Human safety study of a selective neuronal adenylate cyclase 1 inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice.

Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.

nNOS-expressing neurons in the vmPFC transform pPVT-derived chronic pain signals into anxiety behaviors.

Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons.

ASP8477, a fatty acid amide hydrolase inhibitor, exerts analgesic effects in rat models of neuropathic and dysfunctional pain.

Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E2-, prostaglandin F2α-, and bicuculline-induced allodynia in mice, showing broader analgesic spectra than existing drugs. In contrast, however, ASP8477 did not affect acute pain. These results indicate that the FAAH inhibitor ASP8477 exerts analgesic effects on neuropathic and dysfunctional pain, and its pharmacological properties are suitable for use in treating chronic pain.

Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway.

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until up to 72 h. Altogether, these findings provide insight into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.

Soluble epoxide hydrolase inhibitor mediated analgesia lacks tolerance in rat models.

Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.

Effect of catechol-O-methyltransferase (rs4680) single-nucleotide polymorphism on opioid-induced hyperalgesia in adults with chronic pain.

The catechol-O-methyltransferase Val158Met polymorphism has been associated with alterations in pain perception, but the influence of the polymorphism on pain perception in patients with chronic pain receiving daily opioid therapy has not been previously reported. The primary aim of this study was to investigate the effects of the catechol-O-methyltransferase Val158Met polymorphism on heat pain perception in a cohort of adults receiving daily opioid therapy for chronic pain. Adults with chronic pain consecutively admitted to an outpatient pain rehabilitation program who met inclusion criteria and were receiving daily opioid therapy were recruited for study participation (N = 142). Individuals were genotyped for catechol-O-methyltransferase Val158Met (rs4680), and the polymorphism was analyzed using an additive and codominant genotype models. The distribution of the Val158Met genotypes was 25% for Val/Val, 41% for Val/Met and 34% for Met/Met (Hardy-Weinberg, P > 0.05). A main effect of genotype was observed for heat pain perception ( P = 0.028). Under the codominant model of allele effects, exploratory post hoc pairwise comparisons adjusted for morphine equivalent dose and pain catastrophizing demonstrated that individuals with the Val/Met genotype were hyperalgesic compared to individuals with the Val/Val ( P = 0.039) and Met/Met ( P = 0.023) genotypes. No significant association was observed between heat pain perception and genotype under the additive model of allele effects. Among patients with chronic pain who were receiving daily opioids, the Val/Met genotype was associated with hyperalgesia using a measure of heat pain perception that has been previously indicative of opioid-induced hyperalgesia in other heterogeneous samples of adults with chronic pain. This study contributes to the emerging understanding of how catechol-O-methyltransferase activity affects pain perception in the context of daily opioid use, and these findings may be useful in the design of future trials aimed at investigating the potential efficacy of ß-2 adrenergic receptor antagonism for opioid-induced hyperalgesia.

Contribution of Spinal PKCγ Expression to Short- and Long-lasting Pain Behaviors in Formalin-induced Inflamed Mice.

BACKGROUND: Over-expression of spinal protein kinase Cγ(PKCγ) contributes to the induction of persistent bilateral hyperalgesia following inflammatory injury, yet the role of spinal PKCγ in short- and long-lasting pain behavior is poorly understood. OBJECTIVE: This study aimed to characterize the contribution of spinal PKCγ to spontaneous pain and long-lasting bilateral hyperalgesia in formalin-induced inflamed mice using pharmacological inhibition. STUDY DESIGN: Laboratory animal study. SETTING: The study was performed in the Department of Human Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, the Fourth Military Medical University (Xi'an, China) and the Department of Anesthesiology, Fuzhou General Hospital (Fuzhou, China). METHODS: Male mice were unilaterally intraplantarly injected with formalin to induce inflammatory pain. Spontaneous pain behaviors, including flinches and lickings, were recorded by off-line video during the first hour post-injection and counted. Using von Frey tests, long-lasting bilateral mechanical paw withdrawal thresholds were determined before injection and at indicated time points thereafter. Temporal expression of spinal PKCγ was observed by immunohistochemical staining. For pharmacological inhibition, mice were treated daily with intrathecal Tat carrier or selective PKCγ inhibitor KIG31-1, from 1 hour prior to 10 days after formalin injection. Spontaneous pain behaviors and long-lasting bilateral mechanical hyperalgesia were assessed. Spinal PKCγ expression was also observed by using immunohistochemical staining and western blot. RESULTS: The number of PKCγ-immunoreactive (ir) spinal neurons was significantly higher at 10 days, but not 2 hours, after formalin intraplantar injection, and accompanied by long-lasting bilateral hyperalgesia. Furthermore, long-lasting bilateral hyperalgesia could be reversed by pharmacological inhibition of over-expressed spinal PKCγ; however, pretreating with intrathecal KIG31-1 showed no antinociceptive effects on short-term spontaneous pain behaviors. LIMITATIONS: All results were obtained from the mice and no PKCγ inhibitors were available through clinical practice. Therefore, it remains difficult to draw definitive connections between animal research and human application. CONCLUSION: Our findings suggest that spinal PKCγ plays a predominant role in long-lasting bilateral hyperalgesia, but not in the spontaneous pain behaviors induced by formalin. KEY WORDS: Formalin, spontaneous pain, mechanical hyperalgesia, protein kinase C gamma, KIG31-1, mice.

Transcription-independent expression of PKMζ in the anterior cingulate cortex contributes to chronically maintained neuropathic pain.

Protein kinase M ζ is well known for its role in maintaining memory and pain. Previously, we revealed that the activation of protein kinase M ζ in the anterior cingulate cortex plays a role in sustaining neuropathic pain. However, the mechanism by which protein kinase M ζ is expressed in the anterior cingulate cortex by peripheral nerve injury, and whether blocking of protein kinase M ζ using its inhibitor, zeta inhibitory peptide, produces analgesic effects in neuropathic pain maintained chronically after injury, have not previously been resolved. In this study, we show that protein kinase M ζ expression in the anterior cingulate cortex is enhanced by peripheral nerve injury in a transcription-independent manner. We also reveal that the inhibition of protein kinase M ζ through zeta inhibitory peptide treatment is enough to reduce mechanical allodynia responses in mice with one-month-old nerve injuries. However, the zeta inhibitory peptide treatment was only effective for a limited time.

Synthesis and biological evaluation of novel tanshinone IIA derivatives for treating pain.

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC50 120 nmol·L-1) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.

Identification of FAM173B as a protein methyltransferase promoting chronic pain.

Chronic pain is a debilitating problem, and insights in the neurobiology of chronic pain are needed for the development of novel pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread pain. This region includes the coding region for FAM173B, a functionally uncharacterized protein. We demonstrate here that FAM173B is a mitochondrial lysine methyltransferase that promotes chronic pain. Knockdown and sensory neuron overexpression strategies showed that FAM173B is involved in persistent inflammatory and neuropathic pain via a pathway dependent on its methyltransferase activity. FAM173B methyltransferase activity in sensory neurons hyperpolarized mitochondria and promoted macrophage/microglia activation through a reactive oxygen species-dependent pathway. In summary, we uncover a role for methyltransferase activity of FAM173B in the neurobiology of pain. These results also highlight FAM173B methyltransferase activity as a potential therapeutic target to treat debilitating chronic pain conditions.

Src-family kinases activation in spinal microglia contributes to central sensitization and chronic pain after lumbar disc herniation.

Background Lumbar disc herniation is a major cause of radicular pain, but the underlying mechanisms remain largely unknown. Spinal activation of src-family kinases are involved in the development of chronic pain from nerve injury, inflammation, and cancer. In the present study, the role of src-family kinases activation in lumbar disc herniation-induced radicular pain was investigated. Results Lumbar disc herniation was induced by implantation of autologous nucleus pulposus, harvest from tail, in lumbar 4/5 spinal nerve roots of rat. Behavior test and electrophysiologic data showed that nucleus pulposus implantation induced persistent mechanical allodynia and thermal hyperalgesia and increased efficiency of synaptic transmission in spinal dorsal horn which underlies central sensitization of pain sensation. Western blotting and immunohistochemistry staining revealed that the expression of phosphorylated src-family kinases was upregulated mainly in spinal microglia of rats with nucleus pulposus. Intrathecal delivery of src-family kinases inhibitor PP2 alleviated pain behaviors, decreased efficiency of spinal synaptic transmission, and reduced phosphorylated src-family kinases expression. Furthermore, we found that the expression of ionized calcium-binding adapter molecule 1 (marker of microglia), tumor necrosis factor-α, interleukin 1 -ß in spinal dorsal horn was increased in rats with nucleus pulposus. Therapeutic effect of PP2 may be related to its capacity in reducing the expression of these factors. Conclusions These findings suggested that central sensitization was involved in radicular pain from lumbar disc herniation; src-family kinases-mediated inflammatory response may be responsible for central sensitization and chronic pain after lumbar disc herniation.

Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain.

Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future.

Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice.

BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 µl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 µg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 µg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.

Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain.

Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.

Transient inhibition of LIMKs significantly attenuated central sensitization and delayed the development of chronic pain.

Central sensitization represents a key mechanism mediating chronic pain, a major clinical problem lacking effective treatment options. LIM-domain kinases (LIMKs) selectively regulate several substrates, e.g. cofilin and cAMP response element-binding protein (CREB), that profoundly affect neural activities, such as synaptogenesis and gene expression, thus critical in the consolidation of long-term synaptic potentiation and memory in the brain. In this study, we demonstrate that LIMK deficiency significantly impaired the development of multiple forms of chronic pain. Mechanistic studies focusing on spared nerve injury (SNI) model reveal a pivotal role of LIMKs in the up-regulation of spontaneous excitatory synaptic transmission and synaptogenesis after pain induction. Depending on the pain induction methods, LIMKs can be transiently activated with distinct time courses. Accordingly, pharmacological inhibition of LIMKs targeting this critical period remarkably attenuated central sensitization in the spinal cord and alleviated pain behaviors. We propose selectively targeting LIMKs during their activation phase as a potential therapeutic strategy for clinical management of chronic pain, especially for chronic pain with predictable onset and development time courses, such as chronic post-surgical pain (PSP).

Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression.

BACKGROUND: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression. METHODS: Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown. RESULTS: Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression. CONCLUSIONS: These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.

Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice.

The soluble epoxide hydrolase (sEH) is a regulatory enzyme responsible for the metabolism of bioactive lipid epoxides of both omega-6 and omega-3 long chain polyunsaturated fatty acids. These natural epoxides mediate cell signaling in several physiological functions including blocking inflammation, high blood pressure and both inflammatory and neuropathic pain. Inhibition of the sEH maintains the level of endogenous bioactive epoxy-fatty acids (EpFA) and allows them to exert their generally beneficial effects. The Akita (Ins2Akita or Ins2C96Y) mice represent a maturity-onset of diabetes of the young (MODY) model in lean, functionally unimpaired animals, with a sexually dimorphic disease phenotype. This allowed for a test of male and female mice in a battery of functional and nociceptive assays to probe the role of sEH in this system. The results demonstrate that inhibiting the sEH is analgesic in diabetic neuropathy and this occurs in a sexually dimorphic manner. Interestingly, sEH activity is also sexually dimorphic in the Akita model, and moreover correlates with disease status particularly in the hearts of male mice. In addition, in vivo levels of oxidized lipid metabolites also correlate with increased sEH expression and the pathogenesis of disease in this model. Thus, sEH is a target to effectively block diabetic neuropathic pain but also demonstrates a potential role in mitigating the progression of this disease.

PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain.

Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to 55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients' quality of life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate. Recent studies have demonstrated their critical roles in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of PI3K/Akt pathway in the progression of chronic pain through sciatic nerve injury, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia.

AAPT Diagnostic Criteria for Chronic Sickle Cell Disease Pain.

Pain in sickle cell disease (SCD) is associated with increased morbidity, mortality, and high health care costs. Although episodic acute pain is the hallmark of this disorder, there is an increasing awareness that chronic pain is part of the pain experience of many older adolescents and adults. A common set of criteria for classifying chronic pain associated with SCD would enhance SCD pain research efforts in epidemiology, pain mechanisms, and clinical trials of pain management interventions, and ultimately improve clinical assessment and management. As part of the collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks public-private partnership with the U.S. Food and Drug Administration and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy initiative developed the outline of an optimal diagnostic system for chronic pain conditions. Subsequently, a working group of experts in SCD pain was convened to generate core diagnostic criteria for chronic pain associated with SCD. The working group synthesized available literature to provide evidence for the dimensions of this disease-specific pain taxonomy. A single pain condition labeled chronic SCD pain was derived with 3 modifiers reflecting different clinical features. Future systematic research is needed to evaluate the feasibility, validity, and reliability of these criteria. PERSPECTIVE: An evidence-based classification system for chronic SCD pain was constructed for the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy initiative. Applying this taxonomy may improve assessment and management of SCD pain and accelerate research on epidemiology, mechanisms, and treatments for chronic SCD pain.

Targeting AMPK for the Alleviation of Pathological Pain.

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.