Papers: 16 Jul 2022 - 22 Jul 2022

A circuit for sound-induced analgesia has been found in the mouse brain.

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Capsaicin, an agonist at the transient receptor potential vanilloid 1, is used for the topical treatment of peripheral neuropathic pain. Reversible receptor defunctionalization and degeneration and subsequent regeneration of cutaneous nociceptors are discussed as its mechanism of action. Here, we hypothesize an accelerated functional recovery of a sub-class of nociceptive afferents, the peptidergic vasoactive nociceptors, as the potential cause of capsaicin analgesia.In this non-interventional exploratory trial, 23 patients with peripheral neuropathic pain were treated with one topical high-concentration capsaicin application. Baseline pain ratings, co-morbidities and quality-of-life were assessed. Functional laser-speckle-contrast-analysis (fLASCA, heat-evoked neurogenic vasodilatation to assess functional properties of peptidergic nociceptors) and quantitative sensory testing (QST) were performed in the affected skin. Four weeks after treatment fLASCA and questionnaires were repeated. Telephone interviews were conducted at week 2, 10 and 12.Topical capsaicin treatment induced a significant reduction of pain intensity with a maximum at four weeks. At the same time, heat-evoked neurogenic vasodilatation was on average similar to pre-treatment values. Half of the patients not only showed a functional recovery but also an improvement of vasodilatation, indicating regeneration of nerve fibers. Patients with improved heat-evoked neurogenic vasodilatation at week 4 showed a greater pain reduction than patients with deterioration. The degree of vasodilatation significantly correlated with pain reduction.These findings suggest that (i) regeneration of peptidergic nociceptors may be one mechanism of capsaicin-induced analgesia and (ii) that a disease-modifying effect of capsaicin on these fibers already occurs four weeks after application.

The overprescription of opioids to surgical patients is recognized as an important factor contributing to the opioid crisis. However, the value of prescribing opioid analgesia (OA) vs opioid-free analgesia (OFA) after postoperative discharge remains uncertain.

Vestibular migraine is an underdiagnosed but increasingly recognised neurological condition that causes episodic vertigo associated with other features of migraine. It is now thought to be the most common cause of spontaneous (non-positional) episodic vertigo, affecting up to 1% of the population. A meta-analysis of preventative treatments for vestibular migraine was published in 2021 but the authors were unable to establish a preferred treatment strategy due to low quality of evidence and heterogeneity of study design and outcome reporting. There remains therefore a clinical need for pragmatic management guidelines specific to vestibular migraine using the available evidence. Here we provide a practical review utilising a systematic qualitative assessment of the evidence for abortive and preventative interventions in adults. The overall evidence base for vestibular migraine treatment is of low quality. Nevertheless, we provide practical treatment recommendations based on the available evidence and our experience to help guide clinicians treating patients with vestibular migraine. We also discuss how future clinical trials could be designed to improve the quality of evidence in this condition.

The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over 32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator's Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16.

The Infrapatellar Fat Pad (IFP) is a fibro-adipose tissue of the knee recently reconsidered as part of a single anatomo-functional unit (AFU) together with the synovial membrane (SM). Several evidence support the role of this unit in the mechanisms that trigger and perpetuate the onset and progression of osteoarthritis (OA) disease. Additionally, the contribution of IFP-SM AFU in OA-associated pain has also been supposed, but this assumption still needs to be fully elucidated. Within this context, the recent discovery of the mechanoceptive Piezo ion channels (i.e., Piezo1 and Piezo2) in mammals and consciousness on their role in mediating both mechanoceptive and inflammatory stimuli could shed some light on knee OA pain, as well as on the process leading from acute to chronic nociceptive responses. For this purpose, the IFP-SM AFUs of both healthy donors (non-OA IFP-SM AFUs, = 10) and OA patients (OA IFP-SM AFUs, = 10) were processed by histology and immunohistochemistry. After the attribution of a histopathological score to IFP-SM AFUs to confirm intrinsic differences between the two groups, the specimens were investigated for the expression and localization/distribution pattern of the mechanosensors Piezo1 and Piezo2. In addition, the presence of monocytes/macrophages (CD68), peripheral nerve endings (PGP9.5) and neoangiogenesis signs (YAP1) was evaluated for a broad tissue characterization. The study results lead to a better description of the IFP-SM AFU microscopic features in both healthy and pathological conditions, highlighting peculiar differences in the study cohort. Specifically, immunopositivity towards Piezo1/2, CD68 and YAP1 markers was detected at vessels level in the OA- IFP-SM AFUs compartments, differently from the non-OA-group. A correlation with pain was also inferred, paving the way for the identification of new and effective molecules in OA management.

Spastic cerebral palsy (CP) is a movement disorder marked by hypertonia and hyperreflexia; the most prevalent comorbidity is pain. Since spinal nociceptive afferents contribute to both the sensation of painful stimuli as well as reflex circuits involved in movement, we investigated the relationship between prenatal hypoxia-ischemia (HI) injury which can cause CP, and possible changes in spinal nociceptive circuitry. To do this, we examined nociceptive afferents and mechanical and thermal sensitivity of New Zealand White rabbit kits after prenatal HI or a sham surgical procedure. As described previously, a range of motor deficits similar to spastic CP was observed in kits born naturally after HI (40 min at ~70%-80% gestation). We found that HI caused an expansion of peptidergic afferents (marked by expression of calcitonin gene-related peptide) in both the superficial and deep dorsal horn at postnatal day (P)5. Non-peptidergic nociceptive afferent arborization (labeled by isolectin B4) was unaltered in HI kits, but overlap of the two populations (peptidergic and non-peptidergic nociceptors) was increased by HI. Density of glial fibrillary acidic protein was unchanged within spinal cord white matter regions important in nociceptive transmission at P5. We found that mechanical and thermal nociception was enhanced in HI kits even in the absence of motor deficits. These findings suggest that prenatal HI injury impacts spinal sensory pathways in addition to the more well-established disruptions to descending motor circuits. In conclusion, changes to spinal nociceptive circuitry could disrupt spinal reflexes and contribute to pain experienced by individuals with CP.

To provide an estimate of the effectiveness of basivertebral nerve (BVN) radiofrequency ablation (RFA) to treat vertebrogenic low back pain (LBP).

A previously developed educational e-health tool considers both clinical and psychosocial factors when selecting patients with chronic pain for spinal cord stimulation (SCS). The validity of the composite recommendations was evaluated in a retrospective study, demonstrating a strong relationship with patient outcomes after SCS.

Chronic pain is a long-standing unpleasant sensory and emotional feeling that has a tremendous impact on the physiological functions of the body, manifesting itself as a dysfunction of the nervous system, which can occur with peripheral and central sensitization. Many recent studies have shown that a variety of common immune cells in the immune system are involved in chronic pain by acting on the peripheral or central nervous system, especially in the autoimmune diseases. This article reviews the mechanisms of regulation of the sensory nervous system by neutrophils, macrophages, mast cells, B cells, T cells, and central glial cells. In addition, we discuss in more detail the influence of each immune cell on the initiation, maintenance, and resolution of chronic pain. Neutrophils, macrophages, and mast cells as intrinsic immune cells can induce the transition from acute to chronic pain and its maintenance; B cells and T cells as adaptive immune cells are mainly involved in the initiation of chronic pain, and T cells also contribute to the resolution of it; the role of glial cells in the nervous system can be extended to the beginning and end of chronic pain. This article aims to promote the understanding of the neuroimmune mechanisms of chronic pain, and to provide new therapeutic ideas and strategies for the control of chronic pain at the immune cellular level.

Despite years of research and the development of countless awareness campaigns, the number of deaths related to prescription opioid overdose is steadily rising. Often, naive patients undergoing trauma-related surgery are dispensed opioids while in the hospital, resulting in an escalation to long-term opioid misuses. We explored the impact of an educational intervention to modify perceptions of opioid needs at the bedside of trauma inpatients in post-surgery pain management.

Pain modulation of dopamine-producing nuclei is known to contribute to the affective component of chronic pain. However, pain modulation of pain-related cortical regions receiving dopaminergic inputs is understudied. The present study demonstrates that mice with chronic inflammatory injury of the hind paws develop persistent mechanical hypersensitivity and transient anxiety. Peripheral inflammation induced by injection of complete Freund's Adjuvant (CFA) induced potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) currents with a presynaptic component in layer II/III of the ACC. After four days of inflammatory pain, the dopamine-mediated inhibition of AMPAR currents was significantly reduced in the ACC. Furthermore, dopamine enhanced presynaptic modulation of excitatory transmission, but only in mice with inflammatory pain. High-performance liquid chromatography (HPLC) analysis of dopamine tissue concentration revealed that dopamine neurotransmitter concentration in the ACC was reduced three days following CFA. Our results demonstrate that inflammatory pain induces activity-dependent changes in excitatory synaptic transmission and alters dopaminergic homeostasis in the ACC.

Pain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40-60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus.

A role of the immune system in the pathophysiology of pain and hyperalgesia has received growing attention, especially in the context of visceral pain and the gut-brain axis. While acute experimental inflammation can induce visceral hyperalgesia as part of sickness behavior in healthy individuals, it remains unclear if normal plasma levels of circulating pro-inflammatory cytokines contribute to interindividual variability in visceral sensitivity. We herein compiled data from a tightly screened and well-characterized sample of healthy volunteers ( = 98) allowing us to assess associations between visceral sensitivity and gastrointestinal symptoms, and plasma concentrations of three selected pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-8), along with cortisol and stress-related psychological variables. For analyses, we compared subgroups created to have distinct pro-inflammatory cytokine profiles, modelling healthy individuals at putative risk or resilience, respectively, for symptoms of the gut-brain axis, and compared them with respect to rectal sensory and pain thresholds and subclinical GI symptoms. Secondly, we computed multiple regression analyses to test if circulating pro-inflammatory markers predict visceral sensitivity in the whole sample. Despite pronounced subgroup differences in pro-inflammatory cytokine and cortisol concentrations, we observed no differences in measures of visceroception. In regression analyses, cytokines did not emerge as predictors. The pain threshold was predicted by emotional state and trait variables, especially state anxiety, together explaining 10.9% of the variance. These negative results do not support the hypothesis that systemic cytokine levels contribute to normal interindividual variability in visceroception in healthy individuals. Trajectories to visceral hyperalgesia as key marker in disorders of gut-brain interactions likely involve complex interactions of biological and psychological factors in keeping with a psychosocial model. Normal variations in systemic cytokines do not appear to constitute a vulnerability factor in otherwise healthy individuals, calling for prospective studies in at risk populations.

The aim of this study was to compare the limbic structures and covariance network in patients with cluster headache to those of healthy controls. We enrolled 23 patients with newly diagnosed cluster headache and 31 healthy controls. They underwent three-dimensional T1-weighted imaging utilizing a 3.0 Tesla MRI scanner. Volumetric analysis of the subcortical limbic structures, including the hippocampus, amygdala, thalamus, mammillary body, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens, was performed. We examined the limbic covariance network using a graph theory. The volumes of the limbic structures between patients with cluster headache and healthy controls were significantly different. The volume of the left hippocampus in patients with cluster headache was significantly lower than that in healthy controls (0.256 vs 0.291 %, p = 0.002). Patients with cluster headache showed significant alterations of the limbic covariance network. The average strength, global efficiency, local efficiency, mean clustering coefficient, and transitivity were lower (5.238 vs 10.322, p = 0.030; 0.355 vs 0.608, p = 0.020; 0.547 vs 1.553, p = 0.020; 0.424 vs 0.895, p = 0.016; respectively), whereas the characteristic path length was higher (3.314 vs 1.752, p = 0.040) in patients with cluster headache than in healthy controls. We detected alterations of limbic structure volumes in patients with cluster headache compared to healthy controls, especially in the hippocampus. We also found significant alterations in the limbic covariance network in patients with cluster headache who showed decreased segregation and integration. These abnormalities could be related to the pathophysiology of cluster headache.

Brain structural and functional abnormalities have been separately reported in patients with classic trigeminal neuralgia (CTN). However, whether and how the functional deficits are related to the structural alterations remains unclear. This study aims to investigate the anatomical and functional deficits in patients with CTN and explore their association.

Inflammation is a vital process for the injured tissue restoration and one of its hallmarks is inflammatory hyperalgesia. The cyclooxygenase (COX) pathway is strongly related to the inflammatory and painful process. Usually, the COX-1 isoform is described as homeostatic, while COX-2 is characterized as inducible in inflammatory conditions. Although it is well known that neutrophil cells are the first to arrive at the inflamed site and the major source of COX-2 is still unknown, the specific role of neutrophil-derived COX-2 in the pain process is. Thus, in the present study, we demonstrate for the first time that neutrophil-derived COX-2 plays a key role in peripheral inflammatory hyperalgesia. Conditional knockout mice for COX-2 in neutrophils (COX-2) exhibited higher pain sensitivity after carrageenan (CG) injection and long-lasting IL-1β-induced hyperalgesia compared with the control group (COX-2). Also, CG-induced inflammation in COX-2 mice showed COX-1 overexpression, and increased neutrophil migration and pro-inflammatory cytokines (e.g., IL-1β and CXCL1). These findings revealed that neutrophil COX-2 has an important role in the regulation of inflammatory hyperalgesia.

Varicella zoster virus-induced postherpetic neuralgia (PHN) can be alleviated by limited medications with serious side effects. This study aims to investigate the underlying molecular mechanism of miR-199-3p in mediating PHN in mice. 293T cells were transfected with miR-199-3p vectors (mimic/inhibitor). The target relationship between miR-199-3p and MECP2 was confirmed using luciferase reporter assay. PHN mouse model was established by TRX injection. Animal behaviors were evaluated using Hargreaves test and Von Frey test. Western blot was used for protein analysis, and quantitative reverse transcription polymerase chain reaction was performed for messenger RNA quantification. Serum levels of inflammatory mediators were determined using ELISA. Paw withdrawal latency (PWL) and mechanical withdrawal threshold (MWT) were decreased in resiniferatoxin-induced PHN mice. Downregulated miR-199-3p and upregulated MECP2 were found in PHN mice. Upregulated miR-199-3p increased PWL and MWT, but inhibited MECP2 in PHN mice. Besides, increased miR-199-3p suppressed proinflammatory indicators and activated anti-inflammatory mediators. It also found that MECP2 was the target of miR-199-3p. Further study showed miR-199-3p enhanced PWL and MWT, and supported inflammatory response via targeting MECP2. miR-199-3p regulated inflammation by targeting MECP2 to alleviate TRX-induced PHN in mice.

Opioids are powerful analgesics that elicit acute antinociceptive effects through their action the mu opioid receptor (MOR). However opioids are ineffective for chronic pain management, in part because continuous activation of MORs induces adaptive changes at the receptor level and downstream signaling molecules. These adaptations include a decrease in receptor-effector coupling and changes to second messenger systems that can counteract the persistent activation of MORs by opioid agonists. Homeostatic regulation of MORs and downstream signaling cascades are viewed as precursors to developing tolerance. However, despite numerous studies identifying crucial mechanisms that contribute to opioid tolerance, no single regulatory mechanism that governs tolerance in at the cellular and systems level has been identified. Opioid tolerance is a multifaceted process that involves both individual neurons that contain MORs and neuronal circuits that undergo adaptations following continuous MOR activation. The most proximal event is the agonist/receptor interaction leading to acute cellular actions. This review discusses our understanding of mechanisms that mediate cellular tolerance after chronic opioid treatment that, in part, is mediated by agonist/receptor interaction acutely.

The sensory experience of pain depends not only on the transmission of noxious information (nociception), but on the state of the body in a biological, psychological, and social milieu. A brainstem pain-modulating system with its output node in the rostral ventromedial medulla (RVM) can regulate the threshold and gain for nociceptive transmission. This review considers the current understanding of how RVM pain-modulating neurons, namely ON-cells and OFF-cells, are engaged by "top-down" cognitive and emotional factors, as well as by "bottom-up" sensory inputs, to enhance or suppress pain.

Chronic post-surgical pain predictive scores exist, but none has yet demonstrated an impact on patient care. Van Driel and colleagues offer an additional perspective on early postoperative detection of patient at risk of chronic post-surgical pain to enable early interventions in prevention and treatment. The authors derived and validated a model based on four easily obtainable predictors that could help clinicians assess and treat patients at risk. Additional work is needed to prove reliability and clinical benefit of chronic post-surgical pain prediction and intervention.

Pain is a warning signal for the body defense mechanisms and is a critical sensation for supporting life. However, orofacial pain is not a vital sensation, but a disease. However, there are still many unclear points about the pathophysiological mechanism of orofacial pain. This situation makes it difficult for many clinicians to treat orofacial pain hypersensitivity.

Itch occurs in various dermatologic and systemic conditions. Many patients report that certain foods instigate itch, although there is limited published information in dermatology on food-induced pruritus. In addition, itch severity is rarely mentioned. Food can induce pruritus through either ingestion or direct contact with skin or mucosal membranes. The most common type of itch provoked by food is acute urticaria, often through the classical immunoglobulin E (IgE)-mediated pathway. Other mechanisms include non-IgE-mediated, mixed (IgE-mediated and non-IgE-mediated), T-cell-mediated, and nonimmune reactions. For patients presenting with urticaria, generalized pruritus, oral pruritus, or dermatitis, a thorough history is warranted, and possible food associations should be considered and assessed. Although any food seems to have the potential to elicit an immune response, certain foods are especially immunogenic. Treatment includes avoidance of the trigger and symptom management. Careful consideration should be used as to avoid unnecessarily restrictive elimination diets.

Pilates is a popular system of exercise that is recommended for healthy individuals and patients with low back pain (LBP). The restoration of muscle function in lumbopelvic stability and pelvic floor muscles has been fostered by practices based on this strategy. Restoring or sustaining the motor control of the lumbar spine and proper body posture during each exercise is very important. The aim of this umbrella review (UR) of systematic reviews and narrative reviews is to detect the effects of exercise on patients with chronic low back pain (CLBP).

To evaluate whether transcutaneous electrical nerve stimulation (TENS) reduces opioid use after cesarean birth.

To study the effect of time on shift on the opioid prescribing practices of emergency physicians among patients without chronic opioid use.

The role of GABAergic cell transplantation in improving neuropathic pain is controversial. We comprehensively searched the relevant literature to identify animal studies of GABAergic cell transplantation that recorded pain behaviors as an outcome according to the Cochrane Handbook 5.0.2. Controlled studies assessing the administration of GABAergic neurons or GABAergic neuronal progenitor cells to rat or mouse neuropathic pain animal models were included. Basic design information and mechanical allodynia thresholds and heat hyperalgesia thresholds data were collected. The risk of bias for the animal experiments was assessed according to the SYRCLE's tool. This study included 10 full-text articles. GABAergic cells transplantation leads to a statistically significant improvement of allodynia (SMD = 5.26; 95% confidence interval: 3.02-7.51; < 0.001) and hyperalgesia (SMD: 4.10; 95% confidence interval: 1.84-6.35; < 0.001). Differentiated GABAergic cells and without antibiotics using may have a better effect for improving neuropathic pain. GABAergic cell transplantation is a promising treatment for improving neuropathic pain. This systematic review and meta-analysis evaluated the effects of GABAergic cell transplantation on neuropathic pain, which can guide future clinical trials and possible clinical treatments, and better attenuate neuropathic pain caused by abnormal circuit hyperexcitability.

Different studies have confirmed P2X7 receptor-mediated inflammatory mediators play a key role in the development of pain. P2X7 receptor activation can induce the development of pain by mediating the release of inflammatory mediators. In view of the fact that P2X7 receptor is expressed in the nervous system and immune system, it is closely related to the stability and maintenance of the nervous system function. ATP activates P2X7 receptor, opens non-selective cation channels, activates multiple intracellular signaling, releases multiple inflammatory cytokines, and induces pain. At present, the role of P2X7 receptor in inflammatory response and pain has been widely recognized and affirmed. Therefore, in this paper, we discussed the pathological mechanism of P2X7 receptor-mediated inflammation and pain, focused on the internal relationship between P2X7 receptor and pain. Moreover, we also described the effects of some antagonists on pain relief by inhibiting the activities of P2X7 receptor. Thus, targeting to inhibit activation of P2X7 receptor is expected to become another potential target for the relief of pain.

Eczema characterized by itch, sleeplessness, and adverse effects on quality of life is associated with a risk of hematological malignancies. However, there is a controversy pertaining to whether this association implies a greater or lesser risk of hematological cancers. We aimed to explore the link between eczema and hematological malignancies risk.

The COVID-19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID-19 pandemic for chronic pain. Publications were identified related to the COVID-19 pandemic influence on the burden of chronic pain, development of new-onset pain because of long COVID with proposed mechanisms and COVID-19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS-CoV-2 infection could be caused by 'systemic inflammatory-immune mechanisms', 'direct neuropathic mechanisms' or 'secondary mechanisms due to the viral infection or treatment'. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS-CoV-2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New-onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism-based treatments within the domain of multidisciplinary care.

To determine the association between white matter structural changes and PHN by analyzing the diffusion tensor imaging data of patients with herpes zoster (HZ) or postherpetic neuralgia (PHN), and the volunteered healthy controls (HC).

Pulpitis is a commonly seen oral inflammation condition in clinical practice, it can cause much pain for the patient and may induce infections in other systems. Much is still unknown for the pathogenic mechanism of pulpitis. In this work, we discovered that the expression of miR-155 was associated with dental pulpal inflammation both in vivo and in vitro.

Diabetic peripheral neuropathy (DPN) is characterized by progressive loss of peripheral nerves, which causes numbness, weakness, and severe pain. The medications available currently provide only modest relief from the pain of DPN and are associated with various side effects, which has generated an enormous demand for research on new therapeutic approaches. Dysregulation of the endocannabinoid system has been reported in DPN. Cannabinoid-based medications have gained increasing attention as a potential therapy to alleviate DPN pain. Endocannabinoids and cannabinoids' actions are mediated primarily by cannabinoid receptor 1 (CBR) and cannabinoid receptor 2 (CBR). Cannabinoids that activate CBR have demonstrated a profound antinociceptive effect, although CBR is associated with undesirable psychoactive effects. Peripherally restricted CBR agonists help overcome this problem; however, adverse metabolic and cardiovascular effects limit its therapeutic use. In contrast, CBR antagonists, selective CBR agonists, and endocannabinoid metabolizing enzymes inhibitors alleviate DPN pain effectively with minimal side effects. This article provides a concise overview of the preclinical and clinical studies that have tested the therapeutic potential of targeting the endocannabinoid system to treat painful DPN.

The past century has seen significant advances in the practice of obstetric anesthesiology. This article will review the role of Anesthesia & Analgesia and the International Anesthesia Research Society in contributing to fundamental paradigm shifts in our understanding of obstetric anesthesiology.

Francis McMechan, MD, founded the National Anesthesia Research Society (NARS), which was the precursor to the International Anesthesia Research Society (IARS) and the first physician anesthesia organization in the United States that was devoted to the research goals of the specialty. NARS initially sponsored Current Researches in Anesthesia and Analgesia, and IARS remains the main parent organization of the journal to this day. Dr McMechan originally hoped to coordinate the scientific efforts of NARS/IARS with the political activities of several other organizations he had founded to achieve his ultimate goal of building a powerful and well-connected anesthesia community across the nation, and eventually around the world. About a decade after his death, Dr McMechan's sweeping global vision would be fulfilled by the creation of the World Federation of Societies of Anesthesiologists (WFSA). Although Dr McMechan's political organizations would eventually lose ground to the newer American Society of Anesthetists (ASA), his scientific organization and his inspiring international interest-embodied by IARS, Anesthesia & Analgesia, and WFSA-continue to thrive today.