli (USs) in a 2(pain/no pain)×2(aversive/neutral film) design. CSs were neutral pictures depicting contextual details from the films. One day later, participants were re-exposed to CSs during a memory-triggering-task (MTT). We assessed pain-CRs by self-report and an fMRI-based marker of nociceptive pain, the neurologic pain signature (NPS); and recorded spontaneous daily-life pain-intrusions with an e-diary. During conditioning, pain-signaling CSs elicited more self-reported-pain and NPS-responses than no-pain-signaling CSs. Possibly because the aversive-film masked differences in participants' responses to pain-signaling vs. no-pain-signaling CSs, pain-CRs during acquisition only emerged within the neutral-film condition. When participants were re-exposed to CSs during MTT, self-reported-pain-CRs during the neutral-film condition and, though more uncertain, NPS-CRs during the aversive-film condition persisted. Importantly, participants with stronger pain-CRs showed a greater probability and severity of experiencing spontaneous pain intrusions during daily-life. Our data support that pain can emerge as a CR with emotional and sensory components. Classical conditioning presents a possible mechanism explaining pain-intrusions, and more broadly, pain experienced without nociceptive input.

Sex differences in chronic pain are well established with documented predominance in women. This study assessed relationships between age at menarche and chronic pain, site-specific chronic pain, pain characteristics, and chronic widespread pain (CWP). We used data from the Tromsø Study conducted in 2007 to 2008 and 2015 to 2016 (Tromsø 6 and Tromsø 7 waves) including participants aged 30 to 99 years. The associations between age at menarche and chronic pain were examined in Tromsø 6 (n = 6449), Tromsø 7 (n = 5681), and the combination of Tromsø 6 and Tromsø 7 (n = 12,130). Tromsø 7 data were used further to examine the associations between age at menarche and site-specific chronic pain, 4 pain characteristics (pain duration, pain intensity, episode duration, and episode frequency), and CWP. All analyses were adjusted for body mass index, age, and economic status of the household in childhood. Lower age at menarche was associated with an increased risk of chronic pain in all 3 samples (risk ratio for each year delay in menarche 0.98, 95% CI [0.97 to 0.99] across samples). Risk differences were -0.014, CI 95% (-0.02 to -0.005) in Tromsø 6, -0.011, CI 95% (-0.02 to -0.02) in Tromsø 7, and -0.012, CI 95% (-0.02 to -0.01) in the combined sample. Age at menarche was significantly associated with chronic pain in the neck, abdomen, and both arms, and CWP. Of the 4 pain characteristics, pain duration was statistically significant. We conclude that early menarche is an independent risk factor for pain across a broad spectrum of pain outcomes.

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds and showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound , a central pyridine isomer of BMS-986176/LX-9211 (), was 4-fold more potent than in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to in the CCI rat model. However, both and showed an inferior preclinical toxicity profile compared to .

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. ()-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) () was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 () showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 () completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

With the change in lifestyle and aging of the population, osteoarthritis (OA) is emerging as a major medical burden globally. OA is a chronic inflammatory and degenerative disease initially manifesting with joint pain and eventually leading to permanent disability. To date, there are no drugs available for the definitive treatment of osteoarthritis and most therapies have been palliative in nature by alleviating symptoms rather than curing the disease. This coupled with the vague understanding of the early symptoms and methods of diagnosis so that the disease continues as a global problem and calls for concerted research efforts. A cascade of events regulates the onset and progression of osteoarthritis starting with the production of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α; catabolic enzymes, such as matrix metalloproteinases (MMPs)-1, -3, and -13, culminating into cartilage breakdown, loss of lubrication, pain, and inability to load the joint. Although intra-articular injections of small and macromolecules are often prescribed to alleviate symptoms, low residence times within the synovial cavity severely impair their efficacy. This review will briefly describe the factors dictating the onset and progression of the disease, present the current clinically approved methods for its treatment and diagnosis, and finally elaborate on the main challenges and opportunities for the application of nano/micromedicines in the treatment of osteoarthritis. Thus, future treatment regimens will benefit from simultaneous consideration of the mechanobiological, the inflammatory, and tissue degradation aspects of the disease. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.

Neuropathic pain is a clinically relevant complication in individuals with spinal cord injury (SCI). Pharmacological pain treatment is often insufficient and leads to undesirable side effects. Thus, alternative therapeutic approaches such as repetitive transcranial magnetic stimulation (rTMS) are of critical importance. We aimed to evaluate the effectiveness of rTMS in neuropathic pain secondary to SCI.

Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the gene that encodes the α subunit of neuronal voltage-gated Ca2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of Ca2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.

Compared to Non-Hispanic Whites (NHWs), individuals who self-identify as Non-Hispanic Blacks (NHBs) in the United States experience more severe and disabling chronic low back pain (cLBP). We hypothesized that differences in DNA methylation (DNAm) play a role in racial disparities in cLBP.

Adaptation to a constant sensory stimulus involves many sites along the path of sensory volleys towards perception. The evaluation of such phenomenon may be of clinical interest. We studied adaptation to a constant temperature stimulus in healthy subjects to set normative data, and in patients with sensory polyneuropathy (SPN), as proof of concept. Twenty-six healthy subjects and 26 patients with SPN in the context of chemotherapy treatment with oxaliplatin for colon cancer were instructed to express through an electronic VAS system (eVAS) the level of sensation felt when a thermode set at either 39º, 41º, 43º, 45º or 47º was applied to their ventral forearm. The eVAS recordings showed typically an abrupt onset that slowed to approach maximum sensation and continued with a slow decrease indicating adaptation. The time to respond (TR), the velocity of the initial response (VR), the maximum sensation (MA), the time to reach MA (MAt), the onset of adaptation (AO), and the decrease in the sensation level with respect to MA at 30 s after stimulus application (SL30), were dependent on the temperature level in all subjects. However, patients showed significantly delayed TR, slowed VR, decreased MA, delayed AO, and reduced SL30, with respect to healthy subjects. Differences were more pronounced at low temperature levels, with absent AO in 25 patients vs. 2 healthy subjects at temperatures of 39º and 41ºC. The study of adaptation to a constant temperature stimulus can furnish valuable data for the assessment of SPN patients.

The antinociceptive effects of garlic have shown promise in treating different chronic diseases in humans, such as knee osteoarthritis, rheumatoid arthritis, and peripheral arterial occlusive disease stage II. The most common garlic products are garlic powder (dried garlic), steam distilled garlic oils, garlic oil macerate, and aged garlic extract. These commercial products contain organosulfur compounds (OSC) that have been extensively evaluated in preclinical models and some clinical assays to treat different diseases against pain. In this review, we describe the importance of some bioactive compounds found in garlic and its role in treating pain. A systematic search of the literature in Dimensions, PubMed, Scopus, Web of Science was performed. Terms and preselected keywords relating to garlic, its derivates and organusulfur compunds in pain, were used to perform a systematic literature search. Two independent reviewers screened papers for inclusion and assessed the methodological quality. The antinociceptive activity of garlic and its OSC is related to its antioxidant and anti-inflammatory properties, which may be explained by the ability to block the synthesis of PGs, pro-inflammatory cytokines and interferon-γ, by the reduction COX- 2 activity and by increases the levels of anti-inflammatory cytokines. Besides, garlic extract is an activator of TRPA1 and TRPV1, where the principal responsible for this activation are OSC. The relationship between these pathways allows a better understanding how garlic and its derivates could be carrying out its pharmacological action over the management of acute and chronic pain and provide a base by further investigations.

Although the number of SARS-CoV-2 new cases may be declining due to the implementation of the vaccine in the USA, there is a rising cohort of people with long-term effects from the virus. These long-term effects include loss of taste, heart palpitations, and chronic pain syndromes. In this commentary, we assess the current literature to appraise the knowledge of long-term COVID-19 effects related to long-term pain syndromes including testicular pain, headache, chronic pain, and chest pain.

To evaluate the efficacy of adjuvant, capacitive resistive monopolar radiofrequency (CRMRF, INDIBA) treatment at 448 kHz together with physiotherapeutic techniques compared to a sham treatment with the same techniques, for pain reduction and quality of life (QoL) improvements in patients with chronic pelvic pain syndrome (CPPS).

The management of chronic neuropathic pain remains a challenge, because pain is subjective, and measuring it objectively is usually out of question. However, neuropathic pain is also a signal provided by maladaptive neuronal activity. Thus, the integral management of chronic neuropathic pain should not only rely on the subjective perception of the patient, but also on objective data that measures the evolution of neuronal activity. We will discuss different objective and subjective methods for the characterization of neuropathic pain. Additionally, the gaps and proposals for an integral management of chronic neuropathic pain will also be discussed. The current management that relies mostly on subjective measures has not been sufficient, therefore, this has hindered advances in pain management and clinical trials. If an integral characterization is achieved, clinical management and stratification for clinical trials could be based on both questionnaires and neuronal activity. Appropriate characterization may lead to an increase of effectiveness for new therapies, and a better quality of life for neuropathic pain sufferers.

Adenylyl cyclase type 1 (AC1) is involved in signaling for chronic pain sensitization in the central nervous system and is an emerging target for the treatment of chronic pain. AC1 and a closely related isoform AC8 are also implicated to have roles in learning and memory signaling processes. Our team has carried out cellular screening for inhibitors of AC1 yielding a pyrazolyl-pyrimidinone scaffold with low micromolar potency against AC1 and selectivity AC8. Structure-activity relationship (SAR) studies led to analogues with cellular IC values as low as 0.25 μM, selectivity AC8 and other AC isoforms as well as other common neurological targets. A representative analogue displayed modest antiallodynic effects in a mouse model of inflammatory pain. This series represents the most potent and selective inhibitors of Ca/calmodulin-stimulated AC1 activity to date with improved drug-like physicochemical properties making them potential lead compounds for the treatment of inflammatory pain.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a therapeutic tool to alleviate symptoms for neurological and psychiatric diseases such as chronic pain, stroke, Parkinson's disease, major depressive disorder, and others. Although the therapeutic potential of rTMS has been widely explored, the neurological basis of its effects is still not fully understood. Fortunately, the continuous development of imaging techniques has advanced our understanding of rTMS neurobiological underpinnings on the healthy and diseased brain. The objective of the current work is to summarize relevant findings from positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques evaluating rTMS effects. We included studies that investigated the modulation of neurotransmission (evaluated with PET and magnetic resonance spectroscopy), brain activity (evaluated with PET), resting-state connectivity (evaluated with resting-state functional MRI), and microstructure (diffusion tensor imaging). Overall, results from imaging studies suggest that the effects of rTMS are complex and involve multiple neurotransmission systems, regions, and networks. The effects of stimulation seem to not only be dependent in the frequency used, but also in the participants characteristics such as disease progression. In patient populations, pre-stimulation evaluation was reported to predict responsiveness to stimulation, while post-stimulation neuroimaging measurements showed to be correlated with symptomatic improvement. These studies demonstrate the complexity of rTMS effects and highlight the relevance of imaging techniques.

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease characterized by the attack of the immune system on the body's healthy joint lining and degeneration of articular structures. This disease involves an increased release of inflammatory mediators in the affected joint that sensitize sensory neurons and create a positive feedback loop to further enhance their release. Among these mediators, the cytokines and neuropeptides are responsible for the crippling pain and the persistent neurogenic inflammation associated with RA. More importantly, specific proteins released either centrally or peripherally have been shown to play opposing roles in the pathogenesis of this disease: an inflammatory role that mediates and increases the severity of inflammatory response and/or an anti-inflammatory and protective role that modulates the process of inflammation. In this review, we will shed light on the neuroimmune function of different members of the heat shock protein (HSPs) family and the complex manifold actions that they exert during the course of RA. Specifically, we will focus our discussion on the duality in the mechanism of action of Hsp27, Hsp60, Hsp70, and Hsp90.

Neuropathic pain indicates pain caused by damage to the somatosensory system and is difficult to manage and treat. A new treatment strategy urgently needs to be developed. Both autophagy and apoptosis are critical adaptive mechanisms when neurons encounter stress or damage. Recent studies have shown that, after nerve damage, both autophagic and apoptotic activities in the injured nerve, dorsal root ganglia, and spinal dorsal horn change over time. Many studies have shown that upregulated autophagic activities may help myelin clearance, promote nerve regeneration, and attenuate pain behavior. On the other hand, there is no direct evidence that the inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. Most studies have only shown that agents can simultaneously attenuate pain behavior and inhibit apoptotic activities in the injured dorsal root ganglia. Autophagy and apoptosis can crosstalk with each other through various proteins and proinflammatory cytokine expressions. Proinflammatory cytokines can promote both autophagic/apoptotic activities and neuropathic pain formation, whereas autophagy can inhibit proinflammatory cytokine activities and further attenuate pain behaviors. Thus, agents that can enhance autophagic activities but suppress apoptotic activities on the injured nerve and dorsal root ganglia can treat neuropathic pain. Here, we summarized the evolving changes in apoptotic and autophagic activities in the injured nerve, dorsal root ganglia, spinal cord, and brain after nerve damage. This review may help in further understanding the treatment strategy for neuropathic pain during nerve injury by modulating apoptotic/autophagic activities and proinflammatory cytokines in the nervous system.

Mast cells are widely distributed in various parts of the human body and play a vital role in the progression of many diseases. Recently, the close relationship between mast cells and acupoints was elucidated, and the role of mast cells in acupuncture analgesia has attracted the attention of researchers worldwide. Using mast cells, acupuncture analgesia and acupoint as key words to search CNKI, PubMed, Web of Science and other databases, combining the representative articles in these databases with the published research papers of our group, we summarized: The enrichment of mast cells and the dense arrangement of collagen fibers, microvessels, and nerves form the basis for acupoints as the reaction sites of acupuncture; acupuncture can cause the deformation of collagen fibers and activate TRPV channels on mast cells membrane, so as to stimulate mast cells to release bioactive substances and activate nerve receptors to generate analgesic effect; system biology models are set up to explain the quantitative process of information initiation and transmission at acupuncture points, and indicate that the acupuncture effect depends on the local mast cells density. In a conclusion, this review will give a scientific explanation of acupuncture analgesia from the material basis of acupoints, the local initiation, and afferent biological mechanism.

This review summarizes experimental evidence indicating that subcutaneous mast cells are involved in the trigger mechanism of analgesia induced by acupuncture, a traditional oriental therapy, which has gradually become accepted worldwide. The results are essentially based on work from our laboratories. Skin mast cells are present at a high density in acupuncture points where fine needles are inserted and manipulated during acupuncture intervention. Mast cells are sensitive to mechanical stimulation because they express multiple types of mechanosensitive channels, including TRPV1, TRPV2, TRPV4, receptors and chloride channels. Acupuncture manipulation generates force and torque that indirectly activate the mast cells via the collagen network. Subsequently, various mediators, for example, histamine, serotonin, adenosine triphosphate and adenosine, are released from activated mast cells to the interstitial space; they or their downstream products activate the corresponding receptors situated at local nerve terminals of sensory neurons in peripheral ganglia. The analgesic effects are thought to be generated via the reduced electrical activities of the primary sensory neurons. Alternatively, these neurons project such signals to pain-relevant regions in spinal cord and/or higher centers of the brain.

Background Fibromyalgia syndrome is characterised by extensive muscular pain and chronic fatigue. Among the pharmacologic and other nutrient supplements that have been studied, Vitamin D has garnered attention owing to the critical role it plays in inflammatory and pain pathways. We conducted a systematic literature review to examine the efficacy of vitamin D supplemen-tation in improving the clinical status of the patients and alleviating the symptoms of fibrom-yalgia. Methods We searched Cochrane CENTRAL, PubMed, Science Direct, Scopus, grey literature (medrXiv and biorXiv) for observational studies, randomized controlled trials, case-control studies, and case reports published in English from January 2011 to May 2021, using the terms vitamin D and fibromyalgia or FMS. References were reviewed manually and articles were only included if they were specific in their diagnosis of fibromyalgia. Results 2651 studies were retrieved, with 12 studies fulfilling the inclusion criteria. 11 out of these 12 studies were of high quality and showed low risk of bias. 11 of these also demonstrated de-finitive improvement in clinical status and various outcome measures following supplementa-tion with Vitamin D. Conclusions Our study emphasises an association between supplementation of vitamin D and improve-ment of the clinical condition fibromyalgia through a systematic review of high-quality stud-ies. The study also identified areas for future scope for research that is needed for standardis-ing the detection and treatment of this chronic condition through cost-effective supplements such as Vitamin D.

Itch-induced scratching is an evolutionarily conserved behavioral response that protects organisms from potential parasites/irritants in their immediate vicinity. How the exposure to a pruritogen is translated to the perception of itch and how that perception drives scratching directed towards the site of exposure remains poorly understood. In this review, we focus on the recent findings that shed light on the neural pathways in the brain that underlie itch-induced scratching. We compare the molecularly defined itch pathways with the known pain circuits as they have anatomical and functional overlap. We review the roles played by the neurons in the spinoparabrachial pathway-comprising of the neurons in the spinal cord and the parabrachial nucleus (PBN), which acts as a hub for transmitting itch information across the brain. Lastly, we deliberate on scratching as a behavioral measure of the intensity of itch and its implication in unraveling the underlying supraspinal mechanisms. In summary, we provide a resource on the recent advances and discuss a path forward on our understanding of the neural circuits for itch.

A major limitation in treatment outcomes for chronic pain is the heterogeneity of the population. Therefore, a personalized approach to the assessment and treatment of children and adolescents with chronic pain conditions is needed. The objective of the study was to subgroup pediatric patients with chronic MSK pain that will be phenotypically different from each other based on their psychosocial profile, somatosensory function, and pain modulation.

Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. The processing of pain involves complicated modulation at the levels of the periphery, spinal cord, and brain. The pathogenesis of chronic pain is still not fully understood, which makes the clinical treatment challenging. Optogenetics, which combines optical and genetic technologies, can precisely intervene in the activity of specific groups of neurons and elements of the related circuits. Taking advantage of optogenetics, researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission, pain modulation, and chronic pain both in the periphery and the central nervous system. In this review, we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.

The role of the trigeminal system in facial and dural sensitivity has been recognized for a long time. More recently, the trigeminal system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, trigeminal neuralgia, and other orofacial pains. Appreciation of the delicate anatomical arrangement of the trigeminal pathway is one of the keys to understanding these conditions' pathophysiology and to proposing innovative treatments. This review provides a structured presentation of existing knowledge about the trigeminal system, from classical anatomical data to the most recent literature. First, we present the organization of the trigeminal pathway from the trigeminal divisions, nerve, and nuclei to the thalamus and somatosensory cortex. We describe the neurons and fibers' repartition at each level, depending on the location (somatotopic organization) and the type of receptors (modal organization). Such a dual somatotopic-modal arrangement of the trigeminal fibers is especially clear for the juxtapontine segment of the trigeminal nerve and the trigeminal nuclei of the brainstem. It has significant clinical consequences both for diagnosis and treatment. Second, we explore how the trigeminal system is modulated and involved in reflexes, for instance the trigemino-cardiac and the trigemino-autonomic reflexes, which could play an essential role in the autonomic symptoms observed in cluster headache. Finally, we present how to interact with this complex system to relieve pain mediated by the trigeminal system. This section covers both neuromodulatory and lesional approaches.

This consensus statement has been developed by the Thai Interest Group for Endometriosis (TIGE) for use by Thai clinicians in the diagnosis and management of endometriosis. TIGE is a group of clinical and academic gynaecologists with a particular interest in endometriosis. Endometriosis is an oestrogen-dependent inflammatory disease which causes chronic symptoms such as dysmenorrhoea, chronic pelvic pain, dyspareunia and subfertility, and it is common in reproductive-age women. There is limited overall data on its prevalence in different clinical settings in Thailand, but it is clear that the disease causes significant problems for patients in terms of their working lives, fertility, and quality of life, as well as placing a great burden on national healthcare resources. Decisions about selecting the appropriate treatment for women with endometriosis depend on many factors including the age of the patient, the extent and severity of disease, concomitant conditions, economic status, patient preference, access to medication, and fertility need. Several hormonal treatments are available but no consensus has been reached about the best option for long-term prevention of recurrence. Bearing in mind differences in environment, genetics, and access to the healthcare system, this treatment guideline has been tailored to the particular circumstances of Thai women.

Intractable pain after peripheral nerve injury has become a major concern in the field of pain. Current evidence shows that routine medications or surgical treatment is associated with inconsistent results and different curative effects. Stable and effective treatment methods in clinical practice are also lacking. To date, there is no consensus on the pathophysiological mechanisms of pain. The present study investigates the potential regulatory role of regulatory T cells in the differentiation of macrophages on dorsal root ganglion (DRG) and explores the mechanism of nociceptive signals in the signal transfer station. The findings are expected to guide the prevention of various types of peripheral neuropathic pain.

Photobiomodulation therapy (PBM) is often used to treat musculoskeletal disorders such as chronic non-specific low back pain (NSCLBP) as it can have positive effects on biomarkers-creatine kinase (CK) and serum cortisol levels-related to stress caused by physical exercise, such as deep water running (DWR) or by pain. The aim of this study was to evaluate the effects of the combination of PBM and aquatic exercise (DWR) on the intensity of pain, disability, 6-min walk test adapted (6WTA), and on cortisol and creatine kinase (CK) levels in a population with NSCLBP. The participants were allocated into three groups: TG (Photobiomodulation and Training Group), TG (Placebo Photobiomodulation and Training Group), and the G (Photobiomodulation Group). Information regarding anthropometric data, blood pressure, and heart rate were collected, and the questionnaires were applied: IPAQ-Short Form, Oswestry Disability Index, and the Visual Analog Scale for Pain. The submaximal exercise test (6WTA) was performed. Blood was collected for analysis of cortisol and CK levels. The training sessions were performed twice a week, for 4 weeks. In the intragroup comparisons, there were statistically significant changes in the TG and G groups in the outcomes pain intensity, disability (reductions in both groups), and in cortisol (increased in the TG and reduced in the G); in the TG group, there was a statistically significant reduction only in the outcome of pain intensity. In the intergroup comparison, in the comparison between TG and TG, there was a statistically significant difference in the level of cortisol, as well as in the comparison between TG and G, in which there was a statistically significant difference for this same outcome (cortisol) and for the 6WTA outcome. The effects of the combination of PBM and aquatic exercise have positive effects on reducing pain intensity, disability, and cortisol levels, but its effects on other variables (6WTA and CK) are too small to be considered significant. Trial registration number: NCT03465228-April 3, 2019; retrospectively registered (ClinicalTrials.gov).

Neuronal cytotoxic edema is the morphological correlate of the near-complete neuronal battery breakdown called spreading depolarization, or conversely, spreading depolarization is the electrophysiological correlate of the initial, still reversible phase of neuronal cytotoxic edema. Cytotoxic edema and spreading depolarization are thus different modalities of the same process, which represents a metastable universal reference state in the gray matter of the brain close to Gibbs-Donnan equilibrium. Different but merging sections of the spreading-depolarization continuum from short duration waves to intermediate duration waves to terminal waves occur in a plethora of clinical conditions, including migraine aura, ischemic stroke, traumatic brain injury, aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI), spontaneous intracerebral hemorrhage, subdural hematoma, development of brain death, and the dying process during cardio circulatory arrest. Thus, spreading depolarization represents a prime and simultaneously the most neglected pathophysiological process in acute neurology. Aristides Leão postulated as early as the 1940s that the pathophysiological process in neurons underlying migraine aura is of the same nature as the pathophysiological process in neurons that occurs in response to cerebral circulatory arrest, because he assumed that spreading depolarization occurs in both conditions. With this in mind, it is not surprising that patients with migraine with aura have about a twofold increased risk of stroke, as some spreading depolarizations leading to the patient percept of migraine aura could be caused by cerebral ischemia. However, it is in the nature of spreading depolarization that it can have different etiologies and not all spreading depolarizations arise because of ischemia. Spreading depolarization is observed as a negative direct current (DC) shift and associated with different changes in spontaneous brain activity in the alternating current (AC) band of the electrocorticogram. These are non-spreading depression and spreading activity depression and epileptiform activity. The same spreading depolarization wave may be associated with different activity changes in adjacent brain regions. Here, we review the basal mechanism underlying spreading depolarization and the associated activity changes. Using original recordings in animals and patients, we illustrate that the associated changes in spontaneous activity are by no means trivial, but pose unsolved mechanistic puzzles and require proper scientific analysis.

Conceptualizing physical pain and negative affect as potentially interactive, we hypothesized that higher levels of peripheral inflammatory markers would be observed consistently only among individuals with both higher negative affect and pain symptomatology. Participants were generally healthy midlife adults from the Bronx, NY ( ​= ​212,  ​= ​46.77; 60.8% Black, 25.5% Hispanic/Latina/o) recruited as part of a larger study. Key measures were: reported pain intensity and pain interference at baseline, recent negative affect averaged from self-reports 5x/day for 7 days, and peripheral inflammatory markers (C-reactive protein [CRP] and a composite cytokine measure based on seven cytokines). Controlling for age, BMI, gender, and education, recent negative affect significantly interacted with both pain variables to explain variance in CRP, with higher CRP levels observed only in individuals with both higher negative affect and either higher pain intensity or pain interference. These findings contribute to an emerging literature suggesting that negative affect, pain, and inflammation are related in important and complex ways.

Episodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI).

Endometriosis is a painful, chronic inflammatory disorder that is difficult to treat. Studies have suggested that diet may have a therapeutic effect on chronic inflammation. However, only limited information is available regarding the impact of diet on pain perception in relation to endometriosis. As such, the aim of this review was to evaluate if diet has any impact on pain perception in women suffering from endometriosis.

Osteoarthritis (OA) is the most common joint condition. It affects more than 300 million people worldwide, who suffer from pain and physical disability.

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of neurotoxic antineoplastic agents commonly used to treat cancer. Patients with CIPN experience debilitating signs and symptoms, such as combinations of tingling, numbness, pain, and cramping in the hands and feet that inhibit their daily function. Among the limited prevention and treatment options for CIPN, exercise has emerged as a promising new intervention that has been investigated in approximately two dozen clinical trials to date. As additional studies test and suggest the efficacy of exercise in treating CIPN, it is becoming more critical to develop mechanistic understanding of the effects of exercise in order to tailor it to best treat CIPN symptoms and identify who will benefit most. To address the current lack of clarity around the effect of exercise on CIPN, we reviewed the key potential mechanisms (e.g., neurophysiological and psychosocial factors), mediators (e.g., anti-inflammatory cytokines, self-efficacy, and social support), and moderators (e.g., age, sex, body mass index, physical fitness, exercise dose, exercise adherence, and timing of exercise) that may illuminate the relationship between exercise and CIPN improvement. Our review is based on the studies that tested the use of exercise for patients with CIPN, patients with other types of neuropathies, and healthy adults. The discussion presented herein may be used to (1) guide oncologists in predicting which symptoms are best targeted by specific exercise programs, (2) enable clinicians to tailor exercise prescriptions to patients based on specific characteristics, and (3) inform future research and biomarkers on the relationship between exercise and CIPN.

It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain.

Galanin is a neuropeptide expressed in a small percentage of sensory neurons of the dorsal root ganglia and the superficial lamina of the dorsal horn of the spinal cord. In this work, we systematically reviewed the literature regarding the role of galanin and its receptors in nociception at the spinal and supraspinal levels, as well as in chronic pain conditions. The literature search was performed in PubMed, Web of Science, Scopus, ScienceDirect, OVID, TRIP, and EMBASE using "Galanin" AND "pain" as keywords. Of the 1379 papers that were retrieved in the initial search, we included a total of 141 papers in this review. Using the ARRIVE guidelines, we verified that 89.1% of the works were of good or moderate quality. Galanin shows a differential role in pain, depending on the pain state, site of action, and concentration. Under normal settings, galanin can modulate nociceptive processing through both a pro- and anti-nociceptive action, in a dose-dependent manner. This peptide also plays a key role in chronic pain conditions and its antinociceptive action at both a spinal and supraspinal level is enhanced, reducing animals' hypersensitivity to both mechanical and thermal stimulation. Our results highlight galanin and its receptors as potential therapeutic targets in pain conditions.

This review discusses the role of opioids in the corneal surface and the different pathways and therapeutic methods of management. A literature review was performed using PubMed database. For the database search, the main searching words "opioid" and "topical opioid treatment" were used with the descriptors "cornea", "ocular surface", "neuropathic corneal pain", "corneal sensitivity" and "naltrexone"; original scientific articles and reviews were included to achieve the purpose of the review. The endogenous opioid system has relevant functions in the organism, and in daily use, opioids are used as painkillers. However, these drugs may be employed for other indications as opioid pathways have a wide spectrum. The corneal surface for topical treatment is easily accessible, hence sparing the side effects of systemic opioids. Instillation of opioid antagonist substances, such as naltrexone, increases corneal healing rates and stimulates the division of corneal epithelium cells without deleterious effects. The natural modulation of endogenous opioids controls different forms of pain, including inflammatory and neuropathic pain, both in the ocular surface and in the central nervous system. There are diverse methods in controlling pain using opioids, especially in refractory forms. This review attempts to collect the literature about corneal surface and opioid pathways to provide an overview image and a possible direction of the news treatments.

Endometriosis is an estrogen-dependent and chronic inflammatory gynecological disease due to the presence of ectopic endometrial tissue outside the uterine cavity. This disease affects approximately 10% of the female population. In spite of its relatively high prevalence, information about its pathogenesis, diagnosis, and therapy is not complete.

The calcium-permeable cation channel TRPM3 can be activated by heat and the endogenous steroid pregnenolone sulfate. TRPM3's best understood function is its role as a peripheral noxious heat sensor in mice. However, the channel is expressed in various tissues and cell types including neurons as well as glial and epithelial cells. TRPM3 expression patterns differ between species and change during development. Furthermore, a plethora of TRPM3 variants that result from alternative splicing have been identified and the majority of these isoforms are yet to be characterized. Moreover, the mechanisms underlying regulation of TRPM3 are largely unexplored. In addition, a micro-RNA gene (miR-204) is located within the TRPM3 gene. This complexity makes it difficult to obtain a clear picture of TRPM3 characteristics. However, a clear picture is needed to unravel TRPM3's full potential as experimental tool, diagnostic marker and therapeutic target. Therefore, the newest data related to TRPM3 have to be discussed and to be put in context as soon as possible to be up-to-date and to accelerate the translation from bench to bedside. The aim of this review is to highlight recent results and developments with particular focus on findings from studies involving ocular tissues and cells or peripheral neurons of rodents and humans.