Systematic Review and Meta-Analysis of the Effectiveness of Radiofrequency Ablation of the Sacroiliac Joint.

PURPOSE OF REVIEW: To evaluate the effectiveness of radiofrequency neurotomy in managing sacroiliac joint pain utilizing a systematic review with meta-analysis of randomized controlled trials (RCTs) and observational studies. RECENT FINDINGS: The prevalence of sacroiliac joint pain is estimated at around 25% of low back pain cases, and its diagnosis lacks a gold standard. Treatments include exercise therapy, injections, ablation, and fusion, with variable effectiveness. COVID-19 altered utilization patterns of interventions, including sacroiliac joint procedures, and the evidence for these interventions remains inconclusive. Recently, Medicare has issued its local coverage determinations (LCDs) in the United States, which provides noncoverage of sacroiliac joint radiofrequency neurotomy. Additionally, a recent systematic review of sacroiliac joint injections showed Level III or fair evidence. The sacroiliac joint, a critical axial joint linking the spine and pelvis, contributes to low back pain. Its complex innervation pattern varies among individuals. Sacroiliac joint dysfunction, causing pain and stiffness, arises from diverse factors.The present systematic review and meta-analysis aimed to evaluate radiofrequency neurotomy's effectiveness for sacroiliac joint pain management by applying rigorous methodology, considering both RCTs and observational studies. Despite methodological disparities, the evidence from this review, supported by changes in pain scores and functional improvement, suggests Level III evidence with fair recommendation for radiofrequency neurotomy as a treatment option. The review's strengths include its comprehensive approach and quality assessment. However, limitations persist, including variations in criteria and technical factors, underscoring the need for further high-quality studies in real-world scenarios.

Substance P's Impact on Chronic Pain and Psychiatric Conditions-A Narrative Review.

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP's impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP's diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.

The Role of Sex Hormones in Pain-Related Conditions.

Millions of people are affected by pain-related conditions worldwide. Literature has consistently shown that each individual experiences and perceives pain in a unique manner due to biological, environmental, and cultural factors in which they have been raised. It has been established that biological males and females perceive pain differently and that it may be partially explained by their distinct hormonal profiles since birth, which are only further magnified during puberty. For biological males, high levels of testosterone have shown to increase their pain threshold; and for biological females, estrogen fluctuations have shown to increase pain intensity and perception. However, sex hormones have not been studied in the context of pain treatment or their impact on biochemical pathways involved in pain perception. For this purpose, the transgender community serves as a unique population to investigate the impact of hormone replacement therapy on molecular pathways involved in the perception of pain. The purpose of this review is to explore the biochemistry of hormone replacement in transgender patients who also have other pain-related conditions such as headaches, fibromyalgia, temporomandibular myalgia, and visceral pain.

Circadian pain patterns in human pain conditions - A systematic review.

BACKGROUND: Chronobiology is the science of how physiological processes in the body follow a pattern of time. Pain has been shown to follow a circadian rhythm, with different types of pain having variable expression along this rhythm. OBJECTIVE: This article reviews the nature of diurnal variations in pain along with a discussion of the mechanisms of circadian rhythm of pain. EVIDENCE REVIEW: We conducted a literature search on the PubMed and Google Scholar electronic databases, through April 2022. Publications were screened for English language, full-text availability, and human subjects. Randomized controlled trials and observational trials were included. Data were extracted from studies on patients with acute or chronic pain phenotypes, which provide pain severity data and corresponding diurnal time points. FINDINGS: The literature search led to the inclusion of 39 studies. A circadian pattern of pain was found to be present in nociceptive, neuropathic, central, and mixed pain states. Postoperative pain, fibromyalgia, trigeminal neuralgia, and migraines were associated with higher pain scores in the morning. Temporomandibular joint pain, neuropathic pain, labor pain, biliary colic, and cluster headaches increased throughout the day to reach a peak in the evening or night. Arthritis and cancer pain were not associated with any circadian rhythmicity. Furthermore, the circadian rhythm of pain was not found to be altered in patients on analgesics. CONCLUSION: The results of this review suggest that an understanding of diurnal variation may help improve therapeutic strategies in pain management, for instance through analgesic titration.

Low back pain.

Low back pain covers a spectrum of different types of pain (eg, nociceptive, neuropathic and nociplastic, or non-specific) that frequently overlap. The elements comprising the lumbar spine (eg, soft tissue, vertebrae, zygapophyseal and sacroiliac joints, intervertebral discs, and neurovascular structures) are prone to different stressors, and each of these, alone or in combination, can contribute to low back pain. Due to numerous factors related to low back pain, and the low specificity of imaging and diagnostic injections, diagnostic methods for this condition continue to be a subject of controversy. The biopsychosocial model posits low back pain to be a dynamic interaction between social, psychological, and biological factors that can both predispose to and result from injury, and should be considered when devising interdisciplinary treatment plans. Prevention of low back pain is recognised as a pivotal challenge in high-risk populations to help tackle high health-care costs related to therapy and rehabilitation. To a large extent, therapy depends on pain classification, and usually starts with self-care and pharmacotherapy in combination with non-pharmacological methods, such as physical therapies and psychological treatments in appropriate patients. For refractory low back pain, a wide range of non-surgical (eg, epidural steroid injections and spinal cord stimulation for neuropathic pain, and radiofrequency ablation and intra-articular steroid injections for mechanical pain) and surgical (eg, decompression for neuropathic pain, disc replacement, and fusion for mechanical causes) treatment options are available in carefully selected patients. Most treatment options address only single, solitary causes and given the complex nature of low back pain, a multimodal interdisciplinary approach is necessary. Although globally recognised as an important health and socioeconomic challenge with an expected increase in prevalence, low back pain continues to have tremendous potential for improvement in both diagnostic and therapeutic aspects. Future research on low back pain should focus on improving the accuracy and objectivity of diagnostic assessments, and devising treatment algorithms that consider unique biological, psychological, and social factors. High-quality comparative-effectiveness and randomised controlled trials with longer follow-up periods that aim to establish the efficacy and cost-effectiveness of low back pain management are warranted.

Noncanonical function of long myosin light chain kinase in increasing ER-PM junctions and augmentation of SOCE.

Increased endothelial permeability leads to excessive exudation of plasma proteins and leukocytes in the interstitium, which characterizes several vascular diseases including acute lung injury. The myosin light chain kinase long (MYLK-L) isoform is canonically known to regulate the endothelial permeability by phosphorylating myosin light chain (MLC-P). Compared to the short MYLK isoform, MYLK-L contains an additional stretch of ~919 amino acid at the N-terminus of unknown function. We show that thapsigargin and thrombin-induced SOCE was markedly reduced in Mylk-L-/- endothelial cells (EC) or MYLK-L-depleted human EC. These agonists also failed to increase endothelial permeability in MYLK-L-depleted EC and Mylk-L-/- lungs, thus demonstrating the novel role of MYLK-L-induced SOCE in increasing vascular permeability. MYLK-L augmented SOCE by increasing endoplasmic reticulum (ER)-plasma membrane (PM) junctions and STIM1 translocation to these junctions. Transduction of N-MYLK domain (amino acids 1-919 devoid of catalytic activity) into Mylk-L-/- EC rescued SOCE to the level seen in control EC in a STIM1-dependent manner. N-MYLK-induced SOCE augmented endothelial permeability without MLC-P via an actin-binding motif, DVRGLL. Liposomal-mediated delivery of N-MYLK mutant but not ∆DVRGLL-N-MYLK mutant in Mylk-L-/- mice rescued vascular permeability increase in response to endotoxin, indicating that targeting of DVRGLL motif within MYLK-L may limit SOCE-induced vascular hyperpermeability.

A Retrospective Analysis of Gabapentinoid and Opioids to Opioid Monotherapy for Pain Relief in Patients with Chronic Neck and Low Back Pain.

OBJECTIVE: We compared the reduction in pain and opioid consumption in patients with chronic spinal pain on concomitant gabapentinoids and opioids with patients using opioids only. DESIGN: This was a retrospective chart review of patients with chronic neck or low back pain who were on opioids with at least a 24-month follow-up. SETTING: Single-center pain clinic in an urban setting. SUBJECTS: 167 patients with chronic spinal pain lasting at least six months. METHODS: Patients on gabapentin or pregabalin were included in the gabapentinoid group, while the other patients were included in the non-gabapentinoid group. Primary outcome was assessment of pain scores measured via a numeric rating scale (NRS), and secondary outcomes were response to the treatment (>2 point reduction on NRS) and daily opioid use measured in morphine milliequivalents. RESULTS: Pain scores were reduced in the first six months and plateaued after that in both groups. At the end of 24 months, the average pain score was 6.71 in the gabapentinoid group, while the average pain score was 7.18 in the non-gabapentinoid group. There was no statistical significance between the groups (p = 0.28). There was no difference in response to treatment in gabapentinoid group (33.3%) when compared with non-gabapentinoid group (32.7%). We also failed to find any significant difference in daily opioid usage between the two groups. CONCLUSION: Gabapentinoids may not lead to reduction in pain or opioid consumption in patients with chronic spinal pain. A careful approach must be adopted while prescribing gabapentinoids in the chronic spinal pain patient population.

Pulmonary Complications After Hip and Knee Arthroplasty in the United States, 2004-2014.

BACKGROUND: Pulmonary complications after total joint arthroplasty (TJA) are uncommon but have significant cost impact. Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are 2 of the 5 top procedures requiring inpatient stay within the United States. Subsequent pulmonary complications therefore may impose substantial cost burden for US health care. The purpose of this study was to describe the incidence, risk factors, and clinical implications of pulmonary complications (ie, pneumonia, respiratory failure, pulmonary embolism [PE], and aspiration) after TJA in the United States. METHODS: The National Inpatient Sample (NIS) was queried for all patients undergoing primary, elective THA and TKA between years 2004 and 2014. Pulmonary complications were defined as the occurrence of pneumonia, respiratory failure, PE, or aspiration after TJA. Demographic and clinical characteristics, inpatient cost, length of stay (LOS), and mortality were compared between patients with and without documented perioperative pulmonary complications. Given the stratified nature of the NIS database, estimates of incidence throughout the United States were made with application of trend weights to observed database frequencies. Analyses of estimated annual complication rates were made using χ tests. RESULTS: Between 2004 and 2014, an estimated 2,679,351 patients underwent elective primary THA. A total of 5,527,205 patients were estimated to have undergone elective primary TKA. THA 1.42% (95% CI, 1.37%-1.47%) and 1.71% (95% CI, 1.66%-1.76%) of TKA procedures were complicated by pneumonia, respiratory failure, PE, or aspiration. During this time, the incidence of perioperative pulmonary complications decreased from 1.57% (95% CI, 1.41%-1.73%) to 1.01% (95% CI, 0.92%-1.10%) after THA (P < .0001) and from 2.03% (95% CI, 1.88%-2.18%) to 1.33% (95% CI, 1.25%-1.42%) after TKA (P < .0001). The adjusted odds ratio (aOR) of experiencing a pulmonary complication was highest among patients with history of significant weight loss (aOR = 4.77; 99.9% CI, 3.97-5.73), fluid/electrolyte disorders (aOR = 3.33; 99.9% CI, 3.11-3.56), congestive heart failure (CHF; aOR = 3.32; 99.9% CI, 3.07-3.58), preexisting paralytic condition (aOR = 2.03; 99.9% CI, 1.57-2.61), and human immunodeficiency virus infection (aOR = 2.00; 99.9% CI, 1.06-3.78). Perioperative pulmonary complications were associated with increased LOS (THA = 3.03 days; 99.9% CI, 2.76-3.31; TKA = +2.72 days; 99.9% CI, 2.58-2.86), increased hospital costs (THA = +9163 US dollars; 99.9% CI, 8054-10,272; TKA = +7257 US dollars; 99.9% CI, 6650-7865), and increased mortality (THA: aOR = 121; 99.9% CI, 78-187; TKA: aOR = 150; 95% CI, 97-233). CONCLUSIONS: Despite a decline in overall incidence, perioperative pulmonary complications represent a significant potential source of perioperative morbidity and mortality. The current study highlights potential risk factors for pulmonary complications. Recognition of these factors may help to better stratify patients and mitigate risk of potential complications. This is particularly true of respiratory failure as it is associated with the high increases in resource utilization and mortality in this group.

Improving care of chronic pain patients with spinal cord stimulator therapy amidst the opioid epidemic.

The US government and other key stakeholders including professional medical bodies have amended recommendations in recent years to emphasize using no opioids or the lowest effective dose of opioids needed for treatment of chronic pain. However, there remains an unmet need for pain treatments that can both relieve the pain of patients and reduce the doses of opioids they require. The Center for Medicare and Medicaid Services (CMS) is currently considering such treatments through the SUPPORT ACT and has recently conferred with the Health and Human Services (HHS) Inter-agency Pain Management Task Force to consider such therapies. We reviewed literature evidence in PubMed on pain relief and opioid reduction following spinal cord stimulation (SCS) treatment. SCS presents an effective non-pharmacologic pain treatment modality that has been used for decades to reduce chronic pain from trauma or neuropathy and has been shown to either stabilize or reduce opioid use in some patients with painful conditions. A more recently developed high-frequency SCS modality, 10 kHz SCS, has the advantage of being paresthesia-independent. It has been shown to be associated with significant reductions in opioid consumption after stimulation therapy was initiated, and many patients even taking high doses of opioids (> 90 mg morphine equivalent dose per day) were able to reduce their opioid intake to levels associated with less risk. The evidence shows that reduction of opioids as early in the treatment process as possible is desirable to reduce patient risk and improve pain relief from stimulation therapy.

Does Epidural Bupivacaine with or Without Steroids Provide Long-Term Relief? A Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Low back and lower extremity pain have been treated since 1901 with local anesthetics alone and since 1952 in combination with steroids. Over the years, multiple randomized controlled trials, systematic reviews with or without meta-analysis have been reaching discordant conclusions regarding the effectiveness of sodium chloride solution, local anesthetics, and steroids in managing spinal pain. Further, related to lack of understanding, multiple reviewers have considered local anesthetics including lidocaine and bupivacaine as equivalent to placebo based on theory that steroid is the only drug effective in the epidural space. In this review, we assessed effectiveness of epidurally administered bupivacaine with or without steroids to rule out misconceptions of placebo and to show the comparative effectiveness of epidural bupivacaine alone compared to epidural bupivacaine with steroids. RECENT FINDINGS: Multiple systematic reviews performed in assessing the effectiveness of epidural injections have converted epidurally administered lidocaine and bupivacaine to placebo. This led to inappropriate conclusions of lack of effectiveness of epidural local anesthetics with or without steroids as showing equal effectiveness when analyzed with conventional dual-arm meta-analysis. Thus, true placebo control trials with injection of an inactive substance into unrelated structures have been almost non-existent. Epidurally administered bupivacaine alone or with steroids are effective in managing low back and lower extremity pain. The findings of this review provide appropriate information of epidurally administered bupivacaine as an active agent (not a placebo) with level 1 evidence and almost equally effective as bupivacaine with steroids with level II evidence.

Is Percutaneous Adhesiolysis Effective in Managing Chronic Low Back and Lower Extremity Pain in Post-surgery Syndrome: a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: The growing prevalence of spinal pain in the USA continues to produce substantial economic impact and strain on health-related quality of life. Percutaneous adhesiolysis is utilized for recalcitrant, resistant conditions involving spinal pain when epidural injections have failed to provide adequate improvement, especially low back and lower extremity pain, specifically in post-lumbar surgery syndrome. Despite multiple publications and systematic reviews, the debate continues in reference to effectiveness, safety, appropriate utilization, and medical necessity of percutaneous adhesiolysis in chronic pain. This systematic review, therefore, was undertaken to evaluate and to update effectiveness of percutaneous adhesiolysis to treat chronic refractory low back and lower extremity pain, post-surgical patients of the lumbar spine. RECENT FINDINGS: From 2009 to 2016, there was a decline of 53.2% utilization of percutaneous adhesiolysis with an annual decline of 10.3% per 100,000 fee-for-service (FFS) Medicare population. Multiple insurers, including Medicare, with Medicare area contractors of Noridian and Palmetto have issued noncoverage policies for percutaneous adhesiolysis resulting in these steep declines and continued noncoverage by Medicare Advantage plans, Managed Care plans of Medicaid, and other insurers. Since 2005, 4 systematic reviews of percutaneous adhesiolysis were published with 3 of them showing proper methodology and appropriate results with effectiveness of adhesiolysis, whereas one poorly performed systematic review showed negative results. In addition, there were only 4 randomized controlled trials (RCTs) to be included in the previous systematic reviews of post-surgery syndrome, whereas now, the RCTs and other studies have increased. This systematic review shows level I or strong evidence for the effectiveness of percutaneous adhesiolysis in managing chronic low back and lower extremity pain related to post-lumbar surgery syndrome.

The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents.

Tryptophan (TRP) is an essential, aromatic amino acid catabolized by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) enzymes into kynurenine. The IDO enzyme is expressed in peripheral tissues and the central nervous system. Another enzyme of interest in the kynurenine signaling pathway is kynurenine 3-monooxygenase (KMO). The purpose of this review is to discuss the role of TRP and the kynurenine signaling pathway in different chronic pain patients. The IDO-1, IDO-2, and KMO enzymes and the kynurenine metabolite have been shown to be involved in the pathogenesis of neuropathic pain and other painful conditions (migraine, cluster headache, etc.) as well as depressive behavior. We highlighted the analgesic potential of novel agents targeting the enzymes of the kynurenine signaling pathway to explore their efficacy in both future basic science and transitional studies. Upcoming studies conducted on animal models will need to take into consideration the differences in TRP metabolism between human and non-human species. Since chronic painful conditions and depression have common pathophysiological patterns, and the kynurenine signaling pathway is involved in both of them, future clinical studies should aim to have outcomes targeting not only pain, but also functionality, mood changes, and quality of life.

Neurogenic Claudication: a Review of Current Understanding and Treatment Options.

PURPOSE OF REVIEW: With an aging population and increased prevalence of the disease, we set out to evaluate the validity of current diagnostic criteria for neurogenic claudication as well as the efficacy of the treatment options for the main cause, lumbar spinal stenosis (LSS). RECENT FINDINGS: Epidural steroid injections (ESI) were most efficacious when the injectate is a steroid combined with lidocaine or lidocaine only. There are promising results regarding the efficacy of the minimally invasive lumbar decompression (MILD) procedure as well as interspinous process spacers (IPS) compared to surgical alternatives. Spinal cord stimulators are gaining ground as an effective alternative to surgery in patients with lumbar spinal stenosis that is not responsive to conservative measures or epidural injections. We found that there continues to be a lack of consensus on the diagnostic criteria, management, and treatment options for patients with LSS. The Delphi consensus is the most current recommendation to assist clinicians with making the diagnosis. Physical therapy, NSAIDs, gabapentin, and other conservative therapy measures are unproven in providing long-lasting relief. In patients with radicular symptoms, an ESI may be indicated when a combination of lidocaine with steroids is used or using lidocaine alone. In addition, there is not enough high-quality evidence to make a recommendation regarding the use of MILD versus interspinous spacers for neurogenic claudication. There remains a need for high-quality evidence regarding the efficacy of different conservative treatments, interventional procedures, and surgical outcomes in patients with neurogenic claudication in LSS.

An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens.

Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations.

Inhibition of neuronal nitric oxide synthase attenuate the hypothermic effect of ketamine-magnesium sulfate combination in rats.

Ketamine and magnesium as NMDA receptor antagonists interact synergistically to decrease body temperature in rats. The mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination has not been studied until now. The aim of this study was to examine whether nitric oxide (NO) has a role in the hypothermic effect of ketamine (10 mg/kg) and the combination of ketamine (5 mg/kg) and magnesium sulfate (5 mg/kg). The body temperature was measured by insertion of a thermometer probe 5 cm into the colon of unrestrained male Wistar rats (200-250 g). N(ω)-nitro-L-arginine methyl ester (L-NAME 2.5 and 5 mg/kg) as non-selective inhibitor of nitric oxide synthase at a dose of 5 mg/kg antagonized the effect of the ketamine-magnesium sulfate combination at 60 min (p < 0.05) and 90 min (p < 0.01). Ketamine induced hypothermia was not affected by administrating of L-NAME (2.5 and 5 mg/kg). Inhibitor of inducible nitric oxide synthase N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL 1.25 mg/kg and 2.5 mg/kg, sc) did not significantly change the hypothermic response evoked by the ketamine-magnesium sulfate combination. Inhibitor of neuronal nitric oxide synthase N-ω-Propyl-L-arginine hydrochloride (L-NPA) at a dose of 2 mg/kg antagonized the combination at 60 min when it achieved the maximum effect. The NO pathway is not involved in the hypothermic effect of ketamine. Production of NO through neuronal NO synthase, might play a role in the mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination.

The Role of Genetic Polymorphisms in Chronic Pain Patients.

It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia. Furthermore, we discuss the role of CYP450 enzymes involved in metabolism of drugs, which have been used for treatment of chronic pain (amitriptyline, duloxetine, opioids, etc.). We also discuss how pharmacogenetics can be applied towards improving drug efficacy, shortening the time required to achieve therapeutic outcomes, reducing risks of side effects, and reducing medical costs and reliance upon polypharmacy.

S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness.

Activation of sphingosine-1-phosphate receptor 1 (S1PR1) plays a key role in repairing endothelial barrier function. We addressed the role of phosphorylation of the three intracellular tyrosine residues of S1PR1 in endothelial cells in regulating the receptor responsiveness and endothelial barrier function regulated by sphingosine 1-phosphate (S1P)-mediated activation of S1PR1. We demonstrated that phosphorylation of only Y143 site was required for S1PR1 internalization in response to S1P. Maximal S1PR1 internalization was seen in 20 min but S1PR1 returned to the cell surface within 1 h accompanied by Y143-dephosphorylation. Cell surface S1PR1 loss paralleled defective endothelial barrier enhancement induced by S1P. Expression of phospho-defective (Y143F) or phospho-mimicking (Y143D) mutants, respectively, failed to internalize or showed unusually high receptor internalization, consistent with the requirement of Y143 in regulating cell surface S1PR1 expression. Phosphorylation of the five S1PR1 C-terminal serine residues did not affect the role of Y143 phosphorylation in signaling S1PR1 internalization. Thus, rapid reduction of endothelial cell surface expression of S1PR1 subsequent to Y143 phosphorylation is a crucial mechanism of modulating S1PR1 signaling, and hence the endothelial barrier repair function of S1P.

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics.

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.